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Effective and targeted prevention and treatment methods for acute kidney injury (AKI), a common clinical complication, still needs to be explored. Paricalcitol is a biologically active chemical that binds to vitamin D receptors in the body to exert anti-oxidant and anti-inflammatory effects. However, the molecular mechanism of the effect of paricalcitol on AKI remains unclear. The current study uses a paricalcitol pretreatment with a mouse AKI model induced by cisplatin to detect changes in renal function, pathology and ultrastructure. Results showed that paricalcitol significantly improved renal function in mice and reduced inflammatory cell infiltration and mitochondrial damage in renal tissue. Furthermore, paricalcitol markedly suppressed reactive oxygen species and malondialdehyde levels in the kidneys of AKI mice and increased the levels of glutathione, superoxide dismutase, Catalase and total anti-oxidant capacity. In addition, we detected renal necrosis and inflammation-related proteins in AKI mice by immunofluorescence and Western blot, and found that their levels were markedly decreased after paricalcitol pretreatment. Moreover, paricalcitol promotes nuclear factor erythroid 2-related factor 2 (Nrf2) in the nucleus and activates the Nrf2/heme oxygenase-1 (HO-1) signaling pathway; while HO-1 is inhibited, the protective effect of paricalcitol on the kidney is attenuated. In conclusion, paricalcitol exerts a renoprotective effect by decreasing renal oxidative injury and inflammation through Nrf2/HO-1 signaling, providing a new insight into AKI prevention.
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Injúria Renal Aguda , Antioxidantes , Camundongos , Animais , Antioxidantes/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Heme Oxigenase-1/metabolismo , Estresse Oxidativo , Transdução de Sinais , Injúria Renal Aguda/metabolismo , Rim/metabolismo , Inflamação/metabolismoRESUMO
Cisplatin-based chemotherapy causes intestinal mucositis, which causes patients immense suffering and hinders the process of cancer treatment. Dioscin is a natural steroid saponin that exhibits strong anti-inflammatory and immunomodulatory properties. Herein, we investigate the protective effect of dioscin on cisplatin induced mucositis in rats from the perspective of gut microbiota and intestinal barrier. We established a rat model of intestinal mucositis by tail vein injection of cisplatin, and concurrently treated with dioscin oral administration. Parameters, such as body weight, diarrheal incidence, and D-Lactate levels, were assessed in order to evaluate the effects of dioscin on intestinal mucositis in rats. Furthermore, biological samples were collected for microscopic gut microbiota, intestinal integrity, and immune inflammation analyses to elucidate the protective mechanisms of dioscin on intestinal mucositis. The results revealed that administration of dioscin significantly attenuated clinical manifestations, histological injury and inflammation in mucositis rats. Besides this, dioscin markedly inhibited the gut microbiota dysbiosis induced by cisplatin. Meanwhile, dioscin partially alleviated junctions between ileum epithelial cells and increased mucus secretion. Moreover, dioscin effectively inhibited the TLR4-MyD88-NF-κB signal transduction pathway and reduced the secretion of subsequent inflammatory mediators. These results suggested that dioscin effectively attenuated cisplatin-induced mucositis in part by modulating the gut microflora profile, maintaining ileum integrity and inhibiting the inflammatory response through the TLR4-MyD88-NF-κB pathway.
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Microbioma Gastrointestinal , Mucosite , Animais , Cisplatino/farmacologia , Diosgenina/análogos & derivados , Humanos , Inflamação/tratamento farmacológico , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Ratos , Transdução de Sinais , Receptor 4 Toll-Like/metabolismoRESUMO
In order to explore the therapeutic effect of Resveratrol (Res)-activated Natural Killer (NK) cells on canine mammary tumors, this study employed a range of assays, including wound healing, colony formation, Transwell, flow cytometry, and Western blot experiments, to investigate the impact of Res-pretreated NK cells on canine mammary tumor cells in vitro. Additionally, a tumor-bearing mouse model was utilized to further analyze the therapeutic effects of Res-pretreated NK cells in vivo. The results showed that Res enhances the capacity of NK cells to induce apoptosis, pyroptosis, and ferroptosis in canine breast tumor cells, while also augmenting their influence on the migration, invasion, and epithelial-mesenchymal transition of these cells. Furthermore, pretreatment of NK cells with Res significantly amplified their inhibitory effect on breast tumor growth in vivo and promoted tumor tissue apoptosis. Additionally, Res enhanced the recruitment of NK cells to other immune cells in the body. In summary, Res has been shown to enhance the anti-breast-tumor effect of NK cells both in vitro and in vivo, offering a new avenue for optimizing immunotherapy for canine breast tumors.
