Pterostilbene Decreases Cardiac Oxidative Stress and Inflammation via Activation of AMPK/Nrf2/HO-1 Pathway in Fructose-Fed Diabetic Rats.

PURPOSE: Oxidative stress has a pivotal role in the pathogenesis of diabetes-associated cardiovascular problems, which has remained a primary cause of the increased morbidity and mortality in diabetic patients. It is of paramount importance to prevent the diabetes-associated cardiac complications by reducing oxidative stress with the help of nutritional or pharmacological agents. Pterostilbene (PT), the primary antioxidant in blueberries, has recently gained attention for its promising health benefits in metabolic and cardiac diseases. However, the mechanism whereby PT reduces diabetic cardiac complications is currently unknown. METHODS: Sprague-Dawley rats were fed with 65% fructose diet with or without PT (20 mg kg-1 day-1) for 8 weeks. Heart rate and blood pressure were measured by tail-cuff apparatus. Real-time PCR and western blot experiments were executed to quantify the expression levels of mRNA and protein, respectively. RESULTS: Fructose-fed rats demonstrated cardiac hypertrophy, hypertension, enhanced myocardial oxidative stress, inflammation and increased NF-κB expression. Administration of PT significantly decreased cardiac hypertrophy, hypertension, oxidative stress, inflammation, NF-κB expression and NLRP3 inflammasome. We demonstrated that PT improved mitochondrial biogenesis as evidenced by increased protein expression of PGC-1α, complex III and complex V in fructose-fed diabetic rats. Further, PT increased protein expressions of AMPK, Nrf2, HO-1 in cardiac tissues, which may account for the prevention of cardiac oxidative stress and inflammation in fructose-fed rats. CONCLUSIONS: Collectively, PT reduced cardiac oxidative stress and inflammation in diabetic rats through stimulation of AMPK/Nrf2/HO-1 signalling.

Evaluation of the anti-inflammatory effect of an anti-platelet agent crinumin on carrageenan-induced paw oedema and granuloma tissue formation in rats.

The present study was designed to explore the anti-inflammatory activity of an anti-platelet agent crinumin, by various in vitro and in vivo inflammation models. Firstly, crinumin protein was purified through cation exchange chromatography; then, in vitro activity was estimated by albumin denaturation assay and HRBC membrane stabilization assay. Carrageenan-induced paw oedema and cotton pellet-induced granuloma models were used for in vivo anti-inflammatory activity assessment in rats. In both models, rats were pre-treated for 7 days with crinumin (25-50 µg/ml) and diclofenac sodium (50 µg/ml). Expression of P-selectin (in serum and plasma) through ELISA and NF-κB (in paw and granulomatous tissues) through western blotting was checked. Our results showed that crinumin at both doses (25 or 50 µg/kg of b.w.) significantly (p < 0.05) reduced the paw oedema formation in a dose-dependent manner in the second phase of inflammation and significant (p < 0.05) reduction of wet and dry weight of granuloma was observed indicating the anti-inflammatory potential of crinumin. Crinumin decreased the expression of P-selectin and NF-κB indicating its potential role in decreasing platelet activation and healing inflammation. Histopathological studies additionally proved the efficacy of drug in treating inflammation. The results of the study suggest that the crinumin might have an inhibitory role in atherosclerosis as platelet aggregation and inflammation are the key processes involved in atherosclerotic disorders.

Insights on the role of anti-inflammatory and immunosuppressive agents in the amelioration of diabetes.

Diabetes is a major health problem worldwide. It is a chronic metabolic disorder that produces overt hyperglycemic condition that occurs either when the pancreas does not produce enough insulin due to excessive destruction of pancreatic ß-cells (type 1 diabetes) or due to development of insulin resistance (type 2 diabetes). An autoimmune condition known as type 1 diabetes (T1D) results in the targeted immune death of ß-cells that produce insulin. The only available treatment for T1D at the moment is the lifelong use of insulin. Multiple islet autoantibody positivity is used to diagnose T1D. There are four standard autoantibodies observed whose presence shows the development of T1D: antibodies against insulin, glutamic acid decarboxylase (GAD65), zinc T8 transporter (ZnT8), and tyrosine phosphatase-like protein (ICA512). In type 2 diabetes (T2D), an inflammatory response precipitates as a consequence of the immune response to high blood glucose level along with the presence of inflammation mediators produced by macrophages and adipocytes in fat tissue. The slow and chronic inflammatory condition of adipose tissue produces insulin resistance leading to increased stress on pancreatic ß-cells to produce more insulin to compensate for the insulin resistance. Thus, this stress condition exacerbates the apoptosis of ß-cells leading to insufficient production of insulin, resulting in hyperglycemia which signifies late stage T2D. Therefore, the therapeutic utilization of immunosuppressive agents may be a better alternative over the use of insulin and oral hypoglycemic agents for the treatment of T1D and T2D, respectively. This review enlightens the immune intervention for the prevention and amelioration of T1D and T2D in humans with main focus on the antigen-specific immune suppressive therapy.

