Exploring the Comparative Efficacy of Metformin and Resveratrol in the Management of Diabetes-Associated Complications: A Systematic Review of Preclinical Studies

Food-derived bioactive compounds such as resveratrol are increasingly explored for their protective effects against metabolic complications. Evidence supports the strong antioxidant properties and therapeutic effects of resveratrol in managing diabetes and its associated complications. However, evidence informing on the comparative or combination effects of this natural compound with an accomplished and well-characterized antidiabetic agent like metformin has not been revised. Thus, we conducted a comprehensive systematic search of the major electronic databases which included MEDLINE, Cochrane Library, and EMBASE. The cumulative evidence strongly supports the comparative effects of metformin and resveratrol in ameliorating diabetes-associated complications in preclinical settings. In particular, both compounds showed strong ameliorative effects against hyperglycemia, dyslipidemia, insulin resistance, a pro-inflammatory response, and lipid peroxidation in various experimental models of diabetes. Enhancing intracellular antioxidant capacity in addition to activating NAD-dependent deacetylase sirtuin-1 (SIRT1) and AMP-activated protein kinase (AMPK) are the prime mechanisms involved in the therapeutic effects of these compounds. Of interest, preclinical evidence also demonstrates that the combination treatment with these compounds may have a greater efficacy in protecting against diabetes. Thus, confirmation of such evidence in well-organized clinical trials remains crucial to uncover novel therapeutic strategies to manage diabetes and its linked complications.

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On the Antioxidant Properties of L-Kynurenine: An Efficient ROS Scavenger and Enhancer of Rat Brain Antioxidant Defense

Antioxidants ◽

10.3390/antiox11010031 ◽

2021 ◽

Vol 11 (1) ◽

pp. 31

Author(s):

Daniela Ramírez Ortega ◽

Perla Eugenia Ugalde Muñiz ◽

Tonali Blanco Ayala ◽

Gustavo Ignacio Vázquez Cervantes ◽

Rafael Lugo Huitrón ◽

...

Keyword(s):

Rat Brain ◽

Ex Vivo ◽

Antioxidant Properties ◽

Oxidative Degradation ◽

Chronic Administration ◽

Experimental Models ◽

Protective Effects ◽

Oxidative Markers ◽

Neuroprotective Strategy ◽

Endogenous Antioxidant

L-kynurenine (L-KYN) is an endogenous metabolite, that has been used as a neuroprotective strategy in experimental models. The protective effects of L-KYN have been attributed mainly to kynurenic acid (KYNA). However, considering that L-KYN is prone to oxidation, this redox property may play a substantial role in its protective effects. The aim of this work was to characterize the potential impact of the redox properties of L-KYN, in both synthetic and biological systems. First, we determined whether L-KYN scavenges reactive oxygen species (ROS) and prevents DNA and protein oxidative degradation in synthetic systems. The effect of L-KYN and KYNA (0.1–100 µM) on redox markers (ROS production, lipoperoxidation and cellular function) was compared in rat brain homogenates when exposed to FeSO4 (10 µM). Then, the effect of L-KYN administration (75 mg/kg/day for 5 days) on the GSH content and the enzymatic activity of glutathione reductase (GR) and glutathione peroxidase (GPx) was determined in rat brain tissue. Finally, brain homogenates from rats pretreated with L-KYN were exposed to pro-oxidants and oxidative markers were evaluated. The results show that L-KYN is an efficient scavenger of ●OH and ONOO−, but not O2●– or H2O2 and that it prevents DNA and protein oxidative degradation in synthetic systems. L-KYN diminishes the oxidative effect induced by FeSO4 on brain homogenates at lower concentrations (1 µM) when compared to KYNA (100 µM). Furthermore, the sub-chronic administration of L-KYN increased the GSH content and the activity of both GR and GPx, and also prevented the oxidative damage induced by the ex vivo exposure to pro-oxidants. Altogether, these findings strongly suggest that L-KYN can be considered as a potential endogenous antioxidant.

