Adenoviral vectors efficiently target normal liver cells

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

Nonalcoholic steatohepatitis (NASH) is recognized by hepatic lipid accumulation, inflammation, and fibrosis. No studies have evaluated the prolonged‐release pirfenidone (PR‐PFD) properties on NASH features. The aim of this study is to evaluate how PR‐PFD performs on metabolic functions, and provide insight on a mouse model of human NASH. Male C57BL/6J mice were fed with either normo diet or high‐fat/carbohydrate diet for 16 weeks and a subgroup also fed with PR‐PFD (300 mg/kg/day). An insulin tolerance test was performed at the end of treatment. Histological analysis, determination of serum hormones, adipocytokines measurement, and evaluation of proteins by western blot was performed. Molecular docking, in silico site‐directed mutagenesis, and in vitro experiments using HepG2 cultured cells were performed to validate PR‐PFD binding to peroxisome proliferator–activated receptor alpha (PPAR‐α), activation of PPAR‐α promoter, and sirtuin 1 (SIRT1) protein expression. Compared with the high‐fat group, the PR‐PFD‐treated mice displayed less weight gain, cholesterol, very low density lipoprotein and triglycerides, and showed a significant reduction of hepatic macrosteatosis, inflammation, hepatocyte ballooning, fibrosis, epididymal fat, and total adiposity. PR‐PFD restored levels of insulin, glucagon, adiponectin, and resistin along with improved insulin resistance. Noteworthy, SIRT1–liver kinase B1–phospho‐5′ adenosine monophosphate–activated protein kinase signaling and the PPAR‐α/carnitine O‐palmitoyltransferase 1/acyl‐CoA oxidase 1 pathway were clearly induced in high fat + PR‐PFD mice. In HepG2 cells incubated with palmitate, PR‐PFD induced activation and nuclear translocation of both PPARα and SIRT1, which correlated with increased SIRT1 phosphorylated in serine 47, suggesting a positive feedback loop between the two proteins. These results were confirmed with both synthetic PPAR‐α and SIRT1 activators and inhibitors. Finally, we found that PR‐PFD is a true agonist/ligand for PPAR‐α. Conclusions: PR‐PFD provided an anti‐steatogenic effect and protection for inflammation and fibrosis.

Purpose: To report tolerability, safety, and efficacy of a topical triamcinolone acetonide-loaded liposomes formulation (TA-LF) in targeting the macular area in patients with refractory pseudophakic cystoid macular edema (PCME). Methods: For tolerability, safety and efficacy evaluation, 12 eyes of 12 patients with refractory PCME were exposed to one drop of TA-LF (TA at 0.2%) every 2 h for 90 days or until best-corrected visual acuity (BCVA) was achieved. Intraocular pressure (IOP), slit lamp examination, and central foveal thickness (CFT) were analyzed at every visit. Results: Patients with refractory PCME under TA-LF therapy showed a significant improvement in BVCA and CFT without significant IOP modification ( P = 0.94). On average CFT decreased to 206.75 ± 135.72 μm and BCVA improved to 20.08 ± 10.35 letters ( P < 0.0005). BCVA was achieved at 10.58 ± 6.70 weeks (range 2–18). TA-LF was well tolerated in all cases. Neither ocular surface abnormalities nor adverse events were recorded. Conclusion: TA-LF was well tolerated and improved BCVA and CFT on patients with refractory PCME.

In this study, CYP2E1*c2 allele was associated with susceptibility to AC; meanwhile, ADH1B*2 and ALDH2*2 alleles were not. CYP2E1*c2 allele was associated with AC severity, which could probably be attributed to the oxidative stress promoted by this polymorphic form. Further studies to clearly establish CYP2E1*c2 clinical relevance in the development of alcohol-induced liver damage and its usefulness as a probable prognostic marker, should be performed. Also, increasing the number of patients and including a control group conformed by alcoholic patients free of liver damage may render more conclusive results. These findings contribute to the understanding of the influence of gene variations in AC development among populations, alcohol metabolism, and pharmacogenetics.