Potential of some traditionally used edible plants for prevention and cure of diabesity associated comorbidities
Potential of some traditionally used edible plants for prevention and cure of diabesity associated comorbidities
CellMed. 2015. May, 5(2): 8-8
Copyright © 2015, Association of Humanitas Medicine
This is an open access article under the CC BY-NC license. (
  • Received : September 05, 2014
  • Accepted : May 12, 2015
  • Published : May 31, 2015
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About the Authors
Vikas, Kumar
Neuropharmacology Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi-221 005, Uttar Pradesh, India
Ajit Kumar, Thakur
School of Pharmacy, IEC University, Baddi-174103, Solan, Himachal Pradesh
Suruchi, Verma
Neuropharmacology Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi-221 005, Uttar Pradesh, India
Vaishali, Yadav
Neuropharmacology Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi-221 005, Uttar Pradesh, India
Shyam Sunder, Chatterjee
StettinerStraße 1, 76139, Karlsruhe, Germany

Medicinal uses of edible and other plants for prevention and cure of obesity and overweight associated metabolic and mental health problems have since long been known to scholars and practitioners of Ayurvedic and other traditionally known system of medicine. Modernized versions of numerous edible plant derived formulations mentioned in ancient Ayurvedic texts are at present some of the most popular, or best selling, herbal remedies in India and numerous other countries suffering from double burden of diseases caused by malnutrition and obesity. Preclinical and clinical information now available on edible plants and their bioactive constituents justify traditionally known medicinal uses of products derived from them for prevention and cure of obesity associated type-2 diabetes, psychopathologies and other health problems. Such information now available on a few edible Ayurvedic plants and their formulations and suggesting that their stress response regulating effects are involved in their broad spectrums of bioactivity profiles are summarized in this communication. Implications of recent physiological and pharmacological observations made with numerous phytochemicals isolated from edible plants for better understanding of traditionally known medicinal uses of herbal remedies are also pointed out.
Classical Ayurvedic texts are the oldest known ones pointing out that overweight, obesity, and diabetes are closely related lifestyle disorders, and that appropriate food choices and eating habits are necessary not only for proper maintenance of physical and mental health, but also for obtaining optimal therapeutic benefits from medicines and other health care measures ( Rastogi, 2014 ; Sharma and Chandola, 2011a; Sharma and Chandola, 2011b ). Modern nutritional and other researchers have now also well recognized that diverse phytochemicals commonly consumed with everyday meals have beneficial effects against overweight or malnutrition associated metabolic disorders encountered in patients suffering from, or at risk to diabetes, hyperlipidemia, and numerous others chronic diseases ( Dembinska-Kiec et al., 2008 ; Farooqui, 2013 ; Gonzalez-Castejon and Rodriguez-Casado, 2011 ; Manach et al., 2009 ). Consequently, regular consumption of fruits, vegetables and other plant derived products are now highly recommended for reducing the risks of almost all such life threatening and silently progressing diseases ( Anonymous, 2003 ; Agrawal et al., 2014 ). Despite extensive efforts and considerable progress ( Janero, 2014 ; Kar and Roy, 2012 ; Singh et al., 2014a ), prevention and cure of such disorders still continue to be a major challenge for both traditionally known as well as modern systems of medicine
Epidemiological, preclinical, and some clinical evidences now available on numerous edible plants strongly suggest though, that their modulating effects on psycho-biological processes involved pathogenesis and progression of lifestyle associated medical conditions are involved in their traditionally known health benefits ( Dembinska-Kiec et al., 2008 ; Gonzalez-Castejon and Rodriguez-Casado, 2011 ; Baboota et al., 2013 ; Chandrasekaran et al., 2012 ; Chang et al., 2013a ; Tiwari and Rao, 2002 ). It is now also well recognised that structurally and functionally diverse secondary plant metabolites are biosynthesized by them for defending themselves against environmental stress ( Kwon et al., 2009 ), and that their traditionally known health benefits are most probably due to their modulating effects on environmental and metabolic stress triggered psychobiological processes involved in pathogenesis and progression of chronic diseases ( Calabrese et al., 2012 ; Kennedy, 2014a ). Dysregulation of these processes often leads to diverse spectrums of pathologies including obesity and diabetes and other silently progressing metabolic and inflammatory disorders ( Cnop et al., 2012 ; Ozcan et al., 2004 ; Zhao and Ackerman, 2006 ). Amongst them, diabesity, i.e. obesity triggered type-2 diabetes, is the most rapidly spreading global epidemic of the 21 st century now affecting all countries irrespective of their socioeconomic status and cultural background ( Farag and Gaballa, 2011 ). The only currently available interventions with curative potentials against diabesity are bariatric surgeries ( Kahn et al., 2014 ; Tschop and DiMarchi, 2012 ), and it is now well recognized that dietary therapies in combination with some antidiabetic or anti-hyperglycemic drugs (especially metformin) and physical exercise are the most effective means for preventing progression of diabesity associated physical and mental health problems ( Colagiuri, 2010 ; Pratley and Matfin, 2007 ). However, due to socioeconomic, cultural, and diverse other reasons, such therapeutic possibilities and recommendations are either not available, or are not affordable and acceptable, in many economically developing and underdeveloped countries where the burden of diabesity is the utmost ( Pan et al., 1997 ; Ramachandran et al., 2006 ; Ramachandran et al., 2012 ).
Culinary uses of numerous edible plants used in Ayurvedic and other traditionally system of medicine and health care are very popular in all such countries, and irrespective of their socioeconomic and cultural backgrounds, herbal therapies are the most affordable and acceptable health care options for a vast majority of population in most of them. Therefore efforts are now being made in many laboratories to identify edible and other plants with anti-hyperglycemic, anti-inflammatory, insulin sensitivity improving and other diabesity associated pathologies ( Eddouks et al., 2014 ; Chang et al., 2013b ; Leiherer et al., 2013 ). A consistent observation made with diverse types of extracts of numerous such edible and other plants in animal behavioral models has been that their stress response regulating and other efficacies increase with increasing number of days of treatments ( Chatterjee and Kumar, 2012 ; Kumar and Chatterjee, 2014a ). These and numerous other observations made during efforts to define pharmacological activity profiles of several such extracts strongly suggest that biological mechanisms and processes involved in antihyperglycemic or anti-diabetic efficacies of edible plants could as well be due to their stress response modulating effects, and that structurally diverse secondary plant metabolites ubiquitously encountered in many, if not most, edible and other plants are also involved in their such efficacies ( Langstieh et al., 2014 ; Shivavedi et al., 2014a ; Shivavedi et al., 2014b ; Rauniyar et al., 2015 ; Verma et al., 2015 ; Shakya et al., 2015 ). In this communication, available preclinical and clinical information on a few Ayurvedic edible plants justifying these inferences are summarized and critically analyzed and discussed in light of our current understanding on stress response regulating potentials of edible and other phytochemicals.
Brassica juncea (Mustard)
Commonly known as oriental or brown or Indian mustard, Brassica juncea L. is one of the numerous edible plants of the Brassicaceae family now widely used in India and other countries for obtaining mustard seeds and edible oil. It is a draught resistant plant (also often considered as weed by agricultural industries) widely cultivated for meeting the great commercial demand of mustard seeds and oil with nutty taste and pungent aroma. Its green leaves (commonly called mustard green) are also often used as spicy vegetables, salad, and pickled condiment in many Asiatic countries. Medicinal uses of diverse varieties of mustard plants are mentioned in classical Ayurvedic texts, and Brassica juncea is one of the several plants of the family mentioned in such texts ( Manohar et al., 2009 ). Nutritive values of mustard green and diverse medicinal and health care potentials of mustard seeds and oils have been known since long not only in India, but also in numerous other countries. Although nutritive values of edible green leaves of Brassica juncea have also been mentioned in classical Ayurvedic texts, they are seldom used in Ayurvedic pharmaceutical formulations.
Information now available on medicinal phytochemistry of Brassica juncea leaves reveal though, that numerous bioactive phytochemicals encountered in them are either structurally identical or functionally similar to those identified in not only in different varieties mustard seeds, but also in many other pharmacologically and clinically better scrutinized edible plants of the Brassicaceae family. Amongst oil producing plants of this family, Brassica juncea is currently one of the major mustard oil producing crops in India, which is one of the major vegetable oils commonly consumed in the country ( Mishra and Manchanda, 2012 ; Singh et al., 2014b ). It has been suggested that regular consumption of mustard oil together with vegetarian diet could be a feasible dietary means for lowering the risk of ischemic heart diseases in Indian population ( Rastogi et al., 2004 ). Since bitter and pungent taste of mustard oil and all condeiments and vegetables prepared from plants of the Braceacea family are not always well accepted by many consumers (Drewnowski and Gomez-Carneros, 2000 ), they are often not regularly consumed, or are well accepted, for culinary purposess by many consumers. Therefore, efforts are now being made by food and agricultural industries to obtain Brassica juncea products devoid of such tastes ( Sindhu et al., 2012 ).
Another reason for obtaining different cultivars of Brassica juncea is to obtain mustard oil with lower contents of Eruic acid, i.e an omega-9 fatty acids which has been reported to possess adverse health effects ( Singh et al., 2013 ). Since potential adverse health effects of eucric acid ( Sauer and Kramer, 1983 ; Choudhary et al., 2014 ), and also those of the pungent and bitter tasting isothiocyanate and other phytochemicals encountered in Brassica juncea derived products ( Tripathi and Mishra, 2007 ; Inyang et al., 2014 ) have been observed in some animal bioassays, health care authorities of several countries have issued warnings against, or have even banned, edible uses of mustard oils ( Oram et al., 2005 ; Wendlinger et al., 2014 ). However, as yet no very definitive statements based on preclinical, or clinical, or epidemiological evidence on maximally tolerated daily oral doses of such acids and numerous other phytochemicals commonly consumed with diverse types of mustard derived products can be made. This is mainly because appropriate dose response and other studies necessary for estimating their pharmacologically interesting dose ranges, safety profiles, and possible interactions between them are still missing.
On the other hand, the numbers of reports suggesting potential health benefits of diverse types of Brassica juncea leaf and seed extracts and their bioactive constituents have continued to increase during recent decades ( Kumar et al., 2011a ). Apart from vitamins, minerals, and nutritive proteins and lipids, the plant is now well recognized to be a rich source of a numerous phytochemicals often encountered in diverse other edible plants and well known for their cellular stress response modulating and hormetic effects ( Birringer, 2011 ; Calabrese, 2010 ; Calabrese et al., 2010 ). However, since in Ayurvedic system of medicine mustard derived products are always used in combination with other natural products and health care procedures, therapeutic relevance of these findings in their traditionally known medicinal uses still remain questionable or speculative only.
The most extensively studied bitter and pungent tasting secondary metabolites encountered in Brassica juncea are the glucosinolates. Glucobrassicin, neoglucobrassicin, 4-methoxy glucobrassin and 4-hydroxy glucobrassicin are some indole glucosinolates more often encountered in Brassica juncea than in other plants of the family ( Schreiner et al., 2009 ).
Quantitatively though, sinigrin is one of the major glucosinolate encountered in Indian mustard ( Sang et al., 1984 ), which is now often considered to be a bioactive secondary metabolite of several edible plants with anti-cancer and anti-microbial activities ( Patel et al., 2012 ). During processing of mustard seeds glucosinolates are enzymaticaly degraded to allyl-isothiocyanate, which possesses strong bactericidal activities. Therefore, mustard meal powders are often recommended as a natural antimicrobial agent ( Munday and Munday, 2002 ; Dai and Lim, 2014 ). Structurally diverse glucosinolates are also well known for their preventive potentials against cancer and other chronic diseases, including diabetic neuropathy and neurodegenerative diseases ( Halkier and Gershenzon, 2006 ; Fahey et al., 2003 ; Tarozzi et al., 2013 ; Dinkova-Kostova and Kostov, 2012 )
Essential oils of Brassica juncea consists mainly of a group of structurally analogous isothiocyanates. Some of them, also found in edible mustard oil, are allyl isothiocyanate, diallyl trisulfide, 3-butenyl isothiocyanate, allyl isothiocyanate, diallyl trisulfide and 3-butenyl isothiocyanate ( Yu et al., 2003 ). It has been estimated that such oils consists of ca. 11% saturated and 89% unsaturated fatty acid of which about 18% is linoleic and 15% is linolenic fatty acid ( Mishra and Manchanda, 2012 ). Other fatty acids found in Brassica juncea are erucic, eicosanoic, arachidic, nonadecanoic, behenic, oleic and palmitic acids, and arachidonic and α-linolenic acids are also been encounter in its oils ( Kumar et al., 2011a ). Brassicasterol, campesterol, β-sitosterol, Δ5-avenasterol and trace amounts of Δ7-stigmasterol have also been isolated and characterized from the mustard seed oil ( Li et al., 2000 ).
Plant polyphenolics encountered in Brassica juncea , and in numerous other edible plants now attracting major attention of modern nutritionists and herbal researchers ( Wang et al., 2014 ; Xiao and Hogger, 2015 ; Pandey and Rizvi, 2009 ). These are structurally diverse polyphenolic acids, quercetin, kaempferol, isorhamnetin and their naturally occurring conjugates, derivatives, and analogues ( Cartea et al., 2010 ; Kumar and Andy, 2012 ; Kumar et al., 2012 ). Sinapic acid and its conjugates are quantitatively the major polyphenolics of Brassica juncea and it has been reported that it is one of richest natural sources of the acid and its conjugates ( Niciforovic and Abramovic, 2014 ). Like for diverse other polyphenolic of Brassica juncea leaves, sinapic acid has also been identified as an antidiabetic agent with stress response modulating and antidepressant, anxiolytic and other brain function modulating activities ( Cherng et al., 2013 ; Yoon et al., 2007) .
Isorhamnetin is also another Brassica juncea specific and quantitatively major flavonid of mustard green with an analogous broad spectrum of therapeutically interesting bioactivity profile. Although numerous flavonoid glycosides with oxidative stress protecting activities have been isolated from Brassica juncea Leaves ( Jung et al., 2009 ; Kim et al., 2002 ), isorhamnetin glycosides have been reported to be their major antidiabetic component with such activities ( Yokozawa et al., 2002 ; Yokozawa et al., 2003 ). A comparative study on flavonoid contents of 91 vegetables has revealed an unique flavonol aglycone spectrum in mustard green, and found that it has the highest amount isorhamnetin amongst all vegetables analyzed in that study ( Yang et al., 2013 ). It must be mentioned though, that isorhamnetin and its conjugates are also human metabolites of quercetin and other naturally more abundant flavonoids ( Manach et al., 2004 ). However, like for all other plant extracts, the pharmacological activity profiles, or antidiabetic activity, of Brassica juncea leaf extracts cannot be predicted from their contents of phenolic plant metabolites, or by their antioxidative potentials, only ( Thakur et al., 2013a ; Thakur et al., 2013b ; Thakur et al., 2014a ).
Information now available on preclinical pharmacology of diverse types of extracts, and some of their often discussed bioactive constituents, suggesting their preventive and curative potentials against obesity and diabetes associated comorbidities are summarized in Tables 1 and 2 respectively. These and numerous other therapeutic possibilities offered by Brassica juncea and its bioactive secondary metabolites strongly suggest that modulation or regulation of psychological and metabolic stress triggered biological processes involved in etiology, pathogenesis, and progression of diverse lifestyle associated medical conditions and accelerated aging ( Dietrich and Horvath, 2012 ; Epel, 2009 ; Fontana, 2009 ) are involved in their modes of actions. Consequently, efforts are now being made in several laboratories, including ours, to identify stress response modulating secondary metabolites of the plant, necessary for obtaining more rationally standardized extracts of the plant suitable for further developments as phyto-pharmaceuticals, or nutraceuticals, against diabesity and other lifestyle and environmental stress triggered mental health problems.
Pharmacological activities of diverse types ofBrassica junceaextracts suggesting their curative or preventive potentials against diabesity associated comorbidities
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Pharmacological activities of diverse types of Brassica juncea extracts suggesting their curative or preventive potentials against diabesity associated comorbidities
Some major bioactive constituents ofBrassica junceaidentified to date, and their often-cited pharmacological activities
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Some major bioactive constituents of Brassica juncea identified to date, and their often-cited pharmacological activities
For such purposes, or for dietary therapy with Brassica juncea derived food, it is necessary to cultivate, harvest and process the appropriate variety or strain of the plant. This is not only because the content of bioactive secondary metabolites of the plant vary considerably in different strains and cultivars of the plant, but also due to the fact that it is an accumulator of toxic metals like lead, arsenic, cadmium etc. ( John et al., 2009 ; Podar et al., 2004 ; Jakovljevic et al., 2013 ). Blood levels of such metals in diabetic patients are often fairly high ( Akinloye et al., 2013 ; Kuo et al., 2013 ; Afridi et al., 2008 ), and their adverse effect potentials are well known. This is another reason behind the efforts of agricultural and food industries, and researchers to identify Brassica juncea cultivar strains and cultivation conditions for increasing crop yields with lower heavy metal contents. Although some strains of the plant with high crop yields have been identified, many questions concerning their contents of healthy or unhealthy substances still remain to be solved.
