Cyclophosphamide (CP) is a chemotherapeutic agent which is extensively used in the treatment of multiple neoplastic and nonneoplastic diseases like breast cancer, lymphomas, systemic lupus erythematosus, and multiple sclerosis. Dose‐limiting side effects, mainly nephrotoxicity is a major problem hindering its use in the clinical practice. CP induces nephrogenic syndrome of inappropriate antidiuresis mostly via the activation of arginine vasopressin V₂ receptors. Moreover, CP produces reactive metabolites which is responsible for augmentation of lipid peroxidation and oxidative stress. Tolvaptan (TOL) is a selective vasopressin V₂ receptor antagonist used in the treatment of clinically significant hyponatremia, volume overload in heart failure, and liver cirrhosis with edema. The present study aimed to investigate the potential protective effect of TOL in CP‐induced nephrotoxicity. Twenty‐four adult male albino rats were randomly divided into four groups: the control group, TOL group that treated daily with tolvaptan (10 mg/kg/d, orally), CP group where CP was administered intraperitoneally 75 mg/kg on days 3, 4, 5, 19, 20, and 21 of study, and the CP + TOL group where animals were treated with TOL daily with (10 mg/kg/d, orally) for 22 days with concomitant administration of CP as described before. Coadministration of TOL with CP induces significant improvement in the level of urine volume, serum Na+, serum osmolarity, urinary creatinine, and free water clearance in addition to significant reduction of body weight, serum creatinine, urea, serum K+, blood pressure, urine osmolarity, and the fractional excretion of sodium as compared to CP‐treated group. In addition, coadministration of TOL significantly reduced MDA, the marker of lipid peroxidation, and different pro‐inflammatory cytokines. Histopathological changes showed improvement in the signs of nephrotoxicity with the coadministration of TOL. Also, co‐treatment with TOL significantly decreased the level of markers of apoptosis as caspase‐3 and Bax with increased expression of antiapoptotic Bcl‐2 in renal tissue as compared to CP‐treated group.

For clinicians, Pseudomonas aeruginosa is a nightmare pathogen that is one of the top three causes of opportunistic human infections. Therapy of P. aeruginosa infections is complicated due to its natural high intrinsic resistance to antibiotics. Active efflux and decreased uptake of drugs due to cell wall/membrane permeability appear to be important issues in the acquired antibiotic tolerance mechanisms. Bacterial cell wall biosynthesis enzymes have been shown to be essential for pathogenicity of Gram-negative bacteria. However, the role of these targets in virulence has not been identified in P. aeruginosa. Here, we report knockout (k.o) mutants of six cell wall biosynthesis targets (murA, PA4450; murD, PA4414; murF, PA4416; ppiB, PA1793; rmlA, PA5163; waaA, PA4988) in P. aeruginosa PAO1, and characterized these in order to find out whether these genes and their products contribute to pathogenicity and virulence of P. aeruginosa. Except waaA k.o, deletion of cell wall biosynthesis targets significantly reduced growth rate in minimal medium compared to the parent strain. The k.o mutants showed exciting changes in cell morphology and colonial architectures. Remarkably, ΔmurF cells became grossly enlarged. Moreover, the mutants were also attenuated in vivo in a mouse infection model except ΔmurF and ΔwaaA and proved to be more sensitive to macrophage-mediated killing than the wild-type strain. Interestingly, the deletion of the murA gene resulted in loss of virulence activity in mice, and the virulence was restored in a plant model by unknown mechanism. This study demonstrates that cell wall targets contribute significantly to intracellular survival, in vivo growth, and pathogenesis of P. aeruginosa. In conclusion, these findings establish a link between cell wall targets and virulence of P. aeruginosa and thus may lead to development of novel drugs for the treatment of P. aeruginosa infection.