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To improve the mechanical performance of carbon fiber (CF)/epoxy composites in high-temperature environments, a moderately modulus gradient modulus interlayer was constructed at the interface phase region of composites. This involved the design of a "rigid-flexible" synergistic reinforcement structure, incorporating rigid nanoparticle GO@CNTs and a flexible polymer polynaphthyl ether nitrile ketone onto the CF surface. Notably, at 180 °C, compared to commercial CF composites, the CF-GO@CNTs-PPENK composites displayed a remarkable improvement in their mechanical characteristics (interfacial shear, interlaminar shear, flexural strength, and modulus), achieving enhancements of 173.0, 91.5, 225.7, and 376.4%, respectively. The principal reason for this the moderately modulus interface phase composed of GO@CNTs-PPENK (where GO and CNTs predominantly consist of carbon atoms with sp2-hybridized orbitals, forming highly stable C-C structures, while PPENK possesses a "twisted non-coplanar" structure), which exhibited resistance to deformation at high temperatures. Moreover, it greatly improved the mechanical interlocking, wettability, and chemical compatibility between CF and the epoxy. It also played a crucial role in balancing and buffering the modulus disparity. The interface failure behavior and reinforcement mechanisms of the CF composites were analyzed. Furthermore, validation of the presence of a moderately modulus gradient interlayer at the interface phase region of CF-GO@CNTs-PPENK composites was performed by using atomic force microscopy. This study has established a theoretical foundation for the development of high-performance CF composites for use in high-temperature fields.
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BACKGROUND: The treatment of acute kidney injury (AKI), a common disease in dogs, is limited. Therefore, an effective method to prevent AKI in veterinary clinics is particularly crucial. OBJECTIVES: Hydrogen sulfide (H2S) is the third gaseous signal molecule involved in various physiological functions of the body. The present study investigated the effect of H2S on cisplatin-induced AKI and the involved mechanisms in dogs. METHODS: Cisplatin-injected dogs developed AKI symptoms as indicated by renal dysfunction and pathological changes. In the H2S-treated group, 50 mM sodium hydrosulfide (NaHS) solution was injected at 1 mg/kg/h for 30 min before cisplatin injection. After 72 h, tissue and blood samples were collected immediately. We performed biochemical tests, optical microscopy studies, analysis with test kits, quantitative reverse-transcription polymerase chain reaction, and western blot analysis. RESULTS: The study results demonstrated that cisplatin injection increased necroptosis and regulated the corresponding protein expression of receptor interacting protein kinase (RIPK) 1, RIPK3, and poly ADP-ribose polymerase 1; furthermore, it activated the expressions of inflammatory factors, including tumor necrosis factor-alpha, nuclear factor kappa B, and interleukin-1ß, in canine kidney tissues. Moreover, cisplatin triggered oxidative stress and affected energy metabolism. Conversely, an injection of NaHS solution considerably reduced the aforementioned changes. CONCLUSIONS: In conclusion, H2S protects the kidney from cisplatin-induced AKI through the mitigation of necroptosis and inflammation. These findings provide new and valuable clues for the treatment of canine AKI and are of great significance for AKI prevention in veterinary clinics.
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Injúria Renal Aguda , Doenças do Cão , Sulfeto de Hidrogênio , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/veterinária , Adenosina Difosfato Ribose , Animais , Cisplatino/efeitos adversos , Cães , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Inflamação/veterinária , Interleucina-1beta , NF-kappa B , Necroptose , Sulfetos , Fator de Necrose Tumoral alfaRESUMO
Selenium (Se) deficiency significantly impacts the cow breeding industry by reducing the milk quality of dairy cows and affecting the health of calves. The molecular mechanism of Se deficiency-induced damage to calves, however, remains unclear. The present study investigated whether Se deficiency induces oxidative stress, apoptosis, and inflammation in calf liver tissues. We collected the liver tissues of calves with Se deficiency. Experimental results showed that Se deficiency weakened the activity of antioxidant enzymes and increased the accumulation of oxidation products in the liver. Se deficiency also led to excessive fission of the mitochondria and downregulated the expression of the Mfn2 and Opa1 genes in the calf liver. Mitochondrial damage-induced apoptosis by increasing the expression of pro-apoptotic genes such as CytC, Cas3, Cas9, fas, and Cas8, leading to a decrease in energy metabolism. Se deficiency also triggered the expression of inflammatory-related factors such as IL-1ß, IL-6, TNF-α, and NF-κB. Taken together, the results suggest that Se deficiency causes oxidative stress, triggers an inflammatory response, disrupts mitochondrial dynamic balance, and then induces apoptosis, eventually leading to calf liver damage. These findings might provide valuable clues for elucidating the mechanism of Se deficiency-induced injury in domestic animals.
