• Chronic liver disease
• Fatty liver
• Liver fibrosis
• MASLD
• PTM crosstalk
• PTM modulators
• Post translational modifications

• Humans
• Protein Processing, Post-Translational
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Disease Progression
• Animals
• Fatty Liver/metabolism
• Fatty Liver/pathology

• Hepatic stellate cells (HSCs)
• Liver fibrosis
• Metformin
• Mitochondrial dynamics
• Oxidative phosphorylation

• Humans
• Metformin/pharmacology
• Liver/metabolism
• Hepatic Stellate Cells/metabolism
• Mitochondrial Dynamics
• Electron Transport
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/metabolism
• Energy Metabolism
• DNA, Mitochondrial/metabolism
• Adenosine Triphosphate/metabolism

• Apoptosis
• Hepatic fibrosis
• Lamiophlomis rotata
• Polyphenolic glycosides
• TGF-β/Smad

The liver is the site of synthesis of the majority of circulating proteins. Besides initial polypeptide synthesis, sophisticated machinery is involved in the further processing of proteins by removing parts of them and/or adding functional groups and small molecules tailoring the final molecule to suit its physiological purpose. Posttranslational modifications (PTMs) design a network of molecules with the common protein ancestor but with slightly or considerably varying activity/localization/purpose. PTMs can change under pathological conditions, giving rise to aberrant or overmodified proteins. Undesired changes in the structure of proteins most often accompany undesired changes in their function, such as reduced activity or the appearance of new effects. Proper protein processing is essential for the reactions in living beings and crucial for the overall quality control. Modifications that occur on proteins synthesized in the liver whose PTMs are cirrhosis-related are oxidation, nitration, glycosylation, acetylation, and ubiquitination. Some of them predominantly affect proteins that remain in liver cells, whereas others predominantly occur on proteins that leave the liver or originate from other tissues and perform their function in the circulation. Altered PTMs of certain proteins are potential candidates as biomarkers of liver-related diseases, including cirrhosis. This review will focus on PTMs on proteins whose structural changes in cirrhosis exert or are suspected to exert the most serious functional consequences.

• Liver cirrhosis
• Post-translational modifications
• Circulation
• Protein function
• Protein structure
• Chronic liver disease

• Acetylation
• Humans
• Liver Cirrhosis
• Peptides/metabolism
• Phosphorylation
• Protein Processing, Post-Translational
• Proteins/metabolism

Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process.

• ECM degradation
• HSCs
• fibrosis regression
• liver fibrosis
• myofibroblasts
• therapies

• Animals
• Extracellular Matrix/metabolism
• Humans
• Inflammation/pathology
• Liver Cirrhosis/genetics
• Liver Cirrhosis/pathology
• Liver Cirrhosis/physiopathology
• Myofibroblasts/pathology
• Remission Induction
• Vascular Remodeling

Background and purpose: Obesity is becoming a major global health issue and is mainly induced by the accumulation of adipose tissues mediated by adipogenesis, which is reported to be regulated by peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer-binding protein α (C/EBPα). Trichostatin A (TSA) is a novel histone deacetylase inhibitor (HDACI) that was recently reported to exert multiple pharmacological functions. The present study will investigate the inhibitory effect of TSA on adipogenesis, as well as the underlying mechanism.

Methods: The adipogenesis of 3T3-L1 cells was induced by stimulation with a differentiation cocktail (DMI) medium for 8 days. MTT assay was used to measure the cell viability and Oil Red O staining was used to evaluate the adipogenesis of 3T3-L1 cells. The total level of triglyceride and released glycerol were detected to evaluate the lipolysis during 3T3-L1 adipogenesis. The expression levels of Leptin, fatty acid-binding protein 4 (FABP4), and sterol regulatory element-binding protein (SREBP1C) were determined by qRT-PCR. qRT-PCR assay was utilized to detect the expression levels of PPARγ and C/EBPα in 3T3-L1 cells. A high-fat diet (HFD) was used to construct an obese mice model, followed by the treatment with TSA. HE staining was conducted to evaluate the pathological state of adipose tissues. Body weights and the weights of adipose tissues were recorded to evaluate the anti-obesity property of TSA.

Results: Firstly, the promoted lipid accumulation induced by DMI incubation was significantly reversed by the treatment with TSA in a dose-dependent manner. The elevated expression levels of Leptin, FABP4, SREBP1C, PPARγ, and C/EBPα induced by the stimulation with DMI incubation were dramatically inhibited by the introduction of TSA, accompanied by the upregulation of phosphorylated AMP-activated protein kinase (p-AMPK). Secondly, the inhibitory effect of TSA against the expression level of PPARγ and lipid accumulation was greatly abolished by an AMPK inhibitor. Lastly, the increased body weights and visceral adipocyte tissue weight, as well as the enlarged size of adipocytes induced by HFD were pronouncedly reversed by the administration of TSA.

