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Journal of Stress Physiology & Biochemistry, Vol. 19, No. 4, 2023, pp. 163-177 ISSN 1997-0838 Original Text Copyright © 2023 by Moola, Shobana and Janani
REVIEW
PPAR gamma Agonists - Plant Compounds
Anil Kumar Moola 1, Shobana G. 2 and C. Janani 3*
1 Department of Biotechnology, Aditya Degree College, Lakshmi Narayana Nagar, Kakinada, Andhra Pradesh, India - 533 003
2 Department of Biochemistry, Srimad Andavan Arts and Science College, Tiruchirappalli,. Tamil Nadu, India - 622 005
3 Department of Biotechnology, Srimad Andavan Arts and Science College, Tiruchirappalli,. Tamil Nadu, India - 622 005
*E-Mail: janabio. net@gmail.com
Received August 17, 2023
The nuclear receptor peroxisome proliferator activated receptor-gamma (PPARg) controls adipocyte differentiation, as well as lipid metabolism and insulin sensitivity. As a result, PPARg is a promising candidate gene for a variety of human diseases, such as obesity and type 2 diabetes. Hyperglycemia associated with the metabolic syndrome and type 2 diabetes is treated with agonists of the nuclear receptor PPARg. The PPARg agonists of the thiazolidinedione type, despite being effective in normalizing blood glucose levels, have serious side effects, making the discovery of novel ligands extremely important . Natural products have historically proven to be a promising source of structures for drug development, and recent research has focused on the PPARg-activating potential of a wide range of natural products derived from traditionally used medicinal plants or dietary sources. This review highlights recent studies that have advanced our understanding of this receptor's role in metabolism, with a focus on the effects of compounds in the plant
Key words: PPAR gamma, type 2 diabetes, natural products
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Diabetes is a chronic disease that affects a large number of people around the world. It happens when the pancreas doesn't produce enough insulin or when the body can't use the insulin it does produce effectively. Many metabolic changes (obesity, lipid profile, and hypertension) are involved in the etiology of the disease, all of which have a variable impact on the disease's progression. Having the ability to genetically influence diabetes will greatly aid in the proper production of therapeutics and, eventually, the prevention of disease complications, progression, and development. The most common type of diabetes, Type 2 Diabetes Mellitus (T2D), is a complex metabolic disorder that affects 90 percent of diabetic patients worldwide.
Diabetes is a metabolic disease that has grown in importance in modern society as a result of the serious long-term health complications it causes. Type 2 diabetes mellitus (T2DM) has become a global epidemic in the twenty-first century, despite significant advancements in the understanding and management of this complex, multifactorial disease. Type 2 diabetes mellitus (T2DM) is the most common type of diabetes, accounting for over 80% of all cases (Berg et al., 2002; Mlinar et al., 2007; Coman et al., 2012). Disturbances in glucose metabolism are major contributors to diabetes. The hormone responsible for glucose homeostasis is insulin, which is released by pancreatic -cells (Garrett and Grisham, 1999; Sesti, 2006). Insulin stimulates the uptake of glucose from the circulatory system by hepatocytes, myocytes, and adipocytes. Depending on the situation, glucose can be used as an energy source through glycolysis or stored as glycogen in muscle or liver cells. Insulin resistance is defined as the inability of cells to respond to normal levels of circulating insulin (Berg et al., 2002), resulting in the onset of the disease.
Moderate wine intake has been correlated with decrease incidences of cardiovascular sicknesses,
with the aid of using fueloline chromatography and mass spectroscopy with inside the maximum lively wine division. They had an similarity to PPARy much resembling that of the standard pharmaceutical agent rosiglitazone (Zoechling et al., 2011).
Natural compounds may be viable alternatives or complements to currently available treatments for diabetes. They may even lower the disease's risk. A positive aspect is that large amounts can be consumed in everyday diets. A large number of plants and natural biomolecules have been studied for their anti-diabetic properties in the literature. Plants, for example, have been used to prevent diabetes-related conditions since antiquity (Soumyanath, 2006). The mechanism is frequently not fully understood, but more research is being done to better understand the mechanisms of action of various plants and natural compounds. The role of medicinal plants and their active constituents for anti-diabetic agents is discussed in this study. The importance of diabetes management, reducing risks, and using anti-diabetic drugs was also stressed in this research. These extracts/compounds' detailed action mechanisms for their actions are also identified.
