Modulatory effects of perindopril on cisplatin-induced nephrotoxicity in mice: Implication of inflammatory cytokines and caspase-3 mediated apoptosis

Cisplatin-induced nephrotoxicity limits its anticancer effectiveness, thus this study’s aim was to assess the potential modulatory effect of perindopril on cisplatin-induced nephrotoxicity and to elucidate the possible underlying mechanisms. Renal dysfunction was induced in mice by a single injection of cisplatin (10 mg kg–1, i.p.) and perindopril was administered orally (2 mg kg–1, once daily) for 5 days. Perindopril remarkably ameliorated cisplatin-induced perturbations in renal histology, renal levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-10, apoptosis-regulating protein expressions (Bax and Bcl2), and partially normalized Bax to Bcl2 ratio and active caspase 3 protein expression. Conversely, perindopril had no significant effect on cisplatin-induced elevations in serum creatinine and urea, microalbuminuria, kidney to body weight ratio, lipid peroxidation marker, superoxide dismutase and catalase activities and reduced glutathione content. In conclusion, perindopril may be safely used with cisplatin in mice since it ameliorated cisplatin-induced histopathological changes, inflammation and apoptosis without affecting renal biomarkers or oxidative stress

Evaluation of inhaled nitric oxide (iNO) treatment for moderate-to-severe ARDS in critically ill patients with COVID-19: A multicenter cohort study

Background: Inhaled nitric oxide (iNO) is used as rescue therapy in patients with refractory hypoxemia due to severe COVID-19 acute respiratory distress syndrome (ARDS) despite the recommendation against the use of this treatment. To date, the effect of iNO on the clinical outcomes of critically ill COVID-19 patients with moderate-to-severe ARDS remains arguable. Therefore, this study aimed to evaluate the use of iNO in critically ill COVID-19 patients with moderate-to-severe ARDS. Methods: This multicenter, retrospective cohort study included critically ill adult patients with confirmed COVID-19 treated from March 01, 2020, until July 31, 2021. Eligible patients with moderate-to-severe ARDS were subsequently categorized into two groups based on inhaled nitric oxide (iNO) use throughout their ICU stay. The primary endpoint was the improvement in oxygenation parameters 24 h after iNO use. Other outcomes were considered secondary. Propensity score matching (1:2) was used based on the predefined criteria. Results: A total of 1598 patients were screened, and 815 were included based on the eligibility criteria. Among them, 210 patients were matched based on predefined criteria. Oxygenation parameters (PaO2, FiO2 requirement, P/F ratio, oxygenation index) were significantly improved 24 h after iNO administration within a median of six days of ICU admission. However, the risk of 30-day and in-hospital mortality were found to be similar between the two groups (HR: 1.18; 95% CI: 0.77, 1.82; p = 0.45 and HR: 1.40; 95% CI: 0.94, 2.11; p= 0.10, respectively). On the other hand, ventilator-free days (VFDs) were significantly fewer, and ICU and hospital LOS were significantly longer in the iNO group. In addition, patients who received iNO had higher odds of acute kidney injury (AKI) (OR (95% CI): 2.35 (1.30, 4.26), p value = 0.005) and hospital/ventilator-acquired pneumonia (OR (95% CI): 3.2 (1.76, 5.83), p value = 0.001). Conclusion: In critically ill COVID-19 patients with moderate-to-severe ARDS, iNO rescue therapy is associated with improved oxygenation parameters but no mortality benefits. Moreover, iNO use is associated with higher odds of AKI, pneumonia, longer LOS, and fewer VFDs

Modulatory effects of perindopril on cisplatin-induced nephrotoxicity in mice: Implication of inflammatory cytokines and caspase-3 mediated apoptosis

