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BACKGROUND: Endogenous pancreatic β-cell regeneration is a promising therapeutic approach for enhancing β-cell function and neogenesis in diabetes. Various findings have reported that regeneration might occur via stimulating β-cell proliferation, neogenesis, or conversion from other pancreatic cells to β-like cells. Although the current scenario illustrates numerous therapeutic strategies and approaches that concern endogenous β-cell regeneration, all of them have not been successful to a greater extent because of cost effectiveness, availability of suitable donors and rejection in case of transplantation, or lack of scientific evidence for many phytochemicals derived from plants that have been employed in traditional medicine. Therefore, the present study aims to investigate the effect of gymnemic acid (GA) on β-cell regeneration in streptozotocin-induced type 1 diabetic rats and high glucose exposed RIN5-F cells. METHODS: The study involves histopathological and immunohistochemical analysis to examine the islet’s architecture. Quantitative polymerase chain reaction (qPCR) and/or immunoblot were employed to quantify the β-cell regeneration markers and cell cycle proliferative markers. RESULTS: The immunoexpression of E-cadherin, β-catenin, and phosphoinositide 3-kinases/protein kinase B were significantly increased in GA-treated diabetic rats. On the other hand, treatment with GA upregulated the pancreatic regenerative transcription factor viz. pancreatic duodenal homeobox 1, Neurogenin 3, MafA, NeuroD1, and β-cells proliferative markers such as CDK4, and Cyclin D1, with a simultaneous downregulation of the forkhead box O, glycogen synthase kinase-3, and p21(cip1) in diabetic treated rats. Adding to this, we noticed increased nuclear localization of Pdx1 in GA treated high glucose exposed RIN5-F cells. CONCLUSION: Our results suggested that GA acts as a potential therapeutic candidate for endogenous β-cell regeneration in treating type 1 diabetes. GRAPHICAL ABSTRACT: [Image: see text]

Diabetes Mellitus is a metabolic disorder characterized by elevated blood glucose level caused due to deficiency of insulin secretion or insulin action. The management of the blood glucose level is an important approach in the control of diabetes mellitus complications. There are many divergent therapeutic strategies in the management of Type II diabetes. The inhibition of carbohydrate hydrolyzing enzymes such as α-amylase and α-glucosidase can be used to lower postprandial blood glucose levels. The objective of the present study is to evaluate the inhibitory potential of Gymnemic acid in various concentrations on α-amylase and α-glucosidase activities. Gymnemic acid and voglibose show the IC50 value of 68.12 and 46.23 on alpha amylase and IC50 value of 65.77 and 36.67 on alpha glucosidase activity respectively. Insilico docking study between α-amylase and α-glucosidase with gymnemic acid and voglibose depict the similar amino acid binding sites that substantiate that gymnemic acid might be used as a natural and cost-effective alternative to the synthetic drug. This study throws light on the anti-diabetic action of phytomedicine, Gymnemic acid, a component of Gymnema sylvestre.

Diabetic nephropathy (DN), a progressive kidney disease afflicts more than 20 and up to 40% of the diabetic population and it is characterized by persistent microalbuminuria declined glomerular filtration rate. The interesting feature associated with DN is that, even though the progression of the disease correlates with oxidative stress, Nrf2, the master regulator of antioxidant defense system involved in counteracting oxidative stress is also upregulated in the diabetic kidneys of both human as well as experimental animals in early stages of DN. Despite the increased expression, the ability of this protein to get translocated into the nucleus is diminished signifying the functional impairment of Nrf2, implying redox imbalance. Hence, it is understood that agents that boost the translocation of Nrf2 might be beneficial rather than those that quantitatively overexpress Nrf2 in treating DN. The deleterious effects of synthetic Nrf2 activators have instigated the researchers to search for phytochemicals that have ambient Nrf2 boosting ability with no side effects, one such phytochemical is Epigallocatechin-3-gallate (EGCG) and it has shown beneficial effects by preventing the progression of DN via influencing Nrf2/ARE pathway, however, the modus operandi is unclear, despite speculations. This study was designed to find out whether supplementation of Nrf2 booster like EGCG at the crucial time of Nrf2 dysfunction can mitigate the progression of DN. Based on the findings of the present study, it might be concluded that the beneficial effect of EGCG in mitigating DN is mediated mainly through its ability to activate the Nrf2/ARE signaling pathway at multiple stages i.e., by downregulating Keap1 and boosting the nuclear Nrf2 level by disrupting Nrf2-Keap1 interaction. These results emphasize that supplementation of EGCG might be more beneficial at an early stage of DN, where dysfunctional Nrf2 accumulation occurs, which should be further validated.