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Cardioprotective Effects of Sirtuin-1 and Its Downstream Effectors

Circulation Heart Failure ◽

10.1161/circheartfailure.120.007197 ◽

2020 ◽

Vol 13 (9) ◽

Cited By ~ 3

Author(s):

Milton Packer

Keyword(s):

Heart Failure ◽

Experimental Models ◽

Sglt2 Inhibitors ◽

Sirtuin 1 ◽

Nutrient Deprivation ◽

Fibroblast Growth Factor 21 ◽

Downstream Effectors ◽

Sodium Glucose Cotransporter ◽

Cardioprotective Effects ◽

Amp Activated Protein Kinase

The cardioprotective effects of SGLT2 (sodium-glucose cotransporter 2) inhibitors may be related to their ability to induce a fasting-like paradigm, which triggers the activation of nutrient deprivation pathways to promote cellular homeostasis. The most distinctive metabolic manifestations of this fasting mimicry are enhanced gluconeogenesis and ketogenesis, which are not seen with other antihyperglycemic drugs. The principal molecular stimulus to gluconeogenesis and ketogenesis is activation of SIRT1 (sirtuin-1) and its downstream mediators: PGC-1α (proliferator-activated receptor gamma coactivator 1-alpha) and FGF21 (fibroblast growth factor 21). These three nutrient deprivation sensors exert striking cardioprotective effects in a broad range of experimental models. This benefit appears to be related to their actions to alleviate oxidative stress and promote autophagy—a lysosome-dependent degradative pathway that disposes of dysfunctional organelles that are major sources of cellular injury. Nutrient deprivation sensors are suppressed in states of perceived energy surplus (ie, type 2 diabetes mellitus and chronic heart failure), but SGLT2 inhibitors activate SIRT1/PGC-1α/FGF21 signaling and promote autophagy. This effect may be related to their action to trigger the perception of a system-wide decrease in environmental nutrients, but SGLT2 inhibitors may also upregulate SIRT1, PGC-1α, and FGF21 by a direct effect on the heart. Interestingly, metformin-induced stimulation of AMP-activated protein kinase (a nutrient deprivation sensor that does not promote ketogenesis) has not been shown to reduce heart failure events in clinical trials. Therefore, promotion of ketogenic nutrient deprivation signaling by SGLT2 inhibitors may explain their cardioprotective effects, even though SGLT2 is not expressed in the heart.

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Protective and Therapeutic Effects of Ban-zhi-lian on Hepatotoxin-induced Liver Injuries

The American Journal of Chinese Medicine ◽

10.1142/s0192415x9400005x ◽

1994 ◽

Vol 22 (01) ◽

pp. 29-42 ◽

Cited By ~ 6

Author(s):

Song-chow Lin ◽

Chun-ching Lin ◽

Yun-ho Lin ◽

Ching-hsein Chen

Keyword(s):

Liver Damage ◽

Experimental Models ◽

Therapeutic Effects ◽

Protective Effects ◽

Liver Injuries ◽

Serum Glutamate Pyruvate Transaminase ◽

Glutamate Pyruvate ◽

Experimental Liver ◽

Serum Glutamate ◽

Experimental Liver Damage

The hepatoprotective effect of Ban-zhi-lian was investigated in three kinds of experimental models. The animals were treated with Ban-zhi-lian (300 mg/kg, p.o.) at 2, 4, and 10 hours after carbon tetrachloride (32l/kg, i.p.), acetaminophen (600 mg/kg, i.p.), and β-D-galactosamine (188 mg/kg, i.p.) administration. Significant protective effects from these hepatotoxins were expressed. This protection was evidenced by comparing the serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), and histopathologic examination in animals treated and untreated with Ban-zhi-lian. Serum enzyme activities were significantly lower in Ban-zhi-lian-treated groups. In the histopathologic observation, liver damage induced by three hepatotoxins was markedly improved in Ban-zhi-lian treated animals. These results demonstrated that Ban-zhi-lian has a protective effect against experimental liver damage induced by various hepatotoxins.

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Cardioprotection by ginseng: experimental and clinical evidence and underlying mechanisms

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2018-0192 ◽

2018 ◽

Vol 96 (9) ◽

pp. 859-868 ◽

Cited By ~ 4

Author(s):

Xiaohong Tracey Gan ◽

Morris Karmazyn

Keyword(s):

