Hepatoprotective Role of Carvedilol against Ischemic Hepatitis Associated with Acute Heart Failure via Targeting miRNA-17 and Mitochondrial Dynamics-Related Proteins: An In Vivo and In Silico Study.

Acute heart failure (AHF) is one of the most common diseases in old age that can lead to mortality. Systemic hypoperfusion is associated with hepatic ischemia-reperfusion injury, which may be irreversible. Ischemic hepatitis due to AHF has been linked to the pathogenesis of liver damage. In the present study, we extensively investigated the role of mitochondrial dynamics-related proteins and their epigenetic regulation in ischemic liver injury following AHF and explored the possible hepatoprotective role of carvedilol. The biochemical analysis revealed that the ischemic liver injury following AHF significantly elevated the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) enzymes, the level of total and direct bilirubin, and the expression of hepatic mitogen-activated protein kinase (MAPK), dynamin-1-like protein (DNM1L), and hepatic miRNA-17. At the same time, it significantly reduced the serum albumin level, the activity of hepatic superoxide dismutase (SOD), and the expression of mitochondrial peroxisome proliferator-activated receptor-1α (PGC-1α), and mitofusin 2 (Mtf2). The histological examination of the liver tissue revealed degenerated hepatocytes. Interestingly, administration of carvedilol either prior to or after isoprenaline-induced AHF significantly improved the liver function and reversed the deterioration effect of AHF-induced ischemic hepatitis, as demonstrated by biochemical, immunohistochemical, and histological analysis. Our results indicated that the hepatoprotective effect of carvedilol in ameliorating hepatic ischemic damage could be attributed to its ability to target the mitochondrial dynamics-related proteins (Mtf2, DNM1L and PGC-1α), but also their epigenetic regulator miRNA-17. To further explore the mode of action of carvedilol, we have investigated, in silico, the ability of carvedilol to target dynamin-1-like protein and mitochondrial dynamics protein (MID51). Our results revealed that carvedilol has a high binding affinity (-14.83 kcal/mol) toward the binding pocket of DNM1L protein. In conclusion, our study highlights the hepatoprotective pharmacological application of carvedilol to attenuate ischemic hepatitis associated with AHF.

Vitamin D3 Prevents the Deleterious Effects of Testicular Torsion on Testis by Targeting miRNA-145 and ADAM17: In Silico and In Vivo Study.

Testicular torsion (TT) is the most common urological emergency in children and young adults that can lead to infertility in many cases. The ischemia-reperfusion (IR) injury due to TT has been implicated in the pathogenesis of testicular damage. The main pathological mechanisms of contralateral injury after ipsilateral TT are not fully understood. In the presented study, we investigated the molecular and microscopic basis of ipsilateral and contralateral testicular injury following ipsilateral testicular torsion detorsion (T/D) and explored the possible protective role of vitamin D3. The biochemical analysis indicated that IR injury following T/D significantly decreased the activity of testicular glutathione peroxidase (GPx) enzyme, level of serum testosterone, serum inhibin B, and expression of testicular miRNA145, while increased the activity of testicular myeloperoxidase (MPO) enzyme, level of testicular malondialdehyde (MDA), level of serum antisperm-antibody (AsAb), and expression of ADAM-17. The histological and semen analysis revealed that torsion of the testis caused damages on different tissues in testis. Interestingly, administration of vitamin D3 prior to the IR injury reversed the deterioration effect of IR injury on the testicular tissues as indicated by biochemical and histological analysis which revealed normal appearance of the seminiferous tubules with an apparent decrease in collagen fiber deposition in both ipsilateral and contralateral testes. Our results revealed that the protective effect of vitamin D3 treatment could be attributed to target miRNA145 and ADAM17 protein. To further investigate these findings, we performed a detailed molecular modelling study in order to explore the binding affinity of vitamin D3 toward ADAM17 protein. Our results revealed that vitamin D3 has the ability to bind to the active site of ADAM17 protein via a set of hydrophobic and hydrophilic interactions with high docking score. In conclusion, this study highlights the protective pharmacological application of vitamin D3 to ameliorate the damages of testicular T/D on the testicular tissues via targeting miRNA145 and ADAM17 protein.

Modified Potentiometric Screen-Printed Electrodes Based on Imprinting Character for Sodium Deoxycholate Determination.

Potentiometric sensors have a great influence on the determination of most various compounds in their matrices. Therefore, efficient and new sensors were introduced to measure sodium Deoxycholate (NaDC) as a bile acid salt. These sensors are based on NaDC imprinted polymer (MIP) as sensory element. The MIP beads were synthesized using thermal polymerization pathway, in which acrylamide (AAm), ethylene glycol dimethacrylate (EGDMA), NaDC, and benzoyl peroxide (BPO) were used as the functional monomer, cross-linker, template, and initiator, respectively. The proposed sensors were fabricated using a coated screen-printed platform and the sensing membrane was modified by single-walled carbon nanotubes (SWCNTs) as an ion-to-electron transducer. The sensors exhibited high sensitivity that reached 4.7 × 10-5 M of near-Nernestian slope (-60.1 ± 0.9 mV/decade, r2 = 0.999 (n= 5)). In addition, the sensors revealed high selectivity, long lifetime, high potential stability, and conductivity that ensure reproducible and accurate results over a long time. MIP characterization was performed using Fourier Transform-Infrared (FT-IR) and a scanning electron microscope (SEM). Regarding the interaction of NaDC with serum albumin (SA), albumin is determined in human serum samples as human serum albumin (HSA), which was collected from different volunteers of different ages and gender.

