Mechanistic and physiological approaches of fecal microbiota transplantation in the management of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a multifaceted disease allied with various metabolic disorders, obesity and dysbiosis. Gut microbiota plays an influential role in the pathogenesis of NAFLD and other metabolic disorders. However, recent scientific upsurge emphasizes on the utility of beneficial gut microbiota and bacteriotherapy in the management of NAFLD. Fecal microbiota transplantation (FMT) is the contemporary therapeutic approach with state-of-the-art methods for the treatment of NAFLD. Other potential therapies include probiotics and prebiotics supplements which are based on alteration of gut microbes to treat NAFLD. In this review, our major focus is on the pathological association of gut microbiota with progression of NAFLD, historical aspects and recent advances in FMT with possible intervention to combat NAFLD and its associated metabolic dysfunctions.

Calcium sensing receptor as a novel target for treatment of sepsis induced cardio-renal syndrome: Need for exploring mechanisms.

Calcium sensing receptor (CaSR) is localized in various organs and plays diverse physiological and pathological roles. Several scientific contributions have suggested the involvement of this cell surface receptor in cardiac and renal diseases. Sepsis is considered to be one of the major causes of ICU admissions. Cardiac dysfunction and acute kidney injury are major manifestations of sepsis and associated with reduced survival. Presently, the treatment approaches for management of sepsis induced cardiac depression and kidney injury are not satisfactory. Activation of CaSR has been demonstrated to induce cardiomyocyte damage upon lipopolysaccaharde (LPS) exposure by enhancing calcium ion levels, ROS (reactive oxygen species) production, promotion of inflammation and apoptosis. In addition, CaSR seems to be a critical regulator of intracellular calcium ion levels, which is directly implicated in induction of mitochondrial dysfunction and release of various pro-apoptotic pathways during sepsis. Certain evidences have also documented the expression of CaSR on neutrophils and T lymphocytes, where it is involved in activation of neutrophils and induces apoptosis of immune cells. Moreover, the expression of CaSR has been confirmed in podocytes, mesangial cells, proximal tubular cells and its activation is responsible for podocyte effacement, mesangial cell proliferation and proximal tubular cell apoptosis. We have analyzed the existing evidences, and critically discussed the possible mechanisms underlying CaSR activation mediated cardiac and renal dysfunction in sepsis condition.

Improvement of memory and neurological deficit with Ocimum basilicum L. extract after ischemia reperfusion induced cerebral injury in mice.

Oxidative stress is strongly implicated in the pathogenesis of stroke. Strategies using antioxidants to improve neurological functions after stroke have, thus, gained significant attention. Ocimum basilicum L. is used traditionally to treat CNS disorders. Its antioxidant capacity is well established. Our laboratory has reported protective effects of pre-treatment with O. basilicum in experimental stroke, but its curative (post-treatment) effects in ischemic stroke have not been documented. Hence, the present study was aimed to evaluate the effect of O. basilicum leaf extract (OBLE) on functional outcomes following cerebral injury in mice. Cerebral injury was induced in the experimental animals by bilateral common carotid artery occlusion (BCCAO) followed by reperfusion. OBLE treatment (200 and 400 mg/kg; orally, once daily) was given for 7 days after BCCAO. Cognitive outcomes and sensorimotor disturbances were evaluated with Morris Water Maze, Elevated Plus Maze and neurological severity score, respectively. TTC (2,3,5-triphenyltetrazolium chloride) staining was used to measure cerebral infarct size. Thiobarbituric acid reactive substances, reduced glutathione levels and superoxide dismutase activity in mice brain homogenate were estimated to elucidate the neuroprotective mechanism of OBLE. Treatment with OBLE resulted in marked improvement in memory and motor coordination. OBLE also decreased cerebral infarct size and oxidative stress in mice. The extract was standardised with respect to total phenol content; an HPLC-PDA analysis showed the presence of eight phenolic acids in OBLE. It is concluded that treatment with OBLE improves functional outcomes after ischemic stroke and this may be developed as a neuroprotective drug.

Ameliorative role of gemfibrozil against partial abdominal aortic constriction-induced cardiac hypertrophy in rats.

