Evaluation of the Effect of Carvedilol on the Thioredoxin Pathway in H9C2 Rat Cardiomyocytes

The thioredoxin (Trx) system is an endogenous antioxidant system that affects cell function and survival through controlling cellular redox status. Trx and TrxR are the main enzymes in this system while thioredoxin interacting protein (TXNIP) is a negative regulator. This study’s goal was to better understand the Trx system’s involvement in the cardiovascular disease and modulate the pathway through drug treatment. Carvedilol is a non-selective β-blocker that also exhibits antioxidant properties, but the exact mechanism of the antioxidant effect is still unclear. H9c2 rat cardiomyocytes were used to examine the effect of carvedilol on the Trx system under normal conditions. Interestingly, carvedilol was able to decrease TXNIP not through its expression or proteasomal degradation but through increased TXNIP nuclear localization. Immunoprecipitation also showed an increase in TXNIP-PARP complexation in the nucleus and a decrease in Trx-TXNIP complexation in the cytosol. The results indicate that carvedilol may exhibit its antioxidant activity through altering TXNIP subcellular localization. TXNIP is known to be important in both physiologic and pathophysiologic conditions. Western blot data showed that TXNIP in the cytosol will increase with increasing glucose concentration. Oxidative stress inducers such as doxorubicin, hypoxiareoxygenation, and radiation were able to decrease cytosolic TXNIP. Doxorubicin is a commonly utilized anticancer drug that induces oxidative stress and therefore causes cardiac toxicity. A study was conducted to determine if carvedilol could protect against doxorubicin-induced cardiotoxicity through TXNIP modulation. Carvedilol and doxorubicin alone reduced cytosolic TXNIP. Doxorubicin increased mitochondrial translocation of TXNIP accompanied by the induction of apoptosis. However, carvedilol was not able to prevent TXNIP mitochondrial translocation, but it did protect against doxorubicin-induced apoptosis. The complex of Trx2 and the proapoptotic ASK1 in the mitochondria was increased with carvedilol pretreatment followed by doxorubicin exposure. The increase in the ASK1-Trx2 complex can reduce apoptosis through decreased ASK1 activation. This was confirmed through Western blot of cleaved PARP. The findings are consistent with reports of TXNIP’s response to mild oxidative stress conditions. In conclusion, this study shows for the first time that carvedilol impacts TXNIP localization and complexation and that the Trx pathway may be involved in carvedilol’s observed cardioprotective effect

Comparative genomics of food-derived probiotic Lactiplantibacillus plantarum K25 reveals its hidden potential, compactness, and efficiency

This study aimed to investigate the intricate genetic makeup of the Lactiplantibacillus plantarum K25 strain by conducting a comprehensive analysis of comparative genomics. The results of our study demonstrate that the genome exhibits a high-level efficiency and compactness, comprising a total of 3,199 genes that encode proteins and a GC content of 43.38%. The present study elucidates the evolutionary lineage of Lactiplantibacillus plantarum strains through an analysis of the degree of gene order conservation and synteny across a range of strains, thereby underscoring their closely interrelated evolutionary trajectories. The identification of various genetic components in the K25 strain, such as bacteriocin gene clusters and prophage regions, highlights its potential utility in diverse domains, such as biotechnology and medicine. The distinctive genetic elements possess the potential to unveil innovative therapeutic and biotechnological remedies in future. This study provides a comprehensive analysis of the L. plantarum K25 strain, revealing its remarkable genomic potential and presenting novel prospects for utilizing its unique genetic features in diverse scientific fields. The present study contributes to the existing literature on Lactiplantibacillus plantarum and sets the stage for prospective investigations and practical implementations that leverage the exceptional genetic characteristics of this adap organism

GC–MS profiling of Bacillus spp. metabolites with an in vitro biological activity assessment and computational analysis of their impact on epithelial glioblastoma cancer genes

Background: Bacterial metabolites play a crucial role in human health and have proven effective in treating various diseases. In this study, the 16S rRNA method and streaking were employed to isolate and molecularly identify a bacterial strain, with the goal of characterizing bioactive volatile metabolites extracted using nonpolar and polar solvents.Methods: Gas chromatography–mass spectrometry (GC–MS) analysis was conducted to identify 29 compounds in the bacterial metabolites, including key compounds associated with Bacillus spp. The main compounds identified included 2-propanone, 4,4-ethylenedioxy-1-pentylamine, 1,2-benzenedicarboxylic acid, 1,1-butoxy-1-isobutoxy-butane, and 3,3-ethoxycarbonyl-5-hydroxytetrahydropyran-2-one.Results: The literature indicates the diverse biological and pharmacological applications of these compounds. Different concentrations of the metabolites from Bacillus species were tested for biological activities, revealing significant inhibitory effects on anti-diabetic activity (84.66%), anti-inflammatory activity (99%), antioxidant activity (99.8%), and anti-hemolytic activity (90%). Disc diffusion method testing also demonstrated a noteworthy inhibitory effect against tested strains.Conclusion:In silico screening revealed that 1,2-benzenedicarboxylic acid exhibited anticancer activity and promising drug-designing properties against epithelial glioblastoma cancer genes. The study highlights the potential of Bacillus spp. as a valuable target for drug research, emphasizing the significance of bacterial metabolites in the production of biological antibacterial agents

Integrated Mechanisms of Polarity–Based Extracts of Cucumis melo L. Seed Kernels for Airway Smooth Muscle Relaxation via Key Signaling Pathways Based on WGCNA, In Vivo, and In Vitro Analyses