Animal Studies ◽

Large Scale ◽

Clinical Evidence ◽

Artery Bypass ◽

Antioxidant Properties ◽

Experimental Models ◽

Therapeutic Effects ◽

Ischemic And Reperfusion Injury ◽

Underlying Mechanisms ◽

The Many

Protection of the ischemic and reperfused myocardium represents a major therapeutic challenge. Translating results from animal studies to the clinical setting has been disappointing, yet the need for effective intervention, particularly to limit heart damage following infarction or surgical procedures such as coronary artery bypass grafting, is substantial. Among the many compounds touted as cardioprotective agents is ginseng, a medicinal herb belonging to the genus Panax, which has been used as a medicinal agent for thousands of years, particularly in Asian societies. The biological actions of ginseng are very complex and reflect composition of many bioactive components, although many of the biological and therapeutic effects of ginseng have been attributed to the presence of steroid-like saponins termed ginsenosides. Both ginseng and many ginsenosides have been shown to exert cardioprotective properties in experimental models. There is also clinical evidence that traditional Chinese medications containing ginseng exert cardioprotective properties, although such clinical evidence is less robust primarily owing to the paucity of large-scale clinical trials. Here, we discuss the experimental and clinical evidence for ginseng, ginsenosides, and ginseng-containing formulations as cardioprotective agents against ischemic and reperfusion injury. We further discuss potential mechanisms, particularly as these relate to antioxidant properties.

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The Protective Effects of Imperatorin on Acetaminophen Overdose-Induced Acute Liver Injury

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/8026838 ◽

2020 ◽

Vol 2020 ◽

pp. 1-17 ◽

Cited By ~ 2

Author(s):

Zhao Gao ◽

Jiecheng Zhang ◽

Li Wei ◽

Xingping Yang ◽

Yuan Zhang ◽

...

Keyword(s):

Liver Injury ◽

Acute Liver Injury ◽

Farnesoid X Receptor ◽

Sirtuin 1 ◽

Therapeutic Effects ◽

Dependent Manner ◽

Protective Effects ◽

Hepatocyte Apoptosis ◽

Apap Overdose ◽

First Time

Acetaminophen (APAP) toxicity leads to severe acute liver injury (ALI) by inducing excessive oxidative stress, inflammatory response, and hepatocyte apoptosis. Imperatorin (IMP) is a furanocoumarin from Angelica dahurica, which has antioxidant and anti-inflammatory effects. However, its potential to ameliorate ALI is unknown. In this study, APAP-treated genetic knockout of Farnesoid X receptor (FXR) and Sirtuin 1 (SIRT1) mice were used for research. The results revealed that IMP could improve the severity of liver injury and inhibit the increase of proinflammatory cytokines, oxidative damage, and apoptosis induced by overdose APAP in an FXR-dependent manner. We also found that IMP enhanced the activation and translocation of FXR by increasing the expression of SIRT1 and the phosphorylation of AMPK. Besides, single administration of IMP at 4 h after APAP injection can also improve necrotic areas and serum transaminase, indicating that IMP have both preventive and therapeutic effects. Taken together, it is the first time to demonstrate that IMP exerts protective effects against APAP overdose-induced hepatotoxicity by stimulating the SIRT1-FXR pathway. These findings suggest that IMP is a potential therapeutic candidate for ALI, offering promise for the treatment of hepatotoxicity associated with APAP overdose.

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Pseudoginsengenin DQ Exhibits Therapeutic Effects in Cisplatin-Induced Acute Kidney Injury via Sirt1/NF-κB and Caspase Signaling Pathway without Compromising Its Antitumor Activity in Mice

Molecules ◽

10.3390/molecules23113038 ◽

2018 ◽

Vol 23 (11) ◽

pp. 3038 ◽

Cited By ~ 11

Author(s):

Zeng Qi ◽

Zhuo Li ◽

Wei Li ◽

Yunhe Liu ◽

Cuizhu Wang ◽

...

Keyword(s):

