Emerging links between FOXOs and diabetic complications.

Diabetes and its complications are increasing worldwide in the working population as well as in elders. Prolonged hyperglycemia results in damage to blood vessels of various tissues followed by organ damage. Hyperglycemia-induced damage in small blood vessels as in nephrons, retina, and neurons results in diabetic microvascular complications which involve nephropathy, retinopathy, and diabetic neuropathy. Additionally, damage in large blood vessels is considered as a macrovascular complication including diabetic cardiomyopathy. These long-term complications can result in organ failure and thus becomes the leading cause of diabetic-related mortality in patients. Members of the Forkhead Box O family (FOXO) are involved in various body functions including cell proliferation, metabolic processes, differentiation, autophagy, and apoptosis. Moreover, increasing shreds of evidence suggest the involvement of FOXO family members FOXO1, FOXO3, FOXO4, and FOXO6 in several chronic diseases including diabetes and diabetic complications. Hence, this review focuses on the role of FOXO transcription factors in the regulation of diabetic complications.

Biological activities of meroterpenoids isolated from different sources.

Meroterpenoids are natural products synthesized by unicellular organisms such as bacteria and multicellular organisms such as fungi, plants, and animals, including those of marine origin. Structurally, these compounds exhibit a wide diversity depending upon the origin and the biosynthetic pathway they emerge from. This diversity in structural features imparts a wide spectrum of biological activity to meroterpenoids. Based on the biosynthetic pathway of origin, these compounds are either polyketide-terpenoids or non-polyketide terpenoids. The recent surge of interest in meroterpenoids has led to a systematic screening of these compounds for many biological actions. Different meroterpenoids have been recorded for a broad range of operations, such as anti-cholinesterase, COX-2 inhibitory, anti-leishmanial, anti-diabetic, anti-oxidative, anti-inflammatory, anti-neoplastic, anti-bacterial, antimalarial, anti-viral, anti-obesity, and insecticidal activity. Meroterpenoids also possess inhibitory activity against the expression of nitric oxide, TNF- α, and other inflammatory mediators. These compounds also show renal protective, cardioprotective, and neuroprotective activities. The present review includes literature from 1999 to date and discusses 590 biologically active meroterpenoids, of which 231 are from fungal sources, 212 are from various species of plants, and 147 are from marine sources such as algae and sponges.

Autophagy-nutrient sensing pathways in diabetic complications.

The incidence of diabetes has been increasing in recent decades which is affecting the population of both, developed and developing countries. Diabetes is associated with micro and macrovascular complications which predominantly result from hyperglycemia and disrupted metabolic pathways. Persistent hyperglycemia leads to increased reactive oxygen species (ROS) generation, formation of misfolded and abnormal proteins, and disruption of normal cellular functioning. The inability to maintain metabolic homeostasis under excessive energy and nutrient input, which induces insulin resistance, is a crucial feature during the transition from obesity to diabetes. According to various study reports, redox alterations, intracellular stress and chronic inflammation responses have all been linked to dysregulated energy metabolism and insulin resistance. Autophagy has been considered a cleansing mechanism to prevent these anomalies and restore cellular homeostasis. However, disrupted autophagy has been linked to the pathogenesis of metabolic disorders such as obesity and diabetes. Recent studies have reported that the regulation of autophagy has a beneficial role against these conditions. When there is plenty of food, nutrient-sensing pathways activate anabolism and storage, but the shortage of food activates homeostatic mechanisms like autophagy, which mobilises internal stockpiles. These nutrient-sensing pathways are well conserved in eukaryotes and are involved in the regulation of autophagy which includes SIRT1, mTOR and AMPK. The current review focuses on the role of SIRT1, mTOR and AMPK in regulating autophagy and suggests autophagy along with these nutrient-sensing pathways as potential therapeutic targets in reducing the progression of various diabetic complications.

Biochanin A Attenuates Cardiomyopathy in Type 2 Diabetic Rats by Increasing SIRT1 Expression and Reducing Oxidative Stress.

