Quetiapine attenuates cadmium neurotoxicity by suppressing oxidative stress, inflammation, and pyroptosis.

BACKGROUND: Cadmium (Cd) is a heavy metal with extremely harmful toxic effects on the brain. Quetiapine (QTP) has unique neuroprotective effects with anti-inflammatory and antioxidant actions. However, its neuroprotective effect against Cd-induced neurotoxicity has not been previously studied. METHODS: QTP was administered in 10 and 20 mg/kg doses, while Cd was given in a dose of 6.5 mg/kg. RESULTS: In our study, QTP dose-dependently attenuated neuronal injury by downregulating p-tau and ß-amyloid. QTP potently attenuates histological abrasions induced by Cd. QTP counteracted oxidative injury by decreasing neuronal MDA and increased GSH levels mediated by downregulating Keap1 and upregulating Nrf2 and HO-1. QTP mitigated inflammation by decreasing MPO and NO2 and neuronal cytokines TNF-α and IL-1ß and upregulating IL-10 levels mediated by NF-κB downregulation. Additionally, QTP counteracted Cd-induced pyroptosis by downregulating caspase-1, ASC, and NLRP3 protein levels. CONCLUSION: In conclusion, QTP mitigates neurotoxicity induced by Cd through suppression of inflammation, pyroptosis, and oxidative stress by controlling the NF-κB, Keap1/Nrf2, and pyroptosis signals.

The beneficial impacts of nano-propolis liposomes as an anti-stressor agent on broiler chickens kept under cyclic heat stress.

This research assessed the impacts of dietary nano-propolis liposomes (NPRL) inclusion on the growth, blood biochemical components, immune function, and oxidative status of broilers exposed to cyclic heat stress (HS). Birds were fed with a basal diet supplemented with various levels of NPRL at 0 (HS), 100 (NPRL100), 250 (NPRL250) and 400 (NPRL400) mg/kg diets. Diets supplemented with NPRL significantly improved the growth indices and feed utilization, hemoglobin and red blood cells (P < 0.01). White blood cells, lymphocytes and monocytes were significantly decreased by NPRL inclusion (P < 0.001). Dietary supplementation of 250 or 400 mg of NPRL /kg reduced the pathogenic bacteria counts (Salmonella, E. coli and Enterococci) (P < 0.01). The birds fed diets with NPRL (400 mg/kg diet) significantly downregulated the mRNA IFNγ gene (p < 0.001), while both groups (NPRL100 and NPRL250) had similar results (P > 0.05). The iNOS gene was significantly decreased by the dietary NPRL inclusion in a dose-dependent manner. Birds in NRPL groups had inferior levels of the mRNA of interleukin-4 and tumor necrosis factor genes. The lysosome activity was significantly reduced by dietary 250 or 400 mg of NPRL inclusion (P < 0.001). Birds in NPRL250 and NPRL100 had greater IgG (P < 0.05) than the other groups. Regarding oxidative-related biomarkers, dietary NPRL inclusion decreased myeloperoxidase and malondialdehyde levels significantly compared to those with the HS group (P < 0.001). Broilers in the NPRL400 group had the lowest levels of total bilirubin and gamma-glutamyl transferase. NPRL250 had the lowest values of urea compared with other groups (P < 0.001). Dietary NPRL inclusion improved the broiler's hepatic and intestinal architecture exposed to cyclic heat stress. These results indicate that employing NPRL in the diets of stressed broilers can enhance heat resistance by enhancing blood metabolites and immunity, reducing inflammation and oxidative stress.

Vinpocetine attenuates methotrexate-induced hippocampal intoxication via Keap-1/Nrf2, NF-κB/AP-1, and apoptotic pathways in rats.

Methotrexate (MTX) is an anti-folate chemotherapeutic commonly used to treat cancer and autoimmune diseases. Despite its widespread clinical use, MTX has been linked to serious neurotoxicity side effects. Vinpocetine (VNP) has been widely used clinically to treat many neurological conditions. This study was conducted to study the potential neuroprotective effects of VNP against MTX hippocampal intoxication in rats. Thirty-two rats were randomly allocated into 4 groups: (I) control (Vehicle); (II) VNP-treated group (20 mg/kg/day, p.o); (III) MTX-control (20 mg/kg/once, i.p.) group; and (IV) the VNP + MTX group. VNP was administered orally for 10 days, during which MTX was given intraperitoneally once at the end of day 5. Our data indicated that VNP administration significantly improved MTX-induced neuronal cell death, odema, vacuolation and degeneration. VNP attenuated oxidative injury mediated by significant upregulation of the Nrf2, HO-1, and GCLC genes, while the Keap-1 mRNA expression downregulated. Moreover, VNP suppressed cytokines release mediated by increasing IκB expression level while it caused a marked downregulation in NF-κB and AP-1 (C-FOS and C-JUN) levels. Additionally, VNP attenuated apoptosis by reducing hippocampal Bax levels while increasing Bcl2 levels in MTX-intoxicated rats. In conclusion, our results suggested that VNP significantly attenuated MTX hippocampal intoxication by regulating Keap-1/Nrf2, NF-κB/AP-1, and apoptosis signaling in these effects.

