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1.
J Environ Sci (China) ; 145: 1-12, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38844310

RESUMO

The potential association between colorectal cancer (CRC) and environmental pollutants is worrisome. Previous studies have found that some perfluoroalkyl acids, including perfluorooctane sulfonate (PFOS), induced colorectal tumors in experimental animals and promoted the migration of and invasion by CRC cells in vitro, but the underlying mechanism is unclear. Here, we investigated the effects of PFOS on the proliferation and migration of CRC cells and the potential mechanisms involving activating the PI3K/Akt-NF-κB signal pathway and epithelial-mesenchymal transition (EMT). It was found that PFOS promoted the growth and migration of HCT116 cells at non-cytotoxic concentrations and increased the mRNA expression of the migration-related angiogenic cytokines vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). In a mechanistic investigation, the up-stream signal pathway PI3K/Akt-NF-κB was activated by PFOS, and the process was suppressed by LY294002 (PI3K/Akt inhibitor) and BAY11-7082 (NF-κB inhibitor) respectively, leading to less proliferation of HCT116 cells. Furthermore, matrix metalloproteinases (MMP) and EMT-related markers were up-regulated after PFOS exposure, and were also suppressed respectively by LY294002 and BAY11-7082. Moreover, the up-regulation of EMT markers was suppressed by a MMP inhibitor GM6001. Taken together, our results indicated that PFOS promotes colorectal cancer cell migration and proliferation by activating the PI3K/Akt-NF-κB signal pathway and epithelial-mesenchymal transition. This could be a potential toxicological mechanism of PFOS-induced malignant development of colorectal cancer.


Assuntos
Ácidos Alcanossulfônicos , Movimento Celular , Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Fluorocarbonos , Fluorocarbonos/toxicidade , Ácidos Alcanossulfônicos/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Colorretais/patologia , Humanos , Movimento Celular/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Células HCT116 , Proteínas Proto-Oncogênicas c-akt/metabolismo , NF-kappa B/metabolismo , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral
2.
Sci Rep ; 14(1): 12917, 2024 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-38839811

RESUMO

Allii Macrostemonis Bulbus (AMB) is a traditional Chinese medicine with medicinal and food homology. AMB has various biological activities, including anti-coagulation, lipid-lowering, anti-tumor, and antioxidant effects. Saponins from Allium macrostemonis Bulbus (SAMB), the predominant beneficial compounds, also exhibited lipid-lowering and anti-inflammatory properties. However, the effect of SAMB on atherosclerosis and the underlying mechanisms are still unclear. This study aimed to elucidate the pharmacological impact of SAMB on atherosclerosis. In apolipoprotein E deficiency (ApoE-/-) mice with high-fat diet feeding, oral SAMB administration significantly attenuated inflammation and atherosclerosis plaque formation. The in vitro experiments demonstrated that SAMB effectively suppressed oxidized-LDL-induced foam cell formation by down-regulating CD36 expression, thereby inhibiting lipid endocytosis in bone marrow-derived macrophages. Additionally, SAMB effectively blocked LPS-induced inflammatory response in bone marrow-derived macrophages potentially through modulating the NF-κB/NLRP3 pathway. In conclusion, SAMB exhibits a potential anti-atherosclerotic effect by inhibiting macrophage foam cell formation and inflammation. These findings provide novel insights into potential preventive and therapeutic strategies for the clinical management of atherosclerosis.


Assuntos
Aterosclerose , Células Espumosas , Inflamação , Saponinas , Animais , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Saponinas/farmacologia , Camundongos , Inflamação/tratamento farmacológico , Inflamação/patologia , Allium/química , Masculino , Apolipoproteínas E/deficiência , Dieta Hiperlipídica/efeitos adversos , NF-kappa B/metabolismo , Camundongos Endogâmicos C57BL , Lipoproteínas LDL/metabolismo
3.
J Nanobiotechnology ; 22(1): 314, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840113

RESUMO

Osteoporosis is the most common bone metabolic disease that affects the health of middle-aged and elderly people, which is hallmarked by imbalanced bone remodeling and a deteriorating immune microenvironment. Magnesium and calcium are pivotal matrix components that participate in the bone formation process, especially in the immune microenvironment regulation and bone remodeling stages. Nevertheless, how to potently deliver magnesium and calcium to bone tissue remains a challenge. Here, we have constructed a multifunctional nanoplatform composed of calcium-based upconversion nanoparticles and magnesium organic frameworks (CM-NH2-PAA-Ald, denoted as CMPA), which features bone-targeting and pH-responsive properties, effectively regulating the inflammatory microenvironment and promoting the coordination of osteogenic functions for treating osteoporosis. The nanoplatform can efficaciously target bone tissue and gradually degrade in response to the acidic microenvironment of osteoporosis to release magnesium and calcium ions. This study validates that CMPA possessing favorable biocompatibility can suppress inflammation and facilitate osteogenesis to treat osteoporosis. Importantly, high-throughput sequencing results demonstrate that the nanoplatform exerts a good inflammatory regulation effect through inhibition of the nuclear factor kappa-B signaling pathway, thereby normalizing the osteoporotic microenvironment. This collaborative therapeutic strategy that focuses on improving bone microenvironment and promoting osteogenesis provides new insight for the treatment of metabolic diseases such as osteoporosis.