Fibrates are peroxisome proliferator-activated receptor-α agonists and are clinically used for treatment of dyslipidemia and hypertriglyceridemia. Fenofibrate is reported as a cardioprotective agent in various models of cardiac dysfunction; however, limited literature is available regarding the role of gemfibrozil as a possible cardioprotective agent, especially in a non-obese model of cardiac remodelling. The present study investigated the role of gemfibrozil against partial abdominal aortic constriction-induced cardiac hypertrophy in rats. Cardiac hypertrophy was induced by partial abdominal aortic constriction in rats and they survived for 4 weeks. The cardiac hypertrophy was assessed by measuring left ventricular weight to body weight ratio, left ventricular wall thickness, and protein and collagen content. The oxidative stress in the cardiac tissues was assessed by measuring thiobarbituric acid-reactive substances, superoxide anion generation, and reduced glutathione level. The haematoxylin-eosin and picrosirius red staining was used to observe cardiomyocyte diameter and collagen deposition, respectively. Moreover, serum levels of cholesterol, high-density lipoproteins, triglycerides, and glucose were also measured. Gemfibrozil (30 mg/kg, p.o.) was administered since the first day of partial abdominal aortic constriction and continued for 4 weeks. The partial abdominal aortic constriction-induced cardiac oxidative stress and hypertrophy are indicated by significant change in various parameters used in the present study that were ameliorated with gemfibrozil treatment in rats. No significant change in serum parameters was observed between various groups used in the present study. It is concluded that gemfibrozil ameliorates partial abdominal aortic constriction-induced cardiac oxidative stress and hypertrophy and in rats.

Minocycline improves peripheral and autonomic neuropathy in type 2 diabetes: MIND study.

Diabetic peripheral neuropathy and diabetic autonomic neuropathy are serious and common complications of diabetes associated with increased risk of mortality and cardiovascular disease. We sought to evaluate the safety and efficacy of minocycline in type 2 diabetic patients with diabetic peripheral and autonomic neuropathy. In a randomized placebo controlled study, 50 outpatients were randomly assigned to receive 100 mg minocycline or placebo. Outcome measures included the vibration perception threshold (VPT), Leeds assessment of neuropathic symptoms and signs (LANSS), Pain Disability Index (PDI), Visual Analog Scale (VAS), beck depression inventory (BDI), health assessment questionnaire (HAQ) and autonomic neuropathy, assessed by cardiovascular reflex tests according to Ewing and peripheral sympathetic autonomic function was assessed by FDA approved Sudoscan. At baseline there were no significant differences between demographic variables and the neuropathy variables in the minocycline and placebo groups. After treatment, VPT significantly improved in the minocycline group as compared to the placebo group. Mean posttreatment scores on the LANSS, PDI and HAQ were significantly lower in the minocycline group compared with the placebo group. However, BDI and VAS significantly (p = 0.01) improved in both minocycline and placebo groups (Table 2). After treatment with minocycline, heart rate (HR) response to standing significantly improved, while there was a borderline significance toward a reduction in HR response to deep breath. These finding indicate that 6-week oral treatment with minocycline is safe, well tolerated and significantly improves peripheral and autonomic neuropathy in type 2 diabetic patients.

Clinical Significance of Adropin and Afamin in Evaluating Renal Function and Cardiovascular Health in the Presence of CKD-MBD Biomarkers in Chronic Kidney Disease.

AIM: The study aims to test the hypothesis that concentrations of adropin and afamin differ between patients in various stages of chronic kidney disease when compared with healthy controls. The study also investigates the association of the biomarkers (adropin and afamin) with CKD-MBD and traditional cardiovascular risk parameters in CKD patients. METHODOLOGY: The cross-sectional study includes the subjects divided into four groups comprising the control group (healthy volunteers = 50), CKD stages 1-2 patients (n = 50), CKD stages 3-4 patients (n = 50), CKD stage 5 patients (n = 50). Serum concentrations of adropin and afamin were determined using ELISA. Clinical variables (renal, lipid, and CKD-MBD parameters) were correlated to adropin and afamin concentrations. RESULTS: Afamin concentration was found to be higher in group IV, followed by groups III and II when compared to the control group, i.e., (83.243 ± 1.46, 64.233 ± 0.99, and 28.948 ± 0.72 vs. 14.476 ± 0.5) mg/L (p < 0.001), and adropin concentration was found to be lower in group IV as compared to groups III, II, and I (200.342 ± 8.37 vs. 284.682 ± 9.89 vs. 413.208 ± 12.32 vs. 706.542 ± 11.32) pg/mL (p < 0.001), respectively. Pearson correlation analysis showed that afamin was positively correlated with traditional cardiovascular risk biomarkers, while adropin showed a negative correlation. CONCLUSIONS: Adropin and afamin may potentially serve as futuristic predictors for the deterioration of renal function and may be involved in the pathological mechanisms of CKD and its associated complications such as CKD-MBD and high lipid levels.