Type 1 diabetes is a chronic immune-mediated disease caused by pancreatic β-cell dysfunction with consequent severe insulin deficiency. Exacerbated blood glucose levels can cause oxidative stress in the pancreatic β-cells, which leads to inflammation, and apoptosis resulting in islet dysfunction. Although massive studies have been carried out to elucidate the causative factors for β-cell damage in diabetes, the therapeutic approach to pancreatic β-cell damage has not been extensively studied. Hence, the present study has been designed to delineate the role of gymnemic acid (GA) in protecting pancreatic β-cells in diabetic animals, with special reference to inflammation and apoptosis. Our data revealed that the treatment with GA significantly reverted the alteration in both biochemical and histochemical observations in young diabetic rats. Moreover, treatment with the GA downregulates the expression of proinflammatory markers (nuclear factor-κB, tumor necrosis factor-α, interleukin-[IL]-6, and IL-1β), proapoptotic proteins (Bax, cytochrome c, and cleaved caspase-3), as well as upregulates the expression of antiapoptotic protein Bcl-2 in diabetic rats. These findings suggest that the anti-inflammatory and antiapoptotic nature of GA mitigates β-cell damage in hyperglycemic rats.

Type 2 diabetes is delineated by impaired metabolic flexibility, and intramyocellular lipid accumulation, causing insulin resistance, particularly in skeletal muscle by reducing insulin-stimulated glucose uptake. High-fat diet and high fructose (HFD and HF) administration in rodents bestows a model for hyperlipidemia, insulin resistance, and Type 2 diabetes. The current study is focused on elucidating the role of Gymnemic acid in combating hyperglycemia mediated oxidative stress and apoptotic events in the skeletal muscle of HFD and HF induced Type 2 diabetes in Wistar albino rats by boosting antioxidant defense system. Gymnemic acid, a saponin of triterpene glycoside contained in leaves of Gymnema Sylvestre, has potent anti-diabetic properties. Treatment with Gymnemic acid restored the antioxidant status (Gpx, SOD, CAT, GR, Vit C & Vit E) with significant (p

Background: Hyperoxaluria and calcium oxalate crystal deposition in the kidneys lead to overproduction of reactive oxygen species, resulting in the development of oxidative stress and renal injury. At the cellular levels, mitochondria and NADPH oxidase involved in reactive oxygen species production play a crucial role in the pathogenesis of hyperoxaluria-induced renal injury. Objective: The objective was to investigate the therapeutical effect of homoeopathic drug Berberis vulgaris, a potent antioxidant, upon regulation of NADPH oxidase against acute high-grade sodium oxalate-induced hyperoxaluria in rats. Materials and Methods: Hyperoxaluria was induced in male Wistar rats by administering a single dose of sodium oxalate (70 mg/kg body weight) intraperitoneally, and the treatment groups were pre-treated with homoeopathic drug Berberis vulgaris 6c (20 μl/100 g of body weight) ultra low dose for 7 days. Results: Berberis vulgaris significantly reduces hyperoxaluria-induced oxidative stress and restores antioxidant enzyme activities in kidney tissue. Histological analysis depicted that Berberis vulgaris treatment decreases renal epithelial damage and inflammation and restored normal glomerular morphology. Furthermore, immunoblotting analyses of NADPH oxidase revealed significant increased activity in the renal tissue of hyperoxaluric rats when compared to that of control rats. This has been brought back to normal by Berberis vulgaris treatment. Conclusion: Thus, our results emphasised that the Homoeopathy drug Berberis vulgaris has been effective in ameliorating sodium oxalate-induced acute hyperoxaluria in Wistar rats by modulating mitochondrial oxidative stress through the inhibition of NADPH oxidase.