Diabetic cardiomyopathy is one of the major complications in type 2 diabetes associated with myocardial structure abnormality and major cause of morbidity in type 2 diabetic patients. Biochanin A is a methylated isoflavone present in flowering tops of Trifolium pratense reported for anti-inflammatory, anti-oxidant, anti-infective, anti-cancer and anti-diabetic activity. The study was designed to assess the efficacy of Biochanin A in type 2 diabetic cardiomyopathy. Type 2 diabetes was induced in rats feeding high fat diet for two weeks and administration of single low dose of streptozotocin. Biochanin A was administered for 16 weeks orally once in a day (10, 20 and 40 mg/kg of body weight). Various parameters such as blood glucose, cardiac markers, oxidative stress and hemodynamic parameters, immunohistochemical, histopathological investigation and SIRT1 expression were measured at the end of the study. Biochanin A treatment resulted into reduction in plasma concentration of cardiac markers along with reduction in hyperglycemia, hyperlipidemia and oxidative stress in cardiac tissue. Biochanin A treated animals also demonstrated improvement in hemodynamic parameters. Diabetic animals treated with different doses of Biochanin A shown increased SIRT1 expression in cardiac tissue, and also confirmed reduced cardiac hypertrophy and cardiac protection in histopathological study. Outcome of the study indicates that Biochanin A is the potential candidate to control hyperglycemia, oxidative stress and improve SIRT1 expression in cardiac tissue. Biochanin A might be considered as potential candidate to control progression of cardiomyopathy in type 2 diabetes mellitus.

SIRT1-FOXOs activity regulates diabetic complications.

The prevalence of diabetes is continuously increasing in the recent decades. Persistent hyperglycemia, hyperinsulinemia and the subsequent oxidative stress result in diabetic complications, primarily categorized as microvascular (nephropathy, retinopathy and neuropathy) and macrovascular (cardiomyopathy) complications. The complications are prevalent in both type 1 and type 2 diabetic patients. Polyol pathway, elevated AGE production, PKC activation and hexosamine pathway are indeed the critical pathways involved in the progression of diabetic complications. Silent information regulator 2 or SIR2 or more commonly known as sirtuins are NAD+ dependent histone deacetylase. SIRT1, a member of the sirtuin family has been extensively studied for its role in lifespan extension and needs to be explored for its beneficial effects in diabetic complications. Moreover, it is also known to regulate the activity of other proteins and transcription factors. One such substrate of SIRT1 is FOXOs transcription factor which has gained much attention as the mediator of various cellular processes such as cell cycle arrest and proliferation, DNA repair and metabolism. It has been reported that SIRT1 regulates the activity of FOXOs, whereas few recent advances also suggest a role FOXOs in governing the activity of SIRT1, which permits for a crosstalk between SIRT1 and FOXOs. Therefore, the focus of the present review is to describe and explore the interaction between SIRT1 and FOXOs, predominantly FOXO1 and FOXO3 and to understand the underlying mechanism of SIRT1-FOXOs in controlling and alleviating diabetic complications. Thus, this crosstalk suggests that SIRT1 and FOXOs may serve as potential therapeutic targets in treating diabetic complications.

Role of dietary modifications in the management of type 2 diabetic complications.

Diabetes is a chronic metabolic disorder with a high rate of morbidity and mortality. Insufficient insulin secretion and insulin action are two major causes for the development of diabetes, which is characterized by a persistent increase in blood glucose level. Diet and sedentary life style play pivotal role in development of vascular complications in type 2 diabetes. Dietary modification is associated with a reprogramming of nutrient intake, which are proven to be effective for the management of diabetes and associated complications. Dietary modifications modulate various molecular key players linked with the functions of nutrient signalling, regulation of autophagy, and energy metabolism. It activates silent mating type information regulation 2 homolog1 (SIRT1) and AMP-activated protein kinase (AMPK). AMPK mainly acts as an energy sensor and inhibits autophagy repressor Mammalian target of rapamycin (mTOR) under nutritional deprivation. Under calorie restriction (CR), SIRT1 gets activated directly or indirectly and plays a central role in autophagy via the regulation of protein acetylation. Dietary modification is also effective in controlling inflammation and apoptosis by decreasing the level of pro-inflammatory cytokines like nuclear factor kappa- beta (NF-kß), tissue growth factor-beta (TGF-ß), tissue necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). It also improves glucose homeostasis and insulin secretion through beta cell regeneration. This indicates calorie intake plays a crucial role in the pathogenesis of type 2 diabetes-associated complications. The present review, emphasizes the role of dietary modifications in diabetes and associated complications.