Comprehensive mapping of mutations in TDP-43 and α-Synuclein that affect stability and binding.

Abnormal aggregation and amyloid inclusions of TAR DNA-binding protein 43 (TDP-43) and α-Synuclein (α-Syn) are frequently co-observed in amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Several reports showed TDP-43 C-terminal domain (CTD) and α-Syn interact with each other and the aggregates of these two proteins colocalized together in different cellular and animal models. Molecular dynamics simulation was conducted to elucidate the stability of the TDP-43 and Syn complex structure. The interfacial mutations in protein complexes changes the stability and binding affinity of the protein that may cause diseases. Here, we have utilized the computational saturation mutagenesis approach including structure-based stability and binding energy calculations to compute the systemic effects of missense mutations of TDP-43 CTD and α-Syn on protein stability and binding affinity. Most of the interfacial mutations of CTD and α-Syn were found to destabilize the protein and reduced the protein binding affinity. The results thus shed light on the functional consequences of missense mutations observed in TDP-43 associated proteinopathies and may provide the mechanisms of co-morbidities involving these two proteins.Communicated by Ramaswamy H. Sarma.

Mirtazapine attenuated cadmium-induced neuronal intoxication by regulating Nrf2 and NF-κB/TLR4 signals.

Cadmium (Cd) is one of the most hazardous metals to the environment and human health. Neurotoxicity is of the most serious hazards caused by Cd. Mirtazapine (MZP) is a central presynaptic α2 receptor antagonist used effectively in treating several neurological disorders. This study investigated the anti-inflammatory and antioxidant activity of MZP against Cd-induced neurotoxicity. In this study, rats were randomly divided into five groups: control, MZP (30 mg/kg), Cd (6.5 mg/kg/day; i.p), Cd + MZP (15 mg/kg), and Cd + MZP (30 mg/kg). Histopathological examination, oxidative stress biomarkers, inflammatory cytokines, and the impact of Nrf2 and NF-κB/TLR4 signals were assessed in our study. Compared to Cd control rats, MZP attenuated histological abrasions in the cerebral cortex and CA1 and CA3 regions of the hippocampus as well as the dentate gyrus. MZP attenuated oxidative injury by upregulating Nrf2. In addition, MZP suppressed the inflammatory response by decreasing TNF-α, IL-1ß, and IL-6 mediated by downregulating TLR4 and NF-κB. It is noteworthy that MZP's neuroprotective actions were dose-dependent. Collectively, MZP is a promising therapeutic strategy for attenuating Cd-induced neurotoxicity by regulating Nrf2, and NF-κB/TLR4 signals, pending further study in clinical settings.

The Role of Mitochondrial Dysfunction in Alzheimer's: Molecular Defects and Mitophagy-Enhancing Approaches.

Alzheimer's disease (AD), a progressive and chronic neurodegenerative syndrome, is categorized by cognitive and memory damage caused by the aggregations of abnormal proteins, specifically including Tau proteins and ß-amyloid in brain tissue. Moreover, mitochondrial dysfunctions are the principal causes of AD, which is associated with mitophagy impairment. Investigations exploring pharmacological therapies alongside AD have explicitly concentrated on molecules accomplished in preventing/abolishing the gatherings of the abovementioned proteins and mitochondria damages. Mitophagy is the removal of dead mitochondria by the autophagy process. Damages in mitophagy, the manner of diversified mitochondrial degeneracy by autophagy resulting in an ongoing aggregation of malfunctioning mitochondria, were also suggested to support AD. Recently, plentiful reports have suggested a link between defective mitophagy and AD. This treaty highlights updated outlines of modern innovations and developments on mitophagy machinery dysfunctions in AD brains. Moreover, therapeutic and nanotherapeutic strategies targeting mitochondrial dysfunction are also presented in this review. Based on the significant role of diminished mitophagy in AD, we suggest that the application of different therapeutic approaches aimed at stimulating mitophagy in AD would be beneficial for targeting or reducing the mitochondrial dysfunction induced by AD.

