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The kallikrein–kinin system has been implicated in body weight and glucose homeostasis. Their major effectors act by binding to the kinin B2 and B1 receptors. It was assessed the role of the kinin B1 receptor in weight and glucose homeostasis in B1 receptor knockout mice (B1RKO) subjected to a cafeteria diet (CAF). Wild-type (WT) and B1RKO male mice (C57BL/6 background; 8 weeks old) were fed a standard diet (SD) or CAF for 14 weeks, ad libitum , and four groups were formed: WT-SD; B1RKO-SD; WT-CAF; B1RKO-CAF. Body weight and food intake were assessed weekly. It was performed glucose tolerance (GTT) and insulin tolerance tests (ITT), and HOMA-IR, HOMA-β and HOMA-β* 1/HOMA-IR were calculated. Islets from WT and B1RKO were isolated in order to measure the insulin secretion. Western blot was used to assess the hepatic AKT phosphorylation and qPCR to assess gene expression. CAF induced a higher body mass gain in B1RKO compared to WT mice. CAF diet increased epididymal fat depot mass, hepatic fat infiltration and hepatic AKT phosphorylation in both genotypes. However, B1RKO mice presented lower glycemic response during GTT when fed with CAF, and a lower glucose decrease in the ITT. This higher resistance was overcomed with higher insulin secretion when stimulated by high glucose, resulting in higher glucose uptake in the GTT when submitted to CAF, despite lower insulin sensitivity. Islets from B1RKO delivered 4 times more insulin in 3-month-old mice than islets from WT. The higher insulin disposition index and high insulin delivery of B1RKO can explain the decreased glucose excursion during GTT. In conclusion, CAF increased the β-cell function in B1RKO mice, compensated by the diet-induced insulin resistance and resulting in a healthier glycemic response despite the higher weight gain.

Introduction Marginal ulcers are the most prevalent endoscopic abnormality after RYGB. The etiology is still poorly understood; however, an increase in acid secretion has been strongly implicated as a causal agent. Although gastrin is the greatest stimulant of acid secretion, to date, the presence of gastrin producing G cells retained in the gastric pouch, related to the occurrence of marginal ulcers, has not been evaluated. Objective Evaluate the density of G cells and parietal cells in the gastric pouch of RYGB patients with a diagnosis of marginal ulcer on the post-op EGD. Method We retrospectively evaluated 1104 gastric bypasses performed between 2010 and 2020. Patients with marginal ulcer who met the inclusion criteria and controls were selected from this same population. Endoscopic gastric pouch biopsies were evaluated using immunohistochemical study and HE staining to assess G cell and parietal cell density. Results In total, 572 (51.8%) of the patients performed endoscopic follow-up after RYGB. The incidence of marginal ulcer was 23/572 (4%), and 3 patients required revision surgery due to a recalcitrant ulcer. The mean time for ulcer identification was 24.3 months (2–62). G cell count per high-power field (× 400) was statistically higher in the ulcer group ( p  < 0.05). There was no statistical difference in parietal cell density between groups ( p 0.251). Conclusion Patients with a marginal ulcer after gastric bypass present a higher density of gastrin-producing G cells retained in the gastric pouch. Graphical Abstract

The interactions between the gut and liver have been described in the progression of non-alcoholic steatohepatitis (NASH). The aim of this study was to develop an experimental nutritional model of NASH simulating metabolic changes occurring in humans. Adult male Sprague Dawley rats were randomized into two groups: controls (standard diet) and intervention (high-fat and choline-deficient diet) for 16 weeks, each experimental group with 10 animals. Biochemical analysis, hepatic lipid content, microRNAs, inflammatory, gut permeability markers and gut microbiota were measured. Animals in the intervention group showed significantly higher delta Lee index ( =0.017), abdominal circumference ( <0.001), abdominal adipose tissue ( <0.001) and fresh liver weight ( <0.001), as well as higher serum levels of alanine aminotransferase ( =0.010), glucose ( =0.013), total cholesterol ( =0.033), LDL cholesterol ( =0.011), and triglycerides ( =0.011), and lower HDL cholesterol ( =0.006) compared to the control group. Higher TLR4 ( =0.041), TLR9 ( =0.033), MyD88 ( =0.001), Casp1 ( <0.001), NLPR3 ( =0.019), liver inflammation index interleukin (IL)-1β/IL10 ( <0.001), IL6/IL10 ( =0.002) and TNFα/IL10 ( =0.001) were observed in the intervention group, and also lower permeability markers ( =0.003) and ( =0.041). Gene expression of miR-122 increased ( =0.041) and miR-145 ( =0.010) decreased in the intervention group. Liver steatosis, inflammation and fibrosis, along with collagen fiber deposition increment ( <0.001), were seen in the intervention group. Regarding gut microbiota, Bray-Curtis dissimilarity index and number of operational taxonomic units were significantly different ( <0.001) between the groups. Composition of the gut microbiota showed a significant correlation with histopathological score of NAFLD (r=0.694) and index IL-1β/IL-10 (r=0.522). This experimental model mimicking human NASH demonstrated gut and liver interaction, with gut microbiota and intestinal permeability changes occurring in parallel with systemic and liver inflammation, miRNAs regulation and liver tissue damage.