Assuntos
Cálcio , Magnésio , Nanopartículas , Osteogênese , Osteoporose , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Magnésio/farmacologia , Magnésio/química , Cálcio/metabolismo , Animais , Nanopartículas/química , Camundongos , Inflamação/tratamento farmacológico , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Humanos , Microambiente Celular/efeitos dos fármacos , Feminino , NF-kappa B/metabolismo
4.
Front Immunol ; 15: 1361606, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38846937

RESUMO

Introduction: Pathological changes in the articular cartilage (AC) and synovium are major manifestations of osteoarthritis (OA) and are strongly associated with pain and functional limitations. Exosome-derived microRNAs (miRNAs) are crucial regulatory factors in intercellular communication and can influence the progression of OA by participating in the degradation of chondrocytes and the phenotypic transformation in the polarization of synovial macrophages. However, the specific relationships and pathways of action of exosomal miRNAs in the pathological progression of OA in both cartilage and synovium remain unclear. Methods: This study evaluates the effects of fibroblast-like synoviocyte (FLS)-derived exosomes (FLS-Exos), influenced by miR-146a, on AC degradation and synovial macrophage polarization. We investigated the targeted relationship between miR-146a and TRAF6, both in vivo and in vitro, along with the involvement of the NF-κB signaling pathway. Results: The expression of miR-146a in the synovial exosomes of OA rats was significantly higher than in healthy rats. In vitro, the upregulation of miR-146a reduced chondrocyte apoptosis, whereas its downregulation had the opposite effect. In vivo, exosomes derived from miR-146a-overexpressing FLSs (miR-146a-FLS-Exos) reduced AC injury and chondrocyte apoptosis in OA. Furthermore, synovial proliferation was reduced, and the polarization of synovial macrophages shifted from M1 to M2. Mechanistically, the expression of TRAF6 was inhibited by targeting miR-146a, thereby modulating the Toll-like receptor 4/TRAF6/NF-κB pathway in the innate immune response. Discussion: These findings suggest that miR-146a, mediated through FLS-Exos, may alleviate OA progression by modulating cartilage degradation and macrophage polarization, implicating the NF-κB pathway in the innate immune response. These insights highlight the therapeutic potential of miR-146a as a protective agent in OA, underscoring the importance of exosomal miRNAs in the pathogenesis and potential treatment of the disease.


Assuntos
Exossomos , Macrófagos , MicroRNAs , Osteoartrite , Sinoviócitos , Fator 6 Associado a Receptor de TNF , MicroRNAs/genética , Animais , Exossomos/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoartrite/imunologia , Ratos , Macrófagos/imunologia , Macrófagos/metabolismo , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Masculino , Fator 6 Associado a Receptor de TNF/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Condrócitos/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Ratos Sprague-Dawley , Fibroblastos/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Membrana Sinovial/imunologia , Células Cultivadas , Apoptose , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Ativação de Macrófagos
5.
Mol Biol Rep ; 51(1): 709, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824265

RESUMO

BACKGROUND: Cystatin is a protease inhibitor that also regulates genes expression linked to inflammation and plays a role in defense and regulation. METHODS AND RESULTS: Cystatin 10 (Smcys10) was cloned from Scophthalmus maximus and encodes a 145 amino acid polypeptide. The results of qRT-PCR showed that Smcys10 exhibited tissue-specific expression patterns, and its expression was significantly higher in the skin than in other tissues. The expression level of Smcys10 was significantly different in the skin, gill, head kidney, spleen and macrophages after Vibrio anguillarum infection, indicating that Smcys10 may play an important role in resistance to V. anguillarum infection. The recombinant Smcys10 protein showed binding and agglutinating activity in a Ca2+-dependent manner against bacteria. rSmcys10 treatment upregulated the expression of IL-10, TNF-α and TGF-ß in macrophages of turbot and hindered the release of lactate dehydrogenase (LDH) from macrophages after V. anguillarum infection, which confirmed that rSmcys10 reduced the damage to macrophages by V. anguillarum. The NF-κB pathway was suppressed by Smcys10, as demonstrated by dual-luciferase analysis. CONCLUSIONS: These results indicated that Smcys10 is involved in the host antibacterial immune response.


Assuntos
Cistatinas , Doenças dos Peixes , Proteínas de Peixes , Linguados , Macrófagos , Vibrio , Animais , Linguados/imunologia , Linguados/genética , Linguados/metabolismo , Vibrio/patogenicidade , Cistatinas/genética , Cistatinas/metabolismo , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Proteínas de Peixes/imunologia , Macrófagos/metabolismo , Macrófagos/imunologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/genética , Doenças dos Peixes/microbiologia , Vibrioses/imunologia , Vibrioses/veterinária , Vibrioses/genética , NF-kappa B/metabolismo , Clonagem Molecular/métodos , Regulação da Expressão Gênica
6.
Pak J Pharm Sci ; 37(2(Special)): 463-473, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38822551

RESUMO

Solanum lyratum Thunb., a traditional Chinese herbal medicine, has a promising background. However, the anti-inflammatory effects of its component steroid alkaloid have not been explored. In this study, animal and cell experiments were performed to investigate the anti-inflammatory effects and mechanism of action of Solanum lyratum Thunb steroid alkaloid (SLTSA), in order to provide evidence for its potential utilization. SLTSA effectively inhibited ear swelling and acute abdominal inflammation of mice. We observed concentration-dependent inhibition of pro-inflammatory cytokines by SLTSA, as confirmed by the ELISA and RT-qPCR results. Flow cytometry, immunofluorescence and RT-qPCR analyses revealed that SLTSA suppressed TLR4 expression. Western blot results indicated that SLTSA inhibited the activation of the TLR4/MyD88/NF-κB signaling pathway. Our study demonstrated that SLTSA possesses anti-inflammatory properties.