Conclusion: TSA inhibited adipogenesis in 3T3-L1 preadipocytes by activating the AMPK pathway.

• AMPK
• PPARγ
• Trichostatin A
• adipogenesis
• obesity

• Acetylation
• Autophagy
• Beclin1
• C/EBP-α
• Hepatic stellate cells

• 5-Aza-dC
• CYPs
• Taxol
• Trichostatin A
• dexamethasone
• hepatoma cells
• histone deacetylase inhibitors

• 5-Aza-dC
• CYPs
• Taxol
• Trichostatin A
• dexamethasone
• hepatoma cells
• histone deacetylase inhibitors

• non‑coding RNAs
• liver fibrosis
• epigenetics
• methylation
• acetylation
• therapy

Chronic liver diseases (CLD) represent a worldwide health problem. While CLDs may have diverse etiologies, a common pathogenic denominator is the presence of liver fibrosis. Cirrhosis, the end-stage of CLD, is characterized by extensive fibrosis and is markedly associated with the development of hepatocellular carcinoma. The most important event in hepatic fibrogenesis is the activation of hepatic stellate cells (HSC) following liver injury. Activated HSCs acquire a myofibroblast-like phenotype becoming proliferative, fibrogenic, and contractile cells. While transient activation of HSCs is part of the physiological mechanisms of tissue repair, protracted activation of a wound healing reaction leads to organ fibrosis. The phenotypic changes of activated HSCs involve epigenetic mechanisms mediated by non-coding RNAs (ncRNA) as well as by changes in DNA methylation and histone modifications. During CLD these epigenetic mechanisms become deregulated, with alterations in the expression and activity of epigenetic modulators. Here we provide an overview of the epigenetic alterations involved in fibrogenic HSCs transdifferentiation with particular focus on histones acetylation changes. We also discuss recent studies supporting the promising therapeutic potential of histone deacetylase inhibitors in liver fibrosis.

• epigenetics
• histone deacetylases
• liver fibrosis
• precision medicine

• Animals
• DNA Methylation/drug effects
• DNA Methylation/genetics
• Epigenesis, Genetic/drug effects
• Histone Deacetylase Inhibitors/pharmacology
• Histone Deacetylase Inhibitors/therapeutic use
• Histone Deacetylases/metabolism
• Humans
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/genetics
• Molecular Targeted Therapy

Liver fibrosis is characterized by the transdifferentiation of hepatic stellate cells (HSCs) to myofibroblasts and poor response to treatment. This can be attributed to the myofibroblast-specific resistance to phenotype reversal. In this study, we complemented miR-16 into miR-16-deficient myofibroblasts and analyzed the global role of miR-16 using transcriptome profiling and generating a pathway-based action model underlying transcriptomic regulation. Phenotypic analysis of myofibroblasts and fibrogenic characterization were used to understand the effect of miR-16 on phenotypic remodeling of myofibroblasts. miR-16 expression altered the transcriptome of myofibroblasts to resemble that of HSCs. Simultaneous targeting of Smad2 and Wnt3a, etc. by miR-16 integrated signaling pathways of TGF-β and Wnt, etc., which underlay the comprehensive regulation of transcriptome. The synergistic effect of miR-16 on the signaling pathways abolished the phenotypic characteristics of myofibroblasts, including collagen production and inhibition of adipogenesis. In vivo, myofibroblast-specific expression of miR-16 not only eliminated mesenchymal cells with myofibroblast characteristics but also restored the phenotype of HSCs in perisinusoidal space. This phenotypic remodeling resolved liver fibrosis induced by chronic wound healing. Therefore, miR-16 may integrate signaling pathways crucial for the fate determination of myofibroblasts. Its global effect induces the reversal of HSC-to-myofibroblast transdifferentiation and, subsequently, the resolution of fibrogenesis. Taken together, these findings highlight the potential of miR-16 as a promising therapeutic target for liver fibrosis.

• 15d-PGJ2 (PubChem CID: 5311211)
• Atherosclerosis
• C/EBPα
• Foam cell
• GW9662 (PubChem CID: 644213)
• HDAC inhibition
• PPARγ
• Trichostatin A (PubChem CID: 444732)

• ATP Binding Cassette Transporter 1/antagonists & inhibitors
• ATP Binding Cassette Transporter, Subfamily G, Member 1/antagonists & inhibitors
• Animals
• Apolipoproteins E/deficiency
• Apolipoproteins E/genetics
• Atherosclerosis/prevention & control
• CCAAT-Enhancer-Binding Protein-alpha/antagonists & inhibitors
• Diet, High-Fat
• Epigenesis, Genetic/drug effects
• Foam Cells/drug effects
• Histone Deacetylase Inhibitors/pharmacology
• Hydroxamic Acids/pharmacology
• Macrophages, Peritoneal/drug effects
• Mice
• Mice, Knockout
• PPAR gamma/drug effects
• RAW 264.7 Cells

