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INTRODUCTION: Uncontrolled chronic hyperglycemia in diabetic patients could result in various complications, including neurotoxicity. Urtica dioica L. (UD) is known for its hypoglycemic and antioxidant effects. In this study, we evaluated the efficacy of UD and pioglitazone (PIO) in reduction of neurotoxicity and oxidative stress in streptozocin-induced diabetic mice. MATERIALS AND METHODS: Male mice were divided into seven groups: control, diabetic, dimethyl sulfoxide-treated control, PIO-treated, UD-treated, UD-PIO-treated, and vitamin E-treated. For induction of diabetes, streptozocin was injected in a single dose (65 mg/kg, i.p.). All treatments were performed for 5 weeks. Neurotoxicity was evaluated through hot plate and formalin test. Then, animals were killed, brain tissue was separated and the mitochondrial fraction was isolated with different centrifuge technique. Also, oxidative stress markers (reactive oxygen species, lipid peroxidation, protein carbonyl, glutathione) were measured in brain. Mitochondrial function was evaluated by MTT test in brain isolated mitochondria. RESULTS: Elevation of oxidative stress markers and mitochondrial damage were observed in diabetic mice compared to control group. Administration of PIO and UD ameliorated the oxidative stress and mitochondrial damage (p < 0.05) in diabetic mice. Also increase in pain score was shown in diabetic mice that treatment with UD and PIO diminished elevation of pain score in diabetic mice. Interestingly, simultaneous administration of PIO and UD showed synergism effect in attenuation of oxidative stress and hyperglycemia. CONCLUSION: UD showed a therapeutic potential for the attenuation of oxidative stress and diabetes-induced hyperglycemia that can be considered as co-treatment in treatment of diabetic neurotoxicity.
Assuntos
Neuropatias Diabéticas/prevenção & controle , Hipoglicemiantes/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Componentes Aéreos da Planta/química , Extratos Vegetais/uso terapêutico , Urtica dioica/química , Animais , Antioxidantes/isolamento & purificação , Antioxidantes/uso terapêutico , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/enzimologia , Neuropatias Diabéticas/metabolismo , Sinergismo Farmacológico , Quimioterapia Combinada , Hipoglicemiantes/isolamento & purificação , Irã (Geográfico) , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/metabolismo , Fármacos Neuroprotetores/isolamento & purificação , Estresse Oxidativo/efeitos dos fármacos , Pioglitazona , Componentes Aéreos da Planta/crescimento & desenvolvimento , Extratos Vegetais/isolamento & purificação , Carbonilação Proteica/efeitos dos fármacos , Tiazolidinedionas/uso terapêutico , Urtica dioica/crescimento & desenvolvimentoRESUMO
Objectives: The kidney ages faster than other organs due to changes in energy metabolism, mitochondrial dysfunction, and oxidative stress. This study looked into the anti-aging effect of tropisetron. Materials and Methods: D-galactose was administrated subcutaneously in a mouse model for eight weeks in order to induce renal aging. Three separate intraperitoneal doses of tropisetron (1, 3, and 5 mg/kg body weight) were given at the same time. We assessed markers of mitochondrial dysfunction, oxidative stress, and inflammation. Via Real-Time PCR, the expressions of genes linked to aging (SIRT1) and apoptosis (Bax and Bcl-2) were ascertained. In addition, an assessment of histopathological changes, blood urea nitrogen, and creatinine concentrations was done. Results: In kidney tissue, tropisetron reduces mitochondrial dysfunction and oxidative stress, which are caused by D-galactose-induced overproduction of inflammatory mediators. Additionally, tropisetron demonstrated antiapoptotic activity in renal tissue and augmented the decrease in SIRT1 gene expression associated with D-galactose administration. Besides, tropisetron significantly improved the histological alterations in the renal tissues of aged mice and effectively decreased the elevated levels of creatinine and also blood urea nitrogen. Conclusion: The results provided additional insight into the effect of tropisetron on renal aging and the underlying mechanisms, particularly through its ability to modulate SIRT1 signaling.