Such questions can be more rationally answered by collaborative efforts of medicinal phytochemists, herbal pharmacologists and toxicologists only. Availability of a convenient and well validated bioassays for identifying not only the therapy relevant secondary metabolites of the plant, but also for quantifying potential synergistic, antagonistic, additive effects between them is an essential prerequisite for such purposes. Since numerous known bioactive secondary metabolites of Brassica juncea and almost all edible medicinal plants possess physiological stress response regulating activity ( Barrajon-Catalan et al., 2014 ; Joven et al., 2013; Lee et al., 2014 ; Tomas-Menor et al., 2015 ), it now apparent that traditionally known medicinal uses of mustards and other edible plants derived products in Ayurvedic system of medicine and health care is mainly due the presence of specific combinations of such substances in Ayurvedic formulations or in Ayurvedic vegetarian food menus. Therefore, it can safely be suggested that the now well validated mouse bioassay evolving from efforts to identify and pharmacologically characterize the stress response regulating constituents of Brassica juncea and other edible plants ( Langstieh et al., 2014 ) could be an useful one not only for better understanding of Ayurvedic pharmacology, but also for discovering and developing urgently needed novel preventive and curative pharmaco-therapies against diabesity and other lifestyle associated physical and mental health problems.
Piper longum
Piper longum L., commonly known as Pippali or “Indian long pepper”, is a wildly growing and flowering perennial climber belonging to edible plants of Piperaceae family. It is now cultivated also for its fruits, which are usually dried and used as a spice and seasonings. Piper longum fruits have a similar, but somewhat hotter or more pungent taste than its close relative Piper nigrum , from which black, green and white pepper is obtained. The oldest known references of Piper longum come from ancient Ayurvedic texts where diverse medicinal and dietary uses of different parts of the plant are described ( Manoj et al., 2004 ). In traditionally known Chinese system of medicine, the fruits are often used for treatments of hyperlipidemia, and during recent years, at least four structurally diverse anti-hyperlipidemic constituents, i.e. piperine, piperlongumine, pipernonaline, and 7, 4’-dimethyl ether of apigenin, have been identified from the fruits. According to these reports ( Jin et al., 2009 ; Krishna et al., 2014 ), anti-hyperlipidemic efficacies of some of these Piper longum constituents in animal models are comparable to the currently widely used antihyperlipidemic drug simvastatin. However, the numbers of phytochemicals isolated from different parts of Piper longum , and their diverse bioactivities suggesting preventive and curative potentials of the plants against diverse malnutrition and other environmentally triggered inflammatory pathologies are not necessarily limited to these molecules only ( Kumar et al., 2011b ; Zaveri et al., 2010 ).
Reports on structurally and functionally novel secondary metabolites of the plant as well as their novel therapeutically interesting and other bioactivities, or of their since long known secondary metabolites, have continue to appear during recent years ( Yang et al., 2013 ; Ahmed et al., 2014 ; Huang et al., 2010 ; Jiang et al., 2013 ; Ku et al., 2014 ; Yang et al., 2014 , Yadav et al., 2014 ). Apart from proteins, carbohydrates, starch, and other nutritive constituents, and volatilile oils, most known bioactive molecules isolated from different parts of the plant are often structurally classified as alkaloids (alkaloidal amides), saponines, lignans, and phenolics etc. However, none of them are very specific biomarkers of the plant, and all of them have also been isolated from other edible plants of Piperacea and other families. Some of the numerous alkaloids or alkaloidal amides encontered in Piper longum fruits are: piperine, methyl piperine, iperonaline, piperettine, asarinine, pellitorine, piperun decalidine, piperlongumine, piperlonguminine, refractomide A, pregumidiene, brachystamide, brachystamide-A, brachystine, pipercide, piperderidine, longamide and tetrahydropiperine, terahydro piperlongumine, dehydropipernonaline piperidine, piperine, terahydropiperlongumine and trimethoxy cinnamoyl-piperidine and piperlongumine ( Zaveri et al., 2010 ). Piperine is often considered to be quantitatively the major (ca. 3 - 5% on dry weight basis) bioactive constituent of long pepper and it is also the major pungent tasting secondary metabolite of the plant. Therefore, it is now often used as a biomarker for analytically standardizing Piper longum extracts for experimental as well as commercial purposes.
Pungency of piperine is caused by activation of the heat and acidity sensing ion channel TRPV1 on pain sensing nerve cells ( McNamara et al., 2005 ). Such capsaicin like effects of piperine and other pungent alkaloidal amides of Piper longum are most probably also involved in pain response modulating effects of its diverse types of extracts. Altered pain sensitivity is a cardinal symptom of diabetic neuropathy and other inflammatory disorders, and crucial role of TRPV1 channel in etiology, pathogenesis, and progression of diabesity associated pathologies are now well recognized ( Suri and Szallasi, 2008 ). However, the questions concerning the involvement of these ion channels in pain response regulating functions of brain or in observed mental function regulating effects of Piper longum and other herbal extracts, cannot yet be answered with certainty ( Gunthorpe and Szallasi, 2008 ). It remains certain though, that piperine and other alkaloidal amides with pungent and spicy tastes are modulators of the functions of TPRV1 channel ( Rios and Olivo, 2014 ) and that as a desensitizer of this channel piperine is more efficacious than capsaicin ( Szallasi, 2005 ).
Another bioactivity of piperine now attracting major attention of modern researchers is its ability to enhance bioavailability of other nutrients and drugs ( Patil et al., 2011 ). Similar or analogous effects are also known for numerous other edible phytochemicals commonly consumed with every day meals ( Muttepawar et al., 2014 ; Tatiraju et al., 2013 ). Although as yet no very definitive statements on biological mechanisms and process involved in such effects of piperine can be made, it remains certain that its regular consumption can enhance oral bioavailability of other essential nutrients and edible phytochemicals commonly consumed with everyday meals, or with phyto-pharmaceuticals and nutraceuticals. It has been reported, indeed, that piperine enhances oral bioavailability of the edible antidiabetic phytochemical curcumin by 2000% in human ( Shoba et al., 1998 ), which is the quantitatively major bioactive constituent of another Ayurvedic herb Curcuma longa (to be described later). These and numerous other analogous observations made with piperine and other edible phytochemicals strongly suggest that modulations of bioavailability of essential nutrients are also involved in their observed beneficial effects on metabolic disorders, and that proper understanding of their Ayurvedic pharmacology and medicinal values is possible only when due attention is paid to their such properties.
Another major alkaloidal amide encountered in Piper longum and attracting major attention of modern drug discoverers is piperlongumine, or piplartin ( Bezerra et al., 2013 ). It is not encountered in Piper nigrum , the fruits of which are the most commonly consumed spice in the western world and elsewhere ( Bezerra et al., 2013 ). Preclinical information now available on piplartin strongly suggest that it is most probably also one of the major bioactive secondary plant metabolites involved in diverse therapeutically interesting mental and metabolic function modulating effects of Piper longum fruits and roots ( Bezerra et al., 2013 ), and that it could be a promising cancer therapeutic lead as well ( Wu et al., 2014 ). Although piperlongumine and piperine are the two quantitatively the major bioactive constituents of numerous piper species commonly used in numerous Ayurvedic formulations ( Meghwal and Goswami, 2013 ), their quantities vary considerable not only in different piper species but also in different parts of Piper longum and other plants of the species ( Bao et al., 2014 ; Chandra et al., 2014 ).
Piplartin was first isolated from Piper longum roots, dried powder of which are also often used by Ayurvedic and other practitioners of herbal medicine for treatments of insomnia and debility caused by chronic fever ( Murthy, 2009 ), and diverse types of extracts of the roots and their combinations with other herbal extracts are now also commercialized in India as Ayurvedic remedies ( Rajopadhye et al., 2012 ). Such remedies are often used for treatment of rheumatism and other inflammatory conditions, and aqueous suspension of powdered roots of Piper longum root, commonly called Pippalimula in India, has been reported to possess ibuprofen like analgesic activity ( Vedhanayaki et al., 2003 ). During recent years, several reports revealing antidiabetic activities of aqueous and ethanolic extracts of Piper longum roots have also appeared ( Chaurasia and Das, 2013 ; Chaurasia et al., 2012 ; Nabi et al., 2013 ). Extensive psycho-pharmacological and some clinical observations made in our Banaras Hindu University’s Ayurvedic hospital with Piper longum root powder have not only revealed its broad spectrum of therapeutically interesting neuronal function modulating activities, but also indicated that metabolic as well as psychological stress response modulating effects are also involved in its modes of actions. Since stress response regulating properties of a Piper longum fruits containing Ayurvedic formulation has been reported ( Neha and Mishra, 2011 ), and several bioactive phytochemicals encountered in the roots and fruits used in the formulation are the same, it could as well be that the reported antidiabetic activity of the root extracts are also due to the presence of stress response regulating components in them.
Major therapeutically interesting bioactivities of diverse types of Piper longum extracts and their quantitatively major bioactive constituents indicating therapeutic potentials of the plant for prevention and cure of obesity associated comorbidities are summarized in Tables 3 and 4 respectively. Although several recent reports have already revealed anti-obesity activity of piperine containing Piper longum oil in animal models ( BrahmaNaidu et al., 2014 ; Choi et al., 2013 ; Doucette et al., 2013 ; Kumar et al., 2013 ; Noble et al., 2013 ), many questions concernig the roles of other bioactive constituents in such oils still remain open. Moreover, many such reports pay little attention to the fact that piperine and other constituents of such oils also possesses mental function regulating activities ( Cicero Bezerra Felipe et al., 2007 ; Gilhotra and Dhingra, 2014 ; Li et al., 2007a ; Li et al., 2007b ; Mao et al., 2014 ; Pal et al., 2011 ), and that their modulating effects on central nervous system could as well be involved in anti-obesity and other health benefits of Piper longum derived products against type-2 diabetes ( Sandoval et al., 2009 ; Patrone et al., 2014 ; Banks et al., 2012 ). It cannot be ignored though, that due to very hot taste of such products, they might not be well suited for incorporating them in everyday meals in high enough quantities necessary for obtaining health benefits from them.
Some reports suggesting therapeutic potentials ofPiper longumextracts against diabesity and associated comorbidities
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Some reports suggesting therapeutic potentials of Piper longum extracts against diabesity and associated comorbidities
Major bioactive constituents ofPiper longumL. identified to date, and their often-cited pharmacological activities
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Major bioactive constituents of Piper longum L. identified to date, and their often-cited pharmacological activities
Amlaki and Triphala
Amlaki is the Sanskrit name of the edible fruits of Phyllanthus emblica (synonym: Emblica officinalis ; common name: Indian gooseberry) most commonly used in Ayurvedic system of medicine and health care as a tonic and for prevention and cure of physical as well as mental health problems arising from intricate disorders of digestive and excretory organs. It is also one of the most widely used edible fruits in numerous Ayurvedic formulations. One such very popular formulation is Triphala , which consists of equal parts of dried edible fruits of Embelica officinalis , Terminalia chebula , and Terminalia bellirica ( Belapurkar et al., 2014 ; Maheshwari and Rajnee, 2014 ). Preventive and curative use of both Amlaki as well as of Triphala with barley and other dietary measures for treatments of diabetes is recommended in ancient Ayurvedic texts, and their such medicinal uses are now well justified by numerous preclinical and some therapeutic observations reported during recent decades ( Sharma and Chandola, 2011a ; Sharma and Chandola, 2011b ; D’Souza et al., 2014 ; Mohammad and Larijani, 2013 ; Tiwari, 2008 ; Rajan and Antony, 2008 ). In classical Ayurvedic texts numerous other formulations containing them are mentioned also ( Chulet and Pradhan, 2009 ; Chouhan et al., 2013 ), and in traditionally known Indian, Chinese, and Arabic systems of medicine Triphala is more often than not used in combination with other medicinal herbal herbs and other health care practices ( Mohammad and Larijani, 2013 ; Zaki et al., 2014 ). Amongst the three edible fruits constituting Triphala formulations, the one most widely harvested and consumed for culinary purposes is Amlaki .
Recent neuropsychopharmacological observations ( Kumar and Chatterjee, 2014b ; Dhanalakshmi et al., 2007 ; Dhanalakshmi et al., 2006 ; Nariya et al., 2011 ; Rinki and Mishra, 2011 ; Srikumar et al., 2006 ) have revealed a broad spectrum of neuronal function modulating effects of Triphala , and suggest that its modulatory effects against glucose toxicity and diverse metabolic or mental stress triggered biological responses could be involved in its modes of actions. It is a sour, bitter, and astringent tasting fruit, which is often steeped in salt water and turmeric to make the sour fruits palatable. Gallic and Elegiac acids and their conjugates are some of the quantitatively major bioactive constituents of all the three fruits composing Triphala ( Patel and Shah, 2009 ). However, the spectrum of known bioactive secondary plant metabolites encountered in Amlaki is not identical to those known for the other two fruits commonly used in this and numerous other Ayurvedic formulation. Available information on the bioactive constituents, and experimental evidences suggesting therapeutic potentials of Amlaki for treatments of diabesity and diverse other diseases have often been reviewed during recent years ( D’Souza et al., 2014 ; Dasaroju and Gottumukkala, 2014 ; Khosla and Sharma, 2012 ; Krishnaveni and Mirunalini, 2010 ; Sri et al., 2013 ). Amlaki is also one of the several Ayurvedic medicinal herbs currently universally well recognized by modern herbalists and herbal researchers as an herbal adaptogen ( Winston and Maimes, 2007 ). The concept of herbal adaptogens evolved originally in Russia during late 1940s ( Brekhman and Dardymov, 1969 ), and the very first more systematic and detailed report on adaptogenic, or biological stress response regulating, effects of Amlaki and a few other edible and other Ayurvedic medicinal plant appeared in 1999 ( Rege et al., 1999 ). Since then this concept has been well accepted by almost all modern scholars and practitioners of Ayurvedic system of medicine, and efforts are now being made by modern researchers to experimentally verify the efficacies of combinations of Amlaki with other edible plants and Ayurvedic therapeutic practices for prevention and cure of type-2 diabetes ( Tripathi et al., 2012 ; Vaibhavi et al., 2013 ).
One of the several Amlaki formulation specially recommended in classical Ayurvedic texts for treatment of diabetes-associated comorbidities is Nishamlaki , which consists of Amlaki and Turmeric rhizome (to be described later). They are also the two major constituents of a vast majority of herbal formulations currently commonly prescribed in India for treatments of diabesity ( Sarma et al., 2014 ). Therefore, efforts are now being made to better standardize such a formulation that could eventually be more rationally developed and used for prevention and cure of diabetes ( Rao et al., 2013 ; Venkateshwarlu et al., 2013 ). A recent report have revealed though, that inappropriate formulations or doses of such preparations could as well have adverse drug-drug interaction with metformin ( Puranik et al., 2014 ), i.e. one of the main anti-diabetic drugs commonly recommended for treatments of type-2 diabetes. Efforts to answer the question whether Amlaki , or Turmeric, or inappropriate combinations of the two are involved in such herb-drug interaction will be necessary for more rational uses of the two edibles for prevention and cure of diabesity. Moreover, since both Amlaki as well turmeric are often consumed in India with every day meals, and both diabetes and obesity are also the most common metabolic disorders encountered in Indian, China, and other developing countries, efforts to better clarify the situation is urgently needed for obtaining appropriate medicinal benefits from metformin and other antidiabetic drugs in these countries ( Neerati et al., 2012 ).
Available information on medicinal phytochemistry of the other two fruits constituting Triphala strongly suggest that they could also have adverse herb-drug interactions with metformin and other drugs currently often prescribed for prevention and cure of diabesity associated physical and mental health problems ( Fasinu et al., 2012 ). Although a few known bioactive secondary metabolites of Emblica officinalis ( D’Souza et al., 2014 ; Khosla and Sharma, 2012 ; Zhang et al., 2001 ; Rastogi and Mehrotra, 1995 ; Asolkar et al., 1992 ; Dasaroju and Gottumukkala, 2014 ), are not encountered in Terminalia chebula ( Rastogi and Mehrotra, 1995 ; Saleem et al., 2002 ; Kokate et al., 2003 ; Rathinamoorthy and Thilagavathi, 2014 ; Walia and Arora, 2013 ; Gupta, 2012 ) or in Terminalia bellirica ( Saleem et al., 2002 ; Kokate et al., 2003 ; Kadian et al., 2014; Kumudhavalli et al., 2010 ; Saxena et al., 2013 ), all of them are fairly rich sources of tannins, gallic acids and their conjugates, and several other secondary plant metabolites ubiquitously present in many edible and other plants and well known for their modulating effects on drug metabolizing enzymes and their bioavailability ( Serrano et al., 2009 ; Anannarukan et al., 2012 ). It has been reported that drug metabolizing enzyme inhibitory properties of Triphala are involved in such observed effects of the formulation, and that in this respect all the three constituents of the formulation are almost equipotent ( Ponnusankar et al., 2011 ). According to this report, gallic acid and its conjugates and derivatives are also their common polyphenolic constituent involved in such effects of Triphala .
