Prevention and Remission of Diabetes Initiativereplication through the inhibition of Pdx-1 and...

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Prevention and Remission of Diabetes … Initiative P R O D

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Beta-cells oxidative stress and inflammationOxidative stress and chronic inflammation are important pathophysiological phenomena that are well-known to be associated with the development and progression of several metabolic diseases, including insulin-resistance and diabetes.1,2 This emergence of oxidative stress is attributable to an imbalance between the oxidative and anti-oxidative systems of cells and tissues, which per se is a result of over production of oxidative-free radicals and associated reactive oxygen species (ROS). An important outcome of this excessive ROS levels is the modification of structure and function of several cellular proteins and lipids, which in sequence leads to a variety of cellular and tissue aberrations (Box 1).1

In obesity, chronic oxidative stress and associated inflammation are underlying factors, which lead to the development of several cross-linked pathologies, such as insulin resistance, dysregulated pathways of metabolism and diabetes, through impaired signaling and metabolism, thereby resulting in dysfunction to insulin secretion, insulin action and immune responses.1 In all, it is thus accepted that insulin resistance, often associated with over-nutrition and obesity, results from the chronically elevated oxidant stress and chronic inflammation.3

Beta-cell dysfunctionThese effects – mentioned above – could in part be considered as mediated in consequence of the effects that oxidative stress exerts on the pancreatic beta-cells. Loss of beta-cell function is a key event in the pathogenesis of diabetes,4 and oxidative stress induced by reactive oxygen and nitrogen species is critically involved in the impairment of beta-cell function during development and progression of diabetes.5

It has been noted that pancreatic beta-cells are extremely susceptible to oxidative stress due to a high endogenous production of ROS and a low expression of anti-oxidative enzymes (Box 2),6 and that this oxidative stress plays an important role in the neogenesis, proliferation, and survival of beta-cells under both physiological and pathological conditions. Beta-cells are known to have lower anti-oxidative enzymes to combat the continuously generated superoxide anions – they are only equipped with ~50% of the superoxide dismutase (SOD) and 5% of H2O2-scavenging enzymes glutathione peroxidase (GPx) and catalase (CAT) compared to those enzymes found in the liver; thus making beta-cells highly sensitive to ROS related signaling and distinctively susceptible to oxidative stress.6 Besides hyperglycemia, exposure to excessive lipids levels (hyperlipidemia) has also been shown to activate cell

Targeting Beta-Cells Oxidative Stress and Inflammation

Box 1: Effects of excessive levels of ROS on cells and tissues • Cellular dysfunction including:

» Impaired energy metabolism » Altered cell signaling » Altered cell cycle control » Impaired cell transport mechanisms » Overall dysfunctional biological activity

• Immune activation • Inflammation

Source: Newsholme P, Cruzat VF, Keane KN, et al. Molecular mechanisms of ROS production and oxidative stress in diabetes. Biochem J. 2016;473(24):4527-4550.

Box 2: Beta-cells – extremely susceptible to oxidative stressTwo major factors render beta-cells prone to the risk of oxidative stress:

» A high endogenous generation of reactive oxygen species (ROS) induced by stimuli, such as hyperglycemia, hyperlipidemia, hypoxia, endoplasmic reticulum (ER) stress, and

» Low expressions of essential antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx).

Source: Wang J, Wang H. Oxidative stress in pancreatic beta cell regeneration. Oxid Med Cell Longev. 2017;2017: 1930261.

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Figure 1: Oxidative stress plays critical roles in beta-cell cycle

Source: Wang J, Wang H. Oxidative stress in pancreatic beta cell regeneration. Oxid Med Cell Longev. 2017;2017: 1930261.

� On cell-cycle regulators, accumulated ROS in beta-cells suppressed the expression of cyclins D1 and D2, as well as increased cell-cycle inhibitors such as p21 and p27, leading to decreased beta-cell proliferation rate.

