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1.
Mol Biol Rep ; 51(1): 660, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38750264

ABSTRACT

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.


Subject(s)
Cadmium , Inflammation , Oxidative Stress , Pyroptosis , Quetiapine Fumarate , Oxidative Stress/drug effects , Pyroptosis/drug effects , Animals , Cadmium/toxicity , Quetiapine Fumarate/pharmacology , Inflammation/drug therapy , Inflammation/metabolism , Male , Mice , Neuroprotective Agents/pharmacology , NF-E2-Related Factor 2/metabolism , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Neurotoxicity Syndromes/drug therapy , Neurotoxicity Syndromes/metabolism , Antioxidants/pharmacology , Anti-Inflammatory Agents/pharmacology , NF-kappa B/metabolism
2.
Immunopharmacol Immunotoxicol ; 46(1): 11-19, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37493389

ABSTRACT

OBJECTIVES: Methotrexate (MTX) is an antimetabolite agent widely used to manage a variety of tumors and autoimmune diseases. Nonetheless, MTX-induced intestinal intoxication is a serious adverse effect limiting its clinical utility. Inflammation and oxidative stress are possible mechanisms for MTX-induced intestinal toxicity. Vinpocetine (VNP) is a derivative of the alkaloid vincamine with potent anti-inflammatory and antioxidant effects. The current study investigated the protective intestinal impact of VNP in attenuating MTX-induced intestinal intoxication in rats. MATERIALS AND METHODS: VNP was administered orally in a dose of 20 mg/kg, while MTX was injected intraperitoneal in a dose of 20 mg/kg. RESULTS: VNP administration attenuated drastic histological changes induced by MTX and preserved both normal villus and crypt histology. VNP significantly attenuated oxidative injury by upregulating intestinal Nrf2 and HO-1 expression. VNP attenuated inflammation by reducing MPO, NO2-, TNF-α, and IL-1ß levels mediated by downregulating NF-κB, NDAPH-oxidase, IRF3, p-JAK-1, and p-STAT-3 expressions. Moreover, VNP potently counteracted intestinal necroptosis by effectively downregulating RIPK1, RIPK3, MLKL, and caspase-8 proteins. CONCLUSION: Therefore, VNP may represent a promising approach that can attenuate intestinal toxicity in patients receiving MTX.


Subject(s)
Methotrexate , NF-kappa B , Vinca Alkaloids , Humans , Rats , Animals , NF-kappa B/metabolism , Methotrexate/toxicity , Oxidative Stress , Inflammation , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/pharmacology , Janus Kinase 1/metabolism , Protein Kinases/metabolism
3.
Genes (Basel) ; 14(2)2023 02 20.
Article in English | MEDLINE | ID: mdl-36833456

ABSTRACT

Several microRNAs (miRNAs) are known to participate in adipogenesis. However, their role in this process, especially in the differentiation of bovine preadipocytes, remains to be elucidated. This study was intended to clarify the effect of microRNA-33a (miR-33a) on the differentiation of bovine preadipocytes by cell culture, real-time fluorescent quantitative PCR (qPCR), Oil Red staining, BODIPY staining, and Western blotting. The results indicate that overexpression of miR-33a significantly inhibited lipid droplet accumulation and decreased the mRNA and protein expression of adipocyte differentiation marker genes such as peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding protein 1 (SREBP1), and fatty acid-binding protein 4 (FABP4). In contrast, the interference expression of miR-33a promoted lipid droplet accumulation and increased the expression of marker genes. Additionally, miR-33a directly targeted insulin receptor substrate 2 (IRS2) and regulated the phosphorylation level of serine/threonine kinase (Akt). Furthermore, miR-33a inhibition could rescue defects in the differentiation of bovine preadipocytes and the Akt phosphorylation level caused by small interfering IRS2 (si-IRS2). Collectively, these results indicate that miR-33a could inhibit the differentiation of bovine preadipocytes, possibly through the IRS2-Akt pathway. These findings might help develop practical means to improve the quality of beef.


Subject(s)
MicroRNAs , Proto-Oncogene Proteins c-akt , Cattle , Animals , Proto-Oncogene Proteins c-akt/metabolism , Insulin Receptor Substrate Proteins , Cell Differentiation , MicroRNAs/genetics , Adipogenesis/genetics
4.
Oxid Med Cell Longev ; 2021: 6662649, 2021.
Article in English | MEDLINE | ID: mdl-34336111

