Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23.066
Filtrar
1.
Front Immunol ; 15: 1362404, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38745671

RESUMO

Introduction: The anti-inflammatory effect of green tea extract (GTE) has been confirmed in asthmatic mice, however, the pharmacological mechanism is not fully elucidated. Methods: To investigate the therapeutic efficacy of GTE in asthma and identify specific pathways, murine model of allergic asthma was established by ovalbumin (OVA) sensitization and the challenge for 4 weeks, with oral treatment using GTE and dexamethasone (DEX). Inflammatory cell counts, cytokines, OVA-specific IgE, airway hyperreactivity, and antioxidant markers in the lung were evaluated. Also, pulmonary histopathological analysis and western blotting were performed. In vitro, we established the model by stimulating the human airway epithelial cell line NCI-H292 using lipopolysaccharide, and treating with GTE and mitogen-activated protein kinases (MAPKs) inhibitors. Results: The GTE100 and GTE400 groups showed a decrease in airway hyperresponsiveness and the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) compared to the OVA group. GTE treatment also reduced interleukin (IL)-13, IL-5, and IL-4 levels in the BALF, and OVA-specific immunoglobulin E levels in the serum compared to those in the OVA group. GTE treatment decreased OVA-induced mucus secretion and airway inflammation. In addition, GTE suppressed the oxidative stress, and phosphorylation of MAPKs, which generally occurs after exposure to OVA. GTE administration also reduced matrix metalloproteinase-9 activity and protein levels. Conclusion: GTE effectively inhibited asthmatic respiratory inflammation and mucus hyperproduction induced by OVA inhalation. These results suggest that GTE has the potential to be used for the treatment of asthma.


Assuntos
Asma , Células Epiteliais , Metaloproteinase 9 da Matriz , Estresse Oxidativo , Extratos Vegetais , Asma/tratamento farmacológico , Asma/imunologia , Asma/metabolismo , Animais , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Humanos , Extratos Vegetais/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Modelos Animais de Doenças , Chá/química , Feminino , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mucosa Respiratória/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Citocinas/metabolismo , Ovalbumina/imunologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico
2.
CNS Neurosci Ther ; 30(5): e14749, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38739004

RESUMO

AIMS: A bone-invasive pituitary adenoma exhibits aggressive behavior, leading to a worse prognosis. We have found that TNF-α promotes bone invasion by facilitating the differentiation of osteoclasts, however, before bone-invasive pituitary adenoma invades bone tissue, it needs to penetrate the dura mater, and this mechanism is not yet clear. METHODS: We performed transcriptome microarrays on specimens of bone-invasive pituitary adenomas (BIPAs) and noninvasive pituitary adenomas (NIPAs) and conducted differential expressed gene analysis and enrichment analysis. We altered the expression of TNF-α through plasmids, then validated the effects of TNF-α on GH3 cells and verified the efficacy of the TNF-α inhibitor SPD304. Finally, the effects of TNF-α were validated in in vivo experiments. RESULTS: Pathway act work showed that the MAPK pathway was significantly implicated in the pathway network. The expression of TNF-α, MMP9, and p-p38 is higher in BIPAs than in NIPAs. Overexpression of TNF-α elevated the expression of MAPK pathway proteins and MMP9 in GH3 cells, as well as promoted proliferation, migration, and invasion of GH3 cells. Flow cytometry indicated that TNF-α overexpression increased the G2 phase ratio in GH3 cells and inhibited apoptosis. The expression of MMP9 was reduced after blocking the P38 MAPK pathway; overexpression of MMP9 promoted invasion of GH3 cells. In vivo experiments confirm that the TNF-α overexpression group has larger tumor volumes. SPD304 was able to suppress the effects caused by TNF-α overexpression. CONCLUSION: Bone-invasive pituitary adenoma secretes higher levels of TNF-α, which then acts on itself in an autocrine manner, activating the MAPK pathway and promoting the expression of MMP9, thereby accelerating the membrane invasion process. SPD304 significantly inhibits the effect of TNF-α and may be applied in the clinical treatment of bone-invasive pituitary adenoma.


