Rodrigo Aguilar

Background. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 30% of the world population. Progression to its inflammatory state, MASH, is associated with increasing liver fibrosis, leading to end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC). SW033291, an inhibitor of 15-PGDH (the PGE2 degradation enzyme), has been shown to increase in vivo regeneration of liver parenchyma, ameliorating oxidative stress and inflammation. We hypothesized that SW033291 abrogates MASH progression by inducing a paucity of the initial apoptotic switch and restoring physiological collagen’s microenvironment. Methods. The expression levels of the cell metabolic proteins FOXO1, mTOR, and SIRT7 were determined in a diet-induced MASH-mouse model at 16, 20, and 24 weeks. Non-targeted metabolomics in mouse plasma were measured by LC-MS/MS. Liver morphology and apoptotic activity were quantified by the NAS score and TUNEL assay, respectively. Statistical analyses between groups (NMC, HFD, and SW033291) were determined by ANOVA, t-test/Tukey’s post hoc test using GraphPad Prism. Metabolomics data were analyzed using R-lab. Results. The treated group showed significant decreases in total body fat, cellular oxidative stress, and inflammation and an increase in total lean mass with improved insulin resistance and favorable modulation of metabolic protein expressions (p < 0.05). SW033291 significantly decreased GS:SG, citric acid, and corticosterone, NAS scores (9.4 ± 0.2 vs. 6.2 ± 0.1, p < 0.05), liver fibrosis scores (1.3 ± 0.5 vs. 0.25 ± 0.1, p < 0.05), and apoptotic activity (43.9 ± 4.6 vs. 0.38 ± 0.1%, p < 0.05) compared with controls at 24W. Conclusions. The inhibition of 15-PGDH appears to normalize the metabolic and morphological disturbances during MASH progression with a paucity of the initial apoptotic switch, restoring normal collagen architecture. SW033291 warrants further investigation for its translation.

BACKGROUND. Two sequelae of non-alcoholic steatohepatitis (NASH), ESLD and HCC, have become the leading causes for liver transplantation in the Western. The present study aims to approach the cellular metabolic disturbances involved in NASH progression that are associated with microbiota community changes. METHODS. Metabolic effects and microbiota community changes were explored in the murine with NASH progression by blocking the Na/K-ATPase/Src/reactive oxygen amplification loop using the synthetic targeting peptide pNaKtide. DNA from the terminal ileum microbiota habitat was obtained and amplified by PCR to develop DNA bacterial phylogenic sequence analysis of wild type and treated animals at 12, 24 and 48 weeks. Induced changes by pSrc normalization at 24 weeks were correlated with liver morphological changes, intestinal CD4+/CD8+ ratio, and liver macrophage CD14+ expression. Differences among groups were evaluated by ANOVA/t-test and Principal Component Analysis (PCA). RESULTS. Microbiota communities varied significantly at all time points (12, 24 and 48 weeks), with an increase of Verrucomicrobia and a decrease of Bacteroidetes and Firmicutes in the HFD group. Microbiota community changes regressed to their wild-type state at 24 weeks on treated animals, and those changes were associated with a decrease in liver inflammation and senescence, lower ileum CD4+/CD8+ T cells and higher liver CD14+ cells (p<0.05). Concomitantly, the metabolic disturbances in our diet-induced NASH model were normalized by NKA/Src signaling blockage and exercise with a paucity of apoptotic activity, mitigation of cell senescence, and regression of liver fibrosis (p<0.01). CONCLUSIONS. pSrc inhibition at caveolar α1-Na/K-ATPase rescinded NASH-related metabolic disturbances establishing resident physiological microbiota communities with concomitant paucity on apoptotic activity and regression of liver fibrosis; effects that were associated with both gut and liver T-lymphocyte responses.

There is a high prevalence of hypertensive crisis with myocardial injury, as evidenced by elevation in cardiac troponin levels. The risk factors predisposing patients to developing a myocardial injury, detectable troponin, and increase in serial troponin in this population are not known. A retrospective study was designed to include all patients, presenting to the emergency room, diagnosed with hypertensive crisis, using International Classification of Diseases, 10^th revision, Clinical Modification (ICD-10-CM) codes between 2016-2018 (n=467). Logistic regression was used to determine the important predictors of myocardial injury evidenced by troponin elevation >99^th percentile of upper reference level (URL), detectable troponin (> 0.015 ng/ml), and increase in serial troponin levels. The 99^th percentile of the initial troponin level among all patients was 0.433 ng/ml. A total of 15% had a myocardial injury, and the significant risk factors associated with it were body mass index (BMI) < 30 kg/m2 (odds ratio [OR] 0.50, confidence interval [CI] 0.28-0.89), congestive heart failure (CHF; OR 4.28, CI 2.21-8.25) and prior use of aspirin (OR 1.98, CI 1.08-3.63). About 35% had detectable troponin, and BMI < 30 kg/m² (OR 0.62, CI 0.40-0.97), CHF (OR 3.49, CI 2.06-5.9), elevated creatinine (OR 1.17, CI 1.02-1.34) and age 99^th percentile URL, and the majority of these patients have minimal changes in serial troponin. Low BMI was associated with higher initial and serial troponin levels, and this obesity paradox was stronger among females and older patients.