� Meanwhile, ROS promoted nuclear translocation/activation of FoxO1, which in turn prevents beta-cell replication through the inhibition of Pdx-1 and possibly other beta-cell-related gene transcriptions.

� Besides, ROS also directly down-regulate transcription factors such as Pdx-1, MafA, Nkx6.1, and Ngn3, which are crucial in beta-cell proliferation and differentiation.

↓Cyclin D1 ↓Pdx-1

↓MafA

↓Nkx6.1

↓Ngn3

Oxidative stress

↑p21 ↑p27

FoxO1

FoxO1

↑Nuclear translocation

Pdx-1, etc↓Proliferation

↓Differentiation↓Proliferation↓Proliferation

G2

MG1

S

stress responses including oxidative stress, which contributes to lipotoxicity in beta-cells in type 2 diabetes. Concurrently, endoplasmic reticulum (ER) stress is also closely related with oxidative stress, especially in the insulin-producing beta-cells. In this context, it is in fact argued that oxidative stress and ER stress are closely entwined phenomena, fundamentally involved in beta-cell dysfunction by direct effects on insulin biosynthesis and due to consequences of the ER stress-induced unfolded protein response.7 Evidence also indicates that hyperactivation of the unfolded protein response to counteract metabolic stresses is closely related to beta-cell dysfunction and apoptosis.8 All these data suggest that ROS is continuously generated in beta-cells at a considerable amount, thereby affecting their functions; and emerging evidence supports that oxidative stress may play a role in regulating beta-cell cycle (Figure 1). Overall, beta-cell oxidative stress and inflammation are thus important metabolic targets to achieve early remission and prevent the progression of diabetes.

advanced glycation end-products: potent pro-oxidative and pro-inflammatory compounds

Advanced glycation end-products (AGEs) are known pro-oxidative and pro-inflammatory compounds, largely shown to be elevated in the states of oxidative stress and chronic

inflammation, such as in diabetes.9 Traditionally, it was considered that AGEs are generated largely endogenously in response to hyperglycemia; though it is now clear that these deleterious bio-products can also form under conditions of high oxidative stress, even in the absence of high blood glucose. Furthermore, it is not only the endogenous production that contributes to high AGEs levels. In this regard, it is in fact now recognized that many modern foods, especially those processed under dry heat conditions, contribute significantly to the overall body pool of AGEs; high-temperature processed food products contain high amounts of heat accelerated protein- and lipid-associated pro-oxidant AGEs, which add to the overall systemic toxic pool of these powerful pro-oxidants.10 Studies in healthy subjects and in patients with diabetes have indicated a link between exogenous AGEs, circulating AGEs and markers of chronic inflammation and chronic oxidative stress.

Compelling epidemiological evidence suggests that elevated AGEs may be a significant risk factor for beta-cell injury and for peripheral insulin resistance.11 The mechanisms linking

Elevated AGEs may be a significant risk factor for beta-cell injury and for peripheral insulin resistance

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AGEs and insulin resistance are several and complex, though of significant physiopathological importance is the impact of AGEs on survival factor sirtuin 1 (SIRT1) and anti-AGE advanced glycation receptor 1 (AGER1) systems.12 AGEs may contribute to insulin resistance via increased expression of pro-inflammatory receptor for AGEs (RAGE) and reduced expression of SIRT1 and AGER1 – early depletion of these defense mechanisms (AGER1 and SIRT1) underlies the elevated state of basal oxidative stress observed in humans; under chronic high-level AGE conditions, AGER1, SIRT1 and other defenses are down-regulated, thus possibly contributing to beta -cell dysfunction or destruction.