Assuntos
Adenoma , Sistema de Sinalização das MAP Quinases , Metaloproteinase 9 da Matriz , Invasividade Neoplásica , Neoplasias Hipofisárias , Fator de Necrose Tumoral alfa , Fator de Necrose Tumoral alfa/metabolismo , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Humanos , Adenoma/patologia , Adenoma/metabolismo , Animais , Metaloproteinase 9 da Matriz/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Linhagem Celular Tumoral , Feminino , Camundongos , Camundongos Nus , Comunicação Autócrina/fisiologia , Comunicação Autócrina/efeitos dos fármacos , Pessoa de Meia-Idade , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Adulto , Ratos , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos dos fármacos
3.
Am J Reprod Immunol ; 91(5): e13856, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38709906

RESUMO

INTRODUCTION: Endometriosis is a chronic inflammatory disease that leads to a series of pathological reactions. The basis is a changed proinflammatory activated immune system, which results in more pronounced oxidative stress, disturbed function of proteolysis and cell apoptosis. These processes are crucial in the development of the disease because their dysfunctional activities cause the progression of the disease. It is believed that the proteins excreted in the urine interact with each other and promote pathological processes in endometriosis. METHODS: We analyzed the urine proteome of patients and aimed to detect a potential protein biomarker for endometriosis in the urine proteome. We collected urine samples from 16 patients with endometriosis and 16 patients in the control group with functional ovarian cysts. The diagnosis for all patients was confirmed through pathohistological analysis. After the preanalytical preparation of the urine, chromatography and mass spectrometry (LC-MS/MS) used the technology of urine proteome analysis. RESULTS: The main finding was a significantly different concentration of 14 proteins in the urine samples. We recorded a considerably higher concentration of proteins that have a significant role in activating the immune system (SELL), iron metabolism (HAMP) and cell apoptosis (CHGA) in endometriosis compared to controls. Proteins having an antioxidant function (SOD1) and a role in proteolysis of the extracellular matrix (MMP-9) were significantly reduced in endometriosis compared to controls. CONCLUSION: Consistent with the known pathogenesis of endometriosis, the study results complement the pathological responses that occur with disease progression.


Assuntos
Biomarcadores , Endometriose , Humanos , Endometriose/urina , Endometriose/diagnóstico , Feminino , Biomarcadores/urina , Adulto , Superóxido Dismutase-1/urina , Espectrometria de Massas em Tandem , Proteoma , Metaloproteinase 9 da Matriz/urina , Proteômica/métodos , Cromatografia Líquida , Estresse Oxidativo
4.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 40(4): 311-318, 2024 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-38710515

RESUMO

Objective To investigate the effects of mitochondrial transcription factor A (TFAM) on mitochondrial function, autophagy, proliferation, invasion, and migration in cervical cancer HeLa cells and osteosarcoma U2OS cells. Methods TFAM small-interfering RNA (si-TFAM) was transfected to HeLa and U2OS cells for downregulating TFAM expression. Mito-Tracker Red CMXRos staining combined with laser confocal microscopy was used to detect mitochondrial membrane potential (MMP). MitoSOXTM Red labeling was used to test mitochondrial reactive oxygen species (mtROS) levels. The expression of mitochondrial DNA (mtDNA) was detected by real-time quantitative PCR. Changes in the number of autophagosomes were detected by immunofluorescence cytochemistry. Western blot analysis was used to detect the expressions of TFAM, autophagy microtubule associated protein 1 light chain 3A/B (LC3A/B), autophagy associated protein 2A (ATG2A), ATG2B, ATG9A, zinc finger transcription factor Snail, matrix metalloproteinase 2 (MMP2) and MMP9. CCK-8 assay and plate clony formation assay were used to detect cell proliferation, while TranswellTM assay and scratch healing assay were used to detect changes in cell invasion and migration. Results The downregulation of TFAM expression resulted in a decrease in MMP and mtDNA copy number, but an increase in mtROS production. The protein content of LC3A/B decreased significantly compared to the control group and the number of autophagosomes in the cytoplasm decreased significantly. The expressions of ATG2B and ATG9A in the early stage of autophagy were significantly reduced. The expressions of Snail, MMP2 and MMP9 proteins in HeLa and U2OS cells were also decreased. The proliferation, invasion and migration ability of HeLa and U2OS cells were inhibited after being interfered with TFAM expression. Conclusion Downregulation of TFAM expression inhibits mitochondrial function, delays autophagy process and reduces the proliferation, invasion and migration ability of cervical cancer cells and osteosarcoma cells.