Angiotensin-Receptor Blockade Improves Inflammation and Endothelial Dysfunction in Ankylosing Spondylitis: ARB-AS Study.

Cardiovascular (CV) disease is the leading cause of premature death in ankylosing spondylitis (AS). Atherosclerosis and AS share similar pathogenic mechanisms. The proven benefits of angiotensin-receptor blockers (ARBs) in atherosclerotic cardiovascular disease and their role in immune mediation provide strong rationale to investigate its impact with olmesartan on inflammation and endothelial dysfunction in AS. To investigate the effect of olmesartan on inflammation and endothelial dysfunction in AS. 40 AS patients were randomized to receive 24 weeks of treatment with olmesartan (10 mg/day, n = 20) and placebo ( n = 20) as an adjunct to existing stable antirheumatic drugs. Markers of endothelial function included the following: flow-mediated dilation (FMD) assessed by AngioDefender, endothelial progenitor cells (EPCs) estimated by flow cytometry, nitrite (nitric oxide surrogate), intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and inflammatory measures including Bath ankylosing spondylitis disease activity index (BASDAI), ankylosing spondylitis disease activity score (ASDAS) and bath ankylosing spondylitis functional index (BASFI); erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); proinflammatory cytokines (interleukin-1 [IL-1], IL-6, tumor necrosis factor-α [TNF-α]) and marker of oxidative stress- thiobarbituric acid reactive substances (TBARS) estimated at baseline and after treatment. Health assessment questionnaire disability index (HAQDI), 36-item short form survey (SF-36), and systematic coronary risk evaluation (SCORE) were estimated using standard tools. FMD improved significantly in the olmesartan group (5.83 ± 0.31% to 7.68 ± 0.27%, p ≤ 0.05) as compared with placebo (5.89 ± 0.35% to 6.04 ± 0.32%, p = 0.33). EPC population, nitrite, VCAM-1, and TBARS levels improved significantly in olmesartan group as compared with placebo ( p ≤ 0.05). Olmesartan significantly decreased ASDAS, BASDAI, BASFI, ESR, CRP, IL-6, TNF-α, and SCORE as compared with placebo. HAQDI and SF-36 (PH) scores improved significantly in olmesartan group as compared with placebo. Olmesartan reduces inflammatory disease activity, improves quality of life (QOL), and decreases CV risk demonstrating the immunomodulatory, vasculoprotective, and cardioprotective potential of this drug in AS.

Fatty acid synthase inhibition ameliorates diabetes induced liver injury in rodent experimental model.

The abnormal dietary life style leads to hyperlipidemia and insulin resistance with ectopic lipid accumulation and elevated levels of hepatic glucose development which are the underlying pathological characteristics of fatty liver diseases. The pharmacological inhibition of fatty acid synthase of de novo lipogenesis may regulate the dysfunctional lipid biotransformation and reverse the pathological state of diabetic liver injury. The three pharmacological interventions (PTS; Pterostilbene, ARB; Arbutin, PUR; Purpurin) were administered to manage the condition of diabetic liver injury against the high fat diet (HFD) + Streptozotocin (STZ) 30 mg/kg b.wt. rodent animal model to observe the effect of abnormal fatty acid synthesis. The qRT-PCR was used to evaluate the fatty acid synthase (FASN) expression which is independently allied with diabetes associated fatty liver disorders. To determine the therapeutic potential of three selected drugs, the biochemical parameters and histopathological considerations were utilized. Three subsequent dosage of PTS, ARB and PUR administered (i.e., 30,60 & 120 mg/kg/p.o.) for five weeks significantly alter the serum parameters, oxidative burden in HFD-STZ which, in turn, resulted in diabetic liver injury. It was also revealed that increased mRNA expression of fatty acid synthase (FASN), which is known to promote abnormal fatty acid synthesis through different molecular signaling pathways, was associated with the development of diabetes associated liver injury, this expression was observed to be significantly suppressed by PTS, ARB and PUR treatment. Moreover, the studies of histopathology showed that there was substantial structural improvement after PTS, ARB and PUR treatment. All three selected drugs have been shown to be effective for Diabetic liver injury (DLI) care but PTS shows impressive results compared to other selected drugs.