Elevated AGEs activate RAGE, which induces activation of NF-κB, inflammation and NADPH oxidase, thereby further enhancing the oxidation and suppressing protective survival systems AGER1 and SIRT1. The process of ligand binding to RAGE results in activation of NADPH oxidases and increases intracellular ROS formation, leading to further formation of AGEs, which then trigger the damaging mechanisms mediated by them. Additionally, AGEs activate the transcription factor NF-κB, leading to increased expression of several pro-inflammatory cytokines, including interleukin-6 (IL-6) and monocyte chemoattractant peptide-1 (MCP-1), and RAGE. This causes further intensification of the inflammatory response. AGEs have also been shown to affect the insulin signaling and trigger inflammation via oxidative activation and stimulation of PKC-α and upregulation of TNF (Figure 2); glycated albumin induces expression of TNF, leading to further suppression

of insulin signaling. Overall, AGEs thus can deplete host-defenses AGER1 and SIRT1, raise basal oxidative stress and inflammation, and increase susceptibility to dysmetabolic insulin resistance.12,13 As follows, it is rational to consider that a sustained restriction of the external sources of these pro-oxidants and use of anti-oxidants would possibly help restore native resistance to type 2 diabetes and other diseases linked to increased AGEs and high oxidative stress.

resveratrol: a polyphenol with plethora of Biological activities

The above discussion clearly supports the proposition that anti-oxidant status of individuals could affect their vulnerability to oxidative damage, and thus onset and progression of diabetes and its complications;14 sequentially providing an enticing therapeutic opportunity that protection against metabolic disturbances may be increased by augmenting the anti-oxidant milieu of the body. This pressing need and opportunity becomes further attracting and significant when viewed in context of the

Effects induced by resveratrol are strongly related to the capability of this compound to increase expression/activity of AMPK and SIRT1 in various tissues of diabetic subjects

Figure 2: Mechanisms of AGEs-related insulin resistance in insulin-sensitive tissues

Source: Nowotny K, Jung T, Höhn A, et al. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules. 2015;5(1):194-222.

AGE precursor/AGEs

Insulin resistance

Albumin

↑RAGE

Insulin

↑Inflammation, ↓Insulin signaling

↑TNFa↑PKCa

↓Glucose uptake ↓Insulin clearance ↓Insulin release control

↓AGER1, ↓SIRT1

AGEs AGEs

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Figure 3: An overview of the biological (anti-oxidative) activity of resveratrol, and its effect on intermediary genes/enzymes

Source: Rege SD, Geetha T, Griffin GD, et al. Neuroprotective effects of resveratrol in Alzheimer disease pathology. Front Aging Neurosci. 2014;6:218.

Resveratrol

• SIRTUIN 1 • SOD • Catalase • Glutathione • Glutathione

reductase/ peroxidase

• G6PD • PPARg Co-activator • Nitric oxide • NRF2 • AMPK

• COX 1 • NADPH oxidase

Myeloperoxidase • iNOS • Poly ADP-ribose • Lipid peroxidesU

P-R

EG

ULA

TIO

N

DO

WN

RE

GU

LATI

ON

Prevents Apoptosis and Inflammation

fact that current treatment methods for diabetes usually do not exactly address the underlying causes of the disease and have limitations.15 As follows, efforts have been increasingly directed at identifying novel adjuvant therapies to help achieving better control of the deranged metabolic environment for early disease remission, and thereby improve the quality-of-life of diabetic patients. In this regard, several molecules have been under evaluation for use against diabetes and its complications. Resveratrol – a non-flavonoid polyphenol present in plant products – is one such molecule that has been reported to exert a plethora of biological activities - antioxidant, antiinflammatory, chemoprotective, chemopreventive, cardioprotective, neuroprotective – through many different mechanisms of action.16-19 In fact, the versatility of resveratrol and its presence in the human diet have drawn worldwide attention of many research groups in the recent past. This concept of resveratrol use is based on some very exciting developments from the frontiers of scientific research, with effect on oxidative stress possibly being the most important.20,21