Assuntos
Autofagia , Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA , Proteínas Mitocondriais , Invasividade Neoplásica , Osteossarcoma , Fatores de Transcrição , Neoplasias do Colo do Útero , Humanos , Movimento Celular/genética , Osteossarcoma/genética , Osteossarcoma/patologia , Osteossarcoma/metabolismo , Proliferação de Células/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Autofagia/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Feminino , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Potencial da Membrana Mitocondrial/genética , Espécies Reativas de Oxigênio/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Mitocôndrias/metabolismo , Mitocôndrias/genética , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Células HeLa , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética
5.
Mol Biol Rep ; 51(1): 646, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38727931

RESUMO

BACKGROUND: Breast cancer (BC) is one of the most common cancers in the world. Despite the many advances that have been made in treating patients, many patients are still resistant to treatment. CD44 is one of the surface glycoproteins of BC cells that plays an important role in the proliferation of these cells and inhibition of their apoptosis. Therefore, targeting it can be a treatment way for BC patients. METHODS: In this study, the effect of anti-CD44 siRNA on the proliferation, apoptosis, and migration rate of MDA-MB-231 and 4T1 cells was investigated. The techniques used in this study were MTT assay, RT-PCR, and flow cytometry. RESULTS: The apoptosis and proliferation rates in CD44 siRNA-treated cells were higher and lower, respectively, compared to untreated cells. Also, cell migration was less in treated cells compared to untreated cells. CD44 siRNA also decreased the expression of CXCR4, c-myc, Vimentin, ROCK, and MMP-9. CONCLUSION: Finally, CD44 targeting can be a good treatment option to make BC cells more sensitive to apoptosis.


Assuntos
Apoptose , Neoplasias da Mama , Movimento Celular , Proliferação de Células , Receptores de Hialuronatos , RNA Interferente Pequeno , Receptores de Hialuronatos/metabolismo , Receptores de Hialuronatos/genética , Humanos , Apoptose/genética , Linhagem Celular Tumoral , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Feminino , RNA Interferente Pequeno/genética , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Regulação Neoplásica da Expressão Gênica , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Vimentina/metabolismo , Vimentina/genética
6.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(4): 739-747, 2024 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-38708508

RESUMO

OBJECTIVE: To explore the inhibitory effect of Sidaxue, a traditional Miao herbal medicine formula, on articular bone and cartilage destruction and synovial neovascularization in rats with collagen-induced arthritis (CIA). METHODS: In a SD rat model of CIA, we tested the effects of daily gavage of Sidaxue at low, moderate and high doses (10, 20, and 40 g/kg, respectively) for 21 days, with Tripterygium glycosides (GTW) as the positive control, on swelling in the hind limb plantar regions by arthritis index scoring. Pathologies in joint synovial membrane of the rats were observed with HE staining, and serum TNF-α and IL-1ß levels were detected with ELISA. The expressions of NF-κB p65, matrix metalloproteinase 1 (MMP1), MMP2 and MMP9 at the mRNA and protein levels in the synovial tissues were detected using real-time PCR and Western blotting. Network pharmacology analysis was conducted to identify the important target proteins in the pathways correlated with the therapeutic effects of topical Sidaxue treatment for RA, and the core target proteins were screened by topological analysis. RESULTS: Treatment with GTW and Sidaxue at the 3 doses all significantly alleviated plantar swelling, lowered arthritis index scores, improved cartilage and bone damage and reduced neovascularization in CIA rats (P<0.05), and the effects of Sidaxue showed a dose dependence. Both GTW and Sidaxue treatments significantly lowered TNF-α, IL-1ß, NF-κB p65, MMP1, MMP2, and MMP9 mRNA and protein expressions in the synovial tissues of CIA rats (P<0.05). Network pharmacological analysis identified MMPs as the core proteins associated with topical Sidaxue treatment of RA. CONCLUSION: Sidaxue alleviates articular bone and cartilage damages and reduces synovial neovascularization in CIA rats possibly by downregulating MMPs via the TNF-α/IL-1ß/NF-κB-MMP1, 2, 9 signaling pathway, and MMPs probably plays a key role in mediating the effect of Sidaxue though the therapeutic pathways other than oral administration.