The present study aimed to determine the mechanisms responsible for calcium–mediated smooth muscle contractions in C. melo seeds. The phytochemicals of C. melo were identified and quantified with the aid of Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometric (LC/ESI–MS/MS) and high–performance liquid chromatography (HPLC), and then tested in–vitro and in vivo to confirm involvement in smooth muscle relaxation. Allergic asthma gene datasets were acquired from the NCBI gene expression omnibus (GEO) and differentially expressed gene (DEG) analysis, weighted gene co–expression network analysis (WGCNA), and functional enrichment analysis were conducted. Additionally, molecular docking of key genes was carried out. Kaempferol, rutin, and quercetin are identified as phytochemical constituents of C. melo seeds. Results indicated that C. melo seeds exhibit a dose–dependent relaxant effect for potassium chloride (80 mM)– induced spastic contraction and calcium antagonistic response in calcium dose–response curves. The functional enrichment of WGCNA and DEG asthma–associated pathogenic genes showed cytokine–mediated pathways and inflammatory responses. Furthermore, CACNA1A, IL2RB, and NOS2 were identified as key genes with greater binding affinity with rutin, quercitrin, and kaempferol in molecular docking. These results show that the bronchodilator and antidiarrheal effects of C. melo were produced by altering the regulatory genes of calcium–mediated smooth muscle contraction

A European perspective of phylogenomics, sublineages, geographical distribution, epidemiology, and mutational landscape of mpox virus: Emergence pattern may help to fight the next public health emergency in Europe

Background: The 2022 outbreak of the mpox virus (previously monkeypox virus, MPXV) in non-epidemic regions has created a global issue. The emergence of MPXV was first reported in Europe, which was described as the MPXV epicenter, however, no reports are available to illustrate its outbreak patterns in Europe. Methods: The study used numerous in silico and statistical methods to analyze hMPXV1 in European countries. Here, we used different bioinformatics servers and software to evaluate the spread of hMPXV1 in European countries. For analysis, we use various advanced servers like Nextstrain, Taxonium, MpoxSpectrum, etc. Similarly, for the statistical model, we used PAST software. Results: The phylogenetic tree was depicted to illustrate the origin and evolution of hMPXV1 using vas number of genome sequences (n = 675). We found several sublineages in Europe, indicating microevolution. The scatter plot reveals the clustering patterns of the newly developed lineages in Europe. We developed statistical models for the monthly total relative frequency counts of these sublineages. The epidemiology of MPX in Europe was examined in an attempt to capture the epidemiological pattern, total cases, and deaths. Our Study noted the highest number of cases was in Spain (7500 cases) and the second-highest in France (4114 cases). The third highest number of cases was in the UK (3730 cases), which was very similar to Germany (3677 cases). Finally, we noted the mutational landscape throughout European genomes. Significant mutations were observed at the nucleotide and protein levels. We identified several unique homoplastic mutations in Europe. Conclusion: This study reveals several essential aspects of the European outbreak. It might help to eradicate the virus in Europe, assist in strategy formation to fight against the virus, and support working against the next public health emergency in Europe

Designing of a Recombinant Multi-Epitopes Based Vaccine against Enterococcus mundtii Using Bioinformatics and Immunoinformatics Approaches

Enterococcus species are an emerging group of bacterial pathogens that have a significant role in hospital-associated infections and are associated with higher mortality and morbidity rates. Among these pathogens, Enterococcus mundtii is one of the causative agents of multiple hospital associated infections. Currently, no commercially available licensed vaccine is present, and multi-drug resistant strains of the pathogen are prominent. Due to several limitations of experimental vaccinology, computational vaccine designing proved to be helpful in vaccine designing against several bacterial pathogens. Herein, we designed a multi-epitope-based vaccine against E. mundtii using in silico approaches. After an in-depth analysis of the core genome, three probable antigenic proteins (lytic polysaccharide monooxygenase, siderophore ABC transporter substrate-binding protein, and lytic polysaccharide monooxygenase) were shortlisted for epitope prediction. Among predicted epitopes, ten epitopes—GPADGRIAS, TTINHGGAQA, SERTALSVTT, GDGGNGGGEV, GIKEPDLEK, KQADDRIEA, QAIGGDTSN, EPLDEQTASR, AQWEPQSIEA, QPLKFSDFEL—were selected for multi-epitope vaccine construct designing. The screened B- and T-cell epitopes were joined with each other via specific linkers and linked to the cholera toxin B subunit as an adjuvant to enhance vaccine immune protection efficacy. The designed vaccine construct induced cellular and humoral immune responses. Blind docking with immune cell receptors, followed by molecular dynamic simulation results confirms the good binding potency and stability of the vaccine in providing protection against the pathogen

Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice Model

Tivozanib is a triple vascular endothelial growth factor receptor inhibitor, recently approved for the treatment of refractory advanced renal cell carcinoma. Clinical studies showed that around 46% of patients who received tivozanib suffer from hypertension in all grades. Thus, the present study was conducted to identify the role of angiotensin-II (AngII) in the mechanism underlying tivozanib-induced vascular toxicity and hypertension. C57BL/6 male mice received tivozanib (1 mg/kg) with or without losartan (10 or 30 mg/kg) for 3 weeks. Blood pressure was recorded every 3 days, and proteinuria was measured every week. On day 21, all mice were euthanized, and samples were harvested for further analysis. Tivozanib elevated blood pressure until systolic blood pressure reached 163 ± 6.6 mmHg on day 21 of treatment with low urination and high proteinuria. AngII and its receptors, endothelin-1, and oxidative stress markers were significantly increased. While nitric oxide (NO) levels were reduced in plasma and aortic tissues. AngII type 1 receptor blockade by losartan prevented these consequences caused by tivozanib and kept blood pressure within normal range. The results showed that AngII and ET-1 might be potential targets in the clinical studies and management of hypertension induced by tivozanib