It has been noted that effects induced by resveratrol are strongly related to the capability of this compound to increase expression/activity of AMPK and SIRT1 in various tissues of diabetic subjects.22 Moreover, anti-oxidant and anti-inflammatory effects of resveratrol were shown to be also involved in its action in diabetic models. The molecule suppresses oxygen free radical formation by inhibiting pro-oxidative genes such as NADPH oxidase and myeloperoxidase (MPO), and inducing various antioxidant enzymes like SOD, catalase, thioredoxin and glutathione peroxide (GSH-Px), while lowering the activity of enzymes involved in the development of oxidative stress (Figure 3).23 In vitro studies have identified resveratrol as a natural antioxidant, possessing free radical scavenging activity, as well as the fact that it elevates apolipoprotein A-1 (apoA-1)-mediated cholesterol efflux and suppresses oxidative stress.24 Moreover, it may suppress oxidative and inflammatory stress response to a high-carbohydrate, high-fat meal by stimulating the activity of the antioxidant transcription factor nuclear erythroid-2 like factor-2 (Nrf2), which is a master regulator of endogenous

The protective action of resveratrol on pancreatic β-cells is also related to its well-documented anti-oxidative and anti-inflammatory capacity

Resveratrol is capable of improving β-cell function not only in experimental models, but also in humans with type 2 diabetes

cellular defense mechanisms. It controls the expression of many antioxidant and detoxification genes.25 Overall, resveratrol may thus act as a direct scavenger of free radicals production in the body tissues. Doses of resveratrol < 0.5 g per person may be sufficient to improve insulin action, decrease blood glucose levels and to induce other effects. Studies on the toxicity of resveratrol in humans show that this compound is well tolerated.

effect of resveratrol on beta-cells

It is now known that glucotoxicity, lipotoxicity, oxidative stress, inflammation, ER stress and other factors in diabetic patients leads to beta-cell failure and reduction of beta-cell mass.22 Over the past few years, effects of resveratrol were studied using experimental models in which beta-cell mass and blood insulin levels were increased or decreased. Interestingly, the obtained data showed that resveratrol is effective in both

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cases. It is likely that one of the most important mechanisms underlying resveratrol action is attenuation of insulin resistance, as an improvement in insulin action leads to decrease in blood glucose levels and thereby prevents deleterious effects of hyperglycemia on beta-cells (glucotoxicity). Moreover, resveratrol was also demonstrated to reduce blood lipid levels in diabetic subjects and thereby decrease so-called lipotoxicity. The attenuation of both glucotoxicity and lipotoxicity restrain beta-cell failure in diabetes. Another advantage of resveratrol-induced decrease in insulin resistance is the reduced demand of insulin. As a result, less insulin is secreted from β-cells and thereby β-cell failure is also reduced. Besides, the protective action of resveratrol on pancreatic β-cells is also related to its well-documented anti-oxidative and anti-inflammatory capacity. In an experimental model of type 2 diabetes with decreased β-cell mass, resveratrol was shown to improve islet structure and function, reduce oxidative stress, restore islet architecture, decrease islet destruction, markedly reduce islet fibrosis and attenuate other degenerative changes. Moreover, the

molecule partially prevents β-cell failure and increases β-cell mass (Figure 4).22 Beneficial effects of resveratrol on beta-cells were also shown in type 2 diabetic patients, thereby indicating that resveratrol is capable of improving β-cell function not only in experimental models, but also in humans with type 2 diabetes.

curcumin: a non-toxic ingredient of turmeric with potent anti-inflammatory and antioxidant propertiesCurcumin is an active non-toxic ingredient of turmeric that possesses potent anti-inflammatory and antioxidant properties.26 The molecular mechanisms of curcumin are not fully understood; however, the data suggest that curcumin results in activation of AMPK, and decrease the expression of uPA and MMP9 and NF-κB DNA binding activity. The effect can be significant when considering the findings of numerous

Figure 4: Direct and indirect effects of resveratrol on pancreatic islets of models with experimental type 2 diabetes

Source: Szkudelski T, Szkudelska K. Resveratrol and diabetes: from animal to human studies. Biochimica et Biophysica Acta 1852 (2015):1145–1154.