It must be mentioned though, that gallic acid conjugates and other plant polyphenolics are also encountered in numerous other edible and medicinal plants, and that they are now well recognized for their protective effects against oxidative stress triggered pathologies, including diabetes and associated psychopathologies ( Lee et al., 2014 ; Dragan et al., 2015 ; Khadem and Marles, 2010 ; Lephart, 2015 ; Liu et al., 2015 ; Santilli et al., 2015 ). Moreover, analgesic, anti-inflammatory, antidiabetic, anxiolytic, antidepressant, cognitive function modulating, antimicrobial, and diverse other therapeutically interesting bioactivities of diverse types of extracts of Amlaki and Triphala enriched in such phytochemicals also have often been reported. Detailed discussions and critical analysis of these reports dealing with their diverse such bioactivities is beyond the scope of this communication. For such purposes, the already cited references have to be consulted.
It must be mentioned though, that numerous observations made with Amlaki , Triphala , and numerous other edible plant derived products have consistently revealed that their oral efficacies for stress responses modulating and other bioactivities increase with increasing numbers of treatment days ( Kumar and Chatterjee, 2014a ), and that this is most probably due to their modulating effects on microbial ecology inside the gastrointestinal tract ( Thakur et al., 2014b ). Although our current knowledge on the bactericidal constituents of Triphala and its constituents is far from being satisfactory, evidence now available on their diverse types of formulations strongly suggest that Gallic and Ellagic acids and their conjugates and soluble and insoluble polymers (commonly referred to as tannins) are their major secondary metabolites involved in bactericidal activities of their commercialized extracts ( Biradar et al., 2008 ). It is now well recognized that gut microbial ecology plays a crucial role in the etiology, pathogenesis and progression of diabesity ( Burcelin et al., 2011 ; Everard and Cani, 2013 ), and that such and other plant phenolics and their metabolites are regulators of gut microbial ecology ( Bolca et al., 2013 ; van Duynhoven et al., 2011 ). Therefore, it is now apparent that proper understanding of their modulating effects on gut microbial ecology is an essential prerequisite for their more rational uses as dietary therapies against diabesity and associated mental health problems ( Dinan and Cryan, 2012 ; Wang and Tang, 2015 ).
Curcuma longa (Turmeric)
Curcuma longa (synonym: Curcuma domestica and commonly called turmeric) is one of the several plants of the Zingiberaceae family (genus: curcuma), well known since antiquity to the scholars and practitioners of traditionally known systems of medicine for diverse health benefits of their rhizomes. It is now widely cultivated and diversely processed in India, China, and many other countries for obtaining dried roots and other products from them for culinary as well as medicinal purposes ( Li et al., 2011 ). In Ayurvedic and other traditionally known Indian system of medicine, turmeric is now often used as a general tonic and blood purifier and also for prevention and cure of inflammatory diseases. Currently, it is phytochemicallly and pharmacologically one of the more extensively studied edible plant derived products of medicinal interest. Numerous reviews and monographs describing diverse therapeutic possibilities offered by the plant and its bioactive secondary metabolites have appeared during recent years ( Chaudhary et al., 2010 ; Gupta et al., 2013 ; Chempakam and Parthasarathy, 2008 ). Available preclinical and clinical information on anti-diabetic potentials of the plant has also been summarized in a recent issue of this journal ( Ponnusamy et al., 2012 ). Most such reviews and reports often neglect though, that modulating effects of curcumin and other turmeric curcuminoids on brain functions could as well be involved in their modes of actions and health benefits. Some of the reports suggesting such possibility for curcumin and two other Turmeric curcuminoids are summarized in Table 5 .
Some reported neuro-pharmacological activities of Curcumin and of two other Turmeric curcuminoids
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Some reported neuro-pharmacological activities of Curcumin and of two other Turmeric curcuminoids
Amongst numerous known bioactive and therapeutically interesting secondary metabolites of turmeric identified and quantified to date, the three structurally and functionally analogous ones with antioxidative properties, i.e. curcumin, desmethoxycurcumin, and bisdesmethoxycurcumine (often collectively referred to as curcuminoids), have attracted the most attention of modern herbal researchers and drug discoverers ( Aggarwal et al., 2007 ; Ahmed and Gilani, 2014 ; Alappat and Awad, 2010 ; Bradford, 2013 ; Grynkiewicz and Slifirski, 2012 ; Jayaprakasha et al., 2006 ; Lopresti et al., 2014 ; Sahebkar, 2013 ). Hereupon, by far a vast majority of preclinical and clinical reports deal mainly on two major obesity associated medical conditions, i.e. diabetes and cancer ( Zhang et al., 2013 ). These efforts have not only continued to add preclinical and clinical evidences suggesting their therapeutic potentials against these and diverse other malnutrition associated health problems, but also have leaded to better understanding of medicinal phytochemistry and molecular pharmacology of curcuminoids ( Grynkiewicz and Slifirski, 2012 ; Priyadarsini, 2014 ; Brodniewicz and Grynkiewicz, 2012 ). Some reports suggesting therapeutic potentials of Curcuma longa extracts against diabesity and associated comorbidities are summarized in Tables 6 .
Reports suggesting therapeutic potentials ofCurcuma longaextracts against diabesity and associated comorbidities
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Reports suggesting therapeutic potentials of Curcuma longa extracts against diabesity and associated comorbidities
However, curcumin and curcuminoids are not the only bioactive secondary metabolites of Curcuma longa potentially involved in diverse traditionally known, or recently identified therapeutic potentials of turmeric ( Aggarwal et al., 2013 ; Bhanumathy et al., 2013 ; Kasabri et al., 2014 ; Lekshmi et al., 2012 ). Although the list of bioactive phytochemicals, vitamins, and other micronutrients commonly consumed with turmeric, and which could also be involved in traditionally known health benefits of the spice have consistently been enlarged during the past few decades ( Wang et al., 2014 ; Mirmiran et al., 2014 ; Vaidya, 2014 ), many questions concerning oral bioavailability, and the doses and treatment regimen necessary for obtaining therapeutic benefits from curcuminoids, or for that matter for any of the till now known bioactive secondary metabolites of turmeric, cannot yet be answered with any certainty ( Anand et al., 2007 ). Some observations made in vitro , suggest that oral bioavailability of curcuminoids from turmeric could as well be higher than those of pure curcuminoids ( Maheshwari, 2010 ). However, therapeutic relevance of these observations still remains questionable. This is mainly because numerous metabolic and behavioral effects observed after daily oral doses of curcuminoids seldom correlate with their blood levels observed after their single or repeated daily oral doses. Such is specially the case for their stress triggered brain function modulating effects in experimental animals observed after their oral doses commonly used for assessing their therapeutic potentials against diabesity and other metabolic disorders ( Xia et al., 2011 ; Xia et al., 2006 ).
Taken together, these observations clearly suggest that health benefits of curcuminoids and other turmeric phytochemicals are either due to their bioactive metabolites, or that their observed broad spectrum of bioactivities are due to their non-systemic effects. Since turmeric is always consumed with other food ingredients containing diverse other bioactive molecules with broad spectrums of bioactivity profiles, it is almost certain that traditionally known health benefits of turmeric, cannot entirely be due to its curcuminoids contents, or on their blood levels observed after turmeric intake, only. Since analogous is the situation for almost all medicinally used edible plants and phytochemicals, attempts are now being made in several laboratories to use system-biology based pharmacological approaches for more rationally solving such problems ( Goodacre, 2007 ; Nyanginja and Mponda, 2014 ; van Ommen and Stierum, 2002 ). However, during most such efforts attempts are made to better define the cellular and molecular mechanisms potentially involved in their modes of action, and as yet only very little attention has been paid to potential role of the so called microbiota-gut-brain axis in their observed effects in experimental animals and human volunteers and patients ( Thakur et al., 2014b ; Chiou et al., 2014 ; Greiner et al., 2014 ). However, the possibility that modulation of colonic microbiota could be involved in colon cancer prevention has recently been pointed out also ( McFadden et al., 2014 ).
Some major difficulties encountered during efforts to extrapolate preclinical findings made with turmeric extracts and their known bioactivities in terms of traditionally known medicinal uses of the turmeric arise also from the fact that depending on harvesting and processing procedures used for medicinal value and the contents of curcuminoids and other bioactive constituents vary considerably ( Pal et al., 2008 ). A recently reported computer assisted study have revealed that at least 200 structurally and functionally diverse bioactive phytochemicals can be expected to be present in a given turmeric sample ( Balaji and Chempakam, 2010 ), and that many of them have them have adverse effect potential as well. Results of this in silico study have revealed that out of the 200 compounds screened, 184 were predictably toxigenic, 136 mutagenic, 153 carcinogenic, and 64 hepatotoxic, and that only 16 of them are devoid of any of these adverse effects detectable by the in silico procedure used. Although this report supplies an exhaustive list of bioactive secondary metabolites of Curcuma longa , predictive validity of the observations reported there must be judged with caution ( Balaji and Chempakam, 2010 ). Numerous toxicological and safety reports on diverse types of products derived from the plant have always pointed out that their adverse effect can be expected only after their extremely high daily oral doses that cannot be consumed with every day meals or with Ayurvedic formulations containing them ( Chainani-Wu, 2003 ; Joshi et al., 2003 ; Lao et al., 2006 ; Madhu et al., 2013 ; Micucci et al., 2013 ; Qureshi et al., 1992 ; Ulbricht et al., 2011 ; Velusami et al., 2013 ; Liju et al., 2013 ; Hasan et al., 2014 ).
Some high dose adverse effect potentials of phytochemicals often cited deal with their possible effect on liver functions ( Kandarkar et al., 1998 ; Babu and Srinivasan, 1997 ), and those of gastrointestinal tract and skin ( Fetrow and Avila, 1999 ). Unfortunately, as yet only a very few scattered reports on dose response studies necessary for predicting therapeutically interesting and safety margin of Curcuma longa extracts (other than those highly concentrated in curcumin and curcuminoids) have appeared ( Micucci et al., 2013 ; Joshi et al., 2011 ). Results of one such recently reported preliminary study conducted in mice have revealed not only metformin (currently the drug of first choice for prevention and cure of diabesity) like stress response suppressing effects of fairly low daily oral doses of curcumin and some Curcuma longa extracts enriched in curcuminoids, but also suggest that even more than their 50 fold higher daily oral doses are fairly well tolerated by both male and female animals ( Verma et al., 2015 , Verma et al., 2014 ). Recent observations made in our laboratories with turmeric oil devoid of curcumin indicate that analogous is also the case for such oils (manuscript in preparation). These observations, and numerous other revealing that curcumin and diverse other turmeric constituents modulate the functions of stress responses mediated by shock proteins ( Ali and Rattan, 2006 ; Speciale et al., 2011 ), add experimental evidences in support of the convictions that stress response regulating effects of turmeric derived products are involved in their modes of action, and that curcuminoids are not their only antidiabetic or stress response modulating bioactive constituents.
Phytochemicals, stress and diabesity
The term “diabesity” was initially coined during early 1970s to describe strong pathogenic links between obesity and type-2 diabetes ( Sims et al., 1973 ). Although since then it has been well established that complex interactions between obesity, insulin resistance, and pancreatic ß-cell dysfunction cause type-2 diabetes, biological mechanisms and processes regulating the interplay among these impairments still remain to be better defined ( Tschop and DiMarchi, 2012 ; Martinez and Milagro, 2015 ). However, it is now well recognized that even modest reduction of body weight can lead to significant improvements in glucose homeostasis of patients suffering from, or at risk to, diabesity ( Martinez et al., 2014 ; Pati et al., 2014 ), and that uncontrollable stressful events and chronic stress states have significant and positive association with weight gains and type-2 diabesity ( Adam and Epel, 2007 ; Dallman et al., 2005 ; Steptoe et al., 2014 ). This is most probably due to behavioral alterations triggered by environmental or mental stress, which eventually leads to addiction-like eating behavior ( Ahmed et al., 2013 ; Ginty, 2013 ; Ginty et al., 2012 ; Scott and Johnstone, 2012 ; Sinha and Jastreboff, 2013 ). Although several questions concerning individual food components involved in “addictive eating behavior” still remain open ( Ahmed et al., 2013 ; Davis, 2014 ; Meule et al., 2014 ), it is now almost certain that proper modulation of this behavior could indeed be an effective strategy for prevention of obesity associated physical and mental health problems ( Meule et al., 2014 ; Murray et al., 2015 ; Pedram and Sun, 2015 ).
Amongst structurally diverse secondary plant metabolites with stress response modulating and other therapeutically interesting bioactivities, polyphenolics have attracted the most attention of modern nutritional researchers and pharmacologists (Lee et al., 2014 ; Nowak, 2015 ; Pa and Gazzaley, 2014 ). Although their health benefits are often considered to be due to their antioxidative properties, like other diverse phytochemicals (edible or not), they also possess broad spectrums of bactericidal, anti-inflammatory, immune function modulating, and numerous other therapeutically interesting bioactivities ( Kennedy, 2014a ; Kennedy, 2014b ). Mounting preclinical and clinical evidences accumulated during the past few decades strongly suggest that their modulating effects on gut microbial ecology and digestive functions are also involved in their modes of actions ( Thakur et al., 2014b ). It is now well recognized that metabolic and psychological stress responses also alter gut microbial ecology, which in turn alters the functions of the gut-brain axis ( Aroniadis and Brandt, 2013 ; Mayer, 2011 ; Moloney et al., 2014 ). According to the postmodern eco-physiological and pharmacological concept arising from these findings ( Abedon, 2014 ), circulating blood levels of edible phytochemicals observed after their oral intake must not necessarily be very reliable indicators of their brain function modulating effects. Available information on metabolic fate of numerous edible polyphenolics ( van Duynhoven et al., 2011 ) is also in agreement with this inference.
Eco-physiological and other studies have now established that secondary plant metabolites afford survival benefits to plants against enviorenmental stress ( Kennedy, 2014a ; Kennedy, 2014b ; Trowbridge, 2014 ), and that structurally and functionally diverse edible phytochemicals possess pleiotropic protective effects against stress responses and are potentially useful for prevention and cure of diabetes, Alzheimer’s disease and other chronic silently progressing chronic diseases ( Dembinska-Kiec et al., 2008 ; Leiherer et al., 2013 ; Davinelli et al., 2012 ; Vaiserman, 2014 ; Carriba and Comella, 2014 ; Franco and Cedazo-Minguez, 2014 ; Ruden and Lu, 2011 ). However, it has been also reported that depending on the components of whole-food some of them could as well worsen cognitive dysfunctions ( Parrott et al., 2015 ). Available information on dose response relationship of numerous nutritive and other phytochemicals have revealed indeed that their protective or amplifying or adverse effects on stress responses depend on their daily doses and treatment regimen used, and that hereupon their beneficial effects often predominates ( Calabrese et al., 2012 ; Le Bourg and Rattan, 2014 ; McClure et al., 2014 ). Such dose response relationships of bioactive molecules are due to their dose dependant modulating effects on diverse cellular adaptive stress responses ( Birringer, 2011 ; Costantini et al., 2010 ) which often leads to their experimentally observed inverted U or J shaped dose response curves, or hormetic effects, in bioassays ( Bao et al., 2014 ; Lushchak, 2014a ). Evaluation of dynamics of such effects of edible phytochemicals are essential prerequisite for better understanding of their pharmacokinetic and pharmacodynamic properties necessary for obtaining health benefits offered by them ( Lushchak, 2014b ). This is because exposures to short term stress (hormetic stress) can strengthen subsequent response to stress, and prolonged stress exposures leads to toxic stress which shorten life span, and also leads to mental health problems ( Lee et al., 2014 ; Epel and Lithgow, 2014 ; Scapagnini et al., 2014 )
The possibility that physiological or psychological stress is a major contributing factor to health problems triggered or caused by obesity and diabetes have often been pointed out during recent decades ( Brindley and Rolland, 1989 ; Gastaldi and Ruiz, 2009 ; Kelly and Ismail, 2015 ). It is now well recognized also that the functions of all bodily or gas including those of the brain, and gut microbiota are altered by metabolic as well as mental and environmental stress ( Steptoe et al., 2014 ; Carvalho et al., 2015 ; Cryan and Dinan, 2012 ; Foster and McVey Neufeld, 2013 ; Nicholson etal., 2012 ; Rhee et al., 2009 ). Although modern researchers have now well recognized that targeting the central nervous system is a promising approach for discovering drugs against obesity associated diabetes and other metabolic disorders ( Sandoval et al., 2009 ; Lin and Sun, 2010 ; Perez-Tilve et al., 2012 ), most modern drug discoverers still continue to neglect that gut microbial ecology plays a crucial role in regulations of all bodily and mental functions ( Baty et al., 2014 ; Triggle, 2012 ). Recent reports have pointed out though, that dietary phytochemicals are regulators of gut microbial ecology ( D’Aversa et al., 2013 ), and that plant and other natural products libraries are valuable sources for identifying drug leads acting on proteins regulating stress responses ( Davenport et al., 2014 ).