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In this effort, the immobilization of guanidine-sulfonate on the surface of Fe3O4 MNPs (magnetic nanoparticles) as a novel acid nanocatalyst has been successfully reported for the synthesis of N-substituted (Z)-5-arylidene thiazolidine-2,4-dione and related cyclic derivatives, including rhodanine (RHD) and hydantoin (HYD) via a one-pot multiple-component reaction under green conditions. The products were characterized by SEM, TEM, TGA, EDS, BET techniques, VSM, and FTIR. The novel compounds synthesized using this methodology, designated as series La (1-9), Lb (1-8), and Lc (1-8), were subjected to anticancer screening against A549 and MCF7cell lines via MTT assays. Notably, several compounds (L1a, L2a, L3a, L1b, L2b, L3b, and L4b) exhibited potent antiproliferative activities, with observed IC50 values as low as 1.23 µM and 1.02 µM against MCF-7 cells, thereby outperforming the established anticancer drugs doxorubicin and cisplatin. Molecular docking and dynamics simulations revealed that ligands L1a, L2a, and L3a strongly interact with the protein target 3CD8, with L1a displaying significant hydrophobic and hydrogen bonding interactions and L2a engaging in unique pi-pi stacking with key residues. For protein 2WGJ, ligand L4b exhibited exceptional binding affinity, characterized by robust hydrogen bonding, hydrophobic interactions, and additional stabilizing mechanisms such as water bridges and pi interactions. Hence, N-substituted (Z)-5-arylidene thiazolidine-2,4-dione and its cyclic derivatives may serve as promising candidates for further exploration in the development of new multi-target cancer chemotherapy agents. These findings introduce promising anticancer agents and establish Fe3O4 MNPs as a versatile and environmentally sustainable catalytic platform in drug discovery.
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In this study, the immobilization of sulfaguanidine-SA on the surface of FeAl2O4 (hercynite) MNPs (magnetic nanoparticles) as a novel acid nanocatalyst has been successfully reported for the synthesis of 2-(piperazin-1-yl) quinoxaline derivatives via a one-pot multiple-component reaction under green conditions. The products were characterized by SEM, TEM, TGA, EDS, BET technique, VSM, and FTIR. This series of novel 2-piperazinyl quinoxaline derivatives containing isatin-based thio/semicarbazones and/or Schiff bases of Metformin were evaluated for anticancer activity against both human ovarian and colon-derived tumor cell lines by MTT colorimetric assay. Although most of the investigated hybrid compounds exhibited excellent anti-proliferative activities and high selectivity index (SI) values, the promising compounds N'-[4-(quinoxaline-2-yl)-piperazine-1-yl]methyl-5-chloro-1-H-indole,2,3-dion-3-metformin 4c and N'-[4-(quinoxaline-2-yl)-piperazine-1-yl]methyl-5-bromo-1-H-indole,2,3-dion-3-metformin 4b proved to be the most potent anti-proliferative agents (IC50 values < 1 µM). Molecular docking and dynamics simulation suggest that these hybrid compounds can be wrapped in the catalytic cavity of c-Kit tyrosine kinase receptor and the binding pocket of P-glycoprotein with high scores. Thus, 2-piperazinyl quinoxaline linked isatin-based N-Mannich bases of metformin and/or thio/semicarbazones might be served as suitable candidates for further investigations to develop a new generation of multi-target cancer chemotherapy agents.