ABSTRACT

Pumpkin has received significant attention due to its nutritional compounds that have antioxidant, antifatigue, and anti-inflammatory effects. This study is aimed at assessing the antidepressant-like effect of L. Cucurbita pepo, sweet pumpkin, in an animal model of chronic unpredictable mild stress (CUMS) and investigating its effect on the histological structure of hippocampus compared to fluoxetine. Forty male albino rats assigned into the negative control, positive control (CUMS), and Flu-treated and pumpkin-treated groups (n = 10) were utilized in this study. Exposing rats to CUMS continued for 28 days, and treatments used were applied during the last 14 days of exposure. Behavioral, biochemical, and histopathological changes were assessed after 28 days. In this study, pumpkin significantly reduced the immobility time (p = 0.02), corticosterone (p < 0.001), TNF-α, IL-6 (p < 0.001), and malondialdehyde (p = 0.003), whereas it significantly increased the level of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) in the serum of rats exposed to CUMS. Pumpkin markedly relieved the degenerative and atrophic changes observed in the CA3 region and the dentate gyrus of the hippocampus. It significantly reduced caspase-3 and increased glial fibrillary acidic protein (GFAP) immunoexpression in the CA3 and DG. In conclusion, administration of pumpkin extract improved the behavioral, biochemical, and hippocampal pathological alternations induced in rats after exposure to CUMS in a comparable pattern to fluoxetine. This study highlighted the potential efficacy of pumpkin in alleviating depression disorder either alone or in conjugation with conventional antidepressant therapy.


Subject(s)
Apoptosis/drug effects , Cucurbita/chemistry , Gliosis/drug therapy , Hippocampus/drug effects , Neurogenesis/drug effects , Stress, Psychological/drug therapy , Animals , Humans , Male , Rats
5.
Front Pharmacol ; 12: 664248, 2021.
Article in English | MEDLINE | ID: mdl-34054538

ABSTRACT

Background: The antioxidant, hypoglycemic, and insulin-enhancing effects of ginger and cinnamon were previously confirmed in experimental and human studies, while the combined effect of ginger and cinnamon was not thoroughly investigated until now. Objectives: This study was designed to assess the antidiabetic effect of combined administration of ginger (Zingiber officinale Roscoe) and cinnamon (Cinnamomum cassia L.) in streptozotocin (STZ)-induced diabetic rats compared to metformin and to explain the mechanism behind this effect. Materials and methods: STZ was utilized to induce diabetes mellitus in male Sprague-Dawley rats. Assessments of fasting blood glucose level (BGL), the total antioxidant capacity (TAC), serum insulin, HOMA-IR, and HOMA-ß cells were performed. Pancreatic gene expression of ß-catenin and p53 was assessed using RT-PCR. Assessment of histopathological alterations of pancreatic islet cells was performed using routine and immunohistochemical techniques. Results: BGL significantly decreased (p = 0.01), while serum insulin and TAC significantly increased (p < 0.001) in both metformin- and ginger plus cinnamon-treated groups compared to the untreated diabetic group. HOMA-ß cell index significantly increased (p = 0.001) in ginger plus cinnamon, indicating their enhancing effect on insulin secretion in diabetic conditions. p53 gene expression was significantly upregulated (p < 0.001), while ß-catenin was insignificantly downregulated (p = 0.32) in ginger plus cinnamon-treated groups. Insulin immunoexpression in ß cells significantly increased (p = 0.001, p = 0.004) in metformin- and ginger plus cinnamon-treated groups, respectively. Conclusions: The combined administration of ginger and cinnamon has a significant hypoglycemic and antioxidant effect in STZ-induced diabetes mostly through enhancing repair of islet cells mediated via upregulation of pancreatic p53 expression. Therefore, testing this effect in diabetic patients is recommended.

6.
Heliyon ; 7(3): e06255, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33786386

ABSTRACT

BACKGROUND: Chemotherapy remains to be the method of choice used by clinicians to treat acute myeloid leukemia (AML) patients. However, the most common problem usually faced in the course of treatment is multidrug resistance (MDR). Nowadays, combination therapy involving natural products as adjuvant therapy to chemotherapy and radiotherapy has been used for many of health problems. Coumarin is a natural compound with known chemotherapeutic activity, as well as other pharmacological properties. We focused on the combination of coumarin and doxorubicin in overcoming of drug-resistance in acute myeloid leukemia. METHODS: Cell viability, Apoptotic and necrotic cell death with FACS, oxidative stress detection, and protein expression analysis were used in this study. RESULTS: Coumarin as a single drug exerts a significant cell death on Human acute myeloid leukemia (HL60); however, it does not show the same effect on drug-resistant acute myeloid leukemia (HL60/ADR). Comparing the effects of doxorubicin and coumarin as single drugs versus a combination of coumarin and doxorubicin showed a significant apoptotic cell death. CONCLUSION: In AML patients, the development of multiple drug resistance (MDR) is the biggest challenge in treating AML patients. Combination therapy with coumarin may be a good choice to overcome the drug resistance in AML patients.

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