As summarized in this communication, many edible plants traditionally known for their medicinal values are pleiotropic stress protective agents with anti-obesity, antidiabetic, antidepressant, anxiolytic, memory function modulating, analgesic and other brain function modulating activities. Diverse combinations of their secondary metabolites with demonstrated stress response regulating and broad spectrums of pharmacologically interesting bioactivity profiles are encountered in almost all terrestrial plants (medicinal, or not) as well. These findings not only justify their medicinal uses in Ayurvedic and other traditionally known systems of medicine and health care, but also strongly suggest that more holistic pharmacological strategies will be necessary for better understanding of therapeutic potentials of traditionally known medicinal plants, or for obtaining novel therapeutic leads from edible and other plant derived products containing edible phytochemicals. During such efforts due attention has to be paid not only to their stress response regulating and microbicidal properties, but also to the fact their adaptogenics like efficacies increases with increasing number of treatment days.
CONFLICT OF INTEREST The authors do not have any conflict of interest in the present study
Abedon ST 2014 Phage therapy: Eco-physiological pharmacology Scientifica (Cairo) 2014 581639 -
Abu-Taweel GM , Ajarem JS , Ahmad M 2013 Protective effect of curcumin on anxiety, learning behavior, neuromuscular activities, brain neurotransmitters and oxidative stress enzymes in cadmium intoxicated mice J Behav Brain Sci 3 74 - 84    DOI : 10.4236/jbbs.2013.31008
Adam TC , Epel ES 2007 Stress, eating and the reward system Physiol Behav 91 449 - 458    DOI : 10.1016/j.physbeh.2007.04.011
Afridi HI , Kazi TG , Kazi N , Jamali MK , Arain MB , Jalbani N , Baig JA , Sarfraz RA 2008 Evaluation of status of toxic metals in biological samples of diabetes mellitus patients Diabetes Res Clin Pract 80 280 - 288    DOI : 10.1016/j.diabres.2007.12.021
Agarwal NB , Jain S , Agarwal NK , Mediratta PK , Sharma KK 2011 Modulation of pentylenetetrazole-induced kindling and oxidative stress by curcumin in mice Phytomedicine 18 756 - 759    DOI : 10.1016/j.phymed.2010.11.007
Aggarwal B , Sundaram C , Malani N , Ichikawa H 2007 The indian solid gold. In The molecular targets and therapeutic uses of curcumin in health and disease Adv Exp Med Biol 595 1 - 75
Aggarwal BB , Yuan W , Li S , Gupta SC 2013 Curcumin-free turmeric exhibits anti-inflammatory and anticancer activities: Identification of novel components of turmeric Mol Nutr Food Res 57 1529 - 1542    DOI : 10.1002/mnfr.201200838
Agrawal S , Millett CJ , Dhillon PK , Subramanian SV , Ebrahim S 2014 Type of vegetarian diet, obesity and diabetes in adult indian population Nutr J 13 89 -    DOI : 10.1186/1475-2891-13-89
Ahmed B , Tripathi K , Pandey ND , Khan M 2014 Piperone-3 and piperone-4: Two new ketones isolated from Piper longum L. Dried fruits Intl J Pharm Sci Rev Res 26 318 - 321
Ahmed SH , Guillem K , Vandaele Y 2013 Sugar addiction: Pushing the drug-sugar analogy to the limit Curr Opin Clin Nutr Metab Care 16 434 - 439    DOI : 10.1097/MCO.0b013e328361c8b8
Ahmed T , Gilani AH 2014 Therapeutic potential of turmeric in alzheimer’s disease: Curcumin or curcuminoids? Phytother Res 28 517 - 525    DOI : 10.1002/ptr.5030
Akinloye O , Ogunleye K , Oguntibeju OO 2013 Cadmium, lead, arsenic and selenium levels in patients with type 2 diabetes mellitus African J Biotechnol 9 5189 - 5195
Alappat L , Awad AB 2010 Curcumin and obesity: Evidence and mechanisms Nutr Rev 68 729 - 738    DOI : 10.1111/j.1753-4887.2010.00341.x
Ali RE , Rattan SI 2006 Curcumin’s biphasic hormetic response on proteasome activity and heat-shock protein synthesis in human keratinocytes Ann N Y Acad Sci 1067 394 - 399    DOI : 10.1196/annals.1354.056
Anand P , Kunnumakkara AB , Newman RA , Aggarwal BB 2007 Bioavailability of curcumin: Problems and promises Mol Pharm 4 807 - 818    DOI : 10.1021/mp700113r
Anannarukan N , Niwattisaiwong N , Warisnoicharoen W , Winitthana T , Pramyothin P , Chaichantipyuth C , Lawanprasert S 2012 Inhibition of human cytochrome p450 in vitro by phyllanthus amarus and Phyllanthus emblica aqueous extracts Thai J Pharm Sci 36 135 - 143
2003 Position of the american dietetic association and dietitians of canada: Vegetarian diets J Am Diet Assoc 103 748 - 765    DOI : 10.1053/jada.2003.50142
Aroniadis OC , Brandt LJ 2013 Fecal microbiota transplantation: Past, present and future Curr Opin Gastroenterol 29 79 - 84    DOI : 10.1097/MOG.0b013e32835a4b3e
Asolkar LV , Kakkar KK , Chakre OJ 1992 Glossary of indian medicinal plants with active principles, second supplement Publication and Information Directorate, CSIR New Delhi, India
Baboota RK , Bishnoi M , Ambalam P , Kondepudi KK , Sarma SM , Boparai RK , Podili K 2013 Functional food ingredients for the management of obesity and associated co-morbidities - a review J Funct Foods 5 997 - 1012    DOI : 10.1016/j.jff.2013.04.014
Babu PS , Srinivasan K 1997 Hypolipidemic action of curcumin, the active principle of turmeric (Curcuma longa) in streptozotocin induced diabetic rats Mol Cell Biochem 166 169 - 175    DOI : 10.1023/A:1006819605211
Balaji S , Chempakam B 2010 Toxicity prediction of compounds from turmeric (Curcuma longa l) Food Chem Toxicol 48 2951 - 2959    DOI : 10.1016/j.fct.2010.07.032
Banks WA , Owen JB , Erickson MA 2012 Insulin in the brain: There and back again Pharmacol Ther 136 82 - 93    DOI : 10.1016/j.pharmthera.2012.07.006
Bao L , Bai S , Borijihan G 2012 Hypolipidemic effects of a new piperine derivative gb-n from Piper longum in high-fat diet-fed rats Pharm Biol 50 962 - 967    DOI : 10.3109/13880209.2012.654395
Bao N , Ochir S , Sun Z , Borjihan G , Yamagishi T 2014 Occurrence of piperidine alkaloids in piper species collected in different areas J Nat Med 68 211 - 214    DOI : 10.1007/s11418-013-0773-0
Barrajon-Catalan E , Herranz-Lopez M , Joven J , Segura-Carretero A , Alonso-Villaverde C , Menendez JA , Micol V 2014 Molecular promiscuity of plant polyphenols in the management of age-related diseases: Far beyond their antioxidant properties Adv Exp Med Biol 824 141 - 159
Baty V , Mougin B , Dekeuwer C , Carret G 2014 Gut health in the era of the human gut microbiota: From metaphor to biovalue Med Health Care Philos 17 579 - 597    DOI : 10.1007/s11019-014-9552-2
Belapurkar P , Goyal P , Tiwari-Barua P 2014 Immunomodulatory effects of triphala and its individual constituents: A review Indian J Pharm Sci 76 467 - 475
Bezerra DP , Pessoa C , de Moraes MO , Saker-Neto N , Silveira ER , Costa-Lotufo LV 2013 Overview of the therapeutic potential of piplartine (piperlongumine) Eur J Pharm Sci 48 453 - 463    DOI : 10.1016/j.ejps.2012.12.003
Bhanumathy M , Shivaprasad HN , Nargund LVG 2013 Protective effect of Curcuma longa rhizomes against physical stressinduced perturbations in rats J Nat Remedies 14 27 - 32
Bharal N , Sahaya K , Jain S , Mediratta PK , Sharma KK 2008 Curcumin has anticonvulsant activity on increasing current electroshock seizures in mice Phytother Res 22 1660 - 1664    DOI : 10.1002/ptr.2551
Bhatia N , Jaggi A , Singh N , Anand P , Dhawan R 2011 Adaptogenic potential of curcumin in experimental chronic stress and chronic unpredictable stress-induced memory deficits and alterations in functional homeostasis J Nat Med 65 532 - 543    DOI : 10.1007/s11418-011-0535-9
Biradar YS , Jagatap S , Khandelwal KR , Singhania SS 2008 Exploring of antimicrobial activity of triphala mashi-an ayurvedic formulation Evid Based Complement Alternat Med 5 107 - 113    DOI : 10.1093/ecam/nem002
Birringer M 2011 Hormetics: Dietary triggers of an adaptive stress response Pharm Res 28 2680 - 2694    DOI : 10.1007/s11095-011-0551-1
Bolca S , Van de Wiele T , Possemiers S 2013 Gut metabotypes govern health effects of dietary polyphenols Curr Opin Biotechnol 24 220 - 225    DOI : 10.1016/j.copbio.2012.09.009
Bradford PG 2013 Curcumin and obesity Biofactors 39 78 - 87    DOI : 10.1002/biof.1074
Brahma Naidu P , Nemani H , Meriga B , Mehar SK , Potana S , Ramgopalrao S 2014 Mitigating efficacy of piperine in the physiological derangements of high fat diet induced obesity in sprague dawley rats Chem Biol Interact 221 42 - 51    DOI : 10.1016/j.cbi.2014.07.008
Brekhman II , Dardymov IV 1969 New substances of plant origin which increase nonspecific resistance Annu Rev Pharmacol 9 419 - 430    DOI : 10.1146/
Brindley DN , Rolland Y 1989 Possible connections between stress, diabetes, obesity, hypertension and altered lipoprotein metabolism that may result in atherosclerosis Clin Sci (Lond) 77 453 - 461    DOI : 10.1042/cs0770453
Brodniewicz T , Grynkiewicz G 2012 Plant phenolics as drug leads - what is missing Acta Pol Pharm 69 1203 - 1217
Burcelin R , Serino M , Chabo C , Blasco-Baque V , Amar J 2011 Gut microbiota and diabetes: From pathogenesis to therapeutic perspective Acta Diabetol 48 257 - 273    DOI : 10.1007/s00592-011-0333-6
Calabrese EJ 2010 Hormesis is central to toxicology, pharmacology and risk assessment Hum Exp Toxicol 29 249 - 261    DOI : 10.1177/0960327109363973
Calabrese V , Cornelius C , Dinkova-Kostova AT , Iavicoli I , Di Paola R , Koverech A , Cuzzocrea S , Rizzarelli E , Calabrese EJ 2012 Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity Biochim Biophys Acta 1822 753 - 783    DOI : 10.1016/j.bbadis.2011.11.002
Calabrese V , Cornelius C , Trovato A , Cavallaro M , Mancuso C , Di Rienzo L , Condorelli D , De Lorenzo A , Calabrese EJ 2010 The hormetic role of dietary antioxidants in free radical-related diseases Curr Pharm Des 16 877 - 883    DOI : 10.2174/138161210790883615
Carriba P , Comella JX 2014 Amyloid beta, tnfalpha and faim-l; approaching new therapeutic strategies for ad Front Neurol 5 276 -
Cartea ME , Francisco M , Soengas P , Velasco P 2010 Phenolic compounds in brassica vegetables Molecules 16 251 - 280    DOI : 10.3390/molecules16010251
Carvalho LA , Urbanova L , Hamer M , Hackett RA , Lazzarino AI , Steptoe A 2015 Blunted glucocorticoid and mineralocorticoid sensitivity to stress in people with diabetes Psychoneuroendocrinology 51 209 - 218    DOI : 10.1016/j.psyneuen.2014.09.023
Chainani-Wu N 2003 Safety and anti-inflammatory activity of curcumin: A component of tumeric (Curcuma longa) J Altern Complement Med 9 161 - 168    DOI : 10.1089/107555303321223035
Chandra P , Bajpai V , Srivastva M , Kumar KBR , Kumar B 2014 Metabolic profiling of piper species by direct analysis using real time mass spectrometry combined with principal component analysis Anal Methods 6 4234 - 4239    DOI : 10.1039/c4ay00246f
Chandrasekaran C , Vijayalakshmi M , Prakash K , Bansal V , Meenakshi J , Amit A 2012 Review article: Herbal approach for obesity management Am J Plant Sci 3 1003 - 1014    DOI : 10.4236/ajps.2012.327119
Chang CL , Chen YC , Chen HM , Yang NS , Yang WC 2013 Natural cures for type 1 diabetes: A review of phytochemicals, biological actions, and clinical potential Curr Med Chem 20 899 - 907
Chang CL , Lin Y , Bartolome AP , Chen YC , Chiu SC , Yang WC 2013 Herbal therapies for type 2 diabetes mellitus: Chemistry, biology, and potential application of selected plants and compounds Evid Based Complement Alternat Med 2013 378657 -
Chatterjee SS , Kumar V 2012 Holistic psychopharmacology and promiscuous plants and principles of ayurveda Am J Plant Sci 3 1015 - 1021    DOI : 10.4236/ajps.2012.327120
Chaudhary SA , Gadhvi KV , Chaudhary AB 2010 Comprehensive review on world herb trade and most utilized medicinal plant Int J Appl Biol Pharm Tech 1 510 - 517
Chaurasia A , Das D 2012 From 5th World Ayurveda Congress Bhopal MPID. Pa01.07. Evaluation of anti hyperglycemic potential of Piper longum root (linn.) on alloxan induced diabetic mice Anc Sci Life 32 S56 -    DOI : 10.4103/0257-7941.112030
Chaurasia A , Das D 2013 Evaluation of antihyperglycemic potential of Piper longum root (linn.) on alloxan induced diabetic mice Adv Pharmacol Toxicol 14 1 - 6
Chempakam B , Parthasarathy VA , Parthasarathy VA , Chempakam B , Zachariah TJ 2008 Chemistry of spices CAB International Egham, UK Turmeric 97 - 123
Cherng YG , Tsai CC , Chung HH , Lai YW , Kuo SC , Cheng JT 2013 Antihyperglycemic action of sinapic acid in diabetic rats J Agric Food Chem 61 12053 - 12059    DOI : 10.1021/jf403092b
Chimakurthy J , Talasila M 2010 Effects of curcumin on pentylenetetrazole-induced anxiety-like behaviors and associated changes in cognition and monoamine levels Psychol Neurosci 3 239 - 244    DOI : 10.3922/j.psns.2010.2.013
Chiou YS , Wu JC , Huang Q , Shahidi F , Wang YJ , Ho CT , Pan MH 2014 Metabolic and colonic microbiota transformation may enhance the bioactivities of dietary polyphenols J Func Foods 7 3 - 25    DOI : 10.1016/j.jff.2013.08.006
Choi S , Choi Y , Choi Y , Kim S , Jang J , Park T 2013 Piperine reverses high fat diet-induced hepatic steatosis and insulin resistance in mice Food Chem 141 3627 - 3635    DOI : 10.1016/j.foodchem.2013.06.028
Choudhary KM , Mishra A , Poroikov VV , Goel RK 2013 Ameliorative effect of curcumin on seizure severity, depression like behavior, learning and memory deficit in postpentylenetetrazole-kindled mice Eur J Pharmacol 704 33 - 40    DOI : 10.1016/j.ejphar.2013.02.012
Choudhary M , Sangha J , Grover K 2014 Conventional and nonconventional edible oils: An indian perspective J Am Oil Chemists' Soc 91 179 - 206    DOI : 10.1007/s11746-013-2400-3
Chouhan B , Kumawat RC , Kotecha M , Ramamurthy A , Nathani S 2013 Triphala: A comprehensive ayurvedic review Int J Res Ayurveda Pharm 4 612 - 617    DOI : 10.7897/2277-4343.04433
Chulet R , Pradhan P 2009 A review on rasayana Pharmacogn Rev 3 229 - 234
Cicero Bezerra Felipe F , Trajano Sousa Filho J , de Oliveira Souza LE , Alexandre Silveira J , Esdras de Andrade Uchoa D , Rocha Silveira E , Deusdenia Loiola Pessoa O , de Barros Viana GS 2007 Piplartine, an amide alkaloid from piper tuberculatum, presents anxiolytic and antidepressant effects in mice Phytomedicine 14 605 - 612    DOI : 10.1016/j.phymed.2006.12.015