Functional implications and therapeutic targeting of androgen response elements in prostate cancer.

The androgen receptor (AR) plays an essential role in the growth and progression of prostate cancer (CaP). Ligand-activated AR inside the nucleus binds to the androgen response element (ARE) of the target genes in dimeric form and recruits transcriptional machinery to facilitate gene transcription. Pharmacological compounds that inhibit the AR action either bind to the ligand binding domain (LBD) or interfere with the interactions of AR with other co-regulatory proteins, slowing the progression of the disease. However, the emergence of resistance to conventional treatment makes clinical management of CaP difficult. Resistance has been associated with activation of androgen/AR axis that restores AR transcriptional activity. Activated AR signaling in resistance cases can be mediated by several mechanisms including AR amplification, gain-of-function AR mutations, androgen receptor variant (ARVs), intracrine androgen production, and overexpression of AR coactivators. Importantly, in castration resistant prostate cancer, ARVs lacking the LBD become constitutively active and promote hormone-independent development, underlining the need to concentrate on the other domain or the AR-DNA interface for the identification of novel actionable targets. In this review, we highlight the plasticity of AR-DNA binding and explain how fine-tuning AR's cooperative interactions with DNA translate into developing an alternative strategy to antagonize AR activity.

Out-of-Hospital Cardiac Arrest during the COVID-19 Pandemic: A Systematic Review.

Objective: Out-of-hospital cardiac arrest (OHCA) is a prominent cause of death worldwide. As indicated by the high proportion of COVID-19 suspicion or diagnosis among patients who had OHCA, this issue could have resulted in multiple fatalities from coronavirus disease 2019 (COVID-19) occurring at home and being counted as OHCA. Methods: We used the MeSH term "heart arrest" as well as non-MeSH terms "out-of-hospital cardiac arrest, sudden cardiac death, OHCA, cardiac arrest, coronavirus pandemic, COVID-19, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)." We conducted a literature search using these search keywords in the Science Direct and PubMed databases and Google Scholar until 25 April 2022. Results: A systematic review of observational studies revealed OHCA and mortality rates increased considerably during the COVID-19 pandemic compared to the same period of the previous year. A temporary two-fold rise in OHCA incidence was detected along with a drop in survival. During the pandemic, the community's response to OHCA changed, with fewer bystander cardiopulmonary resuscitations (CPRs), longer emergency medical service (EMS) response times, and worse OHCA survival rates. Conclusions: This study's limitations include a lack of a centralised data-gathering method and OHCA registry system. If the chain of survival is maintained and effective emergency ambulance services with a qualified emergency medical team are given, the outcome for OHCA survivors can be improved even more.

Amelioration of diet-induced metabolic syndrome and fatty liver with sitagliptin via regulation of adipose tissue inflammation and hepatic Adiponectin/AMPK levels in mice.

Chronic consumption of unhealthy diet and sedentary lifestyle induces fatty liver and metabolic complications. Adipocytes get overloaded with lipid succeeding low-grade inflammation and disrupting adipokine release. This research aims to investigate the effect of sitagliptin on white adipose tissue inflammation, adipokine level, metabolic syndrome, and fatty liver through 5' adenosine monophosphate-activated protein kinase (AMPK) pathway. In sixteen weeks of the experimental protocol, Swiss albino mice were kept in a standard environment and were fed 60% high-fat diet and 20% fructose water (HFFW) where they developed metabolic syndrome features, adipose tissue inflammation, and altered adipokine profile. Sitagliptin was administered for the last eight weeks. They were allocated to following six groups, control diet with regular water (1), HFFW only (2), HFFW and metformin 100 mg/kg (3), HFFW and sitagliptin 10 mg/kg (4), HFFW and sitagliptin 20 mg/kg (5), and HFFW and sitagliptin 30 mg/kg (6). Fasting serum insulin (FSI), glucagon-like peptide-1 (GLP-1), adipokines (adiponectin and leptin), serum lipid profile, hepatic lipid content, and white adipose tissue inflammation were assessed. Protein expression of P-AMPK, P-Acetyl co-a carboxylase (ACC), and mRNA expression of fatty acid metabolism genes were also evaluated in the liver. Sitagliptin significantly and effectively reversed metabolic syndrome complexity. FSI and GLP-1 levels were improved. A significant reduction in hepatic lipid content and oxidative stress was also observed. Also, sitagliptin significantly ameliorated adipose tissue inflammation and adiponectin levels at 20 mg/kg and 30 mg/kg. P-AMPK and P-ACC expression increased significantly. Moreover, expression of fatty acid synthesis genes was down-regulated, and fatty acid oxidation genes were up-regulated. Sitagliptin significantly ameliorated obesity-induced adipose tissue inflammation, metabolic syndrome, and fatty liver via regulation of adiponectin and AMPK levels in obese mice. Also, increased GLP-1 levels would have induced insulin-independent effects on adipose tissue and liver.

