Role of narL gene in the pathogenesis of Salmonella Typhimurium.

Salmonella Typhimurium (STM) is a facultative anaerobe and one of the causative agents of nontyphoidal salmonellosis (NTS). Its anaerobic metabolism is enabled under the hypoxic environment that is encountered inside macrophages and the gut lumen of the host. In both of these niches, free radicals and oxidative intermediates are released by neutrophils as an inflammatory response. These chemical species further undergo reactions to produce nitrate, which is preferably taken up by STM as an electron acceptor in the absence of oxygen. NarL, the response regulator of the two-component regulatory system NarX/L, and a transcription factor, gets activated under anaerobic nitrate-rich conditions and upregulates the nitrate reduction during anaerobic respiration of STM. To understand the role of NarL in the pathogenesis of STM, we generated a narL-knockout (STM:ΔnarL) as well as a narL-complemented strain of STM. Anaerobically, the mutant displayed no growth defect but a significant attenuation in the swimming (26%) and swarming (61%) motility, and biofilm-forming ability (73%) in vitro, while these morphotypes got rescued upon genetic complementation. We also observed a downregulation in the expression of genes associated with nitrate reduction (narG) and biofilm formation (csgA and csgD) in anaerobically grown STM:ΔnarL. As compared with wild STM, narL mutant exhibited a threefold reduction in the intracellular replication in both intestinal epithelial cells (INT- 407) and monocyte-derived macrophages of poultry origin. Further, in vivo competitive assay in the liver and spleen of the murine model showed a competitive index of 0.48 ± 0.58 and 0.403668 ± 0.32, respectively, for STM:ΔnarL.

Biochanin-A alleviates fibrosis and inflammation in cardiac injury in mice.

Biochanin-A (BCA), is an isoflavonoid, exhibits protective effects against various diseases. This study was conducted to observe the effect of BCA on isoprenaline (ISP)-induced cardiac fibrosis and explore the underlying mechanism. The curative effect of BCA was investigated with oral administration for 14 days in ISP-induced cardiac fibrosis in mice. The fibrotic biomarkers, like collagen I and III, were estimated by ELISA. Commercial kits were used to estimate cholesterol, triglycerides, and creatine kinase-myocardial band (CK-MB) levels. The messenger ribonucleic acid (mRNA) expression studies were performed by quantitative real-time polymerase chain reaction. Gelatin zymography was used to study the expression of matrix metalloproteinases-2 (MMP-2). BCA co-administration significantly improved the morphometric parameters; including heart weight, heart weight to body weight, heart weight to tibial length, and lipid profile. BCA treatment showed a reduction in inflammatory cells and collagen deposition as depicted in the histopathology of heart tissues. The enhanced levels of collagen-I, III, and hydroxyproline were significantly decreased by BCA co-treatment, whereas CK-MB level was reduced slightly. BCA co-administration increased the activity of reduced glutathione enzyme, showing the antioxidative effects of BCA. BCA treatment significantly reduced interleukin-6 (Il6) inflammatory cytokine along with partially decreased mRNA expression of fibrotic signaling markers such as natriuretic peptide type B (Nppb), α-smooth muscle actin (Acta2), connective tissue growth factor (Ctgf), transforming growth factor ß (Tgfb), small mothers against decapentaplegic homolog-3 (Smad-3). However, BCA did not modify Mmp-2 expression, which was significantly increased by ISP. In conclusion, BCA exerts an antifibrotic effect by modulating lipid profile, enhancing antioxidant enzyme, and reducing collagen content and inflammation.

Prophylactic and therapeutic insights into trained immunity: A renewed concept of innate immune memory.

Trained immunity is a renewed concept of innate immune memory that facilitates the innate immune system to have the capacity to remember and train cells via metabolic and transcriptional events to enable them to provide nonspecific defense against the subsequent encounters with a range of pathogens and acquire a quicker and more robust immune response, but different from the adaptive immune memory. Reversing the epigenetic changes or targeting the immunological pathways may be considered potential therapeutic approaches to counteract the hyper-responsive or hypo-responsive state of trained immunity. The efficient regulation of immune homeostasis and promotion or inhibition of immune responses is required for a balanced response. Trained immunity-based vaccines can serve as potent immune stimuli and help in the clearance of pathogens in the body through multiple or heterologous effects and confer protection against nonspecific and specific pathogens. This review highlights various features of trained immunity and its applications in developing novel therapeutics and vaccines, along with certain detrimental effects, challenges as well as future perspectives.