Antitumor Activity ◽

Signaling Pathway ◽

Sirtuin 1 ◽

Tunel Staining ◽

Heme Oxygenase 1 ◽

Renal Tubular Cell ◽

Therapeutic Effects ◽

Related Factor ◽

Protective Effects ◽

Tnf Α

In this study, the protective effects of pseudoginsengenin DQ (PDQ) on cisplatin (CDDP)-induced nephrotoxicity were assessed, with a primary investigation into the mechanisms involved. Our results showed that pretreatment with PDQ remarkably restored levels of blood urea nitrogen (BUN) and creatinine (CRE), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). Meanwhile, PDQ decreased the CDDP-induced overexpression of heme oxygenase 1 (HO-1), cytochrome P450 E1 (CYP2E1), TNF-α, nuclear factor-kappa B (NF-κB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in renal tissues. Hoechst 33258 and TdT-mediated dUTP nick-end labeling (TUNEL) staining showed that CDDP-induced renal tubular cell apoptosis was apparently inhibited by PDQ. Western blotting showed that PDQ reversed the CDDP-induced (1) downregulation of Sirtuin-1 (Sirt-1), nuclear-related factor 2 (Nrf2), and Bcl-2, and (2) upregulation of NF-κB, Nox-4, Bax, caspase-9, and caspase-3. In addition, PDQ enhanced the antitumor activity of cisplatin in Lewis lung cancer xenograft tumor model mice. In conclusion, we found that PDQ exerted a renal protective effect against CDDP-induced acute nephrotoxicity via Sirt1/NF-κB and the caspase signaling pathway without compromising the antitumor activity of CDDP, which provides a new potential strategy for the clinical treatment of cancer and presents a new medicinal application of PDQ.

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Nutrition, Thrombosis, and Cardiovascular Disease

Circulation Research ◽

10.1161/circresaha.120.315892 ◽

2020 ◽

Vol 126 (10) ◽

pp. 1415-1442 ◽

Cited By ~ 1

Author(s):

Francesco Violi ◽

Daniele Pastori ◽

Pasquale Pignatelli ◽

Roberto Carnevale

Keyword(s):

Cardiovascular Disease ◽

Platelet Activation ◽

Fruits And Vegetables ◽

Antioxidant Properties ◽

Underlying Mechanism ◽

Experimental Models ◽

Inverse Association ◽

Protective Effects ◽

Antithrombotic Effects

Previous studies reported an inverse association between healthy dietary patterns (such as Mediterranean diet) and the incidence of cardiovascular events. As the mechanism accounting for cardiovascular disease is prevalently due to the atherothrombosis, where a pivotal role is played by platelet activation, it would be arguable that diets with protective effects against cardiovascular disease exert an anti-atherothrombotic effect via inhibition of platelet activation. There are several and sparse typologies of studies, which investigated if single nutrients by diets recognized as having cardiovascular protection may exert an antithrombotic effect. The most investigated nutrients are key components of the Mediterranean diets such as fruits and vegetables, fish, olive oil, and wine; other diets with protective effects include nuts and cocoa. Here we summarize experimental and human interventional studies which investigated the antithrombotic effects of such nutrients in experimental models of thrombosis or analyzed biomarkers of clotting, platelet, and fibrinolysis activation in human; furthermore in vitro studies explored the underlying mechanism at level of several cell lines such as platelets or endothelial cells. In this context, we analyzed if nutrients affect simultaneously or separately clotting, platelet, and fibrinolysis pathways giving special attention to the relationship between oxidative stress and thrombosis as most nutrients are believed to possess antioxidant properties.

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Protection by melatonin in respiratory diseases: valuable information for the treatment of COVID-19

Melatonin Research ◽

10.32794/mr11250061 ◽

2020 ◽

Vol 3 (3) ◽

pp. 264-275 ◽

Cited By ~ 2

Author(s):

Ruediger Hardeland ◽

Dun-Xian Tan

Keyword(s):

Airway Inflammation ◽

Respiratory Diseases ◽

Antioxidant Properties ◽

Allergic Airway Inflammation ◽

The Body ◽

Sirtuin 1 ◽

Inflammasome Activation ◽

Protective Effects ◽

Beneficial Effects ◽

Obstructive Sleep

High mortality rates in severe progression of COVID-19 are predominantly caused by pulmonary failure due to high-grade airway inflammation. As investigations on the efficacy of melatonin in this disease are still in their beginning, it may be worth-while to recall the body of evidence on protective effects in other respiratory dysfunctions, which have been studied pre-clinically and clinically. In various diseases and corresponding animal models, melatonin has been shown to be protective, mainly because of its anti-inflammatory and antioxidant properties. This was documented in pathologies as different as allergic airway inflammation, toxicologically or radiation-induced acute lung injury, respiratory disorders such as COPD, obstructive sleep apnea, neonatal respiratory distress syndrome, bronchopulmonary dysplasia and asphyxia, impaired respiration in sepsis, idiopathic pulmonary fibrosis, and pulmonary hypertension. The prevailing outcome has been protection or amelioration by melatonin, in conjunction with reduced expression and release of proinflammatory cytokines, such as IL-1β, IL-2, IL-6, IL-8, and TNFα, which was often explained by interference with toll-like receptors, inhibition of NLRP3 inflammasome activation and suppression of NF-κB signaling. In several studies, these beneficial effects were partially related to the upregulation of sirtuin-1 (SIRT1) by melatonin. The body of knowledge on melatonin’s efficacy in respiratory diseases is encouraging for the use of this powerful agent in COVID-19.