The multifaceted therapeutic potential of benfotiamine.

Thiamine, known as vitamin B(1), plays an essential role in energy metabolism. Benfotiamine (S-benzoylthiamine O-monophoshate) is a synthetic S-acyl derivative of thiamine. Once absorbed, benfotiamine is dephosphorylated by ecto-alkaline phosphatase to lipid-soluble S-benzoylthiamine. Transketolase is an enzyme that directs the precursors of advanced glycation end products (AGEs) to pentose phosphate pathway. Benfotiamine administration increases the levels of intracellular thiamine diphosphate, a cofactor necessary for the activation transketolase, resulting in the reduction of tissue level of AGEs. The elevated level of AGEs has been implicated in the induction and progression of diabetes-associated complications. Chronic hyperglycemia accelerates the reaction between glucose and proteins leading to the formation of AGEs, which form irreversible cross-links with many macromolecules such as collagen. In diabetes, AGEs accumulate in tissues at an accelerated rate. Experimental studies have elucidated that binding of AGEs to their specific receptors (RAGE) activates mainly monocytes and endothelial cells and consequently induces various inflammatory events. Moreover, AGEs exaggerate the status of oxidative stress in diabetes that may additionally contribute to functional changes in vascular tone control observed in diabetes. The anti-AGE property of benfotiamine certainly makes it effective for the treatment of diabetic neuropathy, nephropathy and retinopathy. Interestingly, few recent studies demonstrated additional non-AGE-dependent pharmacological actions of benfotiamine. The present review critically analyzed the multifaceted therapeutic potential of benfotiamine.

Serotonin 5HT2A receptor antagonism mediated anti-inflammatory and anti-fibrotic effect in adriamycin-induced CKD in rats.

A selective 5-HT2A receptor antagonist ketanserin has been used preclinically to improve renal blood flow because of its beneficial effect on autoregulation in various chronic kidney disease models. Ketanserin might be able to turn down adriamycin-induced chronic kidney disease, which is characterized by renal fibrosis, inflammation and structural and functional changes in glomeruli. In the present study, we investigated whether ketanserin suppresses these renal alterations or not. Wistar rats were administered with a single dose of adriamycin (6 mg/kg/i.v), which leads to development of severe tubulointerstitial fibrosis with altered renal function. Subsequent ketanserin treatment (5 mg/kg/p.o) for 4 weeks shown significant change in oxidative stress, serum and urine parameters in adriamycin-induced chronic kidney disease rats. Additionally, results showed that mRNA expression of TGF-ß and collagen IV, which are known to promote fibrosis via various signaling pathways involved in the progression of renal disease, was suppressed by ketanserin treatment. Furthermore, expression levels of 5-HT2A and pro-inflammatory marker IL-6 have also been reduced significantly after ketanserin administration in adriamycin-treated animals. Moreover, histopathological studies also reveal the considerable structural changes after ketanserin treatment, and these results are further supported via data obtained from the percentage of glomeruli size changes. In conclusion, ketanserin reduces renal fibrosis and inflammation in adriamycin-induced chronic kidney disease by suppressing 5-HT2A, IL-6, TGF-ß and collagen IV expression in renal tissue.

Investigations on acute oral toxicity studies of purpurin by application of OECD guideline 423 in rodents.

The anticancer, anti-inflammatory and antioxidant properties of Purpurin were generated from in vitro studies, and no scientific reports were found on its safety and efficacy, related to their in vivo studies; thus, the present study was focused on acute oral toxicity of purpurin in female Wistar rats as per the OECD 423 guidelines. In this study, purpurin was administered at starting dosage of 300 mg/kg followed by 2000 mg/kg, p.o, and animals were observed for toxic signs at 24 h and for the next 14 days to different animal groups. Animals were observed for mortality, behavioral changes, biochemistry, hematological parameters, and histopathological examination after a follow up on the 14th day. The oral lethal dose for mice was greater than 2000 mg/kg, b.wt. in female rats and classified under category 5 as per the acute oral toxicity study. It was found that there were no significant differences in body weight changes, food/water intake, hematology, and clinical biochemistry. The histopathological study directly depicted that there were no pathological changes observed in the vital organs of rats treated with the different dose of Purpurin. The present work advocates that an acute oral administration of Purpurin was found to be a non-toxic and safe drug in the tested experimental conditions.

