Analysis of miRNAs Profiles in Serum of Patients With Steatosis and Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most common chronic liver diseases worldwide, affecting 25% of the world population. In recent years, there has been increasing evidence for the involvement of microRNAs in the epigenetic regulation of genes taking part in the development of steatosis and steatohepatitis-two main stages of NAFLD pathogenesis. In the present study, miRNA profiles were studied in groups of patients with steatosis and steatohepatitis to compare the characteristics of RNA-dependent epigenetic regulation of the stages of NAFLD development. According to the results of miRNA screening, 23 miRNAs were differentially expressed serum in a group of patients with steatohepatitis and 2 in a group of patients with steatosis. MiR-195-5p and miR-16-5p are common differentially expressed miRNAs for both steatosis and steatohepatitis. We analyzed the obtained results: the search for target genes for the differentially expressed miRNAs in our study and the subsequent gene set enrichment analysis performed on KEGG and REACTOME databases revealed which metabolic pathways undergo changes in RNA-dependent epigenetic regulation in steatosis and steatohepatitis. New findings within the framework of this study are the dysregulation of neurohumoral pathways in the pathogenesis of NAFLD as an object of changes in RNA-dependent epigenetic regulation. The miRNAs differentially expressed in our study were found to target 7% of genes in the classic pathogenesis of NAFLD in the group of patients with steatosis and 50% in the group of patients with steatohepatitis. The effects of these microRNAs on genes for the pathogenesis of NAFLD were analyzed in detail. MiR-374a-5p, miR-1-3p and miR-23a-3p do not target genes directly involved in the pathogenesis of NAFLD. The differentially expressed miRNAs found in this study target genes largely responsible for mitochondrial function. The role of miR-423-5p, miR-143-5p and miR-200c-3 in regulating apoptotic processes in the liver and hepatocarcinogenesis is of interest for future experimental studies. These miR-374a, miR-143, miR-1, miR-23a, and miR-423 have potential for steatohepatitis diagnosis and are poorly studied in the context of NAFLD. Thus, this work opens up prospects for further studies of microRNAs as diagnostic and therapeutic biomarkers for NAFLD.

The Links of Ghrelin to Incretins, Insulin, Glucagon, and Leptin After Bariatric Surgery.

Type 2 diabetes mellitus (T2DM) is one of the most prominent and socially significant problems. The present study aimed to identify the mechanisms of interaction of critical regulators of carbohydrate metabolism using bioinformatics and experimental methods and to assess their influence on the development of T2DM. We conducted an in silico search for the relationship of hormones and adipokines and performed functional annotation of the receptors for ghrelin and incretins. Hormones and adipokines were assessed in the plasma of obese patients with and without T2DM as well as after laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB) surgeries. Incretin- and ghrelin-associated functions and metabolic processes were discovered. Low ghrelin levels were observed in obese patients without T2DM compared with healthy volunteers and the other groups. The highest ghrelin levels were observed in obese patients with T2DM. This defense mechanism against insulin resistance could be realized through the receptors G-protein-coupled receptor (GPCR), growth hormone secretagogue receptor (GHSR), and growth hormone-releasing hormone receptor (GHRHR). These receptors are associated with proliferative, inflammatory, and neurohumoral signaling pathways and regulate responses to nutrient intake. Signaling through the GPCR class unites ghrelin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide (GLP)-1. Ghrelin impairs carbohydrate and lipid metabolism in obese patients. Ghrelin is associated with elevated plasma levels of insulin, glucagon, and leptin. Specific activation of receptors and modulation by posttranslational modifications of ghrelin can control IR's development in obesity, which is a promising area for research.

IL-6 Reduces Mitochondrial Replication, and IL-6 Receptors Reduce Chronic Inflammation in NAFLD and Type 2 Diabetes.

Interleukin (IL)-6 family cytokines act through a receptor complex with gp130 subunits. IL-6 is a pleiotropic cytokine that regulates inflammation and liver regeneration. Mitochondria are the first to respond to stress and adapt their dynamics in conditions of damage. In this regard, the study aimed to investigate the role of the IL-6 cytokine family (sIL-6Ra, gp130/sIL-6Rb, and IL-11) in the regulation of mitochondrial dynamics in the liver in obese patients and to assess the contribution of these cytokines to the pathogenesis of type 2 diabetes mellitus (T2DM). We studied 134 obese patients with and without T2DM and 41 healthy donors. We found that increasing the concentration of sIL-6Ra and gp130/sIL-6Rb protected against carbohydrate disorders in obese patients and prevented non-alcoholic fatty liver disease (NAFLD) progression in obese patients. An increase in plasma IL-6 levels is associated with decreased, mitochondrial transcription factor A (TFAM) protein production in liver biopsies in obese patients with and without T2DM. Replication, transcription, and division processes in liver biopsy were reduced in patients with T2DM. Inflammatory processes stimulate liver cell apoptosis in obese patients with T2DM. The increase in IL-11 levels is associated with decreased pro-apoptotic Bcl-2-associated X protein (BAX) protein production in obese patients with and without T2DM.