•Alcoholic liver disease (ALD) is the leading cause of alcohol-related deaths worldwide.•The standard of care for patients with ALD has not changed in the last several decades. It is still based on alcohol abstention, yet the mortality of patients with alcoholic hepatitis remains high.•This demonstrates a major gap in development of new therapies and highlights the lack of attention to patients with alcoholic hepatitis.•Limited experimental models make the development of new therapies difficult.•The model discussed here is capable of inducing ALD in early stages with biochemical, histopathologic, and intestinal microbiota composition changes, allowing the study of pathophysiologic mechanisms and new therapeutic strategies. Alcoholic liver disease (ALD) is the leading cause of alcohol-related deaths worldwide. Experimental ALD models are expensive and difficult to reproduce. A low-cost, reproducible ALD model was developed, and liver damage compared with the gut microbiota. The aims of this study were to develop an experimental model of ALD, through a high-fat diet, the chronic use of ethanol, and intragastric alcohol binge; and to evaluate the composition of the gut microbiota and its correlation with markers of inflammatory and liver disease progression in this model. Adult male Wistar rats were randomized (N = 24) to one of three groups: control (standard diet and water + 0.05% saccharin), ALC4 and ALC8 (sunflower seed, 10% ethanol + 0.05% saccharin for 4 and 8 wk, respectively). On the last day, ALC4/8 received alcoholic binge (5 g/kg). Clinical, nutritional, biochemical, inflammatory, pathologic, and gut microbiota data were analyzed. ALC4/8 animals consumed more alcohol and lipids (P < 0.01) and less total energy, liquids, solids, carbohydrates, and proteins (P < 0.01), and gained less weight (P < 0.01) than controls. ALC8 had lower Lee index scores than controls and ALC4 (P < 0.01). Aminotransferases increased and albumin diminished in ALC4/8 but not in the control group (P < 0.03 for all). Glucose and aspartate transaminase/alanine aminotransaminase ratios were higher in the ALC8 rats than in the controls (P < 0.03). Cholesterol was higher in ALC4 and lower in ALC8 compared with controls (P < 0.03). Albumin and high-density lipoprotein cholesterol levels were lower in ALC8 (P < 0.03). Hepatic concentration of triacylglycerols was higher in ALC8 than in ALC4 and controls (P < 0.05). ALC4/8 presented microvesicular grade 2 and 3 steatosis, respectively, and macrovesicular grade 1. No change in the gene expression of inflammatory markers between groups was seen. ALC4/8 had lower fecal bacterial α-diversity and relative abundance of Firmicutes (P < 0.005) and greater Bacterioidetes (P < 0.0007) and Protobacteria (P < 0.001) than controls. Gut microbiota correlated with serum and liver lipids, steatosis, albumin, and aminotransferases (P < 0.01 for all). The model induced nutritional, biochemical, histologic, and gut microbiota changes, and appears to be useful in the study of therapeutic targets.

It is known that the inflammation process leading to oxidative stress and thyroid hormone metabolism dysfunction is highly altered in metabolic dysfunction associated with steatotic liver disease (MASLD). This study aims to address the effect of ornithine aspartate (LOLA) and vitamin E (VitE) in improving these processes. Adult Sprague-Dawley rats were assigned to five groups and treated for 28 weeks: controls (n = 10) received a standard diet (for 28 weeks) plus gavage with distilled water (DW) from weeks 16 to 28. MASLD groups received a high-fat and choline-deficient diet for 28 weeks (MASLD group) and daily gavage with 200 mg/kg/day of LOLA, or twice a week with 150 mg of VitE from weeks 16–28. LOLA diminished collagen deposition (p = 0.006). The same treatment diminished carbonyl, TBARS, and sulfhydryl levels and GPx activity (p < 0.001). Type 3 deiodinase increased in the MASLD group, downregulating T3-controlled genes, which was corrected in the presence of LOLA. LOLA also promoted a near-normalization of complex II, SDH, and GDH activities (p < 0.001) and improved reticulum stress, with a reduction in GRP78 and HSPA9/GRP75 protein levels (p < 0.05). The enhanced energy production and metabolism of thyroid hormones, probably because of GSH replenishment provided by the L-glutamate portion of LOLA, opens a new therapeutic approach for MASLD.