Isolation and characterization of components responsible for neuroprotective effects of Allium cepa outer scale extract against ischemia reperfusion induced cerebral injury in mice.

The antioxidant-mediated neuroprotective effect of Allium cepa outer scale extract (ACE) in mice with cerebral ischemia-reperfusion (I-R) injury was demonstrated in our earlier work. The current investigation aimed at establishing the bioactive component(s) responsible for this activity. Thus ACE was fractionated into ethyl acetate (EF) and aqueous (AF) fractions. These fractions were evaluated against cerebral I-R injury in mice. I-R injury in mice was induced by bilateral common carotid artery occlusion followed by 24 hr reperfusion. Memory, sensorimotor functions, cerebral infarct size, and oxidative stress were measured to address the neuroprotective mechanism of test substances. EF showed marked improvement of memory and sensorimotor functions by reducing brain oxidative stress and infarct size in mice after I-R injury. The bioactive EF was subjected to chromatographic (HPLC-PDA, HPLC-MS, preparative HPLC) and spectroscopic studies to isolate and identify the neuroprotective compounds. This lead to separation of three components, namely quercetin, quercetin 4'-O-glucoside, and the remaining fraction, from EF. The separated components were biologically evaluated. These components showed improvement in mice with I-R injury. But, EF displayed more marked neuroprotective effects as compared to the isolated components. The distinct neuroprotective outcome of EF may be credited to the synergistic action of compounds present in EF. Further studies such as evaluation of neurotoxic effects and other possible neuroprotective mechanisms are required to develop EF as a neuroprotective drug.

In vitro targeted screening and molecular docking of stilbene, quinones, and flavonoid on 3T3-L1 pre-adipocytes for anti-adipogenic actions.

In metabolic disorders like obesity, NAFLD and T2DM, adipocytes are dysfunctional. Hence, pharmacological interventions have importance in preventing differentiation of adipocytes and stimulating lipid uptake. We, therefore, investigated the effects of arbutin (ARB), purpurin (PUR), quercetin (QR), and pterostilbene (PTS) on adipocyte differentiation and lipid uptake using 3T3-L1 adipocytes. Further, in silico docking studies were achieved to investigate interactions of ARB, PUR, QR, and PTS with beta-ketoacyl reductase (KR) and thioesterase (TE) domains of fatty acid synthase (FAS) enzyme. Mature 3T3-L1 adipocytes were used to investigate the anti-adipogenic effect of selected pharmacological agents by Oil Red O staining and in vitro fatty acid uptake analysis. Molecular docking studies were performed to predict the binding interactions of selected compounds with KR and TE domains of FAS enzyme. All these agents significantly decrease the adipocyte differentiation and showed the stimulatory effect on fatty acid uptake in 3T3-L1 adipocytes. However, PTS and PUR proved to be anti-adipogenic, whereas ARB and QR showed significant effect on fatty acid uptake, compared to others. Similarly, all the compounds displayed significant binding interactions with KR and TE domains of FAS enzyme, supporting the results of in vitro studies. Graphical abstract.

Chemical constituents from the leaves of Boehmeria rugulosa with antidiabetic and antimicrobial activities.

Three new flavonoid glycosides, named chalcone-6'-hydroxy-2',3,4-trimethoxy-4'-O-beta-D-glucopyranoside (1), isoflavone-3',4',5,6-tetrahydroxy-7-O-[beta-D-glucopyranosyl-(1-->3)-alpha-L-rhamnopyranoside] (2), and isoflavone-3',4',5,6-tetrahydroxy-7-O-[beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl-(1-->3)-alpha-L-rhamnopyranoside] (3), were isolated from the leaves of Boehmeria rugulosa, together with five known compounds, beta-sitosterol, quercetin, 3,4-dimethoxy-omega-(2'-piperidyl)-acetophenone (4), boehmeriasin A (5), and quercetin-7-O-beta-D-glucopyranoside. The structures of the isolated compounds were determined by means of chemical and spectral data including 2D NMR experiments. The ethanolic extract of leaves showed significant hypoglycemic activity on alloxan-induced diabetic mice. Glibenclamide, an oral hypoglycemic agent (5 mg/kg, p.o.), was used as a positive control. The ethanolic extract of the plant as well as the isolated compounds 1-3 (25 microg/ml) showed potent antimicrobial activity against two bacterial species (Staphylococcus aureus and Streptococcus mutans) and three fungus pathogens (Microsporum gypseum, Microsporum canis, and Trichophyton rubrum). The activities of the isolated compounds 1-3 have been compared with positive controls, novobiocin, and erythromycin (15 microg/ml).