Assuntos
Alcaloides , Anti-Inflamatórios , Transdução de Sinais , Solanum , Animais , Solanum/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Camundongos , Alcaloides/farmacologia , Alcaloides/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Citocinas/metabolismo , Células RAW 264.7 , Fator 88 de Diferenciação Mieloide/metabolismo , Masculino
7.
Cell Mol Biol (Noisy-le-grand) ; 70(6): 211-216, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38836660

RESUMO

This study investigated the regulatory impact of Toll-like receptor 4 (TLR4) gene on glioma cell proliferation and apoptosis, elucidating the molecular mechanisms underlying TLR4-induced growth inhibition in vivo. U-87MG-Sh and U-87MG-NC cells, with silenced TLR4 and negative control plasmid respectively, were established. Eighteen nude mice, divided into transfection, negative control, and blank control groups, were inoculated with corresponding cells. Over four weeks, the transfection group exhibited significantly reduced tumor growth rates, smaller mass and volume, and lower growth activity compared to controls. Histological analysis revealed sparse tumor cells, increased fibrous connective tissue, and slower angiogenesis in the transfection group. Flow cytometry demonstrated a lower proliferation index and increased G0/1 cell count in the transfection group. mRNA levels of TLR4, NF-κB, and CyclinD1 were significantly lower in the transfection group. TLR4 silencing correlated with U-87MG cell proliferation regulation, growth inhibition, NF-κB and CyclinD1 modulation, and induction of cell cycle arrest and apoptosis. These findings suggest TLR4 as a potential gene therapy target for glioma.


Assuntos
Apoptose , Proliferação de Células , Ciclina D1 , Inativação Gênica , Glioma , Camundongos Nus , NF-kappa B , Receptor 4 Toll-Like , Animais , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Glioma/patologia , Glioma/genética , Glioma/metabolismo , Proliferação de Células/genética , Linhagem Celular Tumoral , Apoptose/genética , Humanos , NF-kappa B/metabolismo , Ciclina D1/metabolismo , Ciclina D1/genética , Camundongos , Pontos de Checagem do Ciclo Celular/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Regulação Neoplásica da Expressão Gênica , Camundongos Endogâmicos BALB C
8.
Cell Mol Biol (Noisy-le-grand) ; 70(6): 224-232, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38836655

RESUMO

Asthenospermia is a predominant cause of male infertility, and antioxidant supplements can be effective in treating asthenospermia. We demonstrate the antioxidant potential of traditional Chinese medicine, the Yishenhuoxue (YSHX) formula, in treating polyglycosides of Tripterygium wilfordii (GTW)-induced asthenospermia in rats. Fifty male rats were randomly divided into the normal, model, and treatment groups. HE staining was used to evaluate the improvement of spermatogenic function of rats, and TBA reaction, qRT-PCR, Western Blot and other methods were used to determine the changes of oxidative stress indicators and to evaluate the improvement of antioxidant capacity of rats by YSHX. Comparison with the model group showed significant improvement in pathological damage caused by GTW to seminiferous tubules. MDA and NO content in rat testes decreased, especially in middle- and high-dosage groups. No significant changes were observed in SOD and CAT activity or mRNA expression. GSH-Px activity and GSH mRNA expression were significantly higher in the low-dosage group than in the model group. Compared to the model group, GR activity was significantly lower in the middle and high dosage groups, while the mRNA expression was higher. The PKC-beta level increased, while p-ERK1/2, NF-κB, and the ratio of p-ERK1/2*(ERK1/2)-1 decreased significantly in the treatment groups. Therefore, YSHX can alleviate GTW-induced testicular damage, enhance GSH-Px activity, regulate GSH redox cycling, and mitigate oxidative stress injury. Furthermore, YSHX can promote PKC-beta expression and inhibit the phosphorylation of ERK1/2 and NF-κB. Using YSHX may be an effective way to increase sperm motility via the PKC-ERK1/2-NF-ĸB axis.


Assuntos
Antioxidantes , Astenozoospermia , Medicamentos de Ervas Chinesas , Estresse Oxidativo , Ratos Sprague-Dawley , Animais , Masculino , Antioxidantes/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Astenozoospermia/tratamento farmacológico , Astenozoospermia/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ratos , NF-kappa B/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo , Tripterygium/química , Malondialdeído/metabolismo , Superóxido Dismutase/metabolismo
9.
Cell Mol Life Sci ; 81(1): 255, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38856747