Given the role of oxidative stress in PD pathogenesis and off-target side effects of currently available drugs, several natural phytochemicals seem to be promising in the management of PD. Here, we tested the hypothesis that scopoletin, an active principle obtained from Morinda citrifolia (MC), efficiently quenches oxidative stress through DJ-1/Nrf2 signaling and ameliorates rotenone-induced PD. Despite reducing oxidative stress, the administration of MC extract (MCE) has lessened protein aggregation as evident from decreased levels of nitrotyrosine and α-synuclein. In vitro studies revealed that scopoletin lessened rotenone-induced apoptosis in SH-SY5Y cells through preventing oxidative injury. Particularly, scopoletin markedly upregulated DJ-1, which then promoted the nuclear translocation of Nrf2 and transactivation of antioxidant genes. Furthermore, we found that scopoletin prevents the nuclear exportation of Nrf2 by reducing the levels of Keap1 and thereby enhancing the neuronal defense system. Overall, our findings suggest that scopoletin acts through DJ-1-mediated Nrf2 signaling to protect the brain from rotenone-induced oxidative stress and PD. Thus, we postulate that scopoletin could be a potential drug to treat PD.

Iron is an essential trace element required for several vital physiological and developmental processes, including erythropoiesis, bone, and neuronal development. Iron metabolism and oxygen homeostasis are interlinked to perform a vital role in the functionality of the heart. The metabolic machinery of the heart utilizes almost 90 % of oxygen through the electron transport chain. To handle this tremendous level of oxygen, the iron metabolism in the heart is utmost crucial. Iron availability to the heart is therefore tightly regulated by (i) the hepcidin/ferroportin axis, which controls dietary iron absorption, storage, and recycling, and (ii) iron regulatory proteins 1 and 2 (IRP1/2) via hypoxia inducible factor 1 (HIF1) pathway. Despite iron being vital to the heart, recent investigations have demonstrated that iron imbalance is a common manifestation in conditions of heart failure (HF), since free iron readily transforms between Fe2+ and Fe3+via the Fenton reaction, leading to reactive oxygen species (ROS) production and oxidative damage. Therefore, to combat iron-mediated oxidative stress, targeting Nrf2/ARE antioxidant signaling is rational. The involvement of Nrf2 in regulating several genes engaged in heme synthesis, iron storage, and iron export is beginning to be uncovered. Consequently, it is possible that Nrf2/hepcidin/ferroportin might act as an epicenter connecting iron metabolism to redox alterations. However, the mechanism bridging the two remains obscure. In this review, we tried to summarize the contemporary insight of how cardiomyocytes regulate intracellular iron levels and discussed the mechanisms linking cardiac dysfunction with iron imbalance. Further, we emphasized the impact of Nrf2 on the interplay between systemic/cardiac iron control in the context of heart disease, particularly in myocardial ischemia and HF.

Apoptosis is an active response of cells to altered microenvironments, which is characterized by cell shrinkage, chromatin condensation, and DNA fragmentation, in a variety of cell types such as renal epithelial cells, endothelial cells, mesangial cells, and podocytes. Hyperglycemia is among the microenvironmental factors that may facilitate apoptosis, which plays a decisive role in the initiation of diabetic nephropathy. Transforming growth factor-β emerges as a powerful fibrogenic factor in the development of renal hypertrophy. Although, a number of potential treatment strategies exist for diabetic nephropathy, considering the ease of use and bioavailability, phytochemicals stands distinct as the preeminent option. EGCG, a green tea catechin is one such phytochemical which possesses hypoglycemic and antifibrotic activity. The present study aims to explore the potential of EGCG to prevent apoptosis in a high-fat diet and STZ induced diabetic nephropathy rats by assessing renal function, pro-fibrotic marker, and the expression of apoptotic and antiapoptotic proteins. Our results validate EGCG as a potential antiapoptotic agent evidently by improving renal function via down regulating TGF-β, consequently ameliorating diabetic nephropathy. In accordance with this, EGCG might be regarded as a prospective therapeutic candidate in modulating diabetic nephropathy, thus being a promising treatment.