Antioxidant Effects in plants
A variety of phytochemicals (phenols, terpenoids, nitrogen-containing alkaloids, and sulphur-containing compounds) present in plants have been linked to anti-diabetic properties (Gothai et al., 2016). Phenolic compounds have been linked to changes in inflammatory behavior (CRP, IL-6, IL-1, and TNF-), transpiration factor enzymes (NF-B, PPAR), and genes associated with T2DM (Anuradha 2013). Ginger (Zingiber officinale Roscoe) remains used as an essential cooking spice and natural remedy across the world. Gingerols, the main smelly additives of ginger, are recognised to enhance diabetes, together with the impact of enhancement towards insulin sensitivity. (Priya et al., 2011)
Researchers have looked at the antioxidant and anti-diabetic effects of various plant sections (Kim et al., 2011; Priya et al., 2011; Unuofin, et al., 2018; Unuofin and Lebelo, 2020). Such antioxidants found in the human body, such as glutathione and thioredoxin, mop up ROS
inflammation, and metabolic sicknesses which includes kind 2 diabetes, obesity, and excessive pressure in blood. We studied binding of ligands from exceptional wines to the peroxisome proliferator-activated receptor y (PPARy), a key component in glucose and lipid metabolism. Ellagic acid and epicatechin gallate (ECG) had been diagnosed
by donating reducing counterparts to free radicals in the shape of a hydrogen atom or an electron, rendering them less dangerous in the body environment. In relation to T2DM therapy, some plant-derived compounds have been ascribed the following properties: stimulate the ERK1/2 and AMPK pathways (Yang etal., 2009; Ohno etal., 2013; Ahad et al., 2014). downregulate COX-2 gene expression, resulting in enhanced proinflammatory mediator liberation (Prabhakar, et al., 2013; Guo, et al., 2014) Increase glucose resistance and insulin sensitivity (Choi, et al., 1991; Tsai, et al., 2012); reduce inflammatory cell influx (Li et al., 2009); lower serum levels of proinflammatory cytokines IL-1, IL-6, and TNF-; inhibit NF-B pathway activation (Ahad et al., 2014) and repress macrophage chemostatic protein (MCP-1) and ICAM expression (Kumar et al., 2013) Figure 1 illustrates the possible antioxidant activity of plant secondary metabolites in the T2DM pathway caused by oxidative stress Via ROS/RNS, oxidative stress findings in diabetes were affected with Insulin resistance.
Antioxidants present in natural phytocompounds have received a lot of attention recently, and they're already being used therapeutically to clean up reactive organisms and avoid oxidative stress-related diabetes. Insulin tolerance, beta cell dysfunction, and insulin secretion are all caused by oxidative stress in diabetics, which can be modulated by phytocompounds with high antioxidant capacity by controlling blood sugar levels or attenuating at least one of the mechanisms linked to insulin resistance: beta cell activity, glucose (re)absorption, and incretin-related pathways (Unuofin and Lebelo 2020).
In a cell culture model of rat adipocytes the treatment of anthocyanins PPAR gamma and target adipocyte specific genes (LPL, aP2, and UCP2) were significantly up-regulated. Leptin and adiponectin as well as their mRNA levels were also increased by anthocyanins resulting from the increased phosphorylated MAPK. The mechanisms of action of anthocyanins in the amelioration of obesity can be mediated by upregulation of the thermogenic mithocondrial uncoupling protein 2 (UCP-2) and the lipolytic enzyme hormone sensitive lipase (HSL) as well as by down-regulation of the nuclear factor plasminogen activator inhibitor-1 (PAI-1) (Jayaprakasam et al., 2005). Some of the previous findings have been
also discovered in human adipocytes treated with anthocyanins (Tsuda et al., 2006). Further studies using a diabetic mouse model KK-Ay-mice have shown similar differences after anthocyanin and cyanidin- 3-glucoside administration. Gene expression of TNF-a and MCP-1 in mesenteric WAT was decreased and GLUT-4 increased, while a novel potential target gene retinol binding protein-4 was significantly decreased by 2 g/kg anthocyanin. in diet. The anthocyanin treatment enhanced the energy expenditure related genes UCP-2 and adiponectin and downregulation of PAI-1 that is induced by IL-6 in obese subjects, which suggests that also anti-inflammatory mechanisms of anthocyanins are involved (Moskaug et al., 2004; Abahusian et al., 1993)
Following food intake, lipid-derived ligands such as unsaturated fatty acids bind to this nuclear receptor, which causes the expression of a large number of genes involved in metabolism. PPARs have been shown to interact with structurally unrelated natural products such as flavonoids, polyphenols (e.g., resveratrol), and organic acids such as punicic acid or abscisic acid in micromolar concentrations (Huang et al., 2005; Hontecillas et al., 2009; Guri et al., 2007). However, due to interactions with a number of other proteins, these molecules do not appear to have clear beneficial molecular or physiological in vivo effects, making further development of these compounds difficult. The antidiabetic thiazolidinediones (TZDs), which include the commonly used medication rosiglitazone (Avandia), stimulate PPAR powerfully. These PPAR activators have recently come under fire due to negative clinical side effects (Anonymous 2010) such as weight gain and other disorders (Rosen 2010).