RESUMO

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor; GBM's inevitable recurrence suggests that glioblastoma stem cells (GSC) allow these tumors to persist. Our previous work showed that FOSL1, transactivated by the STAT3 gene, functions as a tumorigenic gene in glioma pathogenesis and acts as a diagnostic marker and potential drug target in glioma patients. Accumulating evidence shows that STAT3 and NF-κB cooperate to promote the development and progression of various cancers. The link between STAT3 and NF-κB suggests that NF-κB can also transcriptionally regulate FOSL1 and contribute to gliomagenesis. To investigate downstream molecules of FOSL1, we analyzed the transcriptome after overexpressing FOSL1 in a PDX-L14 line characterized by deficient FOSL1 expression. We then conducted immunohistochemical staining for FOSL1 and NF-κB p65 using rabbit polyclonal anti-FOSL1 and NF-κB p65 in glioma tissue microarrays (TMA) derived from 141 glioma patients and 15 healthy individuals. Next, mutants of the human FOSL1 promoter, featuring mutations in essential binding sites for NF-κB were generated using a Q5 site-directed mutagenesis kit. Subsequently, we examined luciferase activity in glioma cells and compared it to the wild-type FOSL1 promoter. Then, we explored the mutual regulation between NF-κB signaling and FOSL1 by modulating the expression of NF-κB or FOSL1. Subsequently, we assessed the activity of FOSL1 and NF-κB. To understand the role of FOSL1 in cell growth and stemness, we conducted a CCK-8 assay and cell cycle analysis, assessing apoptosis and GSC markers, ALDH1, and CD133 under varying FOSL1 expression conditions. Transcriptome analyses of downstream molecules of FOSL1 show that NF-κB signaling pathway is regulated by FOSL1. NF-κB p65 protein expression correlates to the expression of FOSL1 in glioma patients, and both are associated with glioma grades. NF-κB is a crucial transcription factor activating the FOSL1 promoter in glioma cells. Mutual regulation between NF-κB and FOSL1 contributes to glioma tumorigenesis and stemness through promoting G1/S transition and inhibiting apoptosis. Therefore, the FOSL1 molecular pathway is functionally connected to NF-κB activation, enhances stemness, and is indicative that FOSL1 may potentially be a novel GBM drug target.


Assuntos
Regulação Neoplásica da Expressão Gênica , NF-kappa B , Células-Tronco Neoplásicas , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-fos , Humanos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , NF-kappa B/metabolismo , Regiões Promotoras Genéticas/genética , Linhagem Celular Tumoral , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glioma/patologia , Glioma/genética , Glioma/metabolismo , Animais , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelA/genética , Proliferação de Células/genética , Camundongos , Transdução de Sinais , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética
10.
Invest Ophthalmol Vis Sci ; 65(6): 2, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38829670

RESUMO

Purpose: The purpose of this study was to investigate the involvement of the TLR4/NF-κB/NLRP3 signaling pathway and its underlying mechanism in diabetic dry eye. Methods: Two models of diabetic dry eye were established in high glucose-induced human corneal epithelial (HCE-T) cells and streptozotocin (STZ)-induced C57BL/6 mice, and the TLR4 inhibitor fosfenopril (FOS) was utilized to suppress the TLR4/NF-κB/NLRP3 signaling pathway. The expression changes in TLR4, NF-κB, NLRP3, and IL-1ß, and other factors were detected by Western blot and RT‒qPCR, the wound healing rate was evaluated by cell scratch assay, and the symptoms of diabetic mice were evaluated by corneal sodium fluorescein staining and tear secretion assay. Results: In the diabetic dry eye model, the transcript levels of TLR4, NF-κB, NLRP3, and IL-1ß were raised, and further application of FOS, a TLR4 inhibitor, downregulated the levels of these pathway factors. In addition, FOS was found to be effective in increasing the wound healing rate of high glucose-induced HCE-T cells, increasing tear production, and decreasing corneal fluorescence staining scores in diabetic mice, as measured by cell scratch assay, corneal sodium fluorescein staining assay, and tear production. Conclusions: The current study found that the TLR4/NF-κB/NLRP3 signaling pathway regulates diabetic dry eye in an in vitro and in vivo model, and that FOS reduces the signs of dry eye in diabetic mice, providing a new treatment option for diabetic dry eye.


Assuntos
Diabetes Mellitus Experimental , Síndromes do Olho Seco , Camundongos Endogâmicos C57BL , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Transdução de Sinais , Receptor 4 Toll-Like , Animais , Humanos , Masculino , Camundongos , Western Blotting , Células Cultivadas , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/metabolismo , Epitélio Corneano/efeitos dos fármacos , Epitélio Corneano/metabolismo , NF-kappa B/metabolismo , NF-kappa B/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Reação em Cadeia da Polimerase em Tempo Real , Lágrimas/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/antagonistas & inibidores
11.
J Agric Food Chem ; 72(23): 13415-13430, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38824655

RESUMO

This study aimed to investigate the hypothesis that dietary konjac glucomannan (KGM) could alleviate Salmonella typhimurium-induced colitis by modulating intestinal microbiota. Mice were fed an isocaloric and isofibrous diet supplemented with either 7% KGM or cellulose and were treated with 5 × 108 CFU of S. typhimurium. The results showed that KGM had an average molecular weight of 936 kDa and predominantly consisted of mannose and glucose at a molar ratio of 1:1.22. In vivo studies demonstrated that dietary KGM effectively mitigated colonic lesions, oxidative stress, disruption of tight junction protein 2 and occludin, and the inflammatory response induced by S. typhimurium. Moreover, KGM administration alleviated the dramatic upregulation of toll-like receptor 2 (TLR2) and phosphonuclear factor κB (NF-κB) protein abundance, induced by Salmonella treatment. Notably, dietary KGM restored the reduced Muribaculaceae and Lactobacillus abundance and increased the abundance of Blautia and Salmonella in S. typhimurium-infected mice. Spearman correlation analysis revealed that the gut microbiota improved by KGM contribute to inhibit inflammation and oxidative stress. These results demonstrated the protective effects of dietary KGM against colitis by modulating the gut microbiota and the TLR2-NF-κB signaling pathway in response to Salmonella infection.


