Current Pharmaceutical Design - Volume 27, Issue 27, 2021

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of targets genes by binding to the 3′-untranslated regions. They play vital roles in diverse biological processes, including the development of hepatic fibrosis (HF). HF is characterized by the accumulation of extracellular matrix (ECM) and hepatic stellate cells (HSCs) are considered a major cell type for producing ECM. Alteration of the HSC phenotype plays a crucial role in the HF pathological process. MiRNAs involved in various biological process, such as differentiation, apoptosis, migration, and their relevant signaling pathways, are expressed in HSCs; however, emerging evidence indicates that numerous miRNAs are abnormally expressed in activated HSCs. In this review, we summarize the categorization of miRNAs in HF and describe the relationships among them. We also discuss miRNAs recently discovered to be related to HF, and attempt to find potential miRNAs that may serve as novel biomarkers for use in HF treatment.

It is well known that muscles can waste away (atrophy) due to a lack of physical activity. Muscle wasting commonly presents with reduced muscle strength and an impaired ability to perform daily tasks. Several studies have attempted to categorize muscle atrophy into three main subgroups: physiologic, pathologic, and neurogenic atrophy. Physiologic atrophy is caused by the general underuse of skeletal muscle (e.g., bedridden). Pathologic atrophy is characterized as the loss of stimulus to a specific region (e.g., aging). Neurogenic atrophy results from damage to the nerve innervating a muscle (e.g., SMA, GBS). Mechanisms have been elucidated for many of these pathways (e.g., ubiquitin-proteasome system, NF-ΚB, etc.). However, many causes of muscle atrophy (e.g., burns, arthritis, etc.) operate through unelucidated signaling cascades. Therefore, this review highlights the underlying mechanisms of each subtype of muscle atrophy while emphasizing the need for additional research in properly classifying and identifying muscle atrophy.

Diabetes mellitus (DM) is a chronic and complex metabolic disorder, and also an important cause of cardiovascular (CV) diseases (CVDs). Subclinical inflammation, observed in patients with type 2 DM (T2DM), cannot be considered the sole or primary cause of T2DM in the absence of classical risk factors, but it represents an important mechanism that serves as a bridge between primary causes of T2DM and its manifestation. Progress has been made in the identification of effective strategies to prevent or delay the onset of T2DM. It is important to identify those at increased risk for DM by using specific biomarkers. Inflammatory markers correlate with insulin resistance (IR) and glycoregulation in patients with DM. Also, several inflammatory markers have been shown to be useful in assessing the risk of developing DM and its complications. However, the intertwining of pathophysiological processes and the not-quite-specificity of inflammatory markers for certain clinical entities limits their practical use. In this review we consider the advantages and disadvantages of various inflammatory biomarkers of DM that have been investigated to date as well as possible future directions. Key features of such biomarkers should be high specificity, non-invasiveness and cost-effectiveness.

The global prevalence of NAFLD is estimated to be over 25% and it is already the leading cause of chronic liver disease in industrialized countries, as a consequence of the spread of obesity and metabolic syndrome. The prognosis of NAFLD is generally benign in the absence of fibrosis, but liver fibrosis rapidly progresses in 20% of the cases and can lead to cirrhosis and/or HCC. This review focuses on non-invasive fibrosis testing strategies for patients with NAFLD in order to increase the efficiency and effectiveness of diagnosis and care, regulating secondary care referral fluxes. An integrated management plan between primary care and secondary care with a defined algorithm of non-invasive testing to stratify the risk of NAFLD fibrosis is indispensable to increase the early diagnosis of fibrosis but also decrease unnecessary referrals.

Background: This study was performed to identify the alterations of Long non-coding RNAs (lncRNAs) induced by oxidative stress and investigate the functional roles of SNHG16 in the pathological angiogenesis by human retinal microvascular endothelial cells (HMRECs). Methods: The expression profiles of lncRNAs and mRNAs induced by oxidative stress were identified by RNA-Seq, and the dysregulation of 16 lncRNAs including SNHG16 was verified in H2O2-treated human umbilical vein endothelial cells (HUVECs). Luciferase reporter assay and RIP analysis were used to investigate the binding relationship of SNHG16 to miR-195. Results: We confirmed that over-expression of SNGH16 attenuated H2O2-induced angiogenesis by HMRECs. In addition, SNHG16 was significantly decreased, whereas miR-195, a predictive target of SNHG16, was upregulated in H2O2, HG, and AGE-treated HMRECs. The binding relationship of SNHG16 to miR-195 was subsequently verified by luciferase reporter assay and RIP analysis. SNHG16 cotransfection abolished miR-195-mediated repression on mitofusin 2 (mfn2) protein level and counteracted the inductive effect of miR-195 on angiogenesis by HMRECs. Conclusion: These results indicated that decreased SNHG16 accelerates oxidative stress-induced pathological angiogenesis in HMRECs by regulating the miR-195/mfn2 axis, providing a potential target for diabetic retinopathy (DR) therapy.