The aim is to test the hypothesis whether the cholesterol loaded lysosomes are capable of mediating lysosomal membrane permeabilization (LMP) during aging and to study the efficacy of epigallocatechin-3-gallate (EGCG) in preserving the lysosomal membrane stability. Aged rats were fed with high cholesterol diet (HCD) and treated with EGCG orally. Serum and tissue lipid status, cholesterol levels in lysosomal fraction, activities of lysosomal enzymes in lysosomal, and cytosolic fractions were measured. Transmission electron microscopic studies (TEM), oil red "O" (ORO) staining, and immunohistochemical analysis of oxidized low density lipoprotein (OxLDL) were carried out. Significant increase in serum, tissue lipid profile, and lysosomal cholesterol levels were observed in aged HCD-fed rats with a concomitant decrease in high density lipoprotein (HDL) levels. We also observed a significant increase in lipid accumulation in hepatocytes of aged HCD-fed rats by TEM, ORO, and immunohistochemical staining. Upon treatment with EGCG to aged HCD-fed animals, we found augmented levels of HDL with a concomitant decrease in lysosomal cholesterol levels and other lipoproteins. TEM studies and immunohistochemistry of OxLDL also showed a marked reduction in lipid deposition of hepatocytes. Thus, EGCG has preserved the lysosomal membrane stability in HCD stressed aged rats. SIGNIFICANCE OF THE STUDY: The research article is focused mainly on the effect of EGCG and its capability on mitigating the release of lysosomal enzymes in aged animals fed with HCD. The study signifies the cellular function of the organelle lysosome following administration of aged rats with HCD, which would make the readers to understand the action of EGCG and the interrelationship of both cholesterol and activity of lysosomes when cholesterol is loaded.

Given the role of oxidative stress in PD pathogenesis and off-target side effects of currently available drugs, several natural phytochemicals seems to be promising in the management of PD. Here, we tested the hypothesis that scopoletin, an active principle obtained from Morinda citrifolia (MC), efficiently quenches oxidative stress through DJ-1/Nrf2 signalling and ameliorates rotenone-induced PD. Despite reducing the oxidative stress, administration of MC extract (MCE) has lessened the protein aggregation as evident from decreased levels of nitrotyrosine and α-Synuclein. In vitro studies revealed that scopoletin lessened rotenone-induced apoptosis in SH-SY5Y cells through preventing oxidative injury. Particularly, scopoletin markedly up-regulated DJ-1, which then promoted the nuclear translocation of Nrf2 and transactivation of antioxidant genes. Furthermore, we found that scopoletin prevent the nuclear exportation of Nrf2 by reducing the levels of Keap1 and thereby enhancing the neuronal defence system. Overall, our findings suggest that scopoletin acts through DJ-1 mediated Nrf2 signalling to protect the brain from rotenone-induced oxidative stress and PD. Thus, we postulate that scopoletin could be a potential drug to treat PD.

Phytochemicals are diverse secondary metabolites derived from plants, and it has been proven that phytochemicals can extend longevity by evolutionarily conserved mechanisms. The positive impact of dietary phytochemicals on overall health and longevity has been studied extensively over the past decade. The emerging role of phytochemicals as an effector of metabolic and longevity signals offers new therapeutic perspectives. In this regard, we will discuss the role of phytochemicals in eliciting the longevity genes and also the various mechanisms involved. This review will give a broad outline of how different phytochemicals modulate signaling pathways that modulate the expression of specific set of genes. This review will also highlight the most exciting perspective for research in the future in this rapidly developing field of signaling pathways which include the genes encoding heat shock protein, genes responsible for the antioxidant response, genes involved in metabolism, etc. and are crucial for the phytochemicals to elicit longevity.