Single-Piece All-Solid-State Potential Ion-Selective Electrodes Integrated with Molecularly Imprinted Polymers (MIPs) for Neutral 2,4-Dichlorophenol Assessment.

A novel single-piece all-solid-state ion-selective electrode (SC/ISE) based on carbon-screen printed is introduced. Polyaniline (PANI) is dissolved in a membrane cocktail that contains the same components used for making a conventional ion-selective polyvinyl chloride (PVC) matrix membrane. The membrane, having the PANI, is directly drop-casted on a carbon substrate (screen-printed-carbon electrode). PANI was added to act as an intermediary between the substrate and the membrane for the charge transfer process. Under non-equilibrium sensing mechanism, the sensors revealed high sensitivity towards 2,4-dichlorophenol (DCP) over the linearity range 0.47 to 13 µM and a detection limit 0.13 µm. The selectivity was measured by the modified separate solution method (MSSM) and showed good selectivity towards 2,4-DCP over the most commonly studied ions. All measurements were done in 30 mm Tris buffer solution at a pH 5.0. Using constant-current chronopotentiometry, the potential drift for the proposed electrodes was checked. Improvement in the potential stability of the SPE was observed after the addition of PANI in the sensing membrane as compared to the corresponding coated-wire electrode (membrane without PANI). The applicability of the sensor has been checked by measuring 2,4-DCP in different water samples and the results were compared with the standard HPLC method.

Zoledronic acid prevents the hepatic changes associated with high fat diet in rats; the potential role of mevalonic acid pathway in nonalcoholic steatohepatitis.

The role of hepatic free cholesterol (FC) in nonalcoholic steatohepatitis (NASH) is raised up and the intervention with cholesterol synthesis will be a potential therapeutic target. This study investigated the hepatoprotective effect of mevalonic acid pathway inhibition by Zoledronic acid (ZA) on the hepatic changes associated with high fat diet (HFD) in rats.Thirty two male Wistar rats were used. They were divided into 2 groups: (I) control naïve (II) NASH: induced by HFD for 12 weeks, this group is subdivided into (A) NASH untreated (B)NASH + ZA (50ug/kg/week) i.p. for 12 weeks (C) NASH + ZA (100µg/kg/week) i.p. for 12 weeks. Portal pressure (PP), liver enzymes AST and ALT, serum glucose, lipid profile, hepatic levels of tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), FC and triglyceride (TG), histopathological changes and expression of both hepatic alpha smooth muscle actin (α-SMA) and Caspase-3 were measured. ZA significantly prevented portal hypertension, worsening in liver function, and dyslipidemia. The hepatic levels of TNF-α, VEGF, FC and TG were significantly decreased in comparison to NASH untreated group. ZA hindered the histopathological changes induced by HFD. ZA inhibited the expression of hepatic α-SMA and Caspase-3 with significant difference favor the high dose intervention. ZA in a dose related manner prevents the hepatic pathological effects of chronic HFD ingestion in rats. This may be largely mediated by its ability to reduce TNF-α and hepatic FC.

Exenatide promotes cardiac lncRNAs HOX transcript antisense RNA (HOTAIR) in Wistar rats with liver cirrhosis; a novel role of GLP-1 receptor agonists in cirrhotic cardiomyopathy.

Long acting non-coding RNAs lncRNAs HOX Transcript Antisense RNA (HOTAIR) is cardioprotective and mediates its effect through sirtulin 1 (SIRT1). The decrease in HOTAIR expression predisposes to various types of cardiomyopathy. We aimed to investigate whether decrease HOTAIR expression is involved in cirrhotic cardiomyopathy or not and the role of glucagon like peptide 1 receptor (GLP-1 receptor) in facilitating its effect through studying the effect of a exenatide (EXA), on cardiac function as well as the expression of some relevant bio-molecules. Rats were used and divided into: naïve, EXA, Thioacetamide (TAA) and TAA + EXA groups. ECG, dobutamine stress test (DST) were done. AST, ALT, fasting blood glucose, troponin I were measured. Cardiac HOTAIR & SIRT1, hepatic and cardiac GLP-1 receptor expression levels were investigated in addition to histological studies. Our results showed that EXA administration in control rats produced no significant changes. TAA induced cirrhosis with insulin resistance and significant changes in cardiac functions. GLP-1 receptor, HOTAIR and SIRT1 expression in cardiac tissue were significantly decreased with a significant increase in troponin I. EXA + TAA group showed a restoration of the hepatic architecture and function. EXA treatment produced significant improvement in cardiac parameters and was associated with increasing the expression of cardiac GLP-1 receptor, HOTAIR. The cardiac muscle showed an apparent decrease in collagen fibers. So we can conclude that EXA promotes the protective effect of HOTAIR on cardiac structure and function in rat model of cirrhosis which may introduce a new therapeutic strategy in cirrhotic cardiomyopathy.