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Proteínas Associadas a CRISPR , Selênio , Animais , Antioxidantes/metabolismo , Apoptose , Proteínas Associadas a CRISPR/metabolismo , Bovinos , Feminino , Interleucina-6/metabolismo , Fígado/metabolismo , Dinâmica Mitocondrial , NF-kappa B/metabolismo , Estresse Oxidativo , Selênio/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Three different blending procedures were used to create multiwalled carbon nanotube (MWCNT)-modified chloroprene rubber (CR)/natural rubber (NR) blended composites (MWCNT/CR-NR). The effects of the blending process on the morphology of the conductive network and interfacial contacts were researched, as well as the resistance-strain response behavior of the composites and the mechanism of composite sensitivity change under different processes. The results show that MWCNT/CR-NR composites have a wide strain range (ε = 300%) and high dynamic resistance-strain response repeatability. Different blending procedures have different effects on the morphology of the conductive network and the interfacial interactions of the composites. If the blending procedures have wider conductive phase spacing and stronger interfacial contacts, the change in the conductive path and tunneling distance occurs more rapidly, and the material has a higher resistance-strain response sensitivity.
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Intestinal injury is one of the main side-effects of cisplatin (CP) chemotherapy, severely limiting the clinical application of CP. Vitamin D3 is an essential nutrient for mammals and exists in a wide range of foods; it regulates immune function and reduces oxidative stress. However, the effect of vitamin D3 on CP-induced intestinal injury is not elucidated. This is the first study to investigate the relationship between ferroptosis and the protective effect of vitamin D3 on CP-induced intestinal injury. An animal model of CP-induced intestinal injury was established to evaluate the effect of vitamin D3 on CP-induced intestinal injury and elucidate the underlying mechanisms. We found that vitamin D3 alleviated intestinal barrier injury and the abnormal morphological structure in CP-induced intestinal injury mice. Vitamin D3 suppressed oxidative stress by increasing the antioxidant capacity, inhibiting the accumulation of ROS and MDA, and reducing intestinal inflammatory responses. Vitamin D3 also decreased excessive mitochondrial fission and increased mitochondrial ATPase activity by inhibiting ROS production, which further alleviated the accumulation of ROS. We also confirmed the involvement of ferroptosis in CP-induced intestinal injury in our animal model using ferrostatin-1 (Fer-1) intervention. Vitamin D3 decreased iron accumulation and reversed GPX4 and DHODH down-regulation. In conclusion, vitamin D3 protected against CP-induced intestinal injury by inhibiting ferroptosis and alleviating oxidative stress and ROS-mediated excessive mitochondrial fission, suggesting that it may be a novel and promising candidate to prevent CP-induced intestinal injury.
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Cisplatino , Ferroptose , Adenosina Trifosfatases , Animais , Antioxidantes/farmacologia , Colecalciferol/farmacologia , Cisplatino/efeitos adversos , Ferro/farmacologia , Mamíferos , Camundongos , Dinâmica Mitocondrial , Estresse Oxidativo , Espécies Reativas de OxigênioRESUMO
Cisplatin is the most widely prescribed drug in chemotherapy, but its gastrointestinal toxicity reduces therapeutic efficacy. Oxidative stress and inflammation are considered to be the main pathogenesis of cisplatin-induced intestinal toxicity. Dioscin is a steroidal saponin with potential anti-cancer, antioxidant, and anti-inflammatory activities. In this study, we established a rat model of intestinal injury by tail vein injection of cisplatin, and intragastrically administered dioscin to evaluate its effect on intestinal injury. Biochemical markers, western blotting, qRT-PCR and histopathological staining were used to analyze intestinal injury according to various molecular mechanisms. The results revealed that dioscin significantly inhibited cisplatin-induced intestinal mucosal damage and decreased DAO levels in rats. Furthermore, dioscin activated the Nrf2/HO-1 pathway to increase the level of antioxidant enzymes and reduce the levels of MDA and H2O2. In addition, dioscin pretreatment significantly reduced ileum epithelial NLRP3 inflammasome formation and decreased the levels of inflammatory factors compared with the cisplatin group. In parallel, Nrf2 inhibitor ML385 blocked the therapeutic effect of dioscin in rat with cisplatin-induced intestinal toxicity. In terms of mechanisms, dioscin reversed cisplatin-induced up-regulation of MAPKs and up-regulated p-PI3K and p-AKT levels. Meanwhile, dioscin potently promoted Wnt3A/ß-catenin signaling to relieve cisplatin-induced proliferation inhibition. In conclusion, our study suggests that dioscin could ameliorate the cisplatin-induced intestinal toxicity by reducing oxidative stress and inflammation.