Cnop M , Foufelle F , Velloso LA 2012 Endoplasmic reticulum stress, obesity and diabetes Trends Mol Med 18 59 - 68    DOI : 10.1016/j.molmed.2011.07.010
Colagiuri S 2010 Diabesity: Therapeutic options Diabetes Obes Metab 12 463 - 473    DOI : 10.1111/j.1463-1326.2009.01182.x
Costantini D , Metcalfe NB , Monaghan P 2010 Ecological processes in a hormetic framework Ecol Lett 13 1435 - 1447    DOI : 10.1111/j.1461-0248.2010.01531.x
Cryan JF , Dinan TG 2012 Mind-altering microorganisms: The impact of the gut microbiota on brain and behaviour Nat Rev Neurosci 13 701 - 712    DOI : 10.1038/nrn3346
D’Souza JJ , D’Souza PP , Fazal F , Kumar A , Bhat HP , Baliga MS 2014 Anti-diabetic effects of the indian indigenous fruit Emblica officinalis gaertn: Active constituents and modes of action Food Funct 5 635 - 644    DOI : 10.1039/c3fo60366k
D’Aversa F , Tortora A , Ianiro G , Ponziani F , Annicchiarico B , Gasbarrini A 2013 Gut microbiota and metabolic syndrome Intern Emerg Med 8 11 - 15    DOI : 10.1007/s11739-013-0916-z
Dai R , Lim LT 2014 Release of allyl isothiocyanate from mustard seed meal powder J Food Sci 79 E47 - 53    DOI : 10.1111/1750-3841.12322
Dallman MF , Pecoraro NC , la Fleur SE 2005 Chronic stress and comfort foods: Self-medication and abdominal obesity Brain Behav Immun 19 275 - 280    DOI : 10.1016/j.bbi.2004.11.004
Dasaroju S , Gottumukkala KM 2014 Current trends in the research of Emblica officinalis (amla): A pharmacological perspective Int J Pharm Sci Rev Res 24 150 - 159
Davenport J , Balch M , Galam L , Girgis A , Hall J , Blagg BS , Matts RL 2014 High-throughput screen of natural product libraries for hsp90 inhibitors Biology (Basel) 3 101 - 138
Davinelli S , Sapere N , Zella D , Bracale R , Intrieri M , Scapagnini G 2012 Pleiotropic protective effects of phytochemicals in alzheimer's disease Oxid Med Cell Longev 2012 386527 -
Davis C 2014 Evolutionary and neuropsychological perspectives on addictive behaviors and addictive substances: Relevance to the “food addiction” construct Subst Abuse Rehabil 5 129 - 137
Dembinska-Kiec A , Mykkanen O , Kiec-Wilk B , Mykkanen H 2008 Antioxidant phytochemicals against type 2 diabetes Br J Nutr 99 ES109 - ES11
Dhanalakshmi S , Devi RS , Srikumar R , Manikandan S , Thangaraj R 2007 Protective effect of triphala on cold stressinduced behavioral and biochemical abnormalities in rats Yakugaku Zasshi 127 1863 - 1867    DOI : 10.1248/yakushi.127.1863
Dhanalakshmi S , Srikumar R , Manikandan S , Parthasarathy NJ , Devi RS 2006 Antioxidant property of triphala on cold stress induced oxidative stress in experimental rats J Health Sci 52 843 - 847    DOI : 10.1248/jhs.52.843
Dietrich MO , Horvath TL 2012 Limitations in anti-obesity drug development: The critical role of hunger-promoting neurons Nat Rev Drug Discov 11 675 - 691    DOI : 10.1038/nrd3739
Dinan TG , Cryan JF 2012 Regulation of the stress response by the gut microbiota: Implications for psychoneuroendocrinology Psychoneuroendocrinology 37 1369 - 1378    DOI : 10.1016/j.psyneuen.2012.03.007
Dinkova-Kostova AT , Kostov RV 2012 Glucosinolates and isothiocyanates in health and disease Trends Mol Med 18 337 - 347    DOI : 10.1016/j.molmed.2012.04.003
Doucette CD , Hilchie AL , Liwski R , Hoskin DW 2013 Piperine, a dietary phytochemical, inhibits angiogenesis J Nutr Biochem 24 231 - 239    DOI : 10.1016/j.jnutbio.2012.05.009
Dragan S , Andrica F , Serban MC , Timar R 2015 Polyphenols-rich natural products for treatment of diabetes Curr Med Chem 22 14 - 22
Drewnowski A , Gomez-Carneros C 2000 Bitter taste, phytonutrients, and the consumer: A review Am J Clin Nutr 72 1424 - 1435
Eddouks M , Bidi A , El Bouhali B , Hajji L , Zeggwagh NA 2014 Antidiabetic plants improving insulin sensitivity J Pharm Pharmacol 66 1197 - 1214    DOI : 10.1111/jphp.12243
Epel ES , Lithgow GJ 2014 Stress biology and aging mechanisms: Toward understanding the deep connection between adaptation to stress and longevity J Gerontol A Biol Sci Med Sci 69 S10 - S16    DOI : 10.1093/gerona/glu055
Epel ES 2009 Psychological and metabolic stress: A recipe for accelerated cellular aging Hormones (Athens) 8 7 - 22    DOI : 10.14310/horm.2002.1217
Everard A , Cani PD 2013 Diabetes, obesity and gut microbiota Best Pract Res Clin Gastroenterol 27 73 - 83    DOI : 10.1016/j.bpg.2013.03.007
Fahey JW , Wade KL , Stephenson KK , Chou FE 2003 Separation and purification of glucosinolates from crude plant homogenates by high-speed counter-current chromatography J Chromatogr A 996 85 - 93    DOI : 10.1016/S0021-9673(03)00607-1
Farag YM , Gaballa MR 2011 Diabesity: An overview of a rising epidemic Nephrol Dial Transplant 26 28 - 35    DOI : 10.1093/ndt/gfq576
Farooqui AA 2013 Metabolic syndrome Springer New York, USA Effect of dietary phytochemicals on metabolic syndrome and neurological disorders 191 - 234
Fasinu PS , Bouic PJ , Rosenkranz B 2012 An overview of the evidence and mechanisms of herb-drug interactions Front Pharmacol 3 69 -
Fetrow CW , Avila JR 1999 Professional’s handbook of complementary and alternative medicines Springhouse Corporation Pennsylvania, USA
Fontana L 2009 Modulating human aging and age-associated diseases Biochim Biophys Acta 1790 1133 - 1138    DOI : 10.1016/j.bbagen.2009.02.002
Foster JA , McVey Neufeld KA 2013 Gut-brain axis: How the microbiome influences anxiety and depression Trends Neurosci 36 305 - 312    DOI : 10.1016/j.tins.2013.01.005
Franco R , Cedazo-Minguez A 2014 Successful therapies for alzheimer's disease: Why so many in animal models and none in humans Front Pharmacol 5 146 -
Garcia-Alloza M , Borrelli LA , Rozkalne A , Hyman BT , Bacskai BJ 2007 Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an alzheimer mouse model J Neurochem 102 1095 - 1104    DOI : 10.1111/j.1471-4159.2007.04613.x
Gastaldi G , Ruiz J 2009 Metabolic dysfunction and chronic stress: A new sight at “diabesity” pandemic Rev Med Suisse 5 1273 - 1277
Ghelardini C , Galeotti N , Di Cesare Mannelli L , Mazzanti G , Bartolini A 2001 Local anaesthetic activity of beta-caryophyllene Farmaco 56 387 - 389    DOI : 10.1016/S0014-827X(01)01092-8
Gilhotra N , Dhingra D 2014 Possible involvement of gabaergic and nitriergic systems for antianxiety-like activity of piperine in unstressed and stressed mice Pharmacol Rep 66 885 - 891    DOI : 10.1016/j.pharep.2014.05.008
Ginty AT , Phillips AC , Higgs S , Heaney JL , Carroll D 2012 Disordered eating behaviour is associated with blunted cortisol and cardiovascular reactions to acute psychological stress Psychoneuroendocrinology 37 715 - 724    DOI : 10.1016/j.psyneuen.2011.09.004
Ginty AT 2013 Blunted responses to stress and reward: Reflections on biological disengagement Int J Psychophysiol 90 90 - 94    DOI : 10.1016/j.ijpsycho.2013.06.008
Gonzalez-Castejon M , Rodriguez-Casado A 2011 Dietary phytochemicals and their potential effects on obesity: A review Pharmacol Res 64 438 - 455    DOI : 10.1016/j.phrs.2011.07.004
Goodacre R 2007 Metabolomics of a superorganism J Nutr 137 259S - 266S
Greiner AK , Papineni RV , Umar S 2014 Chemoprevention in gastrointestinal physiology and disease. Natural products and microbiome Am J Physiol Gastrointest Liver Physiol 307 G1 - 15    DOI : 10.1152/ajpgi.00044.2014
Grover JK , Yadav S , Vats V 2002 Hypoglycemic and antihyperglycemic effect of Brassica juncea diet and their effect on hepatic glycogen content and the key enzymes of carbohydrate metabolism Mol Cell Biochem 241 95 - 101    DOI : 10.1023/A:1020814709118
Grover JK , Yadav SP , Vats V 2003 Effect of feeding murraya koeingii and Brassica juncea diet on [correction] kidney functions and glucose levels in streptozotocin diabetic mice J Ethnopharmacol 85 1 - 5    DOI : 10.1016/S0378-8741(02)00355-0
Grynkiewicz G , Slifirski P 2012 Curcumin and curcuminoids in quest for medicinal status Acta Biochim Pol 59 (2) 201 - 212
Gunthorpe MJ , Szallasi A 2008 Peripheral trpv1 receptors as targets for drug development: New molecules and mechanisms Curr Pharm Des 14 32 - 41    DOI : 10.2174/138161208783330754
Gupta PC 2012 Biological and pharmacological properties of Terminalia chebula retz. (haritaki)-an overview Int J Pharm Pharm Sci 4 62 - 68
Gupta SC , Sung B , Kim JH , Prasad S , Li S , Aggarwal BB 2013 Multitargeting by turmeric, the golden spice: From kitchen to clinic Mol Nutr Food Res 57 1510 - 1528    DOI : 10.1002/mnfr.201100741
Halkier BA , Gershenzon J 2006 Biology and biochemistry of glucosinolates Annu Rev Plant Biol 57 303 - 333    DOI : 10.1146/annurev.arplant.57.032905.105228
Hasan MN , Ferdoushi A , Ara N , Rahman S , Hossan MS , Rahmatullah M 2014 Preliminary phytochemical screening, toxicity, antihyperglycemic and analgesic activity studies with Curcuma longa leaves World J Pharm Pharm Sci 3 81 - 91
Huang H , Morgan CM , Asolkar RN , Koivunen ME , Marrone PG 2010 Phytotoxicity of sarmentine isolated from long pepper (Piper longum) fruit J Agric Food Chem 58 9994 - 10000    DOI : 10.1021/jf102087c
Inyang IJ , Eyo AAO , Olajide TM , Essien A 2014 Effects of ethanolic extract of Brassica juncea (mustard seed) on the brain and kidney tissues of albino wistar rats J Biol Agric Healthc 4 75 - 82
Jakovljevic T , Cvjetko M , Sedak M , Dokic M , Bilandzic N , Vorkapic-Furac J , Redovnikovic IR 2013 Balance of glucosinolates content under cd stress in two brassica species Plant Physiol Biochem 63 99 - 106    DOI : 10.1016/j.plaphy.2012.10.019
Janero DR 2014 Relieving the cardiometabolic disease burden: A perspective on phytometabolite functional and chemical annotation for diabetes management Expert Opin Pharmacother 15 5 - 10    DOI : 10.1517/14656566.2014.852538
Jayaprakasha GK , Rao LJ , Sakariah KK 2006 Antioxidant activities of curcumin, demethoxycurcumin and bisdemethoxycurcumin Food Chem 98 720 - 724    DOI : 10.1016/j.foodchem.2005.06.037
Jiang J , Wang W , Sun YJ , Hu M , Li F , Zhu DY 2007 Neuroprotective effect of curcumin on focal cerebral ischemic rats by preventing blood-brain barrier damage Eur J Pharmacol 561 54 - 62    DOI : 10.1016/j.ejphar.2006.12.028
Jiang ZY , Liu WF , Huang CG , Huang XZ 2013 New amide alkaloids from Piper longum Fitoterapia 84 222 - 226    DOI : 10.1016/j.fitote.2012.12.001
Jin Z , Borjihan G , Zhao R , Sun Z , Hammond GB , Uryu T 2009 Antihyperlipidemic compounds from the fruit of Piper longum L Phytother Res 23 1194 - 1196    DOI : 10.1002/ptr.2630
Jo YS , Park JR , Park SK , Chun SS , Chung SY , Ha BS 1993 Effects of mustard leaf (Brassica juncea) on cholesterol metabolism in rats Korean J Nutr 26 13 - 20
Joardar A , Das S 2007 Effect of fatty acids isolated from edible oils like mustard, linseed or coconut on astrocytes maturation Cell Mol Neurobiol 27 973 - 983    DOI : 10.1007/s10571-007-9204-7
John R , Ahmad P , Gadgil K , Sharma S 2009 Heavy metal toxicity: Effect on plant growth, biochemical parameters and metal accumulation by Brassica juncea L Int J Plant Prod 3 65 - 76
Joshi J , Ghaisas S , Vaidya A , Vaidya R , Kamat DV , Bhagwat AN , Bhide S 2003 Early human safety study of turmeric oil (Curcuma longa oil) administered orally in healthy volunteers J Assoc Physicians India 51 1055 - 1060
Joshi JV , Paradkar PH , Jagtap SS , Agashe SV , Soman G , Vaidya AB 2011 Chemopreventive potential and safety profile of a Curcuma longa extract in women with cervical low-grade squamous intraepithelial neoplasia Asian Pac J Cancer Prev 12 3305 - 3311
Joven J , Rull A , Rodriguez-Gallego E , Camps J , Riera-Borrull M , Hernandez-Aguilera A , Martin-Paredero V , Segura- Carretero A , Micol V , Alonso-Villaverde C , Menendez JA 2013 Multifunctional targets of dietary polyphenols in disease: A case for the chemokine network and energy metabolism Food Chem Toxicol 51 267 - 279    DOI : 10.1016/j.fct.2012.10.004
Jung HA , Woo JJ , Jung MJ , Hwang GS , Choi JS 2009 Kaempferol glycosides with antioxidant activity from Brassica juncea Arch Pharm Res 32 1379 - 1384    DOI : 10.1007/s12272-009-2006-3
Kadian R , Parle M , Yadav M 2014 Therapeutic potential and phytopharmacology of Terminalia bellerica World J Pharm Pharm Sci 3 804 - 819
Kahn SE , Cooper ME , Del Prato S 2014 Pathophysiology and treatment of type 2 diabetes: Perspectives on the past, present, and future Lancet 383 1068 - 1083    DOI : 10.1016/S0140-6736(13)62154-6
Kandarkar SV , Sawant SS , Ingle AD , Deshpande SS , Maru GB 1998 Subchronic oral hepatotoxicity of turmeric in mice--histopathological and ultrastructural studies Indian J Exp Biol 36 675 - 679
Kar S , Roy K 2012 Qsar of phytochemicals for the design of better drugs Expert Opin Drug Discov 7 877 - 902    DOI : 10.1517/17460441.2012.716420
Karakida F , Ikeya Y , Tsunakawa M , Yamaguchi T , Ikarashi Y , Takeda S , Aburada M 2007 Cerebral protective and cognitionimproving effects of sinapic acid in rodents Biol Pharm Bull 30 514 - 519    DOI : 10.1248/bpb.30.514
Kasabri V , Flatt PR , Abdel-Wahab YHA 2014 In vitro modulation of pancreatic insulin secretion, extrapancreatic insulin action and peptide glycation by Curcuma longa aqueous extracts J Exp Integr Med 4 187 - 193
Kelly SJ , Ismail M 2015 Stress and type 2 diabetes: A review of how stress contributes to the development of type 2 diabetes Annu Rev Public Health 36 441 - 462    DOI : 10.1146/annurev-publhealth-031914-122921
Kennedy DO 2014 Plants and the human brain Oxford University Press New York, USA
Kennedy DO 2014 Polyphenols and the human brain: Plant “secondary metabolite” ecologic roles and endogenous signaling functions drive benefits Adv Nutr 5 515 - 533    DOI : 10.3945/an.114.006320
Khadem S , Marles RJ 2010 Monocyclic phenolic acids; hydroxyand polyhydroxybenzoic acids: Occurrence and recent bioactivity studies Molecules 15 7985 - 8005    DOI : 10.3390/molecules15117985
Khan BA , Abraham A , Leelamma S 1997 Anti-oxidant effects of curry leaf, murraya koenigii and mustard seeds, Brassicajuncea in rats fed with high fat diet Indian J Exp Biol 35 148 - 150
Khan BA , Abraham A , Leelamma S 1995 Hypoglycemic action of murraya koenigii (curry leaf) and Brassica juncea (mustard): Mechanism of action Indian J Biochem Biophys 32 106 - 108