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Characterization of Novel Synthetic Polyphenols: Validation of Antioxidant and Vasculoprotective Activities

Antioxidants ◽

10.3390/antiox9090787 ◽

2020 ◽

Vol 9 (9) ◽

pp. 787 ◽

Cited By ~ 1

Author(s):

María Jesús Pérez de Vega ◽

Silvia Moreno-Fernández ◽

Gloria María Pontes-Quero ◽

María González-Amor ◽

Blanca Vázquez-Lasa ◽

...

Keyword(s):

Ex Vivo ◽

Radical Scavenging Activity ◽

Antioxidant Properties ◽

Radical Scavenging ◽

Antioxidant Compounds ◽

Therapeutic Effects ◽

Protective Effects ◽

Therapeutic Benefits ◽

Anti Inflammatory

Antioxidant compounds, including polyphenols, have therapeutic effects because of their anti-inflammatory, antihypertensive, antithrombotic and antiproliferative properties. They play important roles in protecting the cardiovascular and neurological systems, by having preventive or protective effects against free radicals produced by either normal or pathological metabolism in such systems. For instance, resveratrol, a well-known potent antioxidant, has a counteracting effect on the excess of reactive oxygen species (ROS) and has a number of therapeutic benefits, like anti-inflammatory, anti-cancer and cardioprotective activities. Based on previous work from our group, and on the most frequent OH substitutions of natural polyphenols, we designed two series of synthetically accessible bis-polyhydroxyphenyl derivatives, separated by amide or urea linkers. These compounds exhibit high antioxidant ability (oxygen radical absorbance capacity (ORAC) assay) and interesting radical scavenging activity (RSA) values (2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and α,α-diphenyl-β-picrylhydrazyl (DPPH) tests). Some of the best polyphenols were evaluated in two biological systems, endothelial cells (in vitro) and whole aorta (ex vivo), highly susceptible for the deleterious effects of prooxidants under different inflammatory conditions, showing protection against oxidative stress induced by inflammatory stimuli relevant in cardiovascular diseases, i.e., Angiotensin II and IL-1β. Selected compounds also showed strong in vivo antioxidant properties when evaluated in the model organism Saccharomyces cerevisiae.

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Anti-Inflammatory and Organ-Protective Effects of Resveratrol in Trauma-Hemorrhagic Injury

Mediators of Inflammation ◽

10.1155/2015/643763 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 17

Author(s):

Fu-Chao Liu ◽

Yung-Fong Tsai ◽

Hsin-I Tsai ◽

Huang-Ping Yu

Keyword(s):

Intracellular Signaling ◽

Cardiac Contractility ◽

Antioxidant Properties ◽

Organ Damage ◽

Sirtuin 1 ◽

Protective Effects ◽

Species Formation ◽

Mitogen Activated Protein ◽

Liver And Kidney ◽

Anti Inflammatory

Resveratrol, a natural polyphenolic compound of grape and red wine, owns potential anti-inflammatory effects, which results in the reduction of cytokines overproduction, the inhibition of neutrophil activity, and the alteration of adhesion molecules expression. Resveratrol also possesses antioxidant, anti-coagulation and anti-aging properties, and it may control of cell cycle and apoptosis. Resveratrol has been shown to reduce organ damage following traumatic and shock-like states. Such protective phenomenon is reported to be implicated in a variety of intracellular signaling pathways including the activation of estrogen receptor, the regulation of the sirtuin 1/nuclear factor-kappa B and mitogen-activated protein kinases/hemeoxygenase-1 pathway, and the mediation of proinflammatory cytokines and reactive oxygen species formation and reaction. In the recent studies, resveratrol attenuates hepatocyte injury and improves cardiac contractility due to reduction of proinflammatory mediator expression and ameliorates hypoxia-induced liver and kidney mitochondrial dysfunction following trauma and hemorrhagic injuries. Moreover, through anti-inflammatory effects and antioxidant properties, the resveratrol is believed to protect organ function in trauma-hemorrhagic injury. In this review, the organ-protective and anti-inflammatory effects of resveratrol in trauma-hemorrhagic injury will be discussed.

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