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Diosgenina , Fator 2 Relacionado a NF-E2 , Animais , Antioxidantes/uso terapêutico , Cisplatino/toxicidade , Diosgenina/análogos & derivados , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Peróxido de Hidrogênio/farmacologia , Inflamação/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , RatosRESUMO
Background: Troxerutin is a flavonoid compound and possesses potential anti-cancer, antioxidant, and anti-inflammatory activities. Besides, cisplatin is one of the most widely used therapeutic agents, but the clinical uses of cisplatin are often associated with multiple side effects, among which nephrotoxicity is more common. Objective and design: This study explored the protective effects of troxerutin (150 mg kg-1 day-1 for 14 days) against cisplatin-induced kidney injury and the potential mechanism using Wistar rats as an experimental mammalian model. Results: We discovered that troxerutin could significantly alleviate cisplatin-induced renal dysfunction, such as increased levels of blood urea nitrogen and creatinine (P < 0.01), as well as improved abnormal renal tissue microstructure and ultrastructure. Additionally, troxerutin significantly decreased malondialdehyde (MDA), hydrogen peroxide (H2O2), NO, inducible nitric oxide synthase (iNOS) levels (P < 0.01), p-NF-κB p65/NF-κB p65, TNF-α, Pro-IL-1ß, IL-6, B cell lymphoma-2 (Bcl-2)/Bcl-xl associated death promoter (Bad), Cytochrome C (Cyt C), Cleaved-caspase 9, Cleaved-caspase 3, and Cleaved-caspase 8 protein levels (P < 0.01) in the kidney tissues of cisplatin-treated rats; and increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), total antioxidant capacity (T-AOC) activities (P < 0.01), IL-10, Bcl-2 protein levels (P < 0.01). Conclusion: These results suggested that the underlying mechanism might be attributed to the regulation of Phosphoinositide 3 kinase/Protein kinase B (PI3K/AKT) pathway via enhancing MAP4 expression to attenuate cellular apoptosis, alleviating oxidative stress and inflammatory response.
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Heteroatom-doped conductive carbon nanomaterials are promising for energy and catalysis applications, but there are few reports on increasing their heteroatom doping content and conductivity simultaneously. In this manuscript, we use 2-(4-aminophenyl)-5-aminobenzimidazole as the diamine monomer to prepare polyamic acid with asymmetric structural units doped with phosphoric acid (PA) and polyacrylonitrile (PAN) as innovative composite precursors, which are then electrospun into nanofiber films. After stabilization and carbonization, the electrospun fibers are converted into N/P co-doped electrospun carbon nanofiber films (ECNFs) with high heteroatom content, including 4.33% N and 0.98% P. The morphology, structure, and conductivity of ECNFs were systematically characterized. The ECNFs doped with 15 wt.% PA exhibited conductivity that was 47.3% higher than that of the ECNFs undoped with PA, but the BET surface area decreased by 23%. The doped PA in the precursor nanofibers participated in the cyclization of PAN during thermal stabilization, as indicated by infrared spectroscopy and thermogravimetric analysis results. X-ray diffraction and Raman results indicate that a moderate amount of PA doping facilitated the formation of ordered graphitic crystallite structures during carbonization and improved the conductivity of ECNFs.
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The dispersion, electrical conductivities, mechanical properties and resistance-strain response behaviors of multiwalled carbon nanotube (MWCNT)/natural rubber (NR) composites synthesized by the different processing conditions are systematically investigated at both macro- and micro-perspectives. Compared with the solution and flocculation methods, the two roll method produced the best MWCNTs distribution since the materials are mixed by strong shear stress between the two rolls. An excellent segregated conductive network is formed and that a low percolation threshold is obtained (~1 wt.%) by the two roll method. Different from the higher increases in conductivity for the composites obtained by the solution and flocculation methods when the MWCNT content is higher than 3 wt.%, the composite prepared by the two roll method displays obvious improvements in its mechanical properties. In addition, the two roll method promotes good stability, repeatability, and durability along with an ultrahigh sensitivity (GFmax = 974.2) and a large strain range (ε = 109%). The 'shoulder peak' phenomenon has not been observed in the composite prepared by the two roll method, confirming its potential for application as a large deformation monitoring sensor. Moreover, a mathematical model is proposed to explain the resistance-strain sensing mechanism.