Tetramethylpyrazine alleviates diabetic nephropathy through the activation of Akt signalling pathway in rats.

In the whole world, the principal cause of end-stage renal disease is diabetic nephropathy (DN), which is one of the most relentless complications of diabetes. However, there is a shortfall of compelling DN treatments and the mechanism potentially able to alleviate renal injury remains ambiguous. In this experiment, we estimated the preventive actions of tetramethylpyrazine (TMP) on DN in rats and further investigated the underlying mechanism. The different doses of TMP (100 mg/kg, 150 mg/kg and 200 mg/kg) were orally given each day for 8 weeks in streptozotocin (STZ) - nicotinamide (NCT) - induced type-2 diabetic (T2D) rats. The metabolic parameters of diabetes, blood urea nitrogen (BUN), serum creatinine (SCR), urinary protein and oxidative stress parameters were assessed. Microstructural changes in kidney were observed, and the expression of Akt signalling pathway proteins was measured by western blotting. TMP administration in T2D rats improved diabetic condition, as demonstrated by significant (P < 0.05) increase of body weight and fasting serum insulin (FSI) level, reduction of fasting blood glucose (FBG) and glycosylated haemoglobin (HbA1c) level and regulation of lipid profile and oral glucose tolerance in a dose-dependent manner. TMP treatment also reduced BUN, SCR, urinary protein and oxidative stress and prevented renal injury in diabetic rats. TMP activated Akt signalling pathway, increased the levels of p-Akt and Bcl-2, and diminished the expressions of p-GSK-3ß, Bax and cleaved caspase-3. In conclusion, TMP ameliorates diabetic nephropathy in T2D rats by initiating the Akt signalling, improving the metabolic markers of diabetes and suppressing oxidative stress.

Tetramethylpyrazine prevents diabetes by activating PI3K/Akt/GLUT-4 signalling in animal model of type-2 diabetes.

AIMS: The present experiment was conceptualised to explore the therapeutic response of tetramethylpyrazine (TMP), a major active constituent of Ligusticum chuanxiong, a Chinese traditional medicinal plant, in high-fat diet (HFD)-streptozotocin (STZ)-induced diabetes in rats and to identify the possible mechanism of action. MAIN METHODS: Dose-reliant effect of oral treatment of TMP (100, 150 and 200 mg/kg/day) for 28 days was evaluated by calculating the alteration in body weight, level of fasting blood glucose (FBG), plasma insulin, homeostasis model assessment (HOMA), serum lipids, oral glucose & intraperitoneal insulin tolerance and glycosylated haemoglobin in HFD-STZ-induced type-2 diabetic (T2D) rats and underlying molecular mechanisms of TMP was also studied. KEY FINDINGS: TMP treatment prominently reduced the level of FBG, glycosylated haemoglobin and revived body weight gain and level of serum insulin dose-dependently in diabetic rats. TMP treatment considerably improved insulin resistance, as observed in oral glucose tolerance and insulin tolerance tests. Moreover, dose-dependent reduction in the level of pro-inflammatory cytokines, C-reactive protein (CRP) and interleukin-6 (IL-6) was observed and their level was found to be significantly reduced in highest dose TMP (200 mg/kg) treated diabetic rats, pointing towards TMP mediated recovery of insulin signalling and a decrease in insulin resistance. The expressions of p-PI3K-p85/p-Akt/GLUT-4 were also significantly up-regulated by TMP (200 mg/kg), suggesting the connection of the PI3K/Akt signal pathway in the anti-hyperglycemic action of TMP. SIGNIFICANCE: These findings suggest that TMP may be used as a potential agent for type-2 diabetes treatment.

Promising therapeutic potential of pterostilbene and its mechanistic insight based on preclinical evidence.

Pterostilbene (PS) is a well-recognized antioxidant that primarily exists in blueberries, grapevines and heartwood of red sandalwood. Interest in this compound has been renewed in recent years, and studies have found that PS possesses an array of pharmacological properties, including chemopreventive, antiinflammatory, antidiabetic, antidyslipidemic, antiatherosclerotic and neuroprotective effects. However, the greater in vivo bioavailability of PS, as compared to resveratrol, is an added advantage for its efficacy. This review provides a summary regarding the sources, pharmacokinetic aspects and pharmacodynamics of PS, with a focus on the molecular mechanisms underlying its protective effects against cancer, brain injuries and heart disease. Studies regarding the safety profile of PS have also been included. Based on the presently available evidence, we conclude that PS represents an active phytonutrient and a potential drug with pleiotropic health applications.