ResveratrolHyperinsulinemia

with increased β-cell mass

↑ Antioxidant enzymes

↑ SIRT1↓ β-cell mass

↓ ROS↑ Mitochondrial

biogenesis

↓ Fibrosis and degeneration

↓ Triglyceride content

↓ Inflammation

Hypoinsulinemia with decreased

β-cell mass

↓ Oxidative damage

↓ UCP2

β-cell mass and a-cell/β-cell ratio

improved

↑ β-cell mass

↓ β-cell failure

↑ Respiratory chain

ROS – reactive oxygen species, UCP2 – uncoupling protein 2.

Insulin secretion improved

PAncREAtIc ISlEtS

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P. marsupium at a dose of 200 mg/kg could be a better drug in treatment of type 2 diabetes. It causes reduction in blood glucose that may be mediated through enhanced insulin secretion by regeneration of beta-cells of islets of Langerhans

Figure 5: Various inflammatory targets modulated by curcumin

Source: Aggarwal BB, Gupta SC, Sung B. Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers. British Journal of Pharmacology 2013;169:1672–1692.

NF-kBCOX-2

mTOR

IL-8

MCP-1

iNOS

IL-1HMG-CoA reductaseSTAT3

5-LOX

PI3K/AKT

IL-6

CRP

MMP-9

Wnt/ β-catenin

TNF

curcumin

studies, which suggest NF-κB as key player in regulating number of cellular processes, including inflammation. Additionally, this highly safe component of turmeric can block TNF-a action and production in in-vitro models, in animal models and in humans. Figure 5 depicts numerous proposed mechanisms by which curcumin can exhibit anti-inflammatory activity.27 In humans, as little as 150 mg of curcumin has been shown to be effective in reducing serum levels of proinflammatory cytokines. In a study that included patients with type 2 diabetes mellitus, a standardized preparation of curcuminoids was found to improve endothelial function, and reduced the levels of malondialdehyde, IL-6, TNF-a and endothelin-1, thereby showing reductions in not only inflammatory cytokines but markers of oxidative stress also.28

pterocarpus marsupium: a natural drug with anti-diaBetic properties

Pterocarpus marsupium Roxb. is a plant drug belonging to the group called rasayana; which are immunomodulators

and relieve stress in the body. There are several reports on P. marsupium as an anti-diabetic drug, and in fact aqueous extract of the heart-wood of P. marsupium is commonly used in the ayurvedic system of medicine for treatment of diabetes. A study designed to investigate the action of aqueous extract of P. marsupium on TNF-α activity in experimental models of type 2 diabetes noted that aqueous extract of P. marsupium at doses 100 and 200 mg/kg decreased both fasting and postprandial blood glucose, concurrently causing a significant decrease in the elevated TNF-α level in type 2 diabetic experimental models.29 The 200 mg/kg dose had more pronounced effect on postprandial hyperglycemia. The study thus suggested that this P. marsupium induced modulation of the cytokine TNF-α, which has been implicated in insulin resistance, is related with the potential anti-diabetic activity of P. marsupium.

As such, seeing that most of the currently available anti-diabetic therapies reduce the fasting blood glucose but have

In humans, as little as 150 mg of curcumin has been shown to be effective in reducing serum levels of proinflammatory cytokines

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a little impact on postprandial hyperglycemia; P. marsupium at a dose of 200 mg/kg could be a better drug in treatment of type 2 diabetes.29 It causes reduction in blood glucose that may be mediated through enhanced insulin secretion by regeneration of beta-cells of islets of Langerhans. Since rasayana drugs are rejuvenators, there may be regeneration of pancreas. P. marsupium is rich in polyphenols and flavonoids, the antioxidant potential of which coupled with their nutritional value may be responsible for rejuvenation. In all, a decrease in elevated TNF-α by the P. marsupium together with its blood glucose lowering effect suggests that the immunomodulatory property of P. marsupium could be related with its potential anti-diabetic activity.29 Modulation of cytokine TNF-α by P. marsupium is possibly due to the flavonoids present in the drug. A recent in-vitro study also suggested that the alcoholic extract of P. marsupium showed prominent antioxidant, antiglycation property, and inhibited accumulation of sorbitol and aldose reductase enzyme, thus promising a beneficial role in reducing/