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AIMS: The aim of this study was to elucidate the signaling pathway involved in the anti-aging effect of tropisetron and to clarify whether it affects mitochondrial oxidative stress, apoptosis and inflammation in the aging mouse brain by upregulating Sirtuin 1 or silent information regulator 1 (SIRT1). MATERIALS AND METHODS: Aging was induced by d-galactose (DG) at the dose of 200 mg/kg body weight/day subcutaneously injected to male mice for six weeks. Tropisetron was simultaneously administered intraperitoneally once a day at three various doses (1, 3 and 5 mg/kg body weight). Oxidative stress and mitochondrial dysfunction markers were evaluated. Nitric oxide (NO) and pro-inflammatory cytokines levels including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were studied. Besides, the expressions of apoptosis-associated genes (Bax and Bcl-2) and the aging-related gene (SIRT1) were determined by the real time polymerase chain reaction (RT-PCR). In addition, histopathological alterations were assessed. KEY FINDINGS: Tropisetron reversed the induction of oxidative damage, mitochondrial dysfunction and overproduction of inflammatory mediators induced by DG in the brain tissue. In addition, tropisetron suppressed DG-induced apoptosis and found to significantly elevate SIRT1 gene expression. Besides, tropisetron could markedly alleviate DG-induced abnormal changes in the brain morphology. SIGNIFICANCE: Tropisetron exhibited anti-aging effects in the context of DG-induced senescence in mouse brain through various pathways. Our results suggest that tropisetron may attenuate DG-induced brain aging via SIRT1 signaling activation.
Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Sirtuína 1/genética , Tropizetrona/farmacologia , Envelhecimento/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Encéfalo/metabolismo , Encéfalo/patologia , Esquema de Medicação , Galactose/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação , Injeções Intraperitoneais , Injeções Subcutâneas , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
AIMS: Senescence is a state ensuing aging to eliminate age-associated damage with an irreversible cell-cycle arrest mechanism, which is historically believed to be one of the tumor responses to therapy. Doxorubicin as an anti-cancer drug has been used in cancer treatment for a long time. Liposomal doxorubicin (Ldox) is a liposomal formulation of doxorubicin, which increases the doxorubicin permanency. The aim of this study was to examine the toxicity of these two formulations by comparing them in terms of their ability to induce cellular senescence. MAIN METHODS: The study groups included a control group, three DOX (0.75, 0.5, 0.1â¯mg/kg/BW) and three Ldox groups (0.1, 0.05, 0.025â¯mg/kg/BW). Heart tissues were studied regarding oxidative stress assessment, mitochondrial function, inflammatory markers and biochemical and histopathological evaluation. Real-Time PCR was used for P53 and SA ß-gal expression. KEY FINDINGS: Based on the results, the highest doses of Dox and Ldox (0.75 and 0.1â¯mg/kg/BW respectively) significantly increased the level of inflammatory markers and according to other factors especially p53 and SA ß-gal expression, both were able to induce senescence but the changes in Ldox were less tangible than the Dox.
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Senescência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/metabolismo , Animais , Biomarcadores/metabolismo , Doxorrubicina/análogos & derivados , Glutationa Peroxidase/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Aluminum nanoparticles (AlNPs) are among the most abundantly produced nanosized particles in the market. There is limited information about the potential harmful effects of aluminum oxide due to its particle size on human health. Considering the toxic effects of Al on brain as its target tissue, in this study, the toxicity of nanoparticles, microparticles, and ionic forms of Al on rat brain and isolated mitochondria was evaluated. Sixty male Wistar rats were divided into ten groups (six rats each), in which group I was the control, and the other groups were administered different doses of Al nanoparticles, Al microparticles (AlMP), and Al ionic forms (2, 4, and 8 mg/kg, i.p.) for 28 days. After 24 h, the animals were killed, brain tissue was separated, the mitochondrial fraction was isolated, and oxidative stress markers were measured. Also, mitochondrial function was assayed by MTT test. The results showed that all forms of Al particles induced ROS formation, lipid peroxidation, protein oxidation, glutathione depletion, mitochondrial dysfunction, and gait abnormalities in a dose-dependent manner. In addition, Al particles decreased mitochondrial membrane potential. These data indicated that oxidative stress might contribute to the toxicity effects of Al. Comparison of oxidative stress markers between all forms of Al revealed that the toxic effect of AlNP on brain tissue was substantially more than that caused by AlMP and bulk form. This study showed more neurotoxicity of AlNPs compared to other forms on brain oxidative damage that probably is due to more penetration into the brain.