Cisplatin-induced nephrotoxicity limits its anticancer effectiveness, thus this study’s aim was to assess the potential modulatory effect of perindopril on cisplatin-induced nephrotoxicity and to elucidate the possible underlying mechanisms. Renal dysfunction was induced in mice by a single injection of cisplatin (10 mg kg−1, i.p.) and perindopril was administered orally (2 mg kg−1, once daily) for 5 days. Perindopril remarkably ameliorated cisplatin-induced perturbations in renal histology, renal levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-10, apoptosis-regulating protein expressions (Bax and Bcl2), and partially normalized Bax to Bcl2 ratio and active caspase 3 protein expression. Conversely, perindopril had no significant effect on cisplatin-induced elevations in serum creatinine and urea, microalbuminuria, kidney to body weight ratio, lipid peroxidation marker, superoxide dismutase and catalase activities and reduced glutathione content. In conclusion, perindopril may be safely used with cisplatin in mice since it ameliorated cisplatin-induced histopathological changes, inflammation and apoptosis without affecting renal biomarkers or oxidative stress

Impact of Acute Eccentric versus Concentric Running on Exercise-Induced Fat Oxidation and Postexercise Physical Activity in Untrained Men

Introduction. This study aimed at comparing the rate of exercise-induced fat oxidation and postexercise free-living physical activity after constant-load flat running (FR) and downhill running (DHR) bouts at an intensity that elicited maximal fat oxidation. Methods. Participants were 11 healthy untrained men (mean age 25.6±3.3 years; VO2max39.11±8.05 ml/kg/min). The study included four visits. The first two visits determined the intensity of maximal fat oxidation during incremental FR and DHR tests. The second two visits involved constant-load FR or DHR at the intensity that elicited maximal fat oxidation in a counterbalanced order separated by two weeks. Gas exchange analysis was used to measure substrate oxidation during all exercise sessions. Sedentary time and physical activity were measured using ActiGraph triaxial accelerometers for three days including the day of exercise tests (the second day). Results. During the incremental exercise tests, fat oxidation was significantly greater during the first stage of FR (P<0.05) but started to increase during the fourth stage of DHR, although this did not reach significance. Of the 11 participants, 7 had greater fat oxidation during DHR. During continuous constant-load running, fat oxidation was higher during DHR than FR but at only two stages was either significant or borderline significant, and the time/group interaction was not significant. There was no significant effect on sedentary time of time/group interaction (P=0.769), but there was a significant effect of time (P=0.005), and there was no significant effect on total physical activity of time/group interaction (P=0.283) or time (P=0.602). Conclusion. Acute aerobic eccentric exercise at an intensity eliciting maximal fat oxidation enhanced exercise-induced fat oxidation without worsening postexercise free-living physical activity, indicating it could be a useful training modality in weight management programs

Blocking connexin 43 accelerates corneal healing and improves tissue remodeling during the healing of diabetic rat corneas: A histological and immunohistochemical study

Connexin 43 (Cx43) is a potential target for accelerating wound healing. This study aimed at evaluating the therapeutic efficiency of topical application of Gap27, a Cx43 mimetic peptide, on corneal tissue reorganization during wound healing in streptozocin-induced Diabetes in albino rats and its effect on the infiltration of inflammatory cells. Fifty adult male albino Wistar rats were divided equally into two groups: non-diabetic and diabetic. Twenty rats from each group were subjected to corneal injury: 10 untreated and 10 treated with Gap27. The remaining five rats from each group served as negative controls (intact corneas). All rats were sacrificed 3 days after injury. Histological studies were performed to assess signs of cell degeneration, the infiltration of inflammatory cells. Histomorphometric studies were performed to quantify the expression of Cx43. Gap27 promoted corneal wound healing in non-diabetic and diabetic rats. It reduced mononuclear cell infiltration and improved corneal tissue remodeling. However, minor structural changes were still seen in diabetic corneas after treatment with Gap27. Blocking Cx43 was a valuable tool to restore corneal tissue structure, reduce the infiltration of inflammatory cells in non-diabetic and diabetic rats