Nuclear Receptor (PPAR) within the broader nuclear receptor superfamily, PPAR is the third member of a subdivision that also includes PPAR and PPAR (Willson et al., 2000). The name PPAR comes from the discovery that a structurally diverse array of compounds that activate PPAR, the family's first member to be cloned, also increases the size and number of peroxisomes in rodent liver (Issemann & Green, 1990). The fibrate class of lipid-lowering drugs has been shown to target PPAR, which is highly expressed in the liver, kidney, heart, and skeletal muscle. In humans, however, these agents do not promote the proliferation of peroxisomes (Bentley et al.,
1993; Ashby et al., 1994). Although recent studies have suggested that it may be an important regulator of cholesterol trafficking in macrophages, little is known about the physiological role(s) of PPAR, which is expressed in many tissues (Braissant et al., 1996).
In the decade since it was first cloned (Zhu et al., 1993), however, an extensive body of literature relating to the biology of PPAR has emerged. Three mRNA isoforms are produced by different promoter usage and alternate splicing of the gene: PPAR1 and PPAR3 mRNA encode the same protein product; the PPAR2 isoform has an additional 28 amino acids at its N-terminus. PPAR1 is widely expressed, albeit at low levels, in adipose tissue, whereas PPAR2 and PPAR3 are highly expressed. Indeed, the receptor is important for fat cell differentiation, as it promotes the formation of mature lipid-laden adipocytes by inducing the expression of adipocyte-specific genes and inducing the expression of adipocyte-specific genes (Tontonoz et al.1995; Ntambi and Young-Cheul 2000; Janani et al., 2019).
Recent studies with mice genetically engineered to lack PPAR have confirmed its critical role in the development of both white and brown adipocytes in vivo (Barak et al., 1999; Kubota et al., 1999; Rosen et al., 1999; Janani and Ranjitha Kumari 2017), and clinical phenotypes of patients with PPAR gene mutations suggest a similar role in the regulation of human adipose tissue mass (Chatterjee, 2000; Agarwal & Garg, 2002; Hegele et al., 2002).
Role in Type II Diabetes Mellitus
The thiazolidinediones (TZDs) are synthetic compounds that can normalize elevated plasma glucose levels in obese, diabetic rodents and may be efficacious therapeutic agents for the treatment of noninsulin-dependent diabetes mellitus (Christensen et al., 2009)
Thiazolidinediones are insulin sensitizing drugs that target the peroxisome proliferator-activated receptor (PPAR) y. An n-hexane extract of the flowers of Echinacea purpurea was found to activate PPARy without stimulating adipocyte differentiation. Bioassay-guided fractionations yielded five alkamides, of which one was new, and three fatty acids that all activated PPARy. The new alkamide hexadeca-2E,9Z,12Z,14E-tetraenoic acid isobutylamide
(5) was identified by analysis of spectroscopic data and found to activate PPARy with no concurrent stimulation of adipocyte differentiation. Compound five was further shown to increase insulin-stimulated glucose uptake. The data suggest that flowers of E. purpurea contain compounds with potential to manage insulin resistance and type 2 diabetes (Christensen et al., 2009).