Efficacy of Pterocarpus marsupium in treatment-naive patients with type 2 diabetes mellitus: A double blind multicenter randomized controlled trial (IcMR Study Group) • An Indian multicenter study was conducted to compare the blood glucose lowering effect of Pterocarpus marsupium with a

standard pharmacological agent tolbutamide in the management of diabetes.

• A total of 365 newly diagnosed or untreated patients with type 2 diabetes mellitus whose fasting blood glucose was <12.8 mmol/l were randomized to receive either the trial drug (n=182) or the standard pharmacological agent (n=183). The duration of treatment was 36 weeks, with 4 weekly clinic attendance for review and collection of drug.

• As this was a flexible dose trial, the dosage of P. marsupium was 2 to 4 g/day, and of tolbutamide 0.75 to 1.5 g/day. A fasting glucose level of <7.8 mmol/l and postprandial blood glucose level of <11.1 mmol/l was considered satisfactory glycemic control.

• The analysis, including 172 patients from the P. marsupium group and 177 patients from the tolbutamide group, revealed that the mean decrease in either fasting or postprandial blood glucose showed no significant inter-group differences. Eighty six percent of patients in the P. marsupium group and 94% in tolbutamide group attained glycemic control.

• The mean fall in postprandial blood glucose was 4.3 mmol/l from the baseline of 13.9 mmol/l in P. marsupium, compared to 4.4 mmol/l from the baseline of 13.8 mmol/l in the tolbutamide group. Analysis of adverse effects revealed none of them to be specific to the trial drugs.

• The sustainability of blood glucose control with P. marsupium for up to 72 weeks was similar to that recorded with tolbutamide.

• The authors thus concluded that P. marsupium is an effective blood glucose lowering traditional Indian plant agent. Its glycemic effect was comparable to that of tolbutamide in treatment-naive patients with type 2 diabetes, and the drug was free from any significant side effects.

• P. marsupium can be used as a safe therapy for newly diagnosed patients with type 2 diabetes mellitus.Source: ICMR Study Group on the Efficacy of Vijayasar in Type 2 Diabetes Mellitus. Efficacy of Vijayasar (Pterocarpus marsupium) in the treatment of newly diagnosed patients with type 2 diabetes mellitus: A flexible dose double blind multicenter randomized controlled trial. Diabetologia Croatica 2005;34-1:13-20.

delaying diabetic complications.30 These effects may be due to the presence of different types of constituents, specifically phenolic and flavonoid contents.

pterostilbene: phenolic constituent of p. marsupiumPterostilbene, a naturally occurring analog of resveratrol, is an important phenolic constituent of the heartwood of P. marsupium with many health benefits and multiple biomedical applications.31,32 In experimental models with hyperglycemia, pterostilbene was found to significantly lower the blood glucose level with effect comparable to that of metformin.33 The health benefits of pterostilbene are associated with its antioxidant activity, anti-inflammatory effects, and chemopreventive effects, thus proposing pterostilbene a promising natural product for use as a preventive and therapeutic agent for inflammation-related disorders. The antioxidative effects of pterostilbene were attributed to its unique structure that may scavenge extracellular ROS. These effects allowed the use of pterostilbene to diminish free radicals that are responsible for tissue damage during chronic inflammation.31 In a study, pterostilbene exhibited strong inflammatory inhibitory effects in adipocytes and macrophages coculture, significantly inhibited cytokines IL-6 and TNF-a secretion and proinflammatory gene expression including COX-2, iNOS, IL-6, TNF-a, MCP-1, and