Formononetin Ameliorates Diabetic Neuropathy by Increasing Expression of SIRT1 and NGF.

Diabetic neuropathy is commonly observed complication in more than 50 % of type 2 diabetic patients. Histone deacetylases including SIRT1 have significant role to protect neuron from hyperglycemia induced damage. Formononetin (FMNT) is known for its effect to control hyperglycemia and also activate SIRT1. In present study, we evaluated effect of FMNT as SIRT1 activator in type 2 diabetic neuropathy. Type 2 diabetic neuropathy was induced in rats by modification of diet for 15 days using high fat diet and administration of streptozotocin (35 mg/kg/day, i. p.). FMNT treatment was initiated after confirmation of type 2 diabetes. Treatment was given for 16 weeks at 10, 20 and 40 mg/kg/day dose orally. FMNT treatment-controlled hypoglycemia and reduced insulin resistance significantly in diabetic animals. FMNT treatment reduced oxidative stress in sciatic nerve tissue. FMNT treatment also reduced thermal hyperalgesia and mechanical allodynia significantly. It improved conduction velocity in nerve and unregulated SIRT1 and NGF expression in sciatic nerve tissue. Results of present study indicate that continuous administration of FMNT protected diabetic animals from hyperglycemia induced neuronal damage by controlling hyperglycemia and increasing SIRT1 and NGF expression in nerve tissue. Thus, FMNT can be an effective candidate for treatment of type 2 diabetic neuropathy.

Trifolium pratense (Red Clover) Improve SIRT1 Expression and Glycogen Content in High Fat Diet-Streptozotocin Induced Type 2 Diabetes in Rats.

Flowering tops of Trifolium pratense L. (Fabaceae) are known for its traditional medicinal values. In present study, our aim was to investigate effect of standardized aqueous extract of flowering tops of Trifolium pratense L. on insulin resistance and SIRT1 expression in type 2 diabetic rats. Type 2 diabetes was induced by feeding high fat diet and administering low dose of streptozotocin. Diabetic animals were treated with standardized aqueous extract at three different doses. Parameters such as blood glucose, lipid profile, glycohemoglobin, insulin sensitivity, HOMA-IR and liver glycogen content were measured. Changes in morphology and expression of SIRT1 in pancreatic tissue were measured in histopathological and immunohistological studies. Aqueous extract treatment showed reduction in hyperglycemia and improved insulin sensitivity. Extract treatment also showed reduction in formation of glycated hemoglobin and improved liver glycogen level. Histopathological study revealed protecting effect of extract in pancreatic tissue against hyperglycemia induced damage. Treatment increased expression of SIRT1 in rat pancreatic tissue. Results indicate that the aqueous extract of Trifolium pratense had beneficial role in improving insulin sensitivity and SIRT1 expression.

ER stress response mediates diabetic microvascular complications.

Endoplasmic reticulum (ER) homeostasis orchestrates the folding, modification, and trafficking of secretory and membrane proteins to the Golgi compartment, thus governing cellular functions. Alterations in ER homeostasis result in the activation of signaling pathways, such as the unfolded protein response (UPR), to regain ER homeostasis. Nevertheless, failure of UPR leads to activation of autophagy-mediated cell death. Several recent studies emphasized the association of the ER stress (ERS) response with the initiation and progression of diabetes. In this review, we highlight the contribution of the ERS response, such as UPR and autophagy, in the initiation and progression of diabetes and associated microvascular complications, including diabetic nephropathy (DN), retinopathy, and neuropathy, in various experimental models, as well as in humans. We highlight the ERS as a putative therapeutic target for the treatment of diabetic microvascular complications and, thus, the urgent need for the development of improved synthetic and natural inhibitors of ERS.