The use of TZDs to treat type-2 diabetes mellitus is complicated by systemic fluid retention. Guan et al. (2005) found that treatment of mice with amiloride, a collecting duct-specific diuretic, reversed the enhanced renal Na+ absorption, edema, and water weight gain caused by TZDs. Deletion of Pparg in mouse collecting duct blocked TZD-induced weight gain, decreased renal Na+ avidity, and increased plasma aldosterone. Treatment of cultured mouse collecting ducts with TZDs increased amiloride-sensitive Na+ absorption and Scnn1g (600761) mRNA expression through a Pparg-dependent pathway. Guan et al. (2005) concluded that SCNN1G is a PPARG target gene in the collecting duct and that activation of this pathway mediates fluid retention associated with TZDs.
Choi et al. (2010) showed that obesity induced in mice by high fat feeding activates the protein kinase CDK5 (123831) in adipose tissues. This results in phosphorylation of the nuclear receptor PPARG, a dominant regulator of adipogenesis and fat cell gene expression, at ser273. This modification of PPARG does not alter its adipogenic capacity, but leads to dysregulation of a large number of genes whose expression is altered in obesity, including a reduction in the expression of the insulin-sensitizing adipokine adiponectin (605441). The phosphorylation of PPARG by CDK5 is blocked by antidiabetic PPARG ligands such as rosiglitazone and MRL24. This inhibition works both in vitro and vivo, and is completely independent of classic receptor transcriptional agonism. Similarly, inhibition of PPARG phosphorylation in obese patients by rosiglitazone was very tightly associated with the antidiabetic effects of this drug. Choi et al. (2010) concluded that these results suggested that CDK5-mediated phosphorylation of PPARG may be involved in the pathogenesis of insulin resistance and presented an opportunity for development of an improved generation of antidiabetic drugs through PPARG.
Choi et al. (2011) described novel synthetic compounds that have a unique mode of binding to PPAR-gamma, completely lack classic transcriptional agonism, and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity without causing the fluid retention and weight gain that are serious side effects of many of the PPAR-gamma drugs. Also, unlike TZDs, SR1664 does not interfere with bone formation in culture. Choi et al. (2011) concluded that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPAR-gamma. Dutchak et al. (2012) reported that FGF21 (609436) is an inducible, fed-state autocrine factor in adipose tissue that functions in a feed-forward loop to regulate the activity of PPAR-gamma. FGF21 knockout (KO) mice displayed defects in PPAR-gamma signaling including decreased body fat and attenuation of PPAR-gamma-dependent gene expression. Moreover, FGF21-KO mice were refractory to both the beneficial insulin-sensitizing effects and the detrimental weight d edema side effects of the PPAR-gamma agonist rosiglitazone. A9-tetrahydrocannabinol (THC), reasons acute vasorelaxation in diverse arteries. Here we display for the primary time that THC additionally reasons slowly growing vasorelaxation thru activation of peroxisome proliferator-activated receptors gamma (PPARy). In vitro, THC (10 MM) triggered time-established vasorelaxation of rat remoted arteries. Time-established vasorelaxation to THC become just like that produced with the aid of using the PPARy agonist rosiglitazone and become inhibited with the aid of using the PPARy antagonist GW9662 (1 mM), however now no longer the cannabinoid CB1 receptor antagonist AM251 (1 mM). Time-established vasorelaxation to THC calls for an intact endothelium, nitric oxide, manufacturing of hydrogen peroxide, and de novo protein synthesis. This lack of characteristic in FGF21-KO mice become coincident with a marked boom withinside the sumoylation of PPAR-gamma, which reduces its transcriptional activity. Adding lower back FGF21 averted sumoylation and restored PPAR-gamma activity. Dutchak et al. (2012) concluded that FGF21 is a key mediator of the physiologic and pharmacologic movements of PPAR-gamma.