Background Cardiac hypertrophy characterized by excessive oxidative stress leading to collagen deposition, predisposes the heart to failure (HF) if left unresolved. Thus, understanding the signaling mechanisms involved in excessive extracellular matrix deposition is necessary to prevent cardiac remodeling and HF. Here, we tested a hypothesis that hesperetin (HES), a polyphenolic phyto-chemical mediated augmentation of Nrf2/antioxidant signaling suppresses oxidative stress, thereby ameliorates pathological cardiac remodeling. Methods Cardiac hypertrophy was induced in male Wistar rats by subcutaneous injections of isoproterenol (5 mg/kg body weight) for seven days. Basic biochemical assays were carried out to evaluate the Nrf2-dependent antioxidant signaling and oxidative stress markers (i.e. lipid peroxides, protein carbonyls). Protein expression of Nrf2 and its downstream target genes were also studied. Results Our results demonstrate that hesperetin pre-treated rats showed a significant reduction in the heart weight to body weight ratio (p Conclusions Our results conclude that hesperetin could be a potential therapeutic agent targets Nrf2 signaling, thereby ameliorates ISO-induced oxidative stress and prevents pathological cardiac remodelling.

Background: Berberis vulgaris is the most widely used drug in Homoeopathy for treating urolithiasis. However, its mechanism of action in alleviating its consequences remains uncertain. Objective: To explicate the potential role of Homoeopathic preparation of B. vulgaris on in vitro Calcium oxalate (CaOx) crystallization. Materials and Methods: Spectrophotometric crystallization assay was carried out, and the slopes of the nucleation (till the maximum) and aggregation (after the peak) phases were calculated using linear regression analysis, and the percentage inhibition exerted by the modifiers was calculated. Light microscopic observation of CaOx crystals formed in the presence or absence of modifiers was carried out to support the outcome with spectrophotometric crystallization assays and to ascertain the potential role of B. vulgaris in CaOx crystallization. Results: The crystallization studies performed so far signifies B. vulgaris to be a potent drug against CaOx crystallization both at the level of nucleation and aggregation. Conclusion: Our present findings add up to the experimental evidence to support the efficacy of the homeopathic preparation of the B. vulgaris in modulating the primary events of stone formation.

Parkinson's disease is a progressive neurodegenerative movement disorder with the cardinal symptoms of bradykinesia, resting tremor, rigidity, and postural instability, which lead to abnormal movements and lack of activity, which in turn cause muscular damage. Even though studies have been carried out to elucidate the causative factors that lead to muscular damage in Parkinson's disease, apoptotic events that occur in the skeletal muscle and a therapeutical approach to culminate the muscular damage have not been extensively studied. Thus, this study evaluates the impact of rotenone-induced SNPc lesions on skeletal muscle apoptosis and the efficacy of an ethyl acetate extract of Morinda citrifolia in safeguarding the myocytes. Biochemical assays along with apoptotic markers studied by immunoblot and reverse transcription-polymerase chain reaction in the current study revealed that the supplementation of Morinda citrifolia significantly reverted alterations in both biochemical and histological parameters in rotenone-infused PD rats. Treatment with Morinda citrifolia also reduced the expression of pro-apoptotic proteins Bax, caspase-3 and caspase-9 and blocked the release of cytochrome c from mitochondria induced by rotenone. In addition, it augmented the expression of Bcl2 both transcriptionally and translationally. Thus, this preliminary study paves a way to show that the antioxidant and anti-apoptotic activities of Morinda citrifolia can be exploited to alleviate skeletal muscle damage induced by Parkinsonism.