Assuntos
Colite , Colo , Microbioma Gastrointestinal , Mananas , NF-kappa B , Salmonella typhimurium , Transdução de Sinais , Receptor 2 Toll-Like , Animais , Mananas/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Receptor 2 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética , NF-kappa B/metabolismo , NF-kappa B/genética , Colo/microbiologia , Colo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Colite/induzido quimicamente , Colite/metabolismo , Colite/microbiologia , Colite/dietoterapia , Masculino , Humanos , Camundongos Endogâmicos C57BL , Fibras na Dieta/farmacologia , Bactérias/classificação , Bactérias/isolamento & purificação , Bactérias/genética , Bactérias/metabolismo , Bactérias/efeitos dos fármacos , Amorphophallus/química
12.
Cell Signal ; 120: 111241, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38825173

RESUMO

Cardiac fibroblasts (CF) are mesenchymal-type cells responsible for maintaining the homeostasis of the heart's extracellular matrix (ECM). Their dysfunction leads to excessive secretion of ECM proteins, tissue stiffening, impaired nutrient and oxygen exchange, and electrical abnormalities in the heart. Additionally, CF act as sentinel cells in the cardiac tissue microenvironment, responding to various stimuli that may affect heart function. Deleterious stimuli induce an inflammatory response in CF, increasing the secretion of cytokines such as IL-1ß and TNF-α and the expression of cell adhesion molecules like ICAM1 and VCAM1, initially promoting damage resolution by recruiting immune cells. However, constant harmful stimuli lead to a chronic inflammatory process and heart dysfunction. Therefore, it is necessary to study the mechanisms that govern CF inflammation. NFκB is a key regulator of the cardiac inflammatory process, making the search for mechanisms of NFκB regulation and CF inflammatory response crucial for developing new treatment options for cardiovascular diseases. SGK1, a serine-threonine protein kinase, is one of the regulators of NFκB and is involved in the fibrotic effects of angiotensin II and aldosterone, as well as in CF differentiation. However, its role in the CF inflammatory response is unknown. On the other hand, many bioactive natural products have demonstrated anti-inflammatory effects, but their role in CF inflammation is unknown. One such molecule is boldine, an alkaloid obtained from Boldo (Peumus boldus), a Chilean endemic tree with proven cytoprotective effects. However, its involvement in the regulation of SGK1 and CF inflammation is unknown. In this study, we evaluated the role of SGK1 and boldine in the inflammatory response in CF isolated from neonatal Sprague-Dawley rats. The involvement of SGK1 was analyzed using GSK650394, a specific SGK1 inhibitor. Our results demonstrate that SGK1 is crucial for LPS- and IFN-γ-induced inflammatory responses in CF (cytokine expression, cell adhesion molecule expression, and leukocyte adhesion). Furthermore, a conditioned medium (intracellular content of CF subject to freeze/thaw cycles) was used to simulate a sterile inflammation condition. The conditioned medium induced a potent inflammatory response in CF, which was completely prevented by the SGK1 inhibitor. Finally, our results indicate that boldine inhibits both SGK1 activation and the CF inflammatory response induced by LPS, IFN-γ, and CF-conditioned medium. Taken together, our results position SGK1 as an important regulator of the CF inflammatory response and boldine as a promising anti-inflammatory drug in the context of cardiovascular diseases.


Assuntos
Aporfinas , Fibroblastos , Proteínas Imediatamente Precoces , NF-kappa B , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Animais , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ratos , Aporfinas/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Miocárdio/patologia , Miocárdio/metabolismo , Células Cultivadas , Ratos Sprague-Dawley
13.
Pestic Biochem Physiol ; 202: 105941, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38879332

RESUMO

Emamectin benzoate (EMB) is extensively used as a crop protection agent. Overuse of EMB poses a serious threat to the quality of water and non-target organisms in the environment. Resveratrol (RES) is a natural phytoalexin with the function of anti-oxidation and anti-inflammation. Nonetheless, it is unclear whether EMB affects the expression of cytokines and induces autophagy, apoptosis, and necroptosis of hepatocytes (L8824 cell) in grass carp (Ctenopharyngodon idella), and whether RES has an attenuate function in this process. Therefore, we established the L8824 cells model of EMB exposure and treated it with RES. The results showed that compared with the control (CON) group, EMB exposure significantly increased the nitric oxide (NO) content, inducible nitric oxide synthase (iNOS) activity, and the expression of iNOS and phosphorylated nuclear factor kappa B (p-NF-κB) (P < 0.05). In addition, compared with the CON group, the results of flow cytometry and dansylcadaverine (MDC) staining showed a significant increase in apoptosis and autophagy in the EMB-exposed group (P < 0.05) with the activation of the B-cell lymphoma-2 (Bcl-2)/Bcl-2 associated X (Bax)/cysteine-aspartic acid protease 3 (Caspase-3)/cysteine-aspartic acid protease 9 (Caspase-9) pathway and microtubule-associated protein light chain 3 (LC3)/sequestosome 1 (p62)/Beclin1 pathway. EMB exposure significantly increased the mRNA and protein expression of receptor-interacting protein 1 (RIPK1)/receptor-interacting protein 3 (RIPK3)/mixed the lineage kinase domain-like (MLKL) pathway (P < 0.05). Moreover, EMB exposure significantly increased the expression of genes related to immunity (immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin D (IgD), and antimicrobial peptide-related genes expression including ß-defensin and hepcidin) (P < 0.05). The addition of RES significantly diminished autophagy, apoptosis, necroptosis, and immunity-related gene expression by inhibiting iNOS activity, NO content, and the protein expression of iNOS and p-NF-κB. In conclusion, RES attenuated autophagy, apoptosis, and necroptosis in EMB-exposed L8824 cells via suppression of the NO system/NF-κB signaling pathway.