Khan BA , Abraham A , Leelamma S 1996 Murraya koenigii andBrassica juncea-alterations on lipid profile in 1-2 dimethyl hydrazine induced colon carcinogenesis Invest New Drugs 14 365 - 369
Khosla S , Sharma S 2012 A short description on pharmacogenetic properties of Emblica officinalis Spatula DD 2 187 - 193    DOI : 10.5455/spatula.20121112072137
Kiasalari Z , Roghani M , Khalili M , Rahmati B , Baluchnejadmojarad T 2013 Antiepileptogenic effect of curcumin on kainate-induced model of temporal lobe epilepsy Pharm Biol 51 1572 - 1578    DOI : 10.3109/13880209.2013.803128
Kim DSHL , Park S-Y , Kim J-Y 2001 Curcuminoids from Curcuma longa l. (zingiberaceae) that protect pc12 rat pheochromocytoma and normal human umbilical vein endothelial cells from βa(1–142) insult Neurosci Lett 303 57 - 61    DOI : 10.1016/S0304-3940(01)01677-9
Kim HY , Yokozawa T , Cho EJ , Cheigh HS , Choi JS , Chung HY 2003 In vitro and in vivo antioxidant effects of mustard leaf (Brassica juncea) Phytother Res 17 465 - 471    DOI : 10.1002/ptr.1174
Kim JE , Jung MJ , Jung HA , Woo JJ , Cheigh HS , Chung HY , Choi JS 2002 A new kaempferol 7-o-triglucoside from the leaves of Brassica juncea L Arch Pharm Res 25 621 - 624    DOI : 10.1007/BF02976932
Kokate CK , Purohit AP , Gokhale SB 2003 Practical Pharmacognosy Twenty second edition Nirali Prakashan Pune, India
Krishna M , Joy B , Sundaresan A 2014 Effect on oxidative stress, glucose uptake level and lipid droplet content by apigenin 7, 4'-dimethyl ether isolated from Piper longum L J Food Sci Tech 1 - 10
Krishnaveni M , Mirunalini S 2010 Therapeutic potential of Phyllanthus emblica (amla): The ayurvedic wonder J Basic Clin Physiol Pharmacol 21 93 - 105
Ku SK , Kim JA , Bae JS 2014 Vascular barrier protective effects of piperlonguminine in vitro and in vivo Inflamm Res 63 369 - 379    DOI : 10.1007/s00011-014-0708-6
Kulkarni S , Dhir A , Akula KK 2009 Potentials of curcumin as an antidepressant ScientificWorldJournal 9 1233 - 1241    DOI : 10.1100/tsw.2009.137
Kumar A , Panghal S , Mallapur SS , Kumar M , Ram V , Singh BK 2009 Antiinflammatory activity of Piper longum fruit oil Indian J Pharm Sci 71 454 - 456    DOI : 10.4103/0250-474X.57300
Kumar S , Andy A 2012 Health promoting bioactive phytochemicals from brassica Int Food Res J 19 141 - 152
Kumar S , Kamboj J , Sharma S 2011 Overview for various aspects of the health benefits of Piper longum Linn J Acupunct Meridian Stud 4 134 - 140    DOI : 10.1016/S2005-2901(11)60020-4
Kumar S , Sharma S , Vasudeva N 2013 Screening of antidiabetic and antihyperlipidemic potential of oil from Piper longum and piperine with their possible mechanism Expert Opin Pharmacother 14 1723 - 1736    DOI : 10.1517/14656566.2013.815725
Kumar V , Chatterjee SS 2014 A holistic approach for evaluating the potential of triphala extract against neurological disorders PharmaNutrition 2 90 -
Kumar V , Chatterjee SS 2014 Single and repeated dose effects of phytochemicals in rodent behavioural models EC Pharm Sci 1 16 - 18
Kumar V , Thakur A , Chatterjee S , Shankar S , Srivastava RK 2012 Obesity, cancer and psychopathology: Can vegetarian diet be of help? In Nutrition, diet and cancer springer Houten, Netherlands 459 - 491
Kumar V , Thakur AK , Barothia ND , Chatterjee SS 2011 Therapeutic potentials of Brassica juncea: An overview TANG (Humanitas Medicine) 1 1 - 17
Kumudhavalli MV , Mohit V , Jayakar B 2010 Phytochemical and pharmacological evaluation of the plant fruit of Terminalia belerica roxb Int J Pharm Life Sci 1 1 - 11
Kuo CC , Moon K , Thayer KA , Navas-Acien A 2013 Environmental chemicals and type 2 diabetes: An updated systematic review of the epidemiologic evidence Curr Diab Rep 13 831 - 849    DOI : 10.1007/s11892-013-0432-6
Kuo CP , Lu CH , Wen LL , Cherng CH , Wong CS , Borel CO , Ju DT , Chen CM , Wu CT 2011 Neuroprotective effect of curcumin in an experimental rat model of subarachnoid hemorrhage Anesthesiology 115 1229 - 1238
Kuroda M , Mimaki Y , Nishiyama T , Mae T , Kishida H , Tsukagawa M , Takahashi K , Kawada T , Nakagawa K , Kitahara M 2005 Hypoglycemic effects of turmeric (Curcuma longa l. Rhizomes) on genetically diabetic kk-ay mice Biol Pharm Bull 28 937 - 939    DOI : 10.1248/bpb.28.937
Kwon DY , Kim HJ , Yoon SH , Hou CT , Shaw JF 2009 Biocatalysis and agricultural biotechnology CRC Press New York, USA Induction of phenolics and terpenoids in edible plants using plant stress responses 249 - 258
Langstieh AJ , Verma P , Thakur AK , Chatterjee SS , Kumar V 2014 Desensitization of mild stress triggered responses in mice by a Brassica juncea Leaf extract and some ubiquitous secondary plant metabolites Pharmacologia 5 326 - 338    DOI : 10.5567/pharmacologia.2014.326.338
Lao CD , Ruffin MTt , Normolle D , Heath DD , Murray SI , Bailey JM , Boggs ME , Crowell J , Rock CL , renner DE 2006 Dose escalation of a curcuminoid formulation BMC Complement Altern Med 6 10 -    DOI : 10.1186/1472-6882-6-10
Le Bourg E , Rattan SI 2014 Hormesis and trade-offs: A comment Dose Response 12 522 - 524    DOI : 10.2203/dose-response.14-054.LeBourg
Lee HE , Kim DH , Park SJ , Kim JM , Lee YW , Jung JM , Lee CH , Hong JG , Liu X , Cai M , Park KJ , Jang DS , Ryu JH 2012 Neuroprotective effect of sinapic acid in a mouse model of amyloid beta(1-42) protein-induced alzheimer’s disease Pharmacol Biochem Behav 103 260 - 266    DOI : 10.1016/j.pbb.2012.08.015
Lee J , Jo DG , Park D , Chung HY , Mattson MP 2014 Adaptive cellular stress pathways as therapeutic targets of dietary phytochemicals: Focus on the nervous system Pharmacol Rev 66 815 - 868    DOI : 10.1124/pr.113.007757
Lee SA , Hwang JS , Han XH , Lee C , Lee MH , Choe SG , Hong SS , Lee D , Lee MK , Hwang BY 2008 Methylpiperate derivatives from Piper longum and their inhibition of monoamine oxidase Arch Pharm Res 31 679 - 683    DOI : 10.1007/s12272-001-1212-7
Lee SW , Rho MC , Park HR , Choi JH , Kang JY , Lee JW , Kim K , Lee HS , Kim YK 2006 Inhibition of diacylglycerol acyltransferase by alkamides isolated from the fruits of Piper longum and piper nigrum J Agric Food Chem 54 9759 - 9763    DOI : 10.1021/jf061402e
Leiherer A , Mundlein A , Drexel H 2013 Phytochemicals and their impact on adipose tissue inflammation and diabetes Vascul Pharmacol 58 3 - 20    DOI : 10.1016/j.vph.2012.09.002
Lekshmi PC , Arimboor R , Indulekha PS , Menon AN 2012 Turmeric (Curcuma longa l.) volatile oil inhibits key enzymes linked to type 2 diabetes Int J Food Sci Nutr 63 832 - 834    DOI : 10.3109/09637486.2011.607156
Lephart ED , Farooqui T , Farooqui AA 2015 Diet and exercise in cognitive function and neurological diseases John Wiley & Sons, Inc Hoboken, New Jersey, USA Polyphenols and cognitive function 143 - 161
Li J , Ho C-T , Li HE , Tao H , Tao L 2000 Separation of sterols and triterpene alcohols from unsaponifiable fractions of three plant seed oils J Food Lipids 7 11 - 20    DOI : 10.1111/j.1745-4522.2000.tb00156.x
Li S , Wang C , Li W , Koike K , Nikaido T , Wang MW 2007 Antidepressant-like effects of piperine and its derivative, antiepilepsirine J Asian Nat Prod Res 9 421 - 430    DOI : 10.1080/10286020500384302
Li S , Wang C , Wang M , Li W , Matsumoto K , Tang Y 2007 Antidepressant like effects of piperine in chronic mild stress treated mice and its possible mechanisms Life Sci 80 (15) 1373 - 1381    DOI : 10.1016/j.lfs.2006.12.027
Li S , Yuan W , Deng G , Wang P , Yang P , Aggarwal BB 2011 Chemical composition and product quality control of turmeric (Curcuma longa L.) Phytochemistry 2 28 - 54
Liju VB , Jeena K , Kuttan R 2013 Acute and subchronic toxicity as well as mutagenic evaluation of essential oil from turmeric (Curcuma longa L) Food Chem Toxicol 53 52 - 61    DOI : 10.1016/j.fct.2012.11.027
Liju VB , Jeena K , Kuttan R 2011 An evaluation of antioxidant, antiinflammatory, and antinociceptive activities of essential oil from Curcuma longa. L Indian J Pharmacol 4 526 - 531
Lin Y , Sun Z 2010 Current views on type 2 diabetes J Endocrinol 204 1 - 11    DOI : 10.1677/JOE-09-0260
Liu J-Y , Chen X-X , Tang SC-W , Lao L-X , Cho-Wing Sze S , Lee K-F , Zhang KY-B 2015 Edible plants from traditional chinese medicine is a promising alternative for the management of diabetic nephropathy J Func Foods 14 12 - 22    DOI : 10.1016/j.jff.2015.01.034
Liu Z , Yu Y , Li X , Ross CA , Smith WW 2011 Curcumin protects against a53t alpha-synuclein-induced toxicity in a pc12 inducible cell model for parkinsonism Pharmacol Res 63 439 - 444    DOI : 10.1016/j.phrs.2011.01.004
Lopresti AL , Maes M , Maker GL , Hood SD , Drummond PD 2014 Curcumin for the treatment of major depression: A randomised, double-blind, placebo controlled study J Affect Disord 167 368 - 375    DOI : 10.1016/j.jad.2014.06.001
Lushchak VI 2014 Dissection of the hormetic curve: Analysis of components and mechanisms Dose Response 12 466 - 479    DOI : 10.2203/dose-response.13-051.Lushchak
Lushchak VI 2014 Hormesis in biology and pharmacology Biochem Pharmacol 3 1 - 2
Madhu K , Chanda K , Saji MJ 2013 Safety and efficacy of Curcuma longa extract in the treatment of painful knee osteoarthritis: A randomized placebo-controlled trial Inflammopharmacology 21 129 - 136    DOI : 10.1007/s10787-012-0163-3
Maheshwari M 2010 Comparative bioavailability of curcumin, turmeric and biocurcumaxTM in traditional vehicles using noneverted rat intestinal sac model J Func Foods 2 60 - 65    DOI : 10.1016/j.jff.2010.01.004
Maheshwari RK , Rajnee K 2014 Ingenious triphala: A curative preparation for health care Asian J Chem Pharm Res 2 175 - 185
Manach C , Hubert J , Llorach R , Scalbert A 2009 The complex links between dietary phytochemicals and human health deciphered by metabolomics Mol Nutr Food Res 53 1303 - 1315    DOI : 10.1002/mnfr.200800516
Manach C , Scalbert A , Morand C , Remesy C , Jimenez L 2004 Polyphenols: Food sources and bioavailability Am J Clin Nutr 79 727 - 747
Maneesa P , Scholfield CN , Chootip K 2012 Piperine is antihyperlipidemic and improves endothelium-dependent vasorelaxation in rats on a high cholesterol diet J Physiol Biomed Sci 25 27 - 30
Manesh C , Kuttan G 2003 Anti-tumour and anti-oxidant activity of naturally occurring isothiocyanates J Exp Clin Cancer Res 22 193 - 199
Manohar PR , Pushpan R , Rohini S 2009 Mustard and its uses in ayurveda Indian J Tradit Knowl 8 400 - 404
Manoj P , Soniya EV , Banerjee NS , Ravichandran P 2004 Recent studies on well-known spice, Piper longum Linn Nat Prod Radiance 3 222 - 227
Mao QQ , Huang Z , Zhong XM , Xian YF , Ip SP 2014 Brain-derived neurotrophic factor signalling mediates the antidepressant-like effect of piperine in chronically stressed mice Behav Brain Res 261 140 - 145    DOI : 10.1016/j.bbr.2013.12.020
Martinez JA , Milagro FI 2015 Genetics of weight loss: A basis for personalized obesity management Trends Food Sci Tech 42 97 - 115    DOI : 10.1016/j.tifs.2014.12.007
Martinez JA , Navas-Carretero S , Saris WH , Astrup A 2014 Personalized weight loss strategies-the role of macronutrient distribution Nat Rev Endocrinol 10 749 - 760    DOI : 10.1038/nrendo.2014.175
Mayer EA 2011 Gut feelings: The emerging biology of gut-brain communication Nat Rev Neurosci 12 453 - 466
McClure CD , Zhong W , Hunt VL , Chapman FM , Hill FV , Priest NK 2014 Hormesis results in trade-offs with immunity Evolution 68 2225 - 2233
McFadden RMT , Larmonier CB , Midura-Kiela MT , Ramalingam R , Harrison CA , Besselsen DG , Chase J , Caporaso G , Ghishan FK , Kiela PR 2014 The role of curcumin in modulating colonic microbiota during colitis and colon cancer prevention Gastroenterology 146 S66 -
McNamara FN , Randall A , Gunthorpe MJ 2005 Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (trpv1) Br J Pharmacol 144 781 - 790    DOI : 10.1038/sj.bjp.0706040
Meghwal M , Goswami TK 2013 Piper nigrum and piperine: An update Phytother Res 27 1121 - 1130    DOI : 10.1002/ptr.4972
Meule A , Heckel D , Jurowich CF , Vogele C , Kubler A 2014 Correlates of food addiction in obese individuals seeking bariatric surgery Clin Obes 4 228 - 236
Micucci M , Aldini R , Cevenini M , Colliva C , Spinozzi S , Roda G , Montagnani M , Camborata C , Camarda L , Chiarini A , Mazzella G , Budriesi R 2013 Curcuma longa l. As a therapeutic agent in intestinal motility disorders. 2: Safety profile in mouse PLoS One 8 e80925 -    DOI : 10.1371/journal.pone.0080925
Mirmiran P , Bahadoran Z , Azizi F 2014 Functional foods-based diet as a novel dietary approach for management of type 2 diabetes and its complications: A review World J Diabetes 5 267 - 281    DOI : 10.4239/wjd.v5.i3.267
Mishra S , Manchanda SC 2012 Cooking oils for heart health J Prev Cardiol 1 123 - 131
Mohammad K , Larijani B 2013 A systematic review of the antioxidant, anti-diabetic, and anti-obesity effects and safety of triphala herbal formulation J Med Plants Res 7 831 - 844
Moloney RD , Desbonnet L , Clarke G , Dinan TG , Cryan JF 2014 The microbiome: Stress, health and disease Mamm Genome 25 49 - 74    DOI : 10.1007/s00335-013-9488-5
Mori A , Kabuto H , Pei YQ 1985 Effects of piperine on convulsions and on brain serotonin and catecholamine levels in e1 mice Neurochem Res 10 1269 - 1275    DOI : 10.1007/BF00964845
Munday R , Munday CM 2002 Selective induction of phase ii enzymes in the urinary bladder of rats by allyl isothiocyanate, a compound derived from brassica vegetables Nutr Cancer 44 52 - 59    DOI : 10.1207/S15327914NC441_7
Murray S , Kroll C , Avena NM 2015 Food and addiction among the ageing population Ageing Res Rev 20 79 - 85    DOI : 10.1016/j.arr.2014.10.002
Murthy KRS 2009 Bhava prakasha of bhavamisra-english translation Chowkhamba Krishnadas Academy Varanasi, India
Muttepawar SS , Jadhav SB , Kankudate AD , Sanghai SD , Usturge DR , Chavare SS 2014 A review on bioavailability enhancers of herbal origin World J Pharm Pharm Sci 3 667 - 677
Nabi SA , Kasetti RB , Sirasanagandla S , Tilak TK , Kumar MV , Rao CA 2013 Antidiabetic and antihyperlipidemic activity of Piper longum root aqueous extract in STZ induced diabetic rats BMC Complement Altern Med 13 37 -    DOI : 10.1186/1472-6882-13-37
Nariya MB , Shukla VJ , Ravishankar B , Jain SM 2011 Comparison of gastroprotective effects of triphala formulations on stressinduced ulcer in rats Indian J Pharm Sci 73 682 - 687    DOI : 10.4103/0250-474X.100252