P. marsupium can be used as a safe therapy for newly diagnosed patients with type 2 diabetes mellitus

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Disclaimer: The contents of this scientific issue are developed by Passi HealthCom Pvt. Ltd. (formerly Passi Publications Pvt. Ltd.) exclusively for Apex Laboratories Pvt. Ltd. Although great care has been taken in compiling and checking the information, the authors, Passi HealthCom Pvt. Ltd. (formerly Passi Publications Pvt. Ltd.) and its agents and sponsors shall not be responsible, or in any way liable for any errors, omissions or inaccuracies in this publication whether arising from negligence or otherwise, however, or for any consequences arising therefrom.

plasminogen activator inhibitor-1 (PAI-1), and also decreased the migratory ability of macrophages toward adipocytes.34,35 Also, pterostilbene has been observed to decrease the expression of ER stress related proteins such as eIF2α, ICAM1, matrix metallopeptidase 9 (MMP9), and GRP78.34 As oxidative stress and ER stress are closely entwined phenomena fundamentally involved in beta-cell dysfunction, these effects of pterostilbene on ER stress may be significant.7,34

references1. Newsholme P, Cruzat VF, Keane KN, et al. Molecular mechanisms of ROS production

and oxidative stress in diabetes. Biochem J. 2016;473(24):4527-4550.2. Vikram A, Tripathi DN, Kumar A, Singh S. Oxidative stress and inflammation in

diabetic complications. Int J Endocrinol. 2014; 2014: 679754.3. Vlassara H, Uribarri J. Advanced glycation end products (AGE) and diabetes: Cause,

effect, or both? Curr Diab Rep. 2014;14(1):453.4. Halban PA, Polonsky KS, Bowden DW, et al. β-Cell failure in type 2 diabetes:

Postulated mechanisms and prospects for prevention and treatment. Diabetes Care. 2014; 37(6):1751–1758.

5. Drews G, Krippeit-Drews P, Düfer M. Oxidative stress and beta-cell dysfunction. Pflugers Arch. 2010;460(4):703-18.

6. Wang J, Wang H. Oxidative stress in pancreatic beta cell regeneration. Oxid Med Cell Longev. 2017;2017: 1930261.

7. Hasnain SZ, Prins JB, McGuckin MA. Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes. J Mol Endocrinol. 2016;56(2):R33-54.

8. Back SH, Kang SW, Han J, et al. Endoplasmic reticulum stress in the β-cell pathogenesis of type 2 diabetes. Experimental Diabetes Research 2012 (2012);Article ID 618396:11 pages. http://dx.doi.org/10.1155/2012/618396.

9. Schulman CI, Uribarri J, Cai W, et al. Increased circulating advanced glycation endproducts (AGEs) in acute trauma patients. Clin Chem Lab Med. 2014;52(1):10.1515/cclm-2012-0834.

10. Ottum MS, Mistry AM. Advanced glycation end-products: modifiable environmental factors profoundly mediate insulin resistance. J. Clin. Biochem. Nutr. 2015;57(1):1–12.

11. Vlassara H, Uribarri J. Advanced glycation end-products (AGEs) and diabetes: Cause, effect, or both? Curr Diab Rep. 2014;14(1):453.

12. Nowotny K, Jung T, Höhn A, et al. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules. 2015;5(1):194-222.

13. Cai W, Ramdas M, Zhu L, et al. Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1. PNAS 2012;109(39):15888–15893.

14. Pourvali K, Abbasi M, Mottaghi A. Role of superoxide dismutase 2 gene Ala16Val polymorphism and total antioxidant capacity in diabetes and its complications. Avicenna J Med Biotechnol. 2016;8(2):48-56.

15. Sheik Abdulazeez S. Diabetes treatment: A rapid review of the current and future scope of stem cell research. Saudi Pharm J. 2015;23(4):333-40.

16. Olas B, Nowak P, Wachowicz B. Resveratrol protects against peroxynitrite-induced thiol oxidation in blood platelets. Cellular & Molecular Biology Letters 2004;9:pp 577–587.