Assuntos
Carpas , Ivermectina , NF-kappa B , Óxido Nítrico , Resveratrol , Transdução de Sinais , Animais , Carpas/metabolismo , NF-kappa B/metabolismo , Ivermectina/análogos & derivados , Ivermectina/toxicidade , Ivermectina/farmacologia , Óxido Nítrico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resveratrol/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Apoptose/efeitos dos fármacos , Linhagem Celular , Autofagia/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo
14.
Pestic Biochem Physiol ; 202: 105966, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38879343

RESUMO

Atrazine (ATR) is the second most extensively used herbicide which adversely affects the body organs including liver. Salvigenin (SGN) is a flavonoid which demonstrates a wide range of biological and pharmacological abilities. This study was planned to assess the protective ability of SGN to avert ATR induced liver damage in rats. Thirty-two rats (Rattus norvegicus) were divided into four groups including control, ATR (5 mg/kg), ATR (5 mg/kg) + SGN (10 mg/kg) and SGN (10 mg/kg) alone supplemented group. ATR exposure reduced the expression of Nrf-2 while instigating an upregulation in Keap-1 expression. Furthermore, the activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), heme­oxygenase-1 (HO-1) and glutathione reductase (GSR) contents were decreased while increasing reactive oxygen species (ROS) and malondialdehyde (MDA) levels after ATR treatment. Moreover, ATR poisoning increased the levels of ALT, AST, and ALP while reducing the levels of total proteins, and albumin in hepatic tissues of rats. Besides, ATR administration escalated the expressions of Bax and Caspase-3 while inducing a downregulation in the expressions of Bcl-2. Similarly, ATR intoxication increased the levels of Interleukin-6 (IL-6), Nuclear factor kappa-B (NF-κB), Interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and the activity of cyclooxygenase-2 (COX-2). Furthermore, ATR disrupted the normal histology of hepatic tissues. However, SGN treatment remarkably protected the liver tissues via regulating antioxidant, anti, inflammatory, anti-apoptotic as well as histology parameters. Therefore, it is concluded that SGN can be used as therapeutic agent to combat ATR-induced hepatotoxicity.


Assuntos
Atrazina , Doença Hepática Induzida por Substâncias e Drogas , Proteína 1 Associada a ECH Semelhante a Kelch , Fígado , Fator 2 Relacionado a NF-E2 , NF-kappa B , Animais , Atrazina/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Ratos , Masculino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Herbicidas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Isoflavonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo
15.
Int Immunopharmacol ; 136: 112372, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38850784

RESUMO

Hypoxic ischemic encephalopathy (HIE) is a primary cause of neonatal death and disabilities. The pathogenetic process of HIE is closely associated with neuroinflammation. Therefore, targeting and suppressing inflammatory pathways presents a promising therapeutic strategy for the treatment of HIE. Echinatin is an active component of glycyrrhiza, with anti-inflammatory and anti-oxidative properties. It is commonly combined with other traditional Chinese herbs to exert heat-clearing and detoxifying effects. This study aimed to investigate the anti-inflammatory and neuroprotective effects of Echinatin in neonatal rats with hypoxic-ischemic brain damage, as well as in PC12 cells exposed to oxygen-glucose deprivation (OGD). In vivo, Echinatin effectively reduced cerebral edema and infarct volume, protected brain tissue morphology, improved long-term behavioral functions, and inhibited microglia activation. These effects were accompanied by the downregulation of inflammatory factors and pyroptosis markers. The RNA sequencing analysis revealed an enrichment of inflammatory genes in rats with hypoxic-ischemic brain damage, and Protein-protein interaction (PPI) network analysis identified TLR4, MyD88, and NF-κB as the key regulators. In vitro, Echinatin reduced the levels of TLR4 relevant proteins, inhibited nuclear translocation of NF-κB, reduced the expression of downstreams inflammatory cytokines and pyroptosis proteins, and prevented cell membrane destructions. These findings demonstrated that Echinatin could inhibit the TLR4/NF-κB pathway, thereby alleviating neuroinflammation and pyroptosis. This suggests that Echinatin could be a potential candidate for the treatment of HIE.


Assuntos
Hipóxia-Isquemia Encefálica , NF-kappa B , Fármacos Neuroprotetores , Piroptose , Ratos Sprague-Dawley , Transdução de Sinais , Receptor 4 Toll-Like , Animais , Piroptose/efeitos dos fármacos , Ratos , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Transdução de Sinais/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Masculino , Inflamação/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Animais Recém-Nascidos , Microglia/efeitos dos fármacos , Microglia/metabolismo
16.
Immun Inflamm Dis ; 12(6): e1208, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38860759