Assuntos
Artrite Experimental , Artrite Reumatoide , Medicamentos de Ervas Chinesas , Metaloproteinase 1 da Matriz , Ratos Sprague-Dawley , Membrana Sinovial , Fator de Necrose Tumoral alfa , Animais , Ratos , Artrite Reumatoide/tratamento farmacológico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Metaloproteinase 1 da Matriz/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-1beta/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Regulação para Baixo/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , Tripterygium/química , Fator de Transcrição RelA/metabolismo
7.
Cell Death Dis ; 15(5): 310, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38697967

RESUMO

Breast cancer (BC) is the most common cancer and the leading cause of cancer-related deaths in women worldwide. The 5-year survival rate is over 90% in BC patients, but once BC cells metastasis into distal organs, it is dramatically decreasing to less than 30%. Especially, triple-negative breast cancer (TNBC) patients usually lead to poor prognosis and survival because of metastasis. Understanding the underline mechanisms of TNBC metastasis is a critical issue. Non-coding RNAs, including of lncRNAs and microRNAs, are non-protein-coding transcripts and have been reported as important regulators in TNBC metastasis. However, the underline mechanisms for non-coding RNAs regulating TNBC metastasis remain largely unclear. Here, we found that lncRNA MIR4500HG003 was highly expressed in highly metastatic MDA-MB-231 TNBC cells and overexpression of MIR4500HG003 enhanced metastasis ability in vitro and in vivo and promoted MMP9 expression. Furthermore, we found MIR4500HG003 physically interacted with miR-483-3p and reporter assay showed miR-483-3p attenuated MMP9 expression. Importantly, endogenous high expressions of MIR4500HG003 were correlated with tumor recurrence in TNBC patients with tumor metastasis. Taken together, our findings suggested that MIR4500HG003 promotes metastasis of TNBC through miR-483-3p-MMP9 signaling axis and may be used as potential prognostic marker for TNBC patients.


Assuntos
Regulação Neoplásica da Expressão Gênica , Metaloproteinase 9 da Matriz , MicroRNAs , Metástase Neoplásica , RNA Longo não Codificante , Neoplasias de Mama Triplo Negativas , Humanos , MicroRNAs/metabolismo , MicroRNAs/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Feminino , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Linhagem Celular Tumoral , Animais , Camundongos , Camundongos Nus , Movimento Celular/genética , Camundongos Endogâmicos BALB C
8.
Neuropathol Appl Neurobiol ; 50(3): e12982, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38742276

RESUMO

AIMS: Perineuronal nets (PNNs) are an extracellular matrix structure that encases excitable neurons. PNNs play a role in neuroprotection against oxidative stress. Oxidative stress within motor neurons can trigger neuronal death, which has been implicated in amyotrophic lateral sclerosis (ALS). We investigated the spatio-temporal timeline of PNN breakdown and the contributing cellular factors in the SOD1G93A strain, a fast-onset ALS mouse model. METHODS: This was conducted at the presymptomatic (P30), onset (P70), mid-stage (P130), and end-stage disease (P150) using immunofluorescent microscopy, as this characterisation has not been conducted in the SOD1G93A strain. RESULTS: We observed a significant breakdown of PNNs around α-motor neurons in the ventral horn of onset and mid-stage disease SOD1G93A mice compared with wild-type controls. This was observed with increased numbers of microglia expressing matrix metallopeptidase-9 (MMP-9), an endopeptidase that degrades PNNs. Microglia also engulfed PNN components in the SOD1G93A mouse. Further increases in microglia and astrocyte number, MMP-9 expression, and engulfment of PNN components by glia were observed in mid-stage SOD1G93A mice. This was observed with increased expression of fractalkine, a signal for microglia engulfment, within α-motor neurons of SOD1G93A mice. Following PNN breakdown, α-motor neurons of onset and mid-stage SOD1G93A mice showed increased expression of 3-nitrotyrosine, a marker for protein oxidation, which could render them vulnerable to death. CONCLUSIONS: Our observations suggest that increased numbers of MMP-9 expressing glia and their subsequent engulfment of PNNs around α-motor neurons render these neurons sensitive to oxidative damage and eventual death in the SOD1G93A ALS model mouse.