Background: Idiopathic pulmonary fibrosis (IPF) is a serious disease with high mortality rate. Activation of transforming growth factor (TGF)-β1 production and signalling is considered the corner stone in the epithelial-mesenchymal transition (EMT) process. EMT plays a central role in development of fibrosis in many organs including the lungs. Activated platelets are an important source of TGF-β1 and play a pivotal role in EMT and fibrosis process. The antiplatelet, ticagrelor was previously found to inhibit the EMT in different types of cancer cells, but its ability to serve as an anti-pulmonary fibrosis (PF) agent was not previously investigated. Objective: In this study, we aim to investigate the potential ability of ticagrelor to ameliorate bleomycin-induced fibrosis in rats. Methods: PF was induced in rats by intratracheal BLM at a dose of 3 mg/kg. The effect of daily daily 20 mg/kg oral ticagrelor on different histological and biochemical parameters of fibrosis was investigated. Results: Our results revealed that ticagrelor can alleviate lung fibrosis. We found that ticagrelor inhibited TGF-β1 production and suppressed Smad3 activation and signaling pathway with subsequent inhibition of Slug and Snail. In addition, ticagrelor antagonized PI3K/AKT/mTOR pathway signaling. Moreover, ticagrelor inhibited the EMT that revealed by its ability to up-regulate the epithelial markers as E-cadherin (E-cad) and to decrease the expression of the mesenchymal markers as vimentin (VIM) and alpha-smooth muscle actin (α-SMA). Conclusion: Our results suggest that the P2Y12 inhibitor, ticagrelor may have a therapeutic potential in reducing the progression of PF.

Background: Coronavirus disease 2019, COVID‐19, has reached all the corners of the world and was declared by the WHO as a global pandemic and public health emergency of international concern on the January 31, 2020. Allocating quick and specific biomarkers to predict the disease severity upon admission to hospital became a crucial need. This study, therefore, aimed at exploring the relationship between laboratory results in COVID‐19 patients admitted to hospital and the final outcome in these patients.Methods: Retrospective analysis was performed on the medical records of 310 COVID‐19‐positive patients admitted to Uhod Hospital, the referral hospital in the area of Madinah, Kingdom of Saudi Arabia, between the April 13 and the July 29, 2020. The association of laboratory results with the survival/mortality outcomes was studied.Results: It was demonstrated that lymphopenia, prolonged aPTT, high INR, high D. dimer and high CK are valuable prognostic predictors of the severity of the disease at early stages that can determine the outcome. Based on the results of the multiple logistic regression, the variables that are associated with death outcome are aPTT, HR, RR, ALT and CK levelConclusion: It is proposed to perform these tests on admission to hospital for moderate to severe COVID‐19 patients to improve the management of those cases and reduce mortality.

The pathogenesis of pulmonary fibrosis (PF) is extremely complex and involves numerous intersecting pathways. The successful management of PF may require combining multiple agents. There is a growing body of evidence that suggests the potential benefits of niclosamide (NCL), an FDA-approved anthelminthic drug, in targeting different fibrogenesis molecules. This study aimed at investigating the anti-fibrotic potential of NCL alone and in combination with pirfenidone (PRF), an approved drug for PF, in a bleomycin (BLM) induced PF experimental model. PF was induced in rats by intratracheal BLM administration. The effect of NCL and PRF individually and in combination on different histological and biochemical parameters of fibrosis was investigated. Results revealed that NCL and PRF individually and in combination alleviated the histopathological changes, extracellular matrix deposition and myofibroblastic activation induced by BLM. NCL and PRF either individually or in combination inhibited the oxidative stress and subsequent pathways. They modulated the process of fibrogenesis by inhibiting MAPK/NF-κB and downstream cytokines. They inhibited STATs and downstream survival-related genes including BCL-2, VEGF, HIF-α and IL-6. Combining both drugs showed significant improvement in the tested markers in comparison to the monotherapy. NCL, therefore, has a potential synergistic effect with PRF in reducing the severity of PF.