Exosome Limitations in the Treatment of Inflammatory Diseases.

BACKGROUND: Despite the great interest and numerous studies, there is currently no unified standard describing the sequential manipulation with cells to obtain exosomes for clinical use.The use of exosomes has become an attractive alternative to cell therapy, since the flexible nature of these biological vesicles allows scientists to manipulate their composition to produce the desired exosomes carrying specific drugs, RNA and proteins. This study aimed to analyse scientific literature on the changes in the functional characteristics of exosomes, depending on the method of manipulation, potentially contributing to the development of negative effects in the treatment of diseases of inflammatory genesis. RESULTS: The choice of isolation method affects the expressed sets of protein markers, nucleic acids and receptors on microparticles. Various surface receptors present on the exosome membrane can be engineered to target lesions. Exosomes from healthy patients help to reduce inflammation, normalize intercellular communication and have anti-fibrotic, antioxidant, and cytoprotective effects. Exosomes can change the microenvironment, but the microenvironment can also change the composition of exosomes. CONCLUSION: Exosomes obtained from sick patients carry markers characteristic of the corresponding disease. Such exosomes can have pro-inflammatory, pro-fibrotic, cytotoxic, and oncogenic properties, and disrupt cellular cooperation. Until now, questions regarding the dose, reactions to repeated administration, and dosage regimes have not been completely resolved.

Tissue-Specific Role of Macrophages in Noninfectious Inflammatory Disorders.

Chronic inflammation may not begin with local tissue disorders, such as hypoxia, but with the accumulation of critically activated macrophages in one site. The purpose of this review is to analyze the data reported in the scientific literature on the features of the functions of macrophages and their contributions to the development of pathology in various tissues during aseptic inflammation in obese subjects. In individuals with obesity, increased migration of monocytes from the peripheral blood to various tissues, the proliferation of resident macrophages and a change in the balance between alternatively activated anti-inflammatory macrophages (M2) and pro-inflammatory classically activated macrophages (M1) towards the latter have been observed. The primary cause of some metabolic pathologies has been precisely identified as the recruitment of macrophages with an altered phenotype, which is probably typical for many other pathologies. Recent studies have identified phenotypes, such as metabolically activated M (MMe), oxidized (Mox), hemoglobin-related macrophages (Mhem and MHb), M4 and neuroimmunological macrophages (NAM, SAM), which directly and indirectly affect energy metabolism. The high heterogeneity of macrophages in tissues contributes to the involvement of these cells in the development of a wide range of immune responses, including pathological ones. The replenishment of tissue-specific macrophages occurs at the expense of infiltrating monocyte-derived macrophages (MoMFs) in the pathological process. The origin of MoMFs from a general precursor retains their common regulatory mechanisms and similar sensitivity to regulatory stimuli. This makes it possible to find universal approaches to the effect on these cells and, as a consequence, universal approaches for the treatment of various pathological conditions.

Epigenetic regulation as a promising tool for treatment of atherosclerosis.

Atherosclerosis is one of the leading causes of death from cardiovascular disease (CVD) that primarily involves  mid size and large arteries. Atherosclerosis is associated with disruption of lipid metabolism and chronic inflammatory processes. One approach for treatment of atherosclerosis is by virtue of epigenetic control by noncoding RNAs (ncRNA) including miRNA, siRNA and lncRNA,  commonly employing miRNA antagonists and mimic compounds. Here, we review such usages as well as other approaches for correcting the molecular lesions of atherosclerosis including specific activation of atheroprotective miRNAs, as well as use of siRNAs and lcRNA to control aberrant lipid metabolism.  We also discuss some of these technologies that have already shown to be effective in clinical trials and are likely to enter the clinical arena.

Promising Directions in Atherosclerosis Treatment Based on Epigenetic Regulation Using MicroRNAs and Long Noncoding RNAs.

Atherosclerosis is one of the leading causes of mortality from cardiovascular disease (CVD) and is a chronic inflammatory disease of the middle and large arteries caused by a disruption of lipid metabolism. Noncoding RNA (ncRNA), including microRNA (miRNA), small interfering RNA (siRNA) and long noncoding RNA (lncRNA), was investigated for the treatment of atherosclerosis. Regulation of the expression of noncoding RNA targets the constituent element of the pathogenesis of atherosclerosis. Currently, miRNA therapy commonly employs miRNA antagonists and mimic compounds. In this review, attention is focused on approaches to correcting molecular disorders based on the genetic regulation of the transcription of key genes responsible for the development of atherosclerosis. Promising technologies were considered for the treatment of atherosclerosis, and examples are given for technologies that have been shown to be effective in clinical trials.