17. Tomé-Carneiro J, Larrosa M, González-Sarrías A, et al. Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr Pharm Des. 2013;19(34):6064-93.

18. Olas B, Nowak P, Ponczek M, et al. Resveratrol, a natural phenolic compound may reduce carbonylation proteins induced by peroxynitrite in blood platelets. Gen. Physiol. Biophys. 2006;25:215—222.

19. Poulsen MM, Fjeldborg K, Ornstrup MJ, et al. Resveratrol and inflammation: Challenges in translating pre-clinical findings to improved patient outcomes. Biochimica et Biophysica Acta 1852 (2015):1124–1136.

20. Catalgol B, Batirel S, Taga Y, et al. Resveratrol: French paradox revisited. Front Pharmacol. 2012;3:141.

21. Li H, Xia N, Förstermann U. Cardiovascular effects and molecular targets of resveratrol. Nitric Oxide. 2012;26(2):102-10.

22. Szkudelski T, Szkudelska K. Resveratrol and diabetes: from animal to human studies. Biochimica et Biophysica Acta 1852 (2015):1145–1154.

23. Rege SD, Geetha T, Griffin GD, et al. Neuroprotective effects of resveratrol in Alzheimer disease pathology. Front Aging Neurosci. 2014;6:218.

24. Duntas LH. Resveratrol and its impact on aging and thyroid function. J. Endocrinol. Invest. 2011;34:788-792.

25. Smith RE, Tran K, Smith CC, et al. The Role of the Nrf2/ARE Antioxidant System in Preventing Cardiovascular Diseases. Diseases. 2016;4(4):34.

26. Tong W, Wang Q, Sun D, et al. Curcumin suppresses colon cancer cell invasion via AMPK-induced inhibition of NF-κB, uPA activator and MMP9. Oncol Lett. 2016;12(5):4139-4146.

27. Aggarwal BB, Gupta SC, Sung B. Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers. British Journal of Pharmacology 2013;169:1672–1692.

28. Usharani P, Mateen AA, Naidu MU, et al. Effect of NCB-02, atorvastatin and placebo on endothelial function, oxidative stress and inflammatory markers in patients with type 2 diabetes mellitus: a randomized, parallel-group, placebo-controlled, 8-week study. Drugs R D. 2008;9(4):243-50.

29. Halagappa K, Girish HN, Srinivasan BP. The study of aqueous extract of Pterocarpus marsupium Roxb. on cytokine TNF-α in type 2 diabetic rats. Indian J Pharmacol. 2010;42(6):392–396.

30. Gupta P, Jain V, Pareek A, et al. Evaluation of effect of alcoholic extract of heartwood of Pterocarpus marsupium on in vitro antioxidant, anti-glycation, sorbitol accumulation and inhibition of aldose reductase activity. Journal of Traditional and Complementary Medicine 2017;7(3):307-314.

31. Chen RJ, Lee YH, Yeh YL, et al. Autophagy-inducing effect of pterostilbene: A prospective therapeutic/preventive option for skin diseases. J Food Drug Anal. 2017;25(1):125-133.

32. Estrela JM, Ortega A, Mena S, et al. Pterostilbene: Biomedical applications. Critical Reviews in Clinical Laboratory Sciences 2013;50: 65-78.

33. Manickam M, Ramanathan M, Jahromi MA, et al. Antihyperglycemic activity of phenolics from Pterocarpus marsupium. J Nat Prod. 1997;60(6):609-10.

34. Tsai HY, Ho CT, Chen YK. Biological actions and molecular effects of resveratrol, pterostilbene, and 3'-hydroxypterostilbene. Journal of Food and Drug Analysis 25;1:134-147.

35. Hsu CL, Lin YJ, Ho CT, Yen GC. The Inhibitory Effect of Pterostilbene on Inflammatory Responses during the Interaction of 3T3-L1 Adipocytes and RAW 264.7 Macrophages. J. Agric. Food Chem., 2013;61(3):pp 602–610.

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