Evaluation of phage-antibiotic combinations in the treatment of extended-spectrum ß-lactamase-producing Salmonella enteritidis strain PT1.

Foodborne infections caused by Salmonella spp. are among the most common foodborne diseases in the world. We isolated a lytic phage against extended-spectrum beta-lactam producing S. Enteritidis strain PT1 derived from chicken carcass. Results from electronmicrography indicated that phiPT1 belonged to the family, Siphoviridae, in the order, Caudovirales. Phage phiPT1 was stable at temperatures from 4 °C to 60 °C and inactivated at 90 °C. phiPT1 retained a high titer from pH 4 to pH 10 for at least 1 h. Nevertheless, it displayed a significant decrease (p < 0.05) in titer at pH 11 and 12, with phage titers of 5.5 and 2.4 log10 PFU/mL, respectively. The latent time and burst size of phiPT1 were estimated to be 30 min and 252 PFU/infected cell, respectively. The virulence of phage phiPT1 was evaluated against S. Enteritidis strain PT1 at different MOIs. phiPT1 reduced Salmonella proliferation relative to the negative control (MOI 0) at all MOIs (P < 0.05). However, there is no significant difference among the MOIs (P > 0.05). The phage-antibiotic combination analysis (PAS) indicated that synergism was not detected at higher phiPT1 titer (1012 PFU/mL) with all tested antibiotics at all subinhibitory concentrations. However, synergistic activities were recorded at 0.25 × MIC of four tested antibiotics: cefixime, gentamicin, ciprofloxacin, and aztreonam in combination with phage at 104, 106 and 108 PFU/mL (ΣFIC ≤0.5). Synergism was detected for all antibiotics (0.1 × MIC) except meropenem and colistin in combination with phiPT1 at 104, 106 and 108 PFU/mL (ΣFIC ≤0.5). Synergism also displayed at the lowest concentrations of all antibiotics (0.01 MIC) in combination with phiPT1 at all titers except 1012 PFU/mL. Such characteristic features make phiPT1 to be a potential candidate for therapeutic uses.

Impacts of Supplementing Broiler Diets with Biological Curcumin, Zinc Nanoparticles and Bacillus licheniformis on Growth, Carcass Traits, Blood Indices, Meat Quality and Cecal Microbial Load.

The current study aimed to investigate the influence of dietary zinc nanoparticles (ZnNPs), curcumin nanoparticles (CurNPs), and Bacillus licheniformis (Bl) on the growth, carcass, blood metabolites, and the count of some cecal microorganisms of Indian River (IR) broilers. Chicks were allotted into seven experimental groups: control group, 1st, 2nd and 3rd groups were given diets enriched with ZnNPs, CurNPs and Bl (3.0, 5.0 and 2.0 cm3/kg diet, respectively). The 4th, 5th and 6th groups were given diets supplemented with ZnNPs (3.0) + Bl (2.0) (ZP); ZnNPs (3.0) + CurNPs (5.0) (ZC) and ZnNPs (3.0) + CurNPs (5.0) + Bl (2.0) (ZCP) cm3/kg diet, respectively. The results revealed that ZnNPs and CurNPs exhibited a considerable antimicrobial activity against pathogenic bacteria and fungi. They also inhibited the growth of microbes in a range of 50-95 µg/mL. The diet supplemented with ZnNPs, CurNPs, and Bl increased the body weight compared to the control after five weeks of age. Additionally, values of daily feed intake increased in these groups; however, the feed conversion ratio decreased. All values of carcass traits were better than that of the control. The treatments led to decreased abdominal lipids compared to the control. The activity of liver enzymes and malondialdehyde (MDA) activity decreased in the treated groups. In a converse trend, the levels of oxidative enzymes, amylase, protease, lipase and immunoglobulin were higher than that of the control. Meat quality properties were improved and cecal microbial counts were decreased. In conclusion, the ZnNPs, CurNPs, and Bl improved the broiler's weights, carcass traits, meat quality traits, as well as some blood indices and cecal microbial load. Therefore, the inclusion of ZnNPs, CurNPs, or Bl is recommended for broiler feeding regimens to improve the performance and health status.