• Alport syndrome
• CG200745
• Col4a3 knockout
• histone deacetylase

• Animals
• Autoantigens/metabolism
• Cell Line
• Collagen Type IV/deficiency
• Collagen Type IV/metabolism
• Disease Models, Animal
• Fibrosis
• Histone Deacetylase Inhibitors/pharmacology
• Humans
• Hydroxamic Acids/pharmacology
• Kidney Tubules, Proximal/metabolism
• Kidney Tubules, Proximal/pathology
• Male
• Mice
• Mice, Knockout
• Naphthalenes/pharmacology
• Nephritis, Hereditary/drug therapy
• Nephritis, Hereditary/genetics
• Nephritis, Hereditary/metabolism
• Nephritis, Hereditary/pathology
• Rats
• Signal Transduction
• Transforming Growth Factor beta/metabolism

The ecosystem of the gut microbiota consists of diverse intestinal species with multiple metabolic and immunologic activities and it is closely connected with the intestinal epithelia and mucosal immune response, with which it builds a complex barrier against intestinal pathogenic bacteria. The microbiota ensures the integrity of the gut barrier through multiple mechanisms, either by releasing antibacterial molecules (bacteriocins) and anti-inflammatory short-chain fatty acids or by activating essential cell receptors for the immune response. Experimental studies have confirmed the role of the intestinal microbiota in the epigenetic modulation of the gut barrier through posttranslational histone modifications and regulatory mechanisms induced by epithelial miRNA in the epithelial lumen. Any quantitative or functional changes of the intestinal microbiota, referred to as dysbiosis, alter the immune response, decrease epithelial permeability and destabilize intestinal homeostasis. Consequently, the overgrowth of pathobionts (Staphylococcus, Pseudomonas, and Escherichia coli) favors intestinal translocations with Gram negative bacteria or their endotoxins and could trigger sepsis, septic shock, secondary peritonitis, or various intestinal infections. Intestinal infections also induce epithelial lesions and perpetuate the risk of bacterial translocation and dysbiosis through epithelial ischemia and pro-inflammatory cytokines. Furthermore, the decline of protective anaerobic bacteria (Bifidobacterium and Lactobacillus) and inadequate release of immune modulators (such as butyrate) affects the release of antimicrobial peptides, de-represses microbial virulence factors and alters the innate immune response. As a result, intestinal germs modulate liver pathology and represent a common etiology of infections in HIV immunosuppressed patients. Antibiotic and antiretroviral treatments also promote intestinal dysbiosis, followed by the selection of resistant germs which could later become a source of infections. The current article addresses the strong correlations between the intestinal barrier and the microbiota and discusses the role of dysbiosis in destabilizing the intestinal barrier and promoting infectious diseases.

• HIV infection
• dysbiosis
• epigenetic modulation
• immunity
• intestinal microbiota
• liver infections
• sepsis
• short chain fatty acids

• Tumor microenvironment
• epigenetic remodeling
• fibrosis
• hepatic stellate cells

• Animals
• Carcinogenesis/genetics
• DNA Methylation
• Epigenesis, Genetic
• Hepatic Stellate Cells
• Humans
• Liver
• Liver Cirrhosis/genetics

• SAF 2014-54191R Ministerio de Economía, Industria y Competitividad, Gobierno de España
• SAF 2017-88933R Ministerio de Economía, Industria y Competitividad, Gobierno de España

Glioblastomas (GBM) are the most common grade 4 brain tumours; patients have very poor prognosis with an average survival of 15 months after diagnosis. Novel research lines have begun to explore aberrant protein arginine methylation (ArgMe) as a possible therapeutic target in GBM and ArgMe inhibitors are currently in clinical trials. Enzymes known as protein arginine methyltransferases (PRMT1-9) can lead to mono- or di-ArgMe, and in the latter case symmetric or asymmetric dimethylation (SDMA and ADMA, respectively). Using the most common GBM cell line, we have profiled the expression of PRMTs, used ArgMe inhibitors as tools to investigate post-translational modifications cross-talk and measured the effect of ArgMe inhibitors on cell viability. We have identified novel SDMA events upon inhibition of ADMA in GBM cells and spheroids. We have observed cross-talk between ADMA and lysine acetylation in GBM cells and platelets. Treatment of GBM cells with furamidine, a PRMT1 inhibitor, reduces cell viability in 2D and 3D models. These data provide new molecular understanding of a disease with unmet clinical needs.

• arginine methylation
• cross-talk
• glioblastoma
• inhibitor
• lysine acetylation