Assuntos
Esclerose Lateral Amiotrófica , Astrócitos , Modelos Animais de Doenças , Metaloproteinase 9 da Matriz , Camundongos Transgênicos , Microglia , Animais , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/genética , Microglia/metabolismo , Microglia/patologia , Camundongos , Metaloproteinase 9 da Matriz/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Neurônios Motores/patologia , Neurônios Motores/metabolismo , Fagocitose/fisiologia , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia
9.
Viral Immunol ; 37(3): 159-166, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38588555

RESUMO

The high global prevalence of hepatitis B and hepatitis C and the poor prognosis of hepatitis B and hepatitis C-associated hepatocellular carcinoma (HCC), necessitates the early diagnosis and treatment of the disease. Recent studies show that cell-to-cell communication via extracellular vesicles (EVs) is involved in the HCC progression. The objective of the following study was to explore the role of EVs in the progression of viral-induced HCC and investigate their potential for the early diagnosis of cancer. First, the mRNA derived from EVs of HCC patients was compared to the mRNA derived from EVs from the healthy controls. Expression analysis of ANGPTL3, SH3BGRL3, and IFITM3 genes from the EVs was done. Afterward, to confirm whether hepatocytes can uptake EVs, HuH7 cells were exposed to EVs, and the expression analysis of downstream target genes (AKT, TNF-α, and MMP-9) in Huh7 cells was done. Transcriptional analysis showed that in the EVs from HCC patients, the expression levels of ANGPTL3, SH3BGRL3, and IFITM3 were significantly increased by 2.62-, 4.3-, and 9.03-folds, respectively. The downstream targets, AKT, TNF-α, and MMP-9, also showed a considerable change of 4.1-, 1.46-, and 5.05-folds, respectively, in Huh7 cells exposed to HCC EVs. In conclusion, the following study corroborates the role of EVs in HCC progression. Furthermore, the significant alteration in mRNA levels of the selected genes demonstrates their potential to be used as possible biomarkers for the early diagnosis of HCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Carcinoma Hepatocelular , Vesículas Extracelulares , Hepatite B , Hepatite C , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-akt , Fator de Necrose Tumoral alfa/metabolismo , Hepatite C/genética , Biomarcadores/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , RNA Mensageiro/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteína 3 Semelhante a Angiopoietina
10.
Aging (Albany NY) ; 16(8): 6852-6867, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38637126

RESUMO

BACKGROUND: Globally, ischemic stroke (IS) is ranked as the second most prevailing cause of mortality and is considered lethal to human health. This study aimed to identify genes and pathways involved in the onset and progression of IS. METHODS: GSE16561 and GSE22255 were downloaded from the Gene Expression Omnibus (GEO) database, merged, and subjected to batch effect removal using the ComBat method. The limma package was employed to identify the differentially expressed genes (DEGs), followed by enrichment analysis and protein-protein interaction (PPI) network construction. Afterward, the cytoHubba plugin was utilized to screen the hub genes. Finally, a ROC curve was generated to investigate the diagnostic value of hub genes. Validation analysis through a series of experiments including qPCR, Western blotting, TUNEL, and flow cytometry was performed. RESULTS: The analysis incorporated 59 IS samples and 44 control samples, revealing 226 DEGs, of which 152 were up-regulated and 74 were down-regulated. These DEGs were revealed to be linked with the inflammatory and immune responses through enrichment analyses. Overall, the ROC analysis revealed the remarkable diagnostic potential of ITGAM and MMP9 for IS. Quantitative assessment of these genes showed significant overexpression in IS patients. ITGAM modulation influenced the secretion of critical inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α, and had a distinct impact on neuronal apoptosis. CONCLUSIONS: The inflammation and immune response were identified as potential pathological mechanisms of IS by bioinformatics and experiments. In addition, ITGAM may be considered a potential therapeutic target for IS.


Assuntos
AVC Isquêmico , Mapas de Interação de Proteínas , Humanos , AVC Isquêmico/genética , Mapas de Interação de Proteínas/genética , Perfilação da Expressão Gênica , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Redes Reguladoras de Genes , Bases de Dados Genéticas , Apoptose/genética
11.
Int Immunopharmacol ; 133: 112082, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38652958

RESUMO

Psoriasis is an incurable immune-mediated disease affecting the skin or the joints. There are continuing studies on drugs for psoriasis prevention and treatment. This research found that Geniposide (GE) significantly thinned IMQ mice's skin lesions