Neerati P , Ravi Karan M , Kanwar JR 2012 Influence of curcumin on pioglitazone metabolism and pk/pd: Diabetes mellitus J Diabetes Metab S6 1 - 6
Neha J , Mishra RN 2011 Adaptogenic activity of Trikatu megaExt Int J Res Pharm Biomed Sci 2 570 - 574
Nicholson JK , Holmes E , Kinross J , Burcelin R , Gibson G , Jia W , Pettersson S 2012 Host-gut microbiota metabolic interactions Science 336 1262 - 1267    DOI : 10.1126/science.1223813
Niciforovic N , Abramovic H 2014 Sinapic acid and its derivatives: Natural sources and bioactivity Compr Rev Food Sci Food Saf 13 34 - 51    DOI : 10.1111/1541-4337.12041
Noble T , Zingg JM , Paul L , Smith D , Meydani M 2013 The effect of curcumin plus piperine on body weight and fat loss as well as on the plasma levels of inflammatory cytokines in obese mice FASEB J 27 636 -
Nowak D , Dietrich-Muszalska A , Chauhan V , Grignon S 2015 Antioxidant plant polyphenols and cognitive disorders. In Studies on psychiatric disorders Springer New York, USA 521 - 552
Nyanginja RA , Mponda J 2014 Nutrigenomic approach in understanding the antiallergic effects of curcumin Asian J Biomed Pharma Sci 4 1 - 5
Ono K , Hasegawa K , Naiki H , Yamada M 2004 Curcumin has potent anti-amyloidogenic effects for alzheimer’s beta-amyloid fibrils in vitro J Neurosci Res 75 742 - 750    DOI : 10.1002/jnr.20025
Oram RN , Kirk JTO , Veness PE , Hurlstone CJ , Edlington JP , Halsall DM 2005 Breeding indian mustard [Brassica juncea (L.) czern.] for cold-pressed, edible oil production-a review Australian J Agric Res 56 581 - 596    DOI : 10.1071/AR04295
Ozcan U , Cao Q , Yilmaz E , Lee AH , Iwakoshi NN , Ozdelen E , Tuncman G , Gorgun C , Glimcher LH , Hotamisligil GS 2004 Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes Science 306 457 - 461    DOI : 10.1126/science.1103160
Pa J , Gazzaley A 2014 Flavanol-rich food for thought Nat Neurosci 17 1624 - 1625    DOI : 10.1038/nn.3876
Pal A , Nayak S , Sahu PK , Swain T 2011 Piperine protects epilepsy associated depression: A study on role of monoamines Eur Rev Med Pharmacol Sci 15 1288 - 1295
Pal US , Khan K , Sahoo NR , Sahoo G 2008 Development and evaluation of farm level turmeric processing equipment AMA 39 46 - 50
Pan XR , Li GW , Hu YH , Wang JX , Yang WY , An ZX , Hu ZX , Lin J , Xiao JZ , Cao HB , Liu PA , Jiang XG , Jiang YY , Wang JP , Zheng H , Zhang H , Bennett PH , Howard BV 1997 Effects of diet and exercise in preventing niddm in people with impaired glucose tolerance. The da qing igt and diabetes study Diabetes Care 20 537 - 544    DOI : 10.2337/diacare.20.4.537
Pandey KB , Rizvi SI 2009 Plant polyphenols as dietary antioxidants in human health and disease Oxid Med Cell Longev 2 270 - 278    DOI : 10.4161/oxim.2.5.9498
Parrott MD , Winocur G , Bazinet RP , Ma DW , Greenwood CE 2015 Whole-food diet worsened cognitive dysfunction in an alzheimer's disease mouse model Neurobiol Aging 36 90 - 99    DOI : 10.1016/j.neurobiolaging.2014.08.013
Patel D , Patel K , Gadewar M , Tahilyani V 2012 A concise report on pharmacological and bioanalytical aspect of sinigrin Asian Pac J Trop Biomed 2 S446 - S448
Patel JA , Shah US 2009 Hepatoprotective activity of Piper longum traditional milk extract on carbon tetrachloride induced liver toxicity in wistar rats Boletin Latinoamericano y del Caribe de Plantas Medicinales y Aromaticas 8 121 - 129
Patel P , Gohil KJ , Roy SP , Patel N 2014 Investigation of antidepressant and anxiolytic activity of curcumin given alone and in combination with amitriptyline in rats Indian J Res Pharm Biotechnol 2 1173 - 1178
Pathak N , Khandelwal S 2009 Immunomodulatory role of piperine in cadmium induced thymic atrophy and splenomegaly in mice Environ Toxicol Pharmacol 28 52 - 60    DOI : 10.1016/j.etap.2009.02.003
Pati S , Hussain M , Swain S 2014 Characteristics and correlates of diabesity in india: A secondary data analysis of world health survey Obes Rev 15 67 - 68    DOI : 10.1111/obr.12181
Patil UK , Singh A , Chakraborty AK 2011 Role of piperine as a bioavailability enhancer Int J Recent Adv Pharm Res 4 16 - 23
Patrone C , Eriksson O , Lindholm D 2014 Diabetes drugs and neurological disorders: New views and therapeutic possibilities Lancet Diabetes Endocrinol 2 256 - 262    DOI : 10.1016/S2213-8587(13)70125-6
Pedram P , Sun G 2015 Hormonal and dietary characteristics in obese human subjects with and without food addiction Nutrients 7 223 - 238
Peng D , Xin L , Hao-jie L , Wei-feng P , Jian-ying L , Yu M , Wei F , Xin W 2009 Curcumin inhibits amygdaloid kindled seizures in rats Chin Med J 122 1435 - 1438
Perez-Tilve D , Davidson WS , Tschop M , Hofmann SM 2012 Cns regulation of plasma cholesterol Ann Med 44 656 - 663    DOI : 10.3109/07853890.2011.590819
Podar D , Ramsey MH , Hutchings MJ 2004 Effect of cadmium, zinc and substrate heterogeneity on yield, shoot metal concentration and metal uptake by Brassica juncea: Implications for human health risk assessment and phytoremediation New Phytologist 163 313 - 324    DOI : 10.1111/j.1469-8137.2004.01122.x
Ponnusamy S , Zinjarde S , Bhargava S , Kumar AR 2012 Role of Curcuma longa, a traditional ayurvedic medicinal plant, in diabetes TANG (Humanitas Medicine) 2 5 - 11
Ponnusankar S , Pandit S , Babu R , Bandyopadhyay A , Mukherjee PK 2011 Cytochrome p450 inhibitory potential of triphala-a rasayana from ayurveda J Ethnopharmacol 133 120 - 125    DOI : 10.1016/j.jep.2010.09.022
Pratley RE , Matfin G 2007 Pre‐1diabetes: Clinical relevance and therapeutic approach Br J Diabetes Vasc Dis 7 120 - 129    DOI : 10.1177/14746514070070030401
Priyadarsini KI 2014 The chemistry of curcumin: From extraction to therapeutic agent Molecules 19 20091 - 20112    DOI : 10.3390/molecules191220091
Puranik A , Nabar N , Joshi J , Amonkar A , Shah S , Menon S , Vaidya R , Vaidya ADB 2014 Single dose metformin kinetics after co-administration of nisha-amalaki powder or mamejwa ghanavati, ayurvedic anti-diabetic formulations: A randomized crossover study in healthy volunteers J Obes Metab Res 1 99 - 104    DOI : 10.4103/2347-9906.134423
Qin XY , Cheng Y , Yu LC 2010 Potential protection of curcumin against intracellular amyloid beta-induced toxicity in cultured rat prefrontal cortical neurons Neurosci Lett 480 21 - 24    DOI : 10.1016/j.neulet.2010.05.062
Qureshi S , Shah AH , Ageel AM 1992 Toxicity studies on alpinia galanga and Curcuma longa Planta Med 58 124 - 127    DOI : 10.1055/s-2006-961412
Rajan SS , Antony S 2008 Hypoglycemic effect of triphala on selected non insulin dependent diabetes mellitus subjects Anc Sci Life 27 45 - 49
Rajeswary H , Vasuki R , Samudram P , Geetha A 2011 Hepatoprotective action of ethanolic extracts of melia azedarach linn. And Piper longum Linn and their combination on ccl4 induced hepatotoxicity in rats Indian J Exp Biol 49 276 - 281
Rajopadhye AA , Namjoshi TP , Upadhye AS 2012 Rapid validated hptlc method for estimation of piperine and piperlongumine in root of Piper longum extract and its commercial formulation Revista Brasileira de Farmacognosia 22 1355 - 1361    DOI : 10.1590/S0102-695X2012005000113
Ramachandran A , Snehalatha C , Mary S , Mukesh B , Bhaskar AD , Vijay V , Indian Diabetes , Prevention P 2006 The indian diabetes prevention programme shows that lifestyle modification and metformin prevent type 2 diabetes in asian indian subjects with impaired glucose tolerance (idpp-1) Diabetologia 49 289 - 297    DOI : 10.1007/s00125-005-0097-z
Ramachandran A , Snehalatha C , Shetty AS , Nanditha A 2012 Trends in prevalence of diabetes in asian countries World J Diabetes 3 110 - 117    DOI : 10.4239/wjd.v3.i6.110
Rao G , Bhat S , Rao GS , Bhat GP 2013 Antidiabetic and antioxidant efficacy of a powdered mixture of Curcuma longa and Emblica officinalis in diabetic rats in comparison with glyburide WebmedCentral Diabetes 4 1 - 13
Rastogi RP , Mehrotra BN 1995 Compendium of Indian medicinal plants Publication and Information Directorate, CSIR New Delhi, India
Rastogi S 2014 Ayurvedic science of food and nutrition Springer New York, USA
Rastogi T , Reddy KS , Vaz M , Spiegelman D , Prabhakaran D , Willett WC , Stampfer MJ , Ascherio A 2004 Diet and risk of ischemic heart disease in india Am J Clin Nutr 79 582 - 592
Rathinamoorthy R , Thilagavathi G 2014 Terminalia chebula-review on pharmacological and biochemical studies Int J PharmTech Res 6 97 - 116
Rauniyar BK , Shakya A , Thakur AK , Chatterjee SS , Kumar V 2015 Anti-stress activity of phloroglucinol: A transient metabolite of some plant polyphenolics Pharmacologia 6 21 - 30    DOI : 10.5567/pharmacologia.2015.21.30
Rege NN , Thatte UM , Dahanukar SA 1999 Adaptogenic properties of six rasayana herbs used in ayurvedic medicine Phytother Res 13 275 - 291    DOI : 10.1002/(SICI)1099-1573(199906)13:4<275::AID-PTR510>3.0.CO;2-S
Rhee SH , Pothoulakis C , Mayer EA 2009 Principles and clinical implications of the brain-gut-enteric microbiota axis Nat Rev Gastroenterol Hepatol 6 306 - 314    DOI : 10.1038/nrgastro.2009.35
Rinki S , Mishra RN 2011 Adaptogenic activity of triphala megaext Int J Res Pharm Biomed Sci 2 579 - 582
Rios MY , Olivo HF , Atta ur R 2014 Studies in natural products chemistry. Atta ur R ed Elsevier Oxford, UK Chapter 3 - natural and synthetic alkamides: Applications in pain therapy 79 - 121
Roy SJ , Stanely Mainzen Prince P 2012 Protective effects of sinapic acid on lysosomal dysfunction in isoproterenol induced myocardial infarcted rats Food Chem Toxicol 50 3984 - 3989    DOI : 10.1016/j.fct.2012.08.017
Ruden D , Lu X 2011 Personalized nutrigenomics: Tailoring the diet to the aging diabesity population Nutr Diet Suppl 3 31 - 41
Sahebkar A 2013 Why it is necessary to translate curcumin into clinical practice for the prevention and treatment of metabolic syndrome Biofactors 39 197 - 208    DOI : 10.1002/biof.1062
Saleem A , Husheem M , Harkonen P , Pihlaja K 2002 Inhibition of cancer cell growth by crude extract and the phenolics of Terminalia chebula retz. Fruit J Ethnopharmacol 81 327 - 336    DOI : 10.1016/S0378-8741(02)00099-5
Samudram P , Vasuki R. , Rajeshwari H. , Geetha A. , Moorthi P.S 2009 Antioxidant and antihepatotoxic activities of ethanolic crude extract of melia azedarach and Piper longum J Med Plants Res 3 1078 - 1083
Sandoval DA , Obici S , Seeley RJ 2009 Targeting the cns to treat type 2 diabetes Nat Rev Drug Discov 8 386 - 398    DOI : 10.1038/nrd2874
Sang JP , Minchinton IR , Johnstone PK , Truscott RJ 1984 Glucosinolates profiles in the seed, root and leaf tissue of cabbage, mustard, rapeseed, radish and swede Can J Plant Sci 64 77 - 93    DOI : 10.4141/cjps84-011
Sanmukhani J , Anovadiya A , Tripathi CB 2011 Evaluation of antidepressant like activity of curcumin and its combination with fluoxetine and imipramine: An acute and chronic study Acta Pol Pharm 68 769 - 775
Santilli F , Guagnano MT , Vazzana N , La Barba S , Davi G 2015 Oxidative stress drivers and modulators in obesity and cardiovascular disease: From biomarkers to therapeutic approach Curr Med Chem 22 582 - 595    DOI : 10.2174/0929867322666141128163739
Sarma GK , Kalita P , Barthakur M , Sarma RK 2014 Importance of traditionally used medicinal plants: Emblica officinalis (L), Curcuma longa (L) & Syzygium cumini (L) in the management of diabetes mellitus Int Ayurvedic Med J 2 356 - 361
Sauer FD , Kramer JKG , Kramer JKG , Sauer FD , Pigden WJ 1983 The problems associated with the feeding of high erucic acid rapeseed oils and some fish oils to experimental animals. In High and low erucic acid rapeseed oils production, usage, chemistry, and toxicological examination Academic Press Toronto, Canada 253 - n292
Saxena V , Mishra G , Vishwakarma KK , Saxena A 2013 A comparative study on quantitative estimation of tannins in Terminalia chebula, Terminalia belerica, Terminalia arjuna and saraca indica using spectrophotometer Asian J Pharm Clin Res 6 1 - 2
Scapagnini G , Davinelli S , Kaneko T , Koverech G , Koverech A , Calabrese EJ , Calabrese V 2014 Dose response biology of resveratrol in obesity J Cell Commun Signal 8 385 - 391    DOI : 10.1007/s12079-014-0257-3
Schreiner M , Krumbein A , Ruppel S 2009 Interaction between plants and bacteria: Glucosinolates and phyllospheric colonization of cruciferous vegetables by enterobacter radicincitans dsm 16656 J Mol Microbiol Biotechnol 17 124 - 135    DOI : 10.1159/000226589
Scott C , Johnstone AM 2012 Stress and eating behaviour: Implications for obesity Obes Facts 5 277 - 287    DOI : 10.1159/000338340
Serrano J , Puupponen-Pimia R , Dauer A , Aura AM , Saura-Calixto F 2009 Tannins: Current knowledge of food sources, intake, bioavailability and biological effects Mol Nutr Food Res 53 S310 - 329    DOI : 10.1002/mnfr.200900039
Shakya A , Chatterjee SS , Kumar V 2015 Role of fumarates in adaptogenics like efficacies of traditionally used fumaria indica extracts TANG (Humanitas Medicine) 5 28 - 37
Sharma H , Chandola HM 2011 Prameha in ayurveda: Correlation with obesity, metabolic syndrome, and diabetes mellitus. Part 1-etiology, classification, and pathogenesis J Altern Complement Med 17 491 - 496    DOI : 10.1089/acm.2010.0396
Sharma H , Chandola HM 2011 Prameha in ayurveda: Correlation with obesity, metabolic syndrome, and diabetes mellitus. Part 2-management of prameha J Altern Complement Med 17 589 - 599    DOI : 10.1089/acm.2010.0397
Shin DS , Kim KW , Chung HY , Yoon S , Moon JO 2013 Effect of sinapic acid against dimethylnitrosamine-induced hepatic fibrosis in rats Arch Pharm Res 36 608 - 618    DOI : 10.1007/s12272-013-0033-6
Shin HJ , Lee JY , Son E , Lee DH , Kim HJ , Kang SS , Cho GJ , Choi WS , Roh GS 2007 Curcumin attenuates the kainic acidinduced hippocampal cell death in the mice Neuroscience Letters 416 49 - 54    DOI : 10.1016/j.neulet.2007.01.060
Shivavedi N , Chatterjee SS , Kumar V 2014 Evaluation of pharmacologically interesting dose range of ascorbic acid in mice SAJ Neurol 1 101 -
Shivavedi N , Chatterjee SS , Kumar V 2014 Stress response modulating effects of lactic acid in mice Ther Targets Neurol Dis 1 e418 -
