DSpace Collection:https://hdl.handle.net/10171/517972024-03-28T11:57:09Z2024-03-28T11:57:09ZComprehensive analysis of epigenetic and epitranscriptomic genes’ expression in human NAFLDhttps://hdl.handle.net/10171/691812024-03-04T06:06:30Z2023-01-01T00:00:00ZTitle: Comprehensive analysis of epigenetic and epitranscriptomic genes’ expression in human NAFLD
Abstract: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition with a complex etiology. Its incidence is increasing globally in parallel with the obesity epidemic, and it is now considered the most common liver disease in Western countries. The precise mechanisms underlying the development and progression of NAFLD are complex and still poorly understood. The dysregulation of epigenetic and epitranscriptomic mechanisms is increasingly recognized to play pathogenic roles in multiple conditions, including chronic liver diseases. Here, we have performed a comprehensive analysis of the expression of epigenetic and epitranscriptomic genes in a total of 903 liver tissue samples corresponding to patients with normal liver, obese patients, and patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), advancing stages in NAFLD progression. We integrated ten transcriptomic datasets in an unbiased manner, enabling their robust analysis and comparison. We describe the complete landscape of epigenetic and epitranscriptomic genes’ expression along the course of the disease. We identify signatures of genes significantly dysregulated in association with disease progression, particularly with liver fibrosis development. Most of these epigenetic and epitranscriptomic effectors have not been previously described in human NAFLD, and their altered expression may have pathogenic implications. We also performed a comprehensive analysis of the expression of enzymes involved in the metabolism of the substrates and cofactors of epigenetic and epitranscriptomic effectors. This study provides novel information on NAFLD pathogenesis and may also guide the identification of drug targets to treat this condition and its progression towards hepatocellular carcinoma.2023-01-01T00:00:00ZMaresin 1 activates brown adipose tissue and promotes browning of white adipose tissue in micehttps://hdl.handle.net/10171/683212024-02-07T13:55:33Z2023-01-01T00:00:00ZTitle: Maresin 1 activates brown adipose tissue and promotes browning of white adipose tissue in mice
Abstract: Objective: Maresin 1 (MaR1) is a docosahexaenoic acid-derived proresolving lipid mediator with insulin-sensitizing and anti-steatosis properties.
Here, we aim to unravel MaR1 actions on brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning.
Methods: MaR1 actions were tested in cultured murine brown adipocytes and in human mesenchymal stem cells (hMSC)-derived adipocytes.
In vivo effects of MaR1 were tested in diet-induced obese (DIO) mice and lean WT and Il6 knockout (Il6 / ) mice.
Results: In cultured differentiated murine brown adipocytes, MaR1 reduces the expression of inflammatory genes, while stimulates glucose
uptake, fatty acid utilization and oxygen consumption rate, along with the upregulation of mitochondrial mass and genes involved in mitochondrial
biogenesis and function and the thermogenic program. In Leucine Rich Repeat Containing G Protein-Coupled Receptor 6 (LGR6)-depleted brown
adipocytes using siRNA, the stimulatory effect of MaR1 on thermogenic genes was abrogated. In DIO mice, MaR1 promotes BAT remodeling,
characterized by higher expression of genes encoding for master regulators of mitochondrial biogenesis and function and iBAT thermogenic
activation, together with increased M2 macrophage markers. In addition, MaR1-treated DIO mice exhibit a better response to cold-induced BAT
activation. Moreover, MaR1 induces a beige adipocyte signature in inguinal WAT of DIO mice and in hMSC-derived adipocytes. MaR1 potentiates
Il6 expression in brown adipocytes and BAT of cold exposed lean WT mice. Interestingly, the thermogenic properties of MaR1 were abrogated in
Il6 / mice.
Conclusions: These data reveal MaR1 as a novel agent that promotes BAT activation and WAT browning by regulating thermogenic program in
adipocytes and M2 polarization of macrophages. Moreover, our data suggest that LGR6 receptor is mediating MaR1 actions on brown adipocytes,
and that IL-6 is required for the thermogenic effects of MaR1.2023-01-01T00:00:00ZCurrent and novel therapeutic opportunities for systemic therapy in biliary cancerhttps://hdl.handle.net/10171/666352023-06-19T05:17:33Z2020-01-01T00:00:00ZTitle: Current and novel therapeutic opportunities for systemic therapy in biliary cancer
Abstract: Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies that arise in the biliary tree within and outside the liver.
Beyond surgical resection, which is beneficial for only a small proportion of patients, current strategies for treating patients with
BTCs include chemotherapy, as a single agent or combination regimens, in the adjuvant and palliative setting. Increased
characterisation of the molecular landscape of these tumours has facilitated the identification of molecular vulnerabilities, such as
IDH mutations and FGFR fusions, that can be exploited for the treatment of BTC patients. Beyond targeted therapies, active research
avenues explore the development of novel therapeutics that target the crosstalk between cancer and stroma, the cellular pathways
involved in the regulation of cell death, the chemoresistance phenotype and the dysregulation of RNA. In this review, we discuss
the therapeutic opportunities currently available in the management of BTC patients, and explore the strategies that can support
the implementation of precision oncology in BTCs, including novel molecular targets, liquid biopsies and patient-derived
predictive tools.2020-01-01T00:00:00ZBariatric surgery is associated with alcohol-related liver disease and psychiatric disorders associated with AUDhttps://hdl.handle.net/10171/661972023-07-10T05:17:12Z2023-01-01T00:00:00ZTitle: Bariatric surgery is associated with alcohol-related liver disease and psychiatric disorders associated with AUD
Abstract: Background/Aims Bariatric surgery can increase the risk of addictive disorders and nutritional deficiencies. The aim of this study was to evaluate the association between bariatric surgery and alcohol use disorder (AUD), alcohol-related liver disease (ALD), and psychiatric disorders associated with AUD. The impact of vitamin D deficiency in these associations was also investigated.Methods A cross-sectional study was performed using the National Inpatient Sample database and its ICD-9 codes information. Diagnostic and comorbidity data from hospital discharges were obtained from patients with bariatric surgery and other abdominal surgeries between 2005 and 2015. The two groups were then compared for alcohol-related outcomes after propensity-score matching.Results The final study cohort included 537,757 patients with bariatric surgery and 537,757 with other abdominal surgeries. The bariatric surgery group had an increased risk of AUD [odds ratio (OR): 1.90; 95% CI: 1.85-1.95], ALD [OR: 1.29; 95% CI: 1.22-1.37], cirrhosis [OR, 1.39; 95% CI: 1.37-1.42], and psychiatric disorders associated with AUD [OR, 3.59; 95% CI: 3.37-3.84]. Vitamin D deficiency did not impact in the association between bariatric surgery and AUD, ALD, or psychiatric disorders associated with AUD.Conclusions Bariatric surgery is associated with an increased prevalence of AUD, ALD, and psychiatric disorders associated with AUD. These associations appear to be independent from vitamin D deficiency.2023-01-01T00:00:00Z