Bruno Cogliati’s research while affiliated with Universidade Cidade de São Paulo and other places

Purpose: To characterize histologically and stereologically the hepatic steatosis in obese Zucker (fat, n = 6, with a mutation in the leptin receptor – Leprfa) and control Zucker (lean, n = 6) rats, analyzing macroscopic and microscopic differences to understand the influence of obesity on hepatic pathology. Methods: Zucker rats were fed standard chow for 90 days. Macroscopic, qualitative, and histoquantitative (stereological) approaches were used, involving body and liver weight measurement, morphological analysis, and histopathological classification of metabolic dysfunction-associated steatotic liver disease. Results: Zucker fat rats had higher body weight (p = 0.0022), liver weight (p = 0.0022), serum total cholesterol (p = 0.0022), and triacylglycerol (p = 0.0022) compared to Zucker lean rats. Stereological analysis showed that hepatocyte volume density (p = 0.0022) and total hepatocyte volume (p = 0.0001) were lower, and the volume density (p = 0.002) and total volume of steatosis (p = 0.002) were higher in Zucker fat rats compared to lean rats. Conclusion: The findings indicated that obesity induces significant alterations in the hepatic morphology of Zucker rats, showing that hepatocyte volume is lower in obese animals. This study reinforces the utility of the obese Zucker rat model to investigate the effects of obesity on liver health and suggests hepatic steatosis requires therapeutic strategies focused on modulating these parameters. Key words Obesity; Rats, Zucker; Liver; Fatty Liver; Hepatocytes

In this study, we aimed to determine the efficacy of in vivo chimeric antigen receptor (CAR) T cell therapy, generated by targeted lipid nanoparticles (t-LNPs), as an anti-fibrotic in metabolic dysfunction-associated steatotic liver disease. Hepatic fibrosis is a key predictor of mortality in liver disease, driven by fibrogenic hepatic stellate cells (HSCs). In heart, chimeric antigen receptor (CAR) T cells targeting fibroblast activation protein alpha (FAP) reduce murine cardiac fibrosis. However, the value of this approach in liver is unknown. We explored the anti-fibrotic potential of in vivo-generated anti-FAP CAR T cells in metabolic dysfunction-associated steatohepatitis (MASH), a highly prevalent disease with no approved anti-fibrotic therapies. We first established that FAP expression in both human and murine MASH is specific to HSCs. We then used flow cytometry, Sirius Red morphometry, digital pathology analysis, and single nuclear RNA-sequencing to assess the impact of anti-FAP CAR T cell therapy on murine MASH. Anti-CD5 targeted-LNPs carrying anti-FAPCAR mRNA generate activated, transient anti-FAP CAR T cells, which significantly reduced fibrosis by depleting pro-fibrogenic HSCs, and by modulating immune cells, endothelial cells and hepatocytes in a non-cell autonomous manner to mitigate inflammation and restore hepatic homeostasis. These findings reinforce the potential of in vivo CAR T therapy to attenuate a highly morbid and pervasive liver disease through integrated, multicellular salutary effects. One Sentence Summary RNA-based treatment transiently reprograms immune cells to target scar-forming cells in fatty liver disease, thus improving liver health overall.

Inflammatory bowel disease (IBD) in dogs is the most common chronic gastrointestinal disease in dogs. Its etiology evolves an aberrant immunological response towards food antigens and indigenous bacteria in the gut bacteria and, consequently, dysbiosis. Prebiotics provide substrates for the growth of beneficial bacteria and promote the production of beneficial fermentation products. This study aimed to evaluate the effects of oral supplementations of beta-glucans and mannanoligosaccharides (MOSs) over 60 days in fecal microbiota and fecal concentrations of fermentation products in dogs with mild IBD. Eighteen dogs with mild IBD were divided into three experimental groups in a blinded and randomized manner: A—dogs received 0.1% of a beta-glucan-based prebiotic, B—dogs received 0.1% of a MOS + beta-glucan-based prebiotic, and C—dogs received 0.1% of a placebo. Fecal microbiota was analyzed using the latest generation 16S rRNA sequencing (Illumina®). Relative abundances of each taxon were analyzed using a generalized linear model, and fermentation products using a mixed model. A significance level of p was used. The prebiotics positively modulated the bacterial population of Firmicutes and Bacteroidetes. Treatment A improved alpha diversity and populations of beneficial bacteria. Beta-glucan supplementation for 60 days had beneficial effects on modulating intestinal microbiota in dogs with mild IBD.

Rosemary is an herb exhibits biological properties, attenuates inflammation, oxidative stress, and improves lipid profile. Here, we evaluated the effects of rosemary aqueous extract (RE) on mice fed with a high-fat diet (HFD). Male C57BL/6 mice were administered a control diet or HFD for 10 weeks. The treated groups received RE in the diet at different concentrations: 25, 250, and 500 mg/100 g. After 10 weeks, serum concentrations of glucose, lipid, insulin, leptin, adiponectin, and cytokines were evaluated and the oxygen radical absorbance capacity was determined. Histological analysis was performed to determine the concentrations of triacylglycerides (TG), total cholesterol, cytokines, and antioxidant enzymes as well as the expression of genes involved in lipid metabolism, oxidative stress, and inflammation. The dietary RE ameliorated HFD-induced weight gain, adipose tissue weight, glucose intolerance, and insulin, leptin, and free fatty acid levels. Reduction in hepatic TG deposition was observed. The levels of inflammatory cytokines decreased, and the expression of genes involved in lipid metabolism increased. RE mitigated oxidative stress and reduced the production of reactive oxygen species in HepG2 and 3T3-L1 cells. Therefore, RE is a potential therapeutic agent for the prevention of inflammation and oxidative stress outcomes associated with obesity.