Shoba G , Joy D , Joseph T , Majeed M , Rajendran R , Srinivas PS 1998 Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers Planta Med 64 353 - 356    DOI : 10.1055/s-2006-957450
Sims EA , Danforthm E , Jr. Horton ES , Bray GA , Glennon JA , Salans LB 1973 Endocrine and metabolic effects of experimental obesity in man Recent Prog Horm Res 29 457 - 496
Sindhu S , Maya P , Indira TN 2012 A method for preparation of mustard (Brassica juncea) powder with retained pungency and reduced bitterness LWT - Food Sci Tech 49 42 - 47
Singh J , Sharma PC , Sharma SK , Kumar A 2013 Standardization of the fourier transform near-infrared reflectance spectroscopy for estimation of some oil quality parameters in mustard (brassica spp.) Plant Soil Environ 59 478 - 483
Singh K , Shakya R , Mahawar R 2014 Genetic diversity and patterns of variation among Indian mustard (Brassica juncea (l.) czernj. & cosson) varieties SABRAO J Breed Genet 46 329 - 339
Singh N , Kumar S , Singh P , Raj HG , Prasad AK , Parmar VS , Ghosh B 2008 Extract inhibits tnf-alphainduced expression of cell adhesion molecules by inhibiting nfkappab activation and microsomal lipid peroxidation Phytomedicine 15 284 - 291    DOI : 10.1016/j.phymed.2007.06.007
Singh R , Arif T , Khan I , Sharma P 2014 Phytochemicals in antidiabetic drug discovery J Biomed Ther Sci 1 1 - 33
Sinha R , Jastreboff AM 2013 Stress as a common risk factor for obesity and addiction Biol Psychiatry 73 827 - 835    DOI : 10.1016/j.biopsych.2013.01.032
Soni KB , Rajan A , Kuttan R 1992 Reversal of aflatoxin induced liver damage by turmeric and curcumin Cancer Lett 66 115 - 121    DOI : 10.1016/0304-3835(92)90223-I
Speciale A , Chirafisi J , Saija A , Cimino F 2011 Nutritional antioxidants and adaptive cell responses: An update Curr Mol Med 11 770 - 789    DOI : 10.2174/156652411798062395
Sri KS , Kumari DJ , Sivannarayana G 2013 Effect of amla, an approach towards the control of diabetes mellitus Int J Curr Microbiol Appl Sci 2 103 - 108
Srikumar R , Parthasarathy NJ , Manikandan S , Narayanan GS , Sheeladevi R 2006 Effect of triphala on oxidative stress and on cellmediated immune response against noise stress in rats Mol Cell Biochem 28 67 - 74
Steptoe A , Hackett RA , Lazzarino AI , Bostock S , La Marca R , Carvalho LA , Hamer M 2014 Disruption of multisystem responses to stress in type 2 diabetes: Investigating the dynamics of allostatic load Proc Natl Acad Sci U S A 111 15693 - 15698    DOI : 10.1073/pnas.1410401111
Sunila ES , Kuttan G 2004 Immunomodulatory and antitumor activity of Piper longum Linn. And piperine J Ethnopharmacol 90 339 - 346    DOI : 10.1016/j.jep.2003.10.016
Suri A , Szallasi A 2008 The emerging role of trpv1 in diabetes and obesity Trends Pharmacol Sci 29 29 - 36    DOI : 10.1016/
Szallasi A 2005 Piperine: Researchers discover new flavor in an ancient spice Trends Pharmacol Sci 26 437 - 439
Tarozzi A , Angeloni C , Malaguti M , Morroni F , Hrelia S , Hrelia P 2013 Sulforaphane as a potential protective phytochemical against neurodegenerative diseases Oxid Med Cell Longev 2013 415078 -
Tatiraju DV , Bagade VB , Karambelkar PJ , Jadhav VM , Kadam V 2013 Natural bioenhancers: An overview J Pharmacogn Phytochem 2 55 - 60
Thakur AK , Chatterjee SS , Kumar V 2014 Antidepressant-like effects of Brassica juncea L. Leaves in diabetic rodents Indian J Exp Biol 52 613 - 622
Thakur AK , Chatterjee SS , Kumar V 2013 Anxiolytic-like activity of leaf extract of traditionally used Indian-mustard (Brassica juncea) in diabetic rats TANG (Humanitas Medicine) 3 1 - 7
Thakur AK , Chatterjee SS , Kumar V 2013 Beneficial effects of Brassica juncea on cognitive functions in rats Pharm Biol 51 1304 - 1310    DOI : 10.3109/13880209.2013.789917
Thakur AK , Shakya A , Husain GM , Emerald M , Kumar V 2014 Gut-microbiota and mental health: Current and future perspectives J Pharmacol Clin Toxicol 2 1016.1 - 1016.15
Thiyagarajan M , Sharma SS 2004 Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats Life Sci 74 969 - 985    DOI : 10.1016/j.lfs.2003.06.042
Thomas M , Sujatha KS , George S 2009 Protective effect of Piper longum Linn. On monosodium glutamate induced oxidative stress in rats Indian J Exp Biol 47 186 - 192
Tiwari AK , Rao JM 2002 Diabetes mellitus and multiple therapeutic approaches of phytochemicals: Present status and future prospects Curr Sci 83 30 - 38
Tiwari AK 2008 Invigorated barley in diabetes Curr Sci 95 25 - 29
Tomas-Menor L , Barrajon-Catalan E , Segura-Carretero A , Marti N , Saura D , Menendez JA , Joven J , Micol V 2015 The promiscuous and synergic molecular interaction of polyphenols in bactericidal activity: An opportunity to improve the performance of antibiotics Phytother Res 29 466 - 473    DOI : 10.1002/ptr.5296
Triggle DJ 2012 Nous sommes tous des bacteries: Implications for medicine, pharmacology and public health Biochem Pharmacol 84 1543 - 1550    DOI : 10.1016/j.bcp.2012.08.005
Tripathi MK , Mishra AS 2007 Glucosinolates in animal nutrition: a review Anim Feed Sci Tech 132 1 - 27    DOI : 10.1016/j.anifeedsci.2006.03.003
Tripathi S , Raghuram N , Ramarao NH 2012 Validation of an integrated ayurveda-yoga module for residential treatment of patients with type 2 diabetes mellitus - a compilation from traditional literature Int J Ayurvedic Herbal Med 2 921 - 934
Trowbridge A , Monson RK 2014 Ecology and the environment Springer New York, USA The evolutionary ecology of chemically mediated plant-insect interactions 1 - 29
Tschop MH , DiMarchi RD 2012 Outstanding scientific achievement award lecture 2011: Defeating diabesity: The case for personalized combinatorial therapies Diabetes 61 1309 - 1314    DOI : 10.2337/db12-0272
Ulbricht C , Basch E , Barrette E-P , Boon H , Chao W , Costa D , Higdon ERB , Isaac R , Lynch M , Papaliodis G , Grimes Serrano JM , Varghese M , Vora M , Windsor R , Woods J 2011 Turmeric (Curcuma longa): An evidence-based systematic review by the natural standard research collaboration Altern Complement Ther 17 225 - 236
Vaghasiya Y , Nair R , Chanda S 2007 Investigation of piper species for antibacterial and anti-inflammatory property Int J Pharmacol 3 400 - 405    DOI : 10.3923/ijp.2007.400.405
Vaibhavi B , Satyam T , Sanjibkumar P , Raghuram N , Ramarao NH 2013 Effect of holistic module of yoga and ayurvedic panchakarma in type 2 diabetes mellitus-a pilot study Open J Endocr Metab Dis 3 90 - 98    DOI : 10.4236/ojemd.2013.31014
Vaidya AD 2014 Metabolic management: The role of nutraceuticals, nutritionals and naturals J Obes Metab Res 1 79 - 82    DOI : 10.4103/2347-9906.134393
Vaiserman AM 2014 Aging-modulating treatments: From reductionism to a system-oriented perspective Front Genet 5 446 -
van Duynhoven J , Vaughan EE , Jacobs DM , Kemperman RA , van Velzen EJ , Gross G , Roger LC , Possemiers S , Smilde AK , Dore J , Westerhuis JA , Van de Wiele T 2011 Metabolic fate of polyphenols in the human superorganism Proc Natl Acad Sci USA 108 4531 - 4538    DOI : 10.1073/pnas.1000098107
van Ommen B , Stierum R 2002 Nutrigenomics: Exploiting systems biology in the nutrition and health arena Curr Opin Biotechnol 13 517 - 521    DOI : 10.1016/S0958-1669(02)00349-X
Vedhanayaki G , Shastri GV , Kuruvilla A 2003 Analgesic activity of Piper longum Linn. Root Indian J Exp Biol 41 649 - 651
elusami CC , Boddapati SR , Hongasandra Srinivasa S , Richard EJ , Joseph JA , Balasubramanian M , Agarwal A 2013 Safety evaluation of turmeric polysaccharide extract: Assessment of mutagenicity and acute oral toxicity Biomed Res Int 2013 158348 -
Venkateshwarlu G , Venkata NCH , Shantha TR , Kishore KR , Prathapa RM , Raghavendra HL 2013 A comparative physicochemical and pharmacognostical evaluation of nishamalaki- an ayurvedic antidiabetic formulation Sci Tech Arts Res J 2 69 - 78
Verma S , Chatterjee SS , Kumar V 2014 Comparative adaptogenic activity of bioavailable extracts of Curcuma longa and pure curcumin in rodents (NEU-22) Indian J Pharmacol 46 S93 - S94
Verma S , Chatterjee SS , Kumar V 2015 Metformin like stress response modulating effects of turmeric curcuminoids in mice SAJ Neurol 1 102 -
Wakade AS , Shah AS , Kulkarni MP , Juvekar AR 2008 Protective effect of Piper longum L. On oxidative stress induced injury and cellular abnormality in adriamycin induced cardiotoxicity in rats Indian J Exp Biol 46 528 - 533
Walia H , Arora S 2013 Terminalia chebula- a pharmacognistic account J Med Plants Res 7 1351 - 1361
Wang HH , Hsieh HL , Wu CY , Sun CC , Yang CM 2009 Oxidized low-density lipoprotein induces matrix metalloproteinase-9 expression via a p42/p44 and jnk-dependent ap-1 pathway in brain astrocytes Glia 57 24 - 38    DOI : 10.1002/glia.20732
Wang MS , Boddapati S , Emadi S , Sierks MR 2010 Curcumin reduces alpha-synuclein induced cytotoxicity in parkinson’s disease cell model BMC Neurosci 11 57 -    DOI : 10.1186/1471-2202-11-57
Wang S , Moustaid-Moussa N , Chen L , Mo H , Shastri A , Su R , Bapat P , Kwun I , Shen CL 2014 Novel insights of dietary polyphenols and obesity J Nutr Biochem 25 1 - 18    DOI : 10.1016/j.jnutbio.2013.09.001
Wang Y , Tang H , Kochhar S , Martin F-P 2015 Metabonomics and gut microbiota in nutrition and disease Springer London, EK Roles of herbal medicine in modulating gut microbiota associated with health and diseases 185 - 197
Wendlinger C , Hammann S , Vetter W 2014 Various concentrations of erucic acid in mustard oil and mustard Food Chem 153 393 - 397    DOI : 10.1016/j.foodchem.2013.12.073
Winston D , Maimes S 2007 Adaptogens: Herbs for strength, stamina, and stress relief Healing Arts Press Vermont, USA
Wu Y , Min X , Zhuang C , Li J , Yu Z , Dong G , Yao J , Wang S , Liu Y , Wu S , Zhu S , Sheng C , Wei Y , Zhang H , Zhang W , Miao Z 2014 Design, synthesis and biological activity of piperlongumine derivatives as selective anticancer agents Eur J Med Chem 82 545 - 551    DOI : 10.1016/j.ejmech.2014.05.070
Xia X , Cheng G , Pan Y , Xia ZH , Kong LD 2007 Behavioral, neurochemical and neuroendocrine effects of the ethanolic extract from Curcuma longa L. In the mouse forced swimming test J Ethnopharmacol 110 356 - 363    DOI : 10.1016/j.jep.2006.09.042
Xia X , Pan Y , Ou-Yang Z , Wang J , Pan L-L , Zhu Q , Huang J-J , Kong L-D 2011 Pharmacokinetic-pharmacodynamic modeling of monoamine oxidase a inhibitory activity and behavior improvement by curcumin in the mouse forced swimming test Chin J Nat Med 9 293 - 304
Xia X , Pan Y , Zhang WY , Cheng G , Kong LD 2006 Ethanolic extracts from Curcuma longa attenuates behavioral, immune, and neuroendocrine alterations in a rat chronic mild stress model Biol Pharm Bull 29 938 - 944    DOI : 10.1248/bpb.29.938
Xiao JB , Hogger P 2015 Dietary polyphenols and type 2 diabetes: Current insights and future perspectives Curr Med Chem 22 23 - 38
Xu Y , Ku BS , Yao HY , Lin YH , Ma X , Zhang YH , Li XJ 2005 Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats Pharmacol Biochem Behav 82 200 - 206    DOI : 10.1016/j.pbb.2005.08.009
Yadav SP , Vats V , Ammini AC , Grover JK 2004 Brassica juncea (rai) significantly prevented the development of insulin resistance in rats fed fructose-enriched diet J Ethnopharmacol 93 113 - 116    DOI : 10.1016/j.jep.2004.03.034
Yadav V , Kumar V 2014 Advances in modern knowledge of dravyaguna of Piper longum during last five years (REV-15) Indian J Pharmacol 4 S109 -
Yang C , Zhang X , Fan H , Liu Y 2009 Curcumin upregulates transcription factor nrf2, ho-1 expression and protects rat brains against focal ischemia Brain Res 1282 133 - 141    DOI : 10.1016/j.brainres.2009.05.009
Yang F , Lim GP , Begum AN , Ubeda OJ , Simmons MR , Ambegaokar SS , Chen PP , Kayed R , Glabe CG , Frautschy SA , Cole GM 2005 Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo J Biol Chem 280 5892 - 5901    DOI : 10.1074/jbc.M404751200
Yang J , Su Y , Luo J-F , Gu W , Niu H-M , Li Y , Wang Y-H , Long C-L 2013 New amide alkaloids from Piper longum fruits Nat Prod Bioprospect 3 277 - 281    DOI : 10.1007/s13659-013-0073-0
Yang T , Sun S , Wang T , Tong X , Bi J , Wang Y , Sun Z 2014 Piperlonguminine is neuroprotective in experimental rat stroke Int Immunopharmacol 23 447 - 451    DOI : 10.1016/j.intimp.2014.09.016
Yokozawa T , Kim HY , Cho EJ , Choi JS , Chung HY 2002 Antioxidant effects of isorhamnetin 3,7-di-o-beta-dglucopyranoside isolated from mustard leaf (Brassica juncea) in rats with streptozotocin-induced diabetes J Agric Food Chem 50 5490 - 5495    DOI : 10.1021/jf0202133
Yokozawa T , Kim HY , Cho EJ , Yamabi N , Choi JS 2003 Protective effects of mustard leaf (Brassica juncea) against diabetic oxidative stress J Nutr Sci Vitaminol (Tokyo) 49 87 - 93    DOI : 10.3177/jnsv.49.87
Yoon BH , Jung JW , Lee JJ , Cho YW , Jang CG , Jin C , Oh TH , Ryu JH 2007 Anxiolytic-like effects of sinapic acid in mice Life Sci 81 234 - 240    DOI : 10.1016/j.lfs.2007.05.007
Yu JC , Jiang ZT , Li R , Chan SM 2003 Chemical composition of the essential oils of Brassica juncea (L.) coss. Grown in different regions, hebei, shaanxi and shandong, of china J Food Drug Anal 11 22 - 26
Yu SY , Gao R , Zhang L , Luo J , Jiang H , Wang S 2013 Curcumin ameliorates ethanol-induced memory deficits and enhanced brain nitric oxide synthase activity in mice Prog Neuropsychopharmacol Biol Psychiatry 44 210 - 216    DOI : 10.1016/j.pnpbp.2013.03.001
Yu ZF , Kong LD , Chen Y 2002 Antidepressant activity of aqueous extracts of Curcuma longa in mice J Ethnopharmacol 83 161 - 165    DOI : 10.1016/S0378-8741(02)00211-8
Zaki M , Begum W , Bhat TA , Kausar H 2014 Amla (Emblica officinalis gaertn) the wonderful unani drug: A review World J Pharm Pharm Sci 3 1369 - 1381
Zaveri M , Khandhar A , Patel S A P 2010 Chemistry and pharmacology of Piper longum L Int J Pharm Sci Rev Res 5 67 - 76
Zhang DW , Fu M , Gao SH , Liu JL 2013 Curcumin and diabetes: A systematic review Evid Based Complement Alternat Med 636053 -
Zhang YJ , Abe T , Tanaka T , Yang CR , Kouno I 2001 Phyllanemblinins a-f, new ellagitannins from Phyllanthus emblica J Nat Prod 64 1527 - 1532    DOI : 10.1021/np010370g
Zhao L , Ackerman SL 2006 Endoplasmic reticulum stress in health and disease Curr Opin Cell Biol 18 444 - 452    DOI : 10.1016/