Jonker et al. (2012) diagnosed FGF1 (131220) as a important transducer withinside the manner of metabolic homeostasis via dinner party or famine in mice. Jonker et al. (2012) connected the law of FGF1 to the nuclear receptor PPAR-gamma. FGF1 is the prototype of the 22-member FGF own circle of relatives of proteins and has been implicated in a number of physiologic processes, consisting of development, wound healing, and cardiovascular changes. Surprisingly, FGF1 knockout mice displayed no extensive phenotype beneathneath wellknown laboratory conditions. Jonker et al. (2012) confirmed that FGF1 changed into incredibly prompted in adipose tissue in reaction to a high-fats weight-reduction plan and that mice missing FGF1 advanced an competitive diabetic phenotype coupled to aberrant adipose enlargement whilst challenged with a high-fats weight-reduction plan. Further evaluation of adipose depots in FGF1-poor mice discovered a couple of histopathologies withinside the vasculature network, an accentuated inflammatory reaction, aberrant adipocyte length distribution, and ectopic expression of pancreatic lipases. On withdrawal of the high-fats weight-reduction plan, this infected adipose tissue did not well resolve, ensuing in significant fats necrosis. In phrases of mechanisms, Jonker et al. (2012) confirmed that adipose induction of FGF1 withinside the fed kingdom is regulated via way of means of PPAR-gamma appearing via an evolutionarily conserved promoter-proximal PPAR reaction element (PPRE) withinside the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse mounted the PPAR-gamma-FGF1 axis as important for retaining metabolic homeostasis and insulin sensitization.
These fundamental insights have culminated with TZDs being recently approved for use in the management of type 2 diabetes. Troglitazone, the first TZD in widespread clinical use, was withdrawn following concerns regarding its hepatotoxicity (Watkins & Whitcomb, 1998); subsequent studies have suggested, however, that this potentially fatal idiosyncratic adverse event is unlikely to be a class effect, but rather reflects the generation of a specific metabolite unique to troglitazone (Willson et al., 2000).
Although originally synthesized as derivatives of clofibrate, unexpectedly the TZDs were found to exhibit
insulin-sensitizing actions in rodent models of T2DM as far back as the early 1980s, a finding that was later confirmed in man (1999). It is only relatively recently, however, that the molecular basis for this action has been elucidated. In the mid-1990s Kliewer and colleagues reported that TZDs function as selective high-affinity ligands for PPARy (Lehmann et al., 1995). Furthermore, the rank order of their potencies for receptor activation in vitro correlates closely with their glucose lowering activity in vivo (Berger et al., 1996; Willson et al., 1996). Taken together, these data strongly suggested PPARy to be the molecular target for the antidiabetic actions of the TZDs. The therapeutic efficacy of the currently available TZDs is, however, limited, and several side-effects have been reported (Schoonjans & Auwerx, 2000). Accordingly, selective non-TZD PPARy ligands (e.g. tyrosine agonists) have been developed and shown to exert potent antidiabetic effects in preclinical studies and early clinical trials (Fiedorek et al., 2000; Willson et al., 2000), whilst compounds that activate RXR (the heterodimeric partner for PPARy) also improve insulin sensitivity in vivo (Mukherjee et al., 1997), findings which support the contention that this receptor is indeed a key regulator of insulin action. Moreover, a unique chemically distinct PPARy ligand, FMOC-L-leucine (F-L-Leu) has been reported to promote differential cofactor recruitment leading to a modified pattern of target gene activation, which promotes insulin sensitization, yet with less adipogenic activity than other PPARy ligands (Rocchi et al., 2001), a finding which has obvious attractions from the therapeutic standpoint.
Therefore studies have focused on their heterozygous littermates, who appear to exhibit greater insulin sensitivity in hyperinsulinaemic euglycaemic clamp studies (Miles et al., 2000) and are protected against the development of insulin resistance when subjected to high fat feeding (Kubota et al., 1999), as compared with their wild-type counterparts. At first glance these findings may appear counterintuitive, i.e. how can a reduction in PPARy activity in heterozygous null mice protect against insulin resistance when PPARy activators such as TZDs are potent insulin sensitizers. A reduction in PPARy activity, due to heterozygous PPARy deficiency, decreases the triglyceride content of white adipose tissue, skeletal
muscle and liver (possibly as a consequence of enhanced leptin expression and fatty acid combustion), thereby ameliorating high fat diet-induced obesity and insulin resistance. Moreover, although heterozygous PPARy deficiency and TZD treatment exert opposing effects on total white adipose tissue mass, the former also decreases lipogenesis, whereas the latter stimulates adipocyte differentiation and apoptosis, thereby both protecting against the development of adipocyte hypertrophy and, accordingly, alleviating insulin resistance (Yamauchi et al., 2001).
