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Context The molecular mechanism by which Swertiamarin (SM) prevents advanced glycation end products (AGEs) induced diabetic nephropathy (DN) has never been explored. Objective To evaluate the effect of SM in preventing the progression of DN in high fat diet-streptozotocin-induced diabetic rats. Materials and methods After 1 week of acclimatisation, the rats were divided randomly into five groups as follows: (1) Control group, which received normal chow diet; (2) High-fat diet (HFD) group which was fed diet comprising of 58.7% fat, 27.5% carbohydrate and 14.4% protein); (3) Aminoguanidine (AG) group which received HFD + 100 mg/k.b.w.AG (intraperitoneal); (4) Metformin (Met) group which received HFD + 70 mg/k.b.w. the oral dose of Met and (5) SM group which was supplemented orally with 50 mg/k.b.w.SM along with HFD. After 12 weeks all HFD fed animals were given a single 35 mg/k.b.w. dose of streptozotocin with continuous HFD feeding for additional 18 weeks. Later, various biochemical assays, urine analyses, histopathological analysis of kidneys, levels of AGEs, expression of various makers, and in-silico analysis were performed. Results The diabetic group demonstrated oxidative stress, increased levels of AGEs, decreased renal function, fibrosis in the renal tissue, higher expression of the receptor for advanced glycation end products (RAGE), which were ameliorated in the SM treated group. In-silico analysis suggests that SM can prevent the binding of AGEs with RAGE. Conclusions SM ameliorated DN by inhibiting the oxidative stress induced by AGEs.HighlightsSM reduces the levels of hyperglycaemia-induced advanced glycation end products in serum and renal tissue.SM prevents renal fibrosis by inhibiting the EMT in the kidney tissue.The in-silico analysis proves that SM can inhibit the binding of various AGEs with RAGE, thereby inhibiting the AGE-RAGE axis.

BackgroundNitrous oxide (N2O) is the second most common recreational drug used by 16- to 24-year-olds in the UK. Neurological symptoms can occur in some people that use N2O recreationally, but most information comes from small case series.MethodsWe describe 119 patients with N2O-myeloneuropathy seen at NHS teaching hospitals in three of the UK’s largest cities: London, Birmingham and Manchester. This work summarises the clinical and investigative findings in the largest case series to date.ResultsParaesthesia was the presenting complaint in 85% of cases, with the lower limbs more commonly affected than the upper limbs. Gait ataxia was common, and bladder and bowel disturbance were frequent additional symptoms. The mid-cervical region of the spinal cord (C3–C5) was most often affected on MRI T2-weighted imaging. The number of N2O canisters consumed per week correlated with methylmalonic acid levels in the blood as a measure of functional B12deficiency (rho (ρ)=0.44, p=0.04).ConclusionsPreventable neurological harm from N2O abuse is increasingly seen worldwide. Ease of access to canisters and larger cylinders of N2O has led to an apparent rise in cases of N2O-myeloneuropathy in several areas of the UK. Our results highlight the range of clinical manifestations in a large group of patients to improve awareness of risk, aid early recognition, and promote timely treatment.

Increased blood glucose in diabetic individuals results in the formation of advanced glycation end products (AGEs), which result in various adverse effects on kidney cells, leading to diabetic nephropathy (DN). In this study, the antiglycative potential of Swertiamarin (SM) isolated from the methanolic extract of E. littorale was explored. The effect of SM on protein glycation was studied by incubating bovine serum albumin with fructose at 60 °C in the presence and absence of different concentrations of swertiamarin for 24 h. For comparative analysis, metformin was also used at similar concentrations as SM. Further, to understand the role of SM in preventing DN, in vitro studies using NRK-52E cells were done by treating cells with methylglyoxal (MG) in the presence and absence of SM. SM showed better antiglycative potential as compared to metformin. Also, SM could prevent the MG mediated pathogenesis in DN by reducing levels of argpyrimidine, oxidative stress and apoptosis in kidney cells. SM also downregulated the expression of interleukin-6, tumor necrosis factor-α and interleukin-1β. This study, for the first time, reports the antiglycative potential of SM and also provides a novel insight into the molecular mechanisms by which SM prevents toxicity of MG on rat kidney cells.

