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1.
Br J Pharmacol ; 181(7): 1128-1149, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37721089

RESUMO

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice. EXPERIMENTAL APPROACH: Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured. KEY RESULTS: Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF. CONCLUSION AND IMPLICATIONS: TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.


Assuntos
Paclitaxel , Doenças do Sistema Nervoso Periférico , Humanos , Camundongos , Animais , Paclitaxel/toxicidade , PPAR gama , Fator Neurotrófico Derivado do Encéfalo , Fator 2 Relacionado a NF-E2 , Doenças Neuroinflamatórias , Qualidade de Vida , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle
2.
Theriogenology ; 165: 84-91, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33640590

RESUMO

Mycotoxins are natural contaminants of food and feed occurring worldwide. Deoxynivalenol (DON) and fumonisin B1 (FB1) are the most frequent fusariotoxins and induce immune and intestinal toxicity in humans and animals. Recently, an association between mycotoxins exposure and impaired fertility has been suggested. However, the effects of these mycotoxins on the reproductive system are not well established. This study aimed to evaluate the effects of FB1 and DON, in combination or alone, on the ovarian morphology and oxidative responses using porcine explants. Seventy-two explants were obtained from six pigs and submitted to the following treatments: control (MEM medium), DON (10 µM), FB1 (100 µM FB1), and DON + FB1 (10 µM + 100 µM). Histological and immunohistochemical assays were performed to evaluate ovarian changes, cell proliferation, and apoptosis. Oxidative stress response was evaluated through lipid peroxidation and antioxidant capacity response assays. The exposure to mycotoxins induced significant histological changes in the ovaries, which were characterized by a decrease in viable follicles and increase in degenerated follicles. A significant decrease in granulosa cell proliferation was observed in explants exposed to all mycotoxins. In addition the multi-contaminated treatment was responsible for an increase in the cell apoptosis index of growing follicles. On the other hand, the FB1 and multi-contaminated treatments induced a significant decrease in lipid peroxidation accompanied by an increase in antioxidant responses. Altogether, our results indicate a reproductive toxicity induced by fusariotoxins. Moreover, mycotoxins, alone or in combination, modulate oxidative stress response, interfering with the production of free radicals and affecting the reproductive capacity of pigs.


Assuntos
Fumonisinas , Micotoxinas , Toxina T-2 , Tricotecenos , Animais , Feminino , Fumonisinas/toxicidade , Micotoxinas/toxicidade , Ovário , Estresse Oxidativo , Suínos , Tricotecenos/toxicidade
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