Dietary restriction regimens for fighting kidney disease: Insights from rodent studies.

This review critically discusses the research findings on the effects of various dietary restriction regimens in rodent models of kidney disease. Long-term caloric restriction executed at both early and progressive stages of kidney disease was found to exert beneficial effects in rodents. Moreover, some studies have also demonstrated the efficacy of short-term caloric restriction in treating the kidney disease of variable aetiologies possibly by improving mitochondrial dysfunction, autophagy process and suppression of inflammation. However, the mechanisms underlying these short-term caloric restriction mediated protective effects in rodent models of kidney disease are not completely understood. Importantly, few available evidences have also suggested that carbohydrate restriction can exert beneficial effects in aging and experimentally induced renal injury models, but the mechanisms are not explored yet. Interestingly, the benefits of low protein diet in kidney disease models are extensively reported in literature. However, in most of these studies implementation of the low protein dietary regimen was found to associated with increased high carbohydrate and caloric intake (non-isocaloric). Thus, testing the effects of low protein diet under isocaloric conditions might further help to particularly understand the role of dietary protein content in pathology of kidney disease. Moreover, the direct evidences comparing the efficacy of various dietary restriction regimens in rodent models of kidney diseases are also scarce at present.

Metabolic Correlates of Health-Related Quality of Life in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: The increasing prevalence of type 2 diabetes mellitus (T2DM) and associated metabolic complications lead to the development of a syndrome known as "metabolic syndrome" (MetS), which is considered as one of the major risk factor not only for the development of cardiovascular diseases but also have a great impact on the quality of life. RESEARCH DESIGN AND METHODS: A descriptive, observational study involving the recruitment of patients with T2DM with and without MetS was carried out in outpatient department of endocrinology. The MetS was defined as per the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) criteria. Patients with T2DM were screened as per the American Diabetes Association (ADA; ie, fasting blood glucose [FBG] ≥ 126 mg/dL) and who were using oral antidiabetic drugs. Short Form-36 (SF-36) was used to assess the health-related quality of life (HRQoL). RESULTS: Patients were grouped as T2DM with MetS (n = 100) and T2DM without MetS (n = 100). A greater significant decline was observed in physical component summary (PCS) and mental component summary (MCS) in patients with T2DM with MetS as compared to patients without MetS (P ≤ .05). Multiple linear regression analysis revealed that in patients with T2DM having MetS, age and waist circumference (WC) are independent predictors for worsening of both PCS and MCS aspects of health-related quality of life (HRQOL). In addition, high triglycerides and raised FBG were found to be correlated with the decline in PCS and MCS, respectively. CONCLUSION: The study demonstrated that patients with T2DM with MetS have overall poor HRQOL as compared to patients with T2DM without MetS.

Molecular and Pathological Events Involved in the Pathogenesis of Diabetes-Associated Nonalcoholic Fatty Liver Disease.

Diabetes mellitus is a rising epidemic in most part of the world and is often associated with multiple organ disorders such as kidney, liver, and cardiovascular diseases. Liver is a major metabolic hub, and the metabolic disorders associated with diabetes result in liver dysfunctions culminating in spectrum of liver diseases such as fatty liver disorders, cirrhosis, and hepatocellular carcinoma. The intervention strategies to prevent diabetes-associated liver injury require an overall understanding of the key factors and molecular pathways which can be strategically targeted. The present review focuses on some of the key aspects of fatty acid metabolism, fetuin-A regulation, inflammatory pathways, and genetic factors associated with insulin resistance, dyslipidemia, hyperglycemia, oxidative stress, and so on involved in the nexus between diabetes and liver injury. Further recent interventions, pharmacological target, and newer therapeutic agents are discussed briefly for the better clinical management of diabetes-associated hepatic disorders.