Alcohol-induced liver injury implicates inflammation and oxidative stress as important mediators. Despite rigorous research, there is still no Food and Drug Administration (FDA) approved therapies for any stage of alcoholic liver disease (ALD). Interestingly, metformin (Met) and several probiotic strains possess the potential of inhibiting alcoholic liver injury. Therefore, we investigated the effectiveness of combination therapy using a mixture of eight strains of lactic acid-producing bacteria, commercialized as Visbiome® (V) and Met in preventing the ethanol-induced hepatic injury using in vitro and in vivo models. Human HepG2 cells and male Wistar rats were exposed to ethanol and simultaneously treated with probiotic V or Met alone as well as in combination. Endoplasmic reticulum (ER) stress markers, inflammatory markers, lipid metabolism, reactive oxygen species (ROS) production, and oxidative stress were evaluated, using qRT-PCR, Oil red O staining, fluorimetry, and HPLC. In vitro, probiotic V and Met in combination prevented ethanol-induced cellular injury, ER stress, oxidative stress, and regulated lipid metabolism as well as inflammatory response in HepG2 cells. Probiotic V and Met also promoted macrophage polarization towards the M2 phenotype in ethanol-exposed RAW 264.7 macrophage cells. In vivo, combined administration of probiotic V and Met ameliorated the histopathological changes, inflammatory response, hepatic markers (liver enzymes), and lipid metabolism induced by ethanol. It also improved the antioxidant markers (HO-1 and Nrf-2), as seen by their protein levels in both HepG2 cells as well as liver tissue using ELISA. Hence, probiotic V may act, in addition to the Met, as an effective preventive treatment against ethanol-induced hepatic injury.

Background Alcohol consumption is the fourth leading cause of death and disability worldwide. Several cellular pathways contribute to alcohol-mediated tissue injury. Adipose tissue apart from functioning as an endocrine organ secretes several hormones and cytokines known as adipokines that are known to play a significant role in alcohol-induced tissue damage. This study was designed to test the efficacy of diallyl sulfide (DAS) in regulating the alcohol-induced outcomes on adipose tissue. Methods Male Wistar rats were fed with 36% Lieber–DeCarli liquid diet containing ethanol (EtOH) for 4 weeks. Control rats were pair-fed with isocaloric diet containing maltodextrin instead of EtOH. During the last week of feeding protocol, the EtOH-fed rat group was given 200 mg/kg body weight of DAS through diet. We also studied DAS effect on isolated human primary adipocytes. Viability of human primary adipocytes on DAS treatment was assessed by MTT assay. Malondialdehyde (MDA), a marker of oxidative stress, was measured by HPLC and the thiobarbituric acid method. Expression of inflammatory genes and lipogenic genes was studied by qRT-PCR and Western blotting. Serum inflammatory gene expression was studied by ELISA. Results Our study results showed that DAS could alleviate EtOH-induced expression levels of proinflammatory and endoplasmic reticulum (ER) stress genes and improve adipose tissue mass and adipocyte morphology in male Wistar rats fed Lieber–DeCarli diet containing 6% EtOH. Further, we showed that DAS reduced the expression of lipogenic genes and improved lipid accumulation and adipocyte mass in human primary adipocytes treated with EtOH. Subsequently, we also showed that oxidative stress, as measured by the changes in MDA levels, was reduced in both male Wistar rats and human primary adipocytes treated with EtOH plus DAS. Conclusions Our study results prove that DAS is effective in ameliorating EtOH-induced damage to adipose tissue as evidenced by the reduction brought about by DAS in oxidative stress, ER stress, and proinflammatory gene expression levels. DAS treatment also regulated lipogenic gene expression levels, thereby reducing free fatty acid release. In conclusion, this study has clinical implications with respect to alcohol-induced adipose tissue injury among alcohol users.

Alcohol consumption and its abuse are significant prevalent cause for liver diseases and death worldwide. Increased bacterial endotoxin in the portal circulation, the plasma ratio of liver enzymes like alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride implies the symbiotic relation between the gut and liver plays a key function in alcoholic liver disease (ALD). Consumption of alcohol leads to gut dysbiosis and informalities of the intestinal barrier, hyper gut permeability, oxidative stress, inflammation and adversely affect adipose tissue metabolism, and those are mainly recognized as major factors for progression of alcoholic liver disease. Alteration of gut microbiota is referred to as bacterial overgrowth which leads to the release of bacterial products to change in commercial/pathogenic microbiota equilibrium. Lipopolysaccharide (LPS) derived inflammatory signal renders inflammation in alcoholic liver disease. Increase in concentration of lipopolysaccharide leads to activation of toll-like receptor 4 (TLR4) and alteration in micro RNA (miRNA) expression at the transcription level. Activation of myeloid differentiation factor 88 (MyD88) pathways eventually produces pro inflammatory cytokine activation that is an important mediator of alcoholic liver disease. However, there is no effectual Food and Drug Administration (FDA) approved treatment for any stage of alcoholic liver disease. Thus, the potential therapeutic approach for alcoholic liver disease is restoration and alteration of gut microbiota. With the increasing importance of gut microbiota in the onset and occurrence of a variety of diseases, the potential use of probiotics in ALD is receiving more exploration and clinical attention. Probiotic administration is nontoxic, inexpensive and noninvasive strategy with minimal side effects compared to antibiotic therapy and surgery. Yet, there is no substantial evidence on the efficient molecular mechanism regarding mode of action of probiotics on ALD as therapeutics. This review summarizes the research done on gut liver-axis and potential mechanism of probiotic in alcoholic liver disease.