Additional proof of a key function for PPARy in figuring out human adiposity has been furnished with the aid of using the identity of 4 unrelated German topics in whom a missense mutation at codon 115 (Pro115Gln) in PPARy2 became observed to be related to extreme obesity (BMIs starting from 37 to forty seven kg/m2; Ristow et al., 1998). With the previous expertise that phosphorylation of PPARy2 at an adjoining serine residue (Ser114) had formerly been proven to lessen the capacity of the receptor to mediate adipocyte differentiation and lipid accumulation (Hu et al., 1996; Adams et al., 1997), the authors speculated that the Pro115Gln mutation would possibly impair such phosphorylation, main to a receptor with stronger transcriptional activity, adipogenic motion and consequently obesity. Indeed, overexpression of the mutant receptor in murine fibroblasts brought about multiplied differentiation of the cells into adipocytes and extra mobile accumulation of triglyceride whilst in comparison with the wild-kind receptor. Interestingly, the authors speculated that such an activating PPARy mutation is probably anticipated to be related to much less insulin resistance than could commonly be predicted for the diploma of obesity. In help of this contention, they located that overweight topics bearing the Pro115Gln mutation had decrease fasting serum insulin concentrations than different overweight topics of their cohort. However, it ought to be mentioned that 3 in their affected people had already evolved T2DM, and a greater specific estimate of insulin resistance and beta cellular characteristic could be required to verify this hypothesis. Identification of isosilybin a from milk thistle seeds as an agonist of peroxisome proliferator-activated receptor gamma. Likewise some of the plant secondary metabolites
acts as agonist of PPARg expression were listed in Table 1.
Table. 1. PPAR gamma agonists
S.N o Name of the plant Name of the Plant Family Name of the compound Mechanism of action of compound References
1. Cannabis sativa Cannabaceae Ajulemic acid Agonist Lee et al., 2009
Apigenin Chrysin Kaempferol Liang et al., 2001
2. Poria cocos Wolf Polyporaceae Dehydrotrametenoli c acid Agonist Sato et al., 2002
3. Glycyrrhiza uralensis Fisher Fabaceae Prenylflavonoid (Glycycoumarin, glycyrin, dehydroglyasperin C and dehydroglyasperin D Agonist Kuroda et al., 2003
4. Saururus chinensis Saururaceae Saurufuran Agonist Atanas et al., 2013
5. Notopterygium incisum Apiaceae Falcarindiol Agonist Hwang et al., 2002
6. Hydrangea macrophylla var. thunbergii Hydrangeaceae Hydrangeic acid Agonist Zhang et al., 2009
7. Amorpha fruticosa L. Fabaceae Amorfrutins Agonist Weidner et al., 2012
8. Astragalus membranaceusMoench Fabaceae Formononetin Agonist Shen et al., 2006
9. Bixa orellana L. Bixaceae Bixin and norbixin Agonist Takahashi et al., 2009
10. Camellia sinensis (L.) Kuntze Theaceae (-)-Catechin Agonist Shin et al., 2009
11. Cannabis sativaL. Cannabaceae A9- Agonist O'Sullivan et al.,
Tetrahydrocannabin ol 2005
12. Chromolaena odorata (L.) Asteraceae (9S,13R)-12-Oxo-phytodienoic acid Agonist Dat et al., 2009
13. Coix lacryma-jobi var. ma-yuen Poaceae Hydroxy unsaturated fatty acids Agonist Yokoi et al.,2009
14. Cornus alternifolia L.f. Cornaceae Kaempferol-3-O-jB-glucopyranoside Agonist He et al. ,2012
15. Commiphora mukul (Hook. ex Stocks) Burseraceae Commipheric acid Agonist Cornick et al., 2009
16. Cymbopogon citratus (DC.) Stapf Poaceae Citral Agonist Katsukawa et al., 2010
17. Echinacea purpurea (L.) Moench Asteraceae Alkamides Agonist Christensen et al., 2009
18. Elaeis guineensis Jacq. Arecaceae Tocotrienols Agonist Fang et al., 2010
19. Elephantopus scaber L. Asteraceae Deoxyelephantopin Agonist Zou et al.,2008