Cobalt treatment does not prevent glomerular morphological alterations in type 1 diabetic rats.

Early renal morphological alterations including glomerular hypertrophy and mesangial expansion occur in diabetic kidney disease and correlate with various clinical manifestations of diabetes. The present study was designed to investigate the influence of pharmacological modulation of HIF-1α (hypoxia inducible factor-1 alpha) protein levels, on these glomerular changes in rodent model of type 1 diabetes. Male wistar rats were made diabetic (Streptozotocin 45 mg/kg; i.p.) and afterwards treated with HIF activator cobalt chloride for 4 weeks. Renal function was assessed by serum creatinine, albumin, proteinuria levels, oxidative stress: reduced glutathione levels and catalase activity, and renal tissue HIF-1α protein levels were determined by ELISA assay. Histological analysis of kidney sections was done by haematoxylin and eosin (glomeruli diameter), periodic acid Schiff (mesangial expansion and glomerulosclerosis) and sirius red (fibrosis, tubular dilation) staining. Diabetes rats displayed reduced serum albumin levels, marked proteinuria, lower kidney reduced glutathione content, glomerular hypertrophy, glomerulosclerosis, mesangial expansion, tubular dilation and renal fibrosis. Cobalt chloride treatment normalised renal HIF-1α protein levels, reduced development of proteinuria and tubulo-interstitial fibrosis, but the glomerular morphological alterations such as glomerulosclerosis, mesangial expansion, increased glomerular diameter and tubular vacoulations were not abrogated in diabetic kidneys. Glomerular morphological abnormalities might precede the development of proteinuria and renal fibrosis in experimental model of type 1 diabetes. Pharmacological modulation of renal HIF-1α protein levels does not influence glomerular and tubular dilatory changes in diabetic kidney disease.

Amelioration of ischaemia reperfusion-induced cerebral injury in mice by liposomes containing Allium cepa fraction administered intranasally.

Neuroprotection in ischaemic stroke prevents neuronal injury and subsequent death. Our earlier work revealed the neuroprotective effect of ethylacetate fraction (EF) obtained from Allium cepa outer scales in a mouse model of cerebral ischaemia-reperfusion (I-R) injury. The present study was designed to develop and optimize a liposomal delivery system for EF, along with its biological assessment. Thin film hydration method was used for the preparation of liposomal formulation. The prepared liposomes were optimized with respect to particle size, size distribution and encapsulation efficiency (EE) and characterised on the basis of zeta potential, in vitro release, morphology (TEM) and physical stability. The biological activity of the optimized liposomal formulation (EF-L; 8.5 mg/kg, intra-nasal) was evaluated after induction of cerebral injury in the experimental animals. Neuroprotective effects were assessed in terms of improvement of cognitive/sensorimotor functions and reduction of cerebral infarct size and brain oxidative stress. EF-L (particle size of 204.93 ± 7.96 nm; EE of 88.02 ± 2.09%; zeta potential of -20.8 ± 1.24 mV) showed controlled release pattern; spherical shape and were physically stable for 60 days at 4 °C. Intra-nasal administration of EF-L produced significant neuroprotection in mice at 1/10th the oral dose. Thus, EF-L may be developed as a neuroprotective formulation.

Role of orexins in the central and peripheral regulation of glucose homeostasis: Evidences & mechanisms.

Orexins (A & B), neuropeptides of hypothalamic origin, act through G-protein coupled receptors, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R). The wide projection of orexin neurons in the hypothalamic region allows them to interact with the other neurons and regulate food intake, emotional status, sleep wake cycle and energy metabolism. The autonomic nervous system plays an important regulatory role in the energy metabolism as well as glucose homeostasis. Orexin neurons are also under the control of GABAergic neurons. Emerging preclinical as well as clinical research has reported the role of orexins in the glucose homeostasis since orexins are involved in hypothalamic metabolism circuitry and also rely on sensing peripheral metabolic signals such as gut, adipose derived and pancreatic peptides. Apart from the hypothalamic origin, integration and control in various physiological functions, peripheral origin in wide organs, raises the possibility of use of orexins as a therapeutic biomarker in the management of metabolic disorders. The present review focuses the central as well as peripheral roles of orexins in the glucose homeostasis.