Formononetin attenuates kidney damage in type 2 diabetic rats.

AIM: Diabetic nephropathy is the commonly developed complication of vasculature in type 2 diabetic patients. Chronic hyperglycemia leads to nephropathy in diabetics because of the formation of excessive reactive oxygen species and advanced glycation end products which is reflected in the form of glomerulosclerosis, tubular atrophy and interstitial fibrosis. As per the various reports reduction in SIRT1 expression in kidney tissue is key factor in the development of nephropathy in diabetes because its reduction in tissue is linked with excessive formation of ROS. Formononetin is a polyphenolic compound reported for its effect on SIRT1 and ROS. MAIN METHODS: Type 2 diabetes was induced in rats by diet modification using high fat diet for fifteen days prior to streptozotocin regimen (35 mg/kg, i.p.). Treatment of formononetin was started after confirmation of diabetes and continued for 16 weeks. Formononetin was administered orally to the diabetic animals at the dose of 10. 20 and 40 mg/kg. KEY FINDINGS: Formononetin treatment for 16 week was able to control hyperglycemia and insulin resistance in diabetic animals. It has also been reduced triglyceride and cholesterol in blood. Formononetin treatment reduced blood concentration of creatinine, blood urea nitrogen and increased albumin concentration. Formononetin treatment also enhanced creatinine clearance in diabetic animals. Oxidative stress burden was also reduced significantly after formononetin treatment along with increased SIRT1 expression in kidney tissues of diabetic animals. SIGNIFICANCE: Formononetin is a potential molecule which increases the expression of SIRT1 in kidney tissue of diabetic. Thus formononetin is an effective molecule to control nephropathy in type 2 diabetes mellitus.

Reactivation of p53 gene by MDM2 inhibitors: A novel therapy for cancer treatment.

Cancer is an uncontrolled and abnormal growth of cells in the body. Gene that guards the cell cycle and function as tumor suppressor is p53 (also called as the guardian of the genome) which is encoded by the TP53 gene. Various events like DNA damage, heat shock, hypoxia and oncogene over expression, results in activation of p53.Thus, it plays a major role as a regulatory protein which regulates various diverse biological responses, responsible for genetic stability by preventing genome mutation. More than 50% mutations in human cancers along with the increase in expression of murine double minute 2 gene (mdm2), has been found as one of the reason for cancer progression. Murine double minute 2 (MDM2) is the negative regulator of p53 gene forming an autoregulatory feedback loop controlling each other cellular levels. Murine double minute 2 is unique E3 ubiquitin ligase protein which is responsible for ubiquitination and degradation of p53 gene. Many drugs/compounds have been developed for reactivation of p53 gene by inhibiting MDM2 interaction with p53, using MDM2 antagonism, inhibiting E3 ubiquitination of p53. Many compounds have entered clinical trials in haematological malignancies. This review will throw some light on reactivation of p53 gene by MDM2 and its homologues.

Biochanin A improves insulin sensitivity and controls hyperglycemia in type 2 diabetes.

Biochanin A (5,7-Dihydroxy-4'-methoxyisoflavone) is an O-methylated isoflavone known for its anti-inflammatory, lipid lowering and anti-cancer activity. The current study was designed to find out antidiabetic efficacy of Biochanin A in type 2 diabetes in rats. Induction of type 2 diabetes mellitus in experimental animals was carried out by manipulation of diet using high fat diet for fourteen days and then administration of streptozotocin at low dose of 35 mg/kg, i.p. The diabetic animals were treated with 10, 20 and 40 mg/kg of Biochanin A for 28 days. The effect of Biochanin A treatment in diabetic animals was evaluated by measuring changes in body weight, biochemical parameters, insulin sensitivity index, Homeostatic model assessment-Insulin resistance (HOMA-IR), oral glucose tolerance test, glycohaemoglobin and hepatic glycogen level. Changes in histopathological characteristics of pancreatic tissue were also evaluated after treatment with Biochanin A. Immunohistochemical analysis of pancreatic tissue was carried out for the expression of SIRT1. The results showed that the selected doses of (10, 20 and 40 mg/kg) Biochanin A significantly decreased blood glucose (p < 0.001). The higher dose (40 mg/kg) of Biochanin A significantly reduced glucose tolerance (p < 0.001) in diabetic animals. Biochanin A treatment significantly reduced insulin resistance (p < 0.001) and improved inulin sensitivity (p < 0.01 for 10 mg/kg, 20 mg/kg, p < 0.001 for 40 mg/kg) at all selected dose levels. It also improved lipid profile significantly (p < 0.001) at lower, middle and higher dose level. Glycohaemoglobin formation was significantly decreased in diabetic animals (p < 0.001) after treatment with Biochanin A at all three dose levels. Liver glycogen level was also improved significantly after treatment with Biochanin A in diabetic animals at 20 mg/kg and 40 mg/kg dose level. Biochanin A at dose of 40 mg/kg increased SIRT1 expression in pancreatic tissue. In conclusion, Biochanin A has significant effect in type 2 diabetes mellitus which might be linked to its effects on SIRT1.