20. Epimedium elatum C. Morren & Decne. Berberidaceae) Acylated flavonol glycosides Agonist Tantry et al., 2012
21. Euonymus alatus(Thunb.) Siebold Celastraceae Kaempferol and quercetin Agonist Fang et al., 2010
22. Glycine max (L.) Merr. Fabaceae Genistein Agonist Dang et al., 2003
23. Glycyrrhiza glabra L. Fabaceae 5'-Formylglabridin, (2R,3R)-3,4',7- Agonist Kuroda et al., 2010
trihydroxy-3'-prenylflavane, echinatin, (3R)-
2',3',7-trihydroxy-4'-
methoxyisoflavan, kanzonol X, kanzonol W, shinpterocarpin, licoflavanone A, glabrol, shinflavanone, gancaonin L, glabrone
24. Glycyrrhiza inflata Batalin Fabaceae Licochalcone E Agonist Park et al., 2012
25. Glycyrrhiza uralensis Fisch. ex Fabaceae Flavonoids and 3- Agonist Kuroda et al.,
DC. arylcoumarins 2003
26. Limnocitrus littoralis (Miq.) Rutaceae Meranzin Agonist Do et al., 2007
Swingle
27. Magnolia officinalis Rehder & Magnoliaceae Magnolol Agonist Choi et
E.H. Wilson al., 2009
28. Momordica charantia L. Cucurbitaceae Cucurbitane-type Agonist Nhiem et al.,
triterpene glycoside 2012
29. Notopterygium incisum C.T. Ting ex H.T. Chang Apiaceae Polyacetylenes Agonist Atanasov et al., 2013
3G. Origanum vulgare L. Lamiaceae Biochanin A Agonist Mueller et al., 2008
31. Panax ginsengC.A. Mey. Araliaceae Ginsenoside 20(S)- Agonist Han et al., 2006
protopanaxatriol
32. Pseudolarix amabilis (J. Pinaceae Pseudolaric acid B Agonist Jaradat et al.,
Nelson) Rehder 2002
33. Robinia pseudoacaciavar. umbraculifer DC. Fabaceae Amorphastilbol Agonist Kim et al. ,2012
34. Pueraria thomsonii Benth. Fabaceae Daidzein Agonist Shen et al.,
2006
35. Sambucus nigraL. Adoxaceae a-Linolenic acid, Agonist Christensen etal
linoleic acid, and naringenin .,2010
36. Silybum marianum (L.) Gaertn. Asteraceae Isosilybin A Agonist Pferschy-
Wenzig et al., 2014
37. Terminalia bellerica Roxb. Combretaceae Gallotannins Agonist Yang et al.,
2013
38. Thymus vulgarisL. Lamiaceae Carvacrol Agonist Hotta et al., 2010
39. Vitis vinifera L. Vitaceae Ellagic acid, Agonist Zoechling et al.,
epicatechin gallate 2011
40. Wolfiporia extensa (Peck) Polyporaceae Dehydrotrametenoli Agonist Sato et al., 2002
Ginns c acid
41. Zingiber officinaleRoscoe Zingiberaceae 6-Shogaol Agonist Isa et al., 2008
42. Pistacia lentiscus L. Anacardiaceae Oleanonic acid Agonist Petersen et al., 2011
43. Piper chaba Piperaceae Retrofractamide A Agonist Mourad et al., 2013
44. Kaempferia parviflora Zingiberaceae Methoxyflavonols Agonist Matsuda et al., 2011
45. Stevia rebaudiana Asteraceae Austroinulin Agonist Metibemu et
al., 2017
Reactive Oxygen Species Reactive Nitrogen Species
Endogenous Antioxidants like glutathione, lipoic acid, bilirubin, ferritin, superoxide dismutase. catalase. and glutathione peroxidase.
Oxidative Stress "Nitrosative Stress
i
Insulin resistance
Hyperglycemia
Exogenous Antioxidants like Tocopherol. Ascorbate. (5 Carotene, Flavonoids.
Type II Diabetes
Figure. 1. Potential of antioxidants in Type II Diabetes
CONCLUSION
The study of the reviewed information of the numerous PPAR gamma will become obvious that, despite the fact that those dealers are classed collectively in keeping with their important PPAR target, they have got very unique and on occasion conflicting scientific benefit and unfavorable occasion profiles. It is speculated that that is due to their unique residences and specificities for the unique PPAR receptors (every of which goals specific genes). The maximum placing is the conflicting kind 2 diabetes. In scientific practice, PPAR-a agonists, consisting of the fibrates, enhance dyslipidaemia, even as the PPAR-y agonists, consisting of the plant secondary metabolites will enhance insulin resistance and diabetes.
CONFLICT OF INTERESTS
The authors declare that they have no potential conflicts of interest.
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