Dupilumab efficacy and safety in patients with moderate to severe asthma: A systematic review and meta-analysis.

Background: Dupilumab is a human monoclonal antibody directed against the alpha subunit of the interleukin-4 receptor and inhibits the signaling of IL-4 and IL-13. It is approved for treating asthma and other type-2 inflammatory diseases. There is a conflict in the literature regarding the safety and efficacy of dupilumab. Thus, we aimed to assess the safety and efficacy of dupilumab in patients with moderate to severe asthma. Methods: Six databases (PubMed, Embase, Scopus, Web of Science, Cochrane library, and clinicaltrials.gov registry) were searched until January 2022. We included randomized controlled trials that compared dupilumab with the placebo in moderate to severe asthma patients. We extracted the data at 12 and 24 weeks and analyzed them using review manager 5.4. Findings: Thirteen trials were included. Dupilumab significantly improved the forced expiratory volume in 1 s, asthma control questionnaire score, the fraction of exhaled nitric oxide level, and immunoglobulin E level at 12 and 24 weeks (p < 0.05). However, it was associated with increased blood eosinophils at 12 and 24 weeks. Dupilumab was generally a safe agent for asthmatic patients. It showed no significant difference compared with the placebo regarding most adverse events. Conclusion: Dupilumab improves pulmonary function and reduces local and systemic inflammatory markers with minimal adverse events in patients with moderate to severe asthma.

Resveratrol alleviates cardiac apoptosis following exposure to fenitrothion by modulating the sirtuin1/c-Jun N-terminal kinases/p53 pathway through pro-oxidant and inflammatory response improvements: In vivo and in silico studies.

Fenitrothion (FNT), a commonly used organophosphate, can cause oxidative damage and apoptosis on various organs. However, the underlying mechanisms for FNT-induced cardiotoxicity did not formally report. Here, we have evaluated the possible ameliorative roles of resveratrol (RSV) against FNT-induced cardiac apoptosis in male rats through the sirtuin1 (SIRT1)/c-Jun N-terminal kinase (c-JNK)/p53 pathway concerning pro-oxidant and inflammatory cytokines. Forty-eight male rats were equally grouped into control, RSV (20 mg/kg), 5-FNT (5 mg/kg), 10-FNT (10 mg/kg), 20-FNT (20 mg/kg), 5-FNT-RSV, 10-FNT-RSV, and 20-FNT-RSV where all doses administrated by gavage for four weeks. The present findings demonstrated that RSV markedly diminished the level of hyperlipidemia and elevation in lactate dehydrogenase (LDH), total creatine kinase (CK-T), and troponin T (TnT) levels following FNT intoxication. Furthermore, RSV significantly reduced FNT-induced cardiac oxidative injury by reducing malondialdehyde (MDA) level and improving the levels of glutathione (GSH), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and acetylcholinesterase (AchE). Also, the levels of interleukin-1ß (IL1ß,), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were significantly attenuated in the co-treated groups. Moreover, RSV alleviated the histopathological changes promoted by FNT and repaired the transcript levels of SIRT1, c-JNK, and caspase-9/3 along with p53 immunoreactivity. In silico study revealed that the free binding energies of RSV complexes with protein and DNA sequences of SIRT1 were lower than docked complexes of FNT. Therefore, RSV reserved myocardial injury-induced apoptosis following exposure to FNT by modulating the SIRT1/c-JNK/p53 pathway through cellular redox status and inflammatory response improvements.

Alpha-mangostin attenuates the apoptotic pathway of abamectin in the fetal rats' brain by targeting pro-oxidant stimulus, catecholaminergic neurotransmitters, and transcriptional regulation of reelin and nestin.