RESUMO

BACKGROUND: Banxia Xiexin decoction (BXD) can control irinotecan (CPT-11)-caused delayed diarrhea, but the corresponding mechanism remains undefined. AIMS: This paper aimed to uncover the mechanism of BXD in regulating CPT-11-caused delayed diarrhea. MATERIALS & METHODS: Sprague-Dawley (SD) rats were assigned into the control, model, BXD low-dose (BXD-L, 5 g/kg), BXD medium-dose (BXD-M, 10 g/kg), BXD high-dose (BXD-H, 15 g/kg), 5-aminosalicylic acid (5-ASA, 10 mL/kg), and BXD-M + 5-ASA groups. Rats were injected intraperitoneally with 150 mg/kg CPT-11 at Day 4 and Day 5 to induce delayed diarrhea, and later treated with various doses (low, medium, and high) of BXD and 5-ASA for 9 days, except for rats in control group. The body weight of rats was measured. The rat colon tissue injury, inflammatory cytokine levels, and the activation of toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling pathway were detected. RESULTS: BXD (5, 10, or 15 g/kg) or 5-ASA (10 mL/kg) alleviated body weight loss and colon tissue injury, decreased levels of inflammatory cytokines, and inactivated TLR4/NF-κB signaling pathway in CPT-11-induced model rats. BXD at 10 g/kg (the optimal concentration) could better treat CPT-11-induced intestinal dysfunction, as evidenced by the resulting approximately 50% reduction on injury score of model rats. Moreover, BXD-M (10 g/kg) synergistic with 5-ASA (10 mL/kg) further strengthened the inhibition on rat body weight loss, colon tissue injury, inflammatory cytokine levels, and TLR4/NF-κB signaling pathway. CONCLUSION: To sum up, BXD has a protective effect against CPT-11-induced intestinal dysfunction by inhibiting inflammation through inactivation TLR4/NF-κB signaling pathway. In particular, the combined use of BXD and 5-ASA holds great promise for treating CPT-11-induced delayed diarrhea.


Assuntos
Diarreia , Medicamentos de Ervas Chinesas , Irinotecano , Mesalamina , NF-kappa B , Ratos Sprague-Dawley , Transdução de Sinais , Receptor 4 Toll-Like , Animais , Receptor 4 Toll-Like/metabolismo , NF-kappa B/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Irinotecano/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Diarreia/tratamento farmacológico , Diarreia/induzido quimicamente , Diarreia/prevenção & controle , Masculino , Mesalamina/farmacologia , Mesalamina/administração & dosagem , Modelos Animais de Doenças , Quimioterapia Combinada
17.
Nat Commun ; 15(1): 5056, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38871792

RESUMO

Type 2 innate lymphoid cells (ILC2) initiate early allergic inflammation in the lung, but the factors that promote subsequent resolution of type 2 inflammation and prevent prolonged ILC2 activation are not fully known. Here we show that SLAM-family receptors (SFR) play essential roles in this process. We demonstrate dynamic expression of several SFRs on ILC2s during papain-induced type 2 immunity in mice. SFR deficiency exacerbates ILC2-driven eosinophil infiltration in the lung, and results in a significant increase in IL-13 production by ILC2s exclusively in mediastinal lymph nodes (MLN), leading to increased dendritic cell (DC) and TH2 cell numbers. In MLNs, we observe more frequent interaction between ILC2s and bystander T cells, with T cell-expressed SFRs (especially SLAMF3 and SLAMF5) acting as self-ligands to suppress IL-13 production by ILC2s. Mechanistically, homotypic engagement of SFRs at the interface between ILC2s and T cells delivers inhibitory signaling primarily mediated by SHIP-1. This prevents activation of NF-κB, driven by IL-7 and IL-33, two major drivers of ILC2-mediated type 2 immunity. Thus, our study shows that an ILC2-DC-TH2 regulatory axis may promote the resolution of pulmonary type 2 immune responses, and highlights SLAMF3/SLAMF5 as potential therapeutic targets for ameliorating type 2 immunity.


Assuntos
Imunidade Inata , Inflamação , Pulmão , Linfócitos , Camundongos Endogâmicos C57BL , Família de Moléculas de Sinalização da Ativação Linfocitária , Animais , Camundongos , Inflamação/imunologia , Inflamação/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Pulmão/imunologia , Pulmão/patologia , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Papaína , Células Th2/imunologia , Interleucina-13/metabolismo , Interleucina-13/imunologia , Linfonodos/imunologia , Linfonodos/metabolismo , Interleucina-33/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Camundongos Knockout , Transdução de Sinais , NF-kappa B/metabolismo
18.
Phytomedicine ; 130: 155542, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38823343

RESUMO

BACKGROUND: Malassezia globosa is a commensal basidiomycetous yeast occurring on the skin that causes pityriasis versicolor (PV) and seborrheic dermatitis, but that has also been implicated in other dermatoses. Cinnamaldehyde (CM) has antibacterial, antioxidant, and anti-inflammatory activities, but the effect of CM on M. globosa-infected PV has not been clarified. PURPOSE: The study aimed to investigate the possible antifungal and antibiofilm activities of CM against M. globosa-infected PV in vivo and in vitro. METHODS: The broth microdilution method was used to determine the minimum inhibitory concentration (MIC) of CM against M. globosa. The crystal violet staining assay and XTT assay were used to investigate the inhibition of CM on biofilm formation and the eradication of mature biofilms. The visualizations of the biofilm and cell distribution in the biofilm matrix were performed with a scanning electron microscope and confocal laser scanning microscope. The kits of antioxidant kinase were used to determine the activities of oxidative stress markers in M. globosa-stimulated HaCaT cells. Western blot assays were used to evaluate the role of TLR2/NF-κB in vitro. Furthermore, the protective effect of CM was assessed in M. globosa-associated PV mice. The expressions of inflammatory cytokines and apoptosis were screened using ELISA assays. The expressions of interleukin-6 and tumor necrosis factor-α were measured by an immunohistochemistry method in vivo. RESULTS: Our results showed that the MIC of CM against planktonic cells of M. globosa was 4 µg/ml and treatment with 20 × MIC CM eradicated mature biofilms of M. globosa. In vitro, after CM treatment the levels of oxidative stress indicators (i.e., superoxide dismutase, catalase, glutathione) significantly increased, while the levels of malondialdehyde decreased. In addition, the expression of TLR2/NF-κB in HaCaT cells was significantly reduced after CM treatment. On the other hand, an in vivo therapeutic effect of CM was assessed against M. globosa-infected mice. The fungal load on the skin decreased after treatment with CM compared to the M. globosa-infected group. In addition, the uninfected animals showed a normal skin structure, whereas, the M. globosa-infected mice showed extensive infiltration of neutrophils in skin tissues that improved after treatment with CM. Meanwhile, the levels of inflammatory and apoptotic factors improved after CM treatment. CONCLUSION: Our results showed that CM inhibits the biofilm formation of M. globosa and eradicates mature biofilms of M. globosa. Treatment with CM significantly decreased oxidative stress, apoptosis, and inflammatory markers in the skin tissue and HaCaT cells. Hence, this study suggests that CM is a good candidate therapeutic agent against M. globosa-induced PV infections because of its antifungal, antibiofilm, and anti-inflammatory properties.