Characterization of Mechanisms of Glutathione Conjugation with Halobenzoquinones in Solution and HepG2 Cells

Halobenzoquinones (HBQs) are a class of emerging disinfection byproducts. Chronic exposure to chlorinated drinking water is potentially associated with an increased risk of human bladder cancer. HBQ-induced cytotoxicity involves depletion of cellular glutathione (GSH), but the underlying mechanism remains unclear. Here we used ultrahigh performance liquid chromatography–high resolution mass spectrometry and electron paramagnetic resonance spectroscopy to study interactions between HBQs and GSH and found that HBQs can directly react with GSH, forming various glutathionyl conjugates (HBQ-SG) in both aqueous solution and HepG2 cells. We found that the formation of HBQ-SG varies with the initial molar ratio of GSH to HBQ in reaction mixtures. Higher molar ratios of GSH to HBQ facilitate the conjugation of more GSH molecules to an HBQ molecule. We deduced the reaction mechanism between GSH and HBQs, which involves redox cycling-induced formation of halosemiquinone (HSQ) free radicals and glutathione disulfide, Michael addition, as well as nucleophilic substitution. The proposed reaction rates are in the following order: formation of HSQ radicals > substitution of bromine by GSH > Michael addition of GSH on the benzoquinone ring > substitution of chlorine by GSH > substitution of the methyl group by GSH. The conjugates identified in HBQ-treated HepG2 cells were the same as those found in aqueous solution containing a 5:1 ratio of GSH:HBQs

The effective adsorption of arsenic from polluted water using modified Halloysite nanoclay

The presented research applied the modified Halloysite nanoclay to boost the adsorption efficacy of heavy metals from the water. To improve As (III) adsorption effectiveness from water, the study assessed the characteristics of the prepared materials and improved the experimental conditions. The study was optimized the experimental condition with a dosage of 1 g/L, contact time of 90 min, the solution pH of 8, and the initial concentration of 5 ppm of As (III). The optimization was performed in distilled water and later the experiments were conducted in the real polluted water. The modified Halloysite nanoclay’s physical characteristics were investigated using techniques like X-ray diffraction, scanning and transmission electron microscopy, Fourier transform infrared spectroscopy, and surface area analysis. The experimental result shows the adsorption efficiency of 82.4 % of As (III) at the optimized condition during the usage of modified Halloysite nanoclay. To create a suitable mathematical model for a better description of the interactions between pollutants and solid adsorbents, it is helpful to analyze the process kinetically. The removal process of As (III) was studied kinetically and the observation shows the pseudo-second order kinetics

Generation of Combinatorial Lentiviral Vectors Expressing Multiple Anti-Hepatitis C Virus shRNAs and Their Validation on a Novel HCV Replicon Double Reporter Cell Line

Despite the introduction of directly acting antivirals (DAAs), for the treatment of hepatitis C virus (HCV) infection, their cost, patient compliance, and viral resistance are still important issues to be considered. Here, we describe the generation of a novel JFH1-based HCV subgenomic replicon double reporter cell line suitable for testing different antiviral drugs and therapeutic interventions. This cells line allowed a rapid and accurate quantification of cell growth/viability and HCV RNA replication, thus discriminating specific from unspecific antiviral effects caused by DAAs or cytotoxic compounds, respectively. By correlating cell number and virus replication, we could confirm the inhibitory effect on the latter of cell over confluency and characterize an array of lentiviral vectors expressing single, double, or triple cassettes containing different combinations of short hairpin (sh)RNAs, targeting both highly conserved viral genome sequences and cellular factors crucial for HCV replication. While all vectors were effective in reducing HCV replication, the ones targeting viral sequences displayed a stronger antiviral effect, without significant cytopathic effects. Such combinatorial platforms as well as the developed double reporter cell line might find application both in setting-up anti-HCV gene therapy approaches and in studies aimed at further dissecting the viral biology/pathogenesis of infection