Background: Biogenic amines (BAs) secreted by the sympathetic neural apparatus of rat uterus are reported to be conducive to the uterine functional activity during postpartum involution; the imbalance in BAs ratio could confer postpartum reproductive disorders including improper postpartum involution. Objective: The objective of this study is to identify the changes in the density of uterine sympathetic nerves implicated in the pathology of endometriosis, adenomyosis, and delayed uterine involution. The present study aims to ascertain ‘serotonin’ and ‘catecholamine’ concentrations in mesenteric mast cells (MCs), and structural elements of nerve fibers across the perivascular plexuses (PPs) and single sympathetic nerve terminals (SST). Methods: Furthermore, the density of their spatial distribution (SDP and SDT) in the uterine body, cervix, and mesometrium was determined during postpartum involution. Tissue specimens of postpartum uterus were obtained from 55 nulliparous female Wistar outbred strain rats, which were grouped according to the days after parturition at the time of sacrifice. The nerve fibers of PP and SST exhibited emerald green fluorescence, which was detected by glyoxylic acid fluorescence technique; the fluorescence invoked by BAs was identified by microspectrofluorimetry. Results: Concentrations of BAs were extensive in the varicosities of PP and SST on the 10th day. However, the highest BA concentrations were found in structural elements of PP in the uterine mesometrium in the initial days of postpartum. In mesenteric MC, serotonin and catecholamines were at the highest concentration on the 10th day of postpartum. Histamines peaked on the 6th day. Conclusion: SDP and SDT were increased significantly in all structural elements of uterine nerve fibers in the uterine body and cervix compared to SDP in mesentery. Considering that catecholamines and serotonin are antagonists in many aspects of their biological action, the ratio of BAs should be well-balanced to maintain anabolic- catabolic equilibrium in the rat uterus.

Background: In patients admitted to the Intensive Care Unit (ICU), mortality is high due to multiple organ damage. Mitochondrial dysfunction and impaired oxygen consumption, as causative mechanisms, play a significant role in reducing the activity of immune cells in sepsis, resulting in the progression of the multiple organ dysfunction syndromes (MODS). The evaluation of mitochondrial function in critical care patients in the immune cells, especially in lymphocytes, could reveal the target point that determines mitochondrial failure. Objective: To find the relationship between mitochondrial reactive oxygen species production (mROS), mitochondrial membrane potential (ΔΨm), and mitochondrial oxygen consumption (mVO2) in peripheral plasma lymphocytes collected from ICU patients. We also compared these three characteristic mitochondrial functions with C-reactive protein (CRP), serum lactate, and central venous saturation (SvO2) that would enable the prediction of the ultimate outcome. Methods: Isolated lymphocytes from 54 critical care patients with SIRS by sepsis and non-sepsis etiologies were analyzed with flow cytometry by staining with dihydroethidium and JC-1, measuring mROS, ΔΨm, and mVO2. Clinical variables, such as serum lactate (mmol/L) and C-reactive protein (mg/L) from peripheral blood, were measured in the first 24 hours of admission. A confounding analysis was performed using logistic regression, and a p-value of <0.05 was considered statistically significant. Results: It has been confirmed that there is a drastic increase in reactive oxygen species (ROS) and mVO2 in critically ill patients immediately after exposure to the insult pathogen-associated molecular pattern /damageassociated molecular pattern (PAMPS/DAMPS) and continued for the first 24 hours thereafter. The results showed no significant alterations in the mitochondrial membrane potential (ΔΨm) compared with the lymphocytes in controls. A significant correlation between CRP and SvO2 and a strong positive relationship between CRP, values above 3 mg/l, and white blood cells were observed. Conclusion: Lymphocytes from patients with SIRS displayed higher mitochondrial respiratory capacities and reactive oxygen species production compared with controls. Clinical markers of inflammation indirectly evaluate the mitochondrial function, most of which have been validated in a clinical setting.