Assuntos
Acroleína , Antifúngicos , Biofilmes , Malassezia , Testes de Sensibilidade Microbiana , Tinha Versicolor , Receptor 2 Toll-Like , Biofilmes/efeitos dos fármacos , Acroleína/análogos & derivados , Acroleína/farmacologia , Animais , Malassezia/efeitos dos fármacos , Humanos , Receptor 2 Toll-Like/metabolismo , Tinha Versicolor/tratamento farmacológico , Antifúngicos/farmacologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Células HaCaT , NF-kappa B/metabolismo , Interleucina-6/metabolismo , Antioxidantes/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Pele/efeitos dos fármacos , Pele/microbiologia
19.
Nat Immunol ; 25(6): 969-980, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38831104

RESUMO

Rare genetic variants in toll-like receptor 7 (TLR7) are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localization into endosomes. In the present study, we identify two new variants in UNC93B1 (T314A, located proximally to the TLR7 transmembrane domain, and V117L) in a cohort of east Asian patients with childhood-onset systemic lupus erythematosus. The V117L variant was associated with increased expression of type I interferons and NF-κB-dependent cytokines in patient plasma and immortalized B cells. THP-1 cells expressing the variant UNC93B1 alleles exhibited exaggerated responses to stimulation of TLR7/-8, but not TLR3 or TLR9, which could be inhibited by targeting the downstream signaling molecules, IRAK1/-4. Heterozygous mice expressing the orthologous Unc93b1V117L variant developed a spontaneous lupus-like disease that was more severe in homozygotes and again hyperresponsive to TLR7 stimulation. Together, this work formally identifies genetic variants in UNC93B1 that can predispose to childhood-onset systemic lupus erythematosus.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico , Receptor 7 Toll-Like , Lúpus Eritematoso Sistêmico/genética , Humanos , Animais , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo , Camundongos , Criança , Feminino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Masculino , Idade de Início , Variação Genética , NF-kappa B/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Adolescente , Células THP-1 , Interferon Tipo I/metabolismo
20.
Phytomedicine ; 130: 155756, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38833791

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a persistent liver condition that affects both human health and animal productive efficiency on a global scale. A number of naturally occurring compounds activate nuclear factor erythroid 2-related factor 2 (Nrf2) as a transcription factor with important protective effects against many liver diseases, including NAFLD. Raffinose (Ra), an oligosaccharide extracted from several plants, exhibits diverse biological functions. However, the uncertainty lies in determining whether the activation of Nrf2 by Ra can provide a preventive effect on liver lipotoxicity. PURPOSE: The aim of this study was to shed light on the molecular pathways by which Ra possesses its protective benefits against NAFLD. METHODS: Experimental protocols were established using WT and Nrf2-null (Nrf2-/-) mice. Liver samples from each group were collected for Western blot, RT-qPCR, H & E, Sirius red and Oil red O staining. Additionally, serums were processed for ELISA. ALM12 cells were gathered for Western blot and immunofluorescence. Moreover, to elucidate the molecular mechanism of Ra, molecular docking was performed. RESULTS: Our results indicated that Ra remarkably alleviated liver lipotoxic in vivo and in vitro. Ra treatment effectively corrected hepatic steatosis, the release of AST, ALT, TG, and TC, as well as the depletion of HDL and LDL. Meanwhile, Ra efficiently prevented inflammation by inhibiting the TLR4-MyD88-NF-κB pathway and pyroptosis. Additionally, these findings implied that Ra reduced the production of fibrosis-related proteins, which enhanced collagen deposition. Molecular docking revealed that Ra possessed the ability to bind specific regions of Nrf2, resulting in the enhancement of Nrf2 activation and nuclear translocation. Ra treatment restored serum redox factors and antioxidant enzymes to normal levels; however, these alterations were clearly reversed in Nrf2-/- mice. CONCLUSION: This study reveals novel information on Ra's protective benefits against liver injury caused by abnormal lipid metabolism; these effects are mostly mediated by Nrf2 activation, suggesting a potential new medicine or treatment strategy for NAFLD.


Assuntos
Fator 2 Relacionado a NF-E2 , Hepatopatia Gordurosa não Alcoólica , Piroptose , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Piroptose/efeitos dos fármacos , Camundongos , Receptor 4 Toll-Like/metabolismo , Masculino , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Inflamação/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Simulação de Acoplamento Molecular , Antioxidantes/farmacologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo
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