Abamectin, an avermectin member, can induce significant neurodegeneration symptoms in non-target organisms. However, its neurodevelopmental influences in mammals are unclear. Here, we focus on the antiapoptotic action of alpha-mangostin against the developmental neurotoxicity of abamectin with the possible involvement of reelin and nestin mRNA gene expression. Thirty-two pregnant rats were allocated to four groups (8 rats/group); control, alpha-mangostin (20 mg/kg/d), abamectin (0.5 mg/kg), and co-treated group (alpha-mangostin + abamectin). The animals have gavaged their doses during the gestation period. The fetotoxicity and many signs of growth retardation were observed in the abamectin-intoxicated rats. In comparison with the control group, abamectin prompted a significant elevation (p < 0.05) in the levels of malondialdehyde and nitric oxide, along with many symptoms of histopathological changes in the fetal cerebral cortex. However, the glutathione, dopamine, and serotonin concentrations together with the activities of glutathione-S-transferase, catalase, and superoxide dismutase were markedly decreased (p < 0.05) in the abamectin group. Moreover, abamectin remarkably upregulated (p < 0.05) the brain mRNA gene expression of reelin, nestin, and caspase-9 as well as the immunoreactivity of Bax and caspase-3 proteins in the cerebral cortex. It should be noted that alpha-mangostin mitigated the developmental neurotoxicity of abamectin to the normal range by recovering the levels of oxidant/antioxidant biomarkers, catecholamines; and apoptosis-related proteins with the involvement of reelin and nestin genes regulation. Those records revealed that the transcription regulation of reelin and nestin could be involved in the neuroprotective efficacy of alpha-mangostin, especially avermectin's developmental neurotoxicity.

Quercetin ameliorates the hepatic apoptosis of foetal rats induced by in utero exposure to fenitrothion via the transcriptional regulation of paraoxonase-1 and apoptosis-related genes.

BACKGROUND & PURPOSE: Exposure to organophosphorus during different phases of pregnancy induces many adverse impacts on the developing foetuses due to their immature detoxification system. We have estimated the potential amelioration role of quercetin against hepatic injury-induced apoptosis in rat foetuses following gestational exposure to fenitrothion and probable involvement of paraoxonase-1. METHODS: Forty pregnant rats were allocated into four groups; the first one kept as control, the second intubated with quercetin (100 mg/kg), the third orally administrated fenitrothion (4.62 mg/kg) and the last group received quercetin two hours before fenitrothion intoxication. RESULTS: Fenitrothion significantly elevated the foetal hepatic levels of thiobarbituric acid reactive substances, protein carbonyl, and nitric oxide, but it reduced the enzymatic activities of glutathione-S-transferase, superoxide dismutase, catalase, and acetylcholinesterase. Furthermore, fenitrothion provoked many histopathological changes in the foetal liver and markedly up-regulated the mRNA gene expression of p53, caspase-9 along with elevation in the immunoreactivity of Bax and caspase-3, but it down-regulated the expression level of paraoxonase-1. Remarkably, quercetin co-treatment successfully ameliorated the hepatic oxidative injury and apoptosis prompted by fenitrothion. CONCLUSIONS: Dietary supplements with quercetin can be used to reduce the risk from organophosphorus exposure probably through paraoxonase-1 up-regulation and enhancement of the cellular antioxidant system.

Quercetin Attenuates the Oxidative Injury-Mediated Upregulation of Apoptotic Gene Expression and Catecholaminergic Neurotransmitters of the Fetal Rats' Brain Following Prenatal Exposure to Fenitrothion Insecticide.

The association between gestational exposure to organophosphate and neurodevelopmental deficits is an area of particular interest, since the developing brain is sensitively susceptible to this neurotoxic pesticide. Instead, the neuroprotective role of quercetin has been suggested, but its exact protective mechanism against the developmental neurotoxicity of organophosphate did not previously notify. In this study, we have evaluated the anti-apoptotic role of quercetin against the developmental neurotoxicity of fenitrothion. Forty timed pregnant rats (from the 5th to the 19th day) were divided into four groups: control, quercetin (100 mg/kg/day), fenitrothion (2.31 mg/kg/day), and quercetin-fenitrothion co-treated groups where all animals received the corresponding doses by gavage. The embryotoxicity and many symptoms of the fetal growth retardation were recorded in the fenitrothion-intoxicated group. As compared with the control, fenitrothion brought significant (p < 0.05) elevation in the fetal brain dopamine, serotonin, and malondialdehyde levels as well as the activities of superoxide dismutase and catalase. However, fenitrothion decreased the glutathione concentration together with the activities of acetylcholinesterase, glutathione-S-transferase, and glutathione reductase. Moreover, fenitrothion induced some of the histopathological alterations in fetal brain and remarkably (p < 0.05) upregulated the mRNA gene expression of Bax and caspase-3 plus their protein immunoreactivity. It is worth mentioning that quercetin co-treatment alleviated (p Ë‚ 0.05) the fetal growth shortfalls, neurotransmission disturbances, lipid peroxidation, antioxidant disorders, and apoptosis evoked by fenitrothion with frequent repair to the control range. These results revealed that the downregulation of apoptosis-related genes and catecholamines is an acceptable indicator for the neuroprotective efficiency of quercetin especially during gestational exposure to organophosphate.