Formononetin Treatment in Type 2 Diabetic Rats Reduces Insulin Resistance and Hyperglycemia.

Type 2 diabetic mellitus is a multifactorial metabolic disorder affecting huge population around the world. This indicates that there is an urgent unmet need of cost effective, new treatment strategies for type 2 diabetes mellitus with no or less side effects. Phenolic compounds including isoflavones are known for their beneficial effect in metabolic disorders. The present work was intended to find out efficacy of formononetin, an isoflavone treatment in experimental model of type 2 diabetes. Type 2 diabetes mellitus was induced by feeding high fat diet for 2 weeks prior to streptozotocin administration in Sprague Dawley rats. Diabetic animals were treated with formononetin for 28 days at three dose level, i.e., 10, 20, and 40 mg/kg body weight orally. The effect of formononetin treatment on various parameters such as plasma glucose, glucose tolerance, insulin, HOMA-IR, lipid profile, hepatic glycogen content, glycohaemoglobin and SIRT1 expression in pancreatic tissue was measured. Histopathological changes in pancreatic tissue were also studied. Results of the study demonstrate that formononetin treatment reduces blood glucose level significantly (p < 0.001) at all the three dose level. It also improved glucose tolerance, insulin sensitivity and lipid profile along with reduction in glycohaemoglobin content in blood. Formononetin treatment also improved hepatic glycogen level profoundly in diabetic rats. Determination of SIRT1 expression in pancreatic tissue by immunohistochemical analysis showed that formononetin treatment increases the expression of SIRT1 in pancreatic tissue. Histopathological study showed that treatment with formononetin protects pancreatic beta cells from necro-degeneration and atrophic effect. It can be concluded that formononetin treatment reduces insulin resistance and attenuate hyperglycemia in type 2 diabetes which may be due to increasing expression of SIRT1 in pancreatic tissues.

Traditional uses, phytochemistry and pharmacology of the medicinal species of the genus Cordia (Boraginaceae).

OBJECTIVES: Cordia (family Boraginaceae) is a genus of deciduous flowering trees or shrubs comprising more than 300 species distributed widely in the tropical regions. The aim of this review was to provide exhaustive scientific information on traditional uses, phytochemistry and pharmacological activities of the 36 important species with medicinal value from the genus Cordia, to divulge prospects for further research on its therapeutic potential. KEY FINDINGS: Leaves, fruit, bark and seed of a majority of the species were found to possess abundant ethnomedicinal value, but leaves were found to be used most frequently to treat many ailments such as respiratory disorders, stomach pain, wound, inflammation, myalgia, cough, dysentery and diarrhoea. The phytochemical investigation of 36 species resulted in isolation of 293 chemical constituents from various chemical classes. The crude extracts, fractions, essential oils and pure compounds isolated from various Cordia species were reported to have a varied range of pharmacological activities. SUMMARY: Many of the traditional uses of the genus Cordia were supported by the results obtained from pharmacological studies performed using various extracts or pure compounds. More attention should be given to the biological evaluation using pure phytochemicals and to identify the mechanism of actions and exploring this genus for new drug discovery.