Background Nuclear changes are typical in the carcinogenesis of hepatocellular carcinoma (HCC). Morphometry and chromatin texture analysis are quantitative methods for their quantification. In this study, we analyzed nuclear morphometry and chromatin texture parameters in samples of hepatocellular carcinoma from liver transplant patients and their associations with clinicopathologic variables. Methods Samples of HCC and adjacent tissue from 34 individuals were collected in tissue microarray blocks. Stained slides were microphotographed using an optical microscope and nuclear parameters analyzed in ImageJ (FracLac plug-in). ROC curve analysis was used to find accurate cut-offs for differentiation of neoplastic and non-neoplastic cells. The inter-rater agreement was also evaluated. Results Nuclear morphometric and textural differences were observed between the samples of HCC and adjacent tissue of liver transplant patients. Lower mean gray value ( p  = 0.034) and Feret diameter ( p  = 0.024) were associated with higher Model for End-Stage Liver Disease (MELD) scores. Nuclei with larger area ( p  = 0.014) and larger Feret diameter ( p  = 0.035) were associated with lower survival. Lower aspect ratio was associated with HCC recurrence after the transplant ( p  = 0.048). The cut-off of 1.13 μm ( p  =  < 0.001) for aspect ratio and cut-off of 21.15 μm ( p  = 0.038) for perimeter were established for the differentiation of neoplastic and non-neoplastic cells. The morphometric analysis was reproducible to area, circularity, Feret diameter, mean gray value and aspect ratio between observers ( p  =  < 0.001). Conclusions Nuclear morphometric differences between the HCC and the adjacent tissue samples were associated with prognostic variables (MELD scores, recurrence and survival) and may predict liver transplant patients’ outcomes.

PurposeObesity is a major risk factor for nonalcoholic fatty liver disease (NAFLD), affecting 25% of the worldwide population. Weight loss through bariatric surgery can improve much of the liver steatosis, inflammation, and fibrosis. However, it is not known whether there is reversal of the elastic fiber deposition process, triggered by hepatic damage and related to worse prognosis.Materials and MethodsIndividuals submitted to bariatric surgery at our institution, from March 2016 to June 2017, with intraoperative liver biopsy confirming NAFLD were approached. Those who consented were submitted to a second liver biopsy 1 year later and were included. Specimens were sliced and stained with hematoxylin-eosin and Sirius red for histological assessment according to Brunt’s criteria and with orcein for digital analysis morphometrics using ImageJ®. Quantification of elastic fibers was accomplished by corrected integrated density.ResultsThirty-seven patients were included. Body mass index, metabolic markers, NAFLD activity score, and fibrosis improved 1 year after the procedure. The elastic fiber density showed a significant decrease: 239.3 × 103 absorbance micrometer2 (141.08–645.32) to 74.62 × 103 absorbance micrometer2 (57.42–145.17), p = 0.007.ConclusionLiver elastic fiber density decreases with the reversal of NAFLD through weight loss.

Hepatocellular carcinoma (HCC) is one of the most lethal human cancers worldwide because of its high incidence, its metastatic potential and the low efficacy of conventional treatment. Inactivation of apoptosis is implicated in tumour progression and chemotherapy resistance, and has been linked to the presence of endoplasmic reticulum stress. Melatonin, the main product of the pineal gland, exerts anti-proliferative, pro-apoptotic and anti-angiogenic effects in HCC cells, but these effects still need to be confirmed in animal models. Male Wistar rats in treatment groups received diethylnitrosamine (DEN) 50 mg/kg intraperitoneally twice/once a week for 18 weeks. Melatonin was given in drinking water at 1 mg/kg/d, beginning 5 or 12 weeks after the start of DEN administration. Melatonin improved survival rates and successfully attenuated liver injury, as shown by histopathology, decreased levels of serum transaminases and reduced expression of placental glutathione S-transferase. Furthermore, melatonin treatment resulted in a significant increase of caspase 3, 8 and 9 activities, polyadenosine diphosphate (ADP) ribose polymerase (PARP) cleavage, and Bcl-associated X protein (Bax)/Bcl-2 ratio. Cytochrome c, p53 and Fas-L protein concentration were also significantly enhanced by melatonin. Melatonin induced an increased expression of activating transcription factor 6 (ATF6), C/EBP-homologous protein (CHOP) and immunoglobulin heavy chain-binding protein (BiP), while cyclooxygenase (COX)-2 expression decreased. Data obtained suggest that induction of apoptosis and ER stress contribute to the beneficial effects of melatonin in rats with DEN-induced HCC.

•The cafeteria diet rapidly and effectively causes metabolic dysfunction–associated fatty liver disease.•The cafeteria diet does not modulate genes involved in intestinal permeability but does alter the local flora by increasing Firmicutes and decreasing Bacteroidetes.•Dietary restriction minimizes cafeteria diet–induced liver damage and influences hepatic pro- and antiinflammatory genes.•Nicotinamide riboside alone or in combination with dietary restriction decreases metabolic dysfunction–associated fatty liver disease biomarkers.•Nicotinamide riboside inhibits liver fibrosis and gut Cyanobacteria proliferation. No specific therapy is available for metabolic dysfunction–associated fatty liver disease. We investigated nicotinamide riboside (NR) and dietary restriction (DR) effects in liver lipids, inflammation, histology, intestinal permeability, and gut microbiota in a cafeteria diet (CAFD)-induced obesity model. Adult male Wistar rats were randomly assigned to standard diet (SD) or CAFD. After 6 wk, they were subdivided into six groups—SD + vehicle (Veh) (distilled water), SD + NR (400 mg/kg), DR + Veh, DR + NR, CAFD + Veh, and CAFD + NR—for 4 wk more until euthanasia. CAFD increased the hepatic content of lipids, triacylglycerols, and total cholesterol and promoted hepatomegaly, steatosis, steatohepatitis, and liver fibrosis. DR intervention successfully delayed the onset of CAFD-induced liver abnormalities except for steatosis and fibrosis. CAFD suppressed Sirt1 expression in the liver and DR increased Sirt3 expression. CAFD did not affect hepatic inflammatory genes but DR enhanced Il10 expression while decreasing Il1β expression. CAFD reduced Firmicutes and increased Bacteroidetes and Cyanobacteria, with no changes in intestinal permeability. Gut microbiota patterns in animals exposed to DR were similar to those of animals in SD. NR, specifically in CAFD, reduced hepatic triacylglycerols and total cholesterol deposition and collagen fiber accumulation in the liver and limited the colonization of CAFD-induced Cyanobacteria. NR combined with DR decreased the liver's relative weight and Tnfα expression and suppressed Sirt1 and Sirt3 hepatic expression. This study suggests that NR can be a potential adjuvant to metabolic dysfunction–associated fatty liver disease therapy, encouraging further research in this field.

Chronic liver disease is an important cause of morbidity and mortality among people living with human immunodeficiency virus (HIV) and is frequently related to non-alcoholic fatty liver disease (NAFLD). The objective is to estimate the prevalence and risk factors of hepatic steatosis among consecutive patients with stable HIV infection on antiretroviral therapy (ART). Also, the use of transient elastography (TE) as a mean to identify a subgroup at risk for non-alcoholic steatohepatitis (NASH) and/or liver fibrosis. HIV infected patients were enrolled between August2016 and February2017. Inclusion criteria: ≥18 years with undetectable HIV viral load. Exclusion criteria: pregnancy; alcohol intake ≥20 g/day and co-infection B or C viruses. Patients underwent ultrasound (US) to diagnose liver steatosis. Significant fibrosis (≥F2) was estimated if at least one of the following were present: APRI > 1.0, FIB4 > 3 and/or liver stiffness ≥7.1kPa. Subjects with TE ≥ 7.1kPa were proposed a liver biopsy and NAFLD Scoring System (NAS) ≥ 3 was considered as diagnosis of NASH. A total of 98 patients were included. Liver steatosis was diagnosed in 31 patients (31.6%) and was independently associated with male gender, BMI, ALT and total bilirubin levels. The prevalence of significant fibrosis assessed by TE, APRI and FIB4 was 26.9%, 6.4% and 3.2%, respectively. Seven patients had a TE result ≥7.1kPa. NASH was found in 5 (83.3%). Among HIV infected patients undergoing ART, almost one third have NAFLD. Neither TE, APRI or FIB4 were able to act as surrogates for significant liver fibrosis. Nevertheless, TE ≥ 7.1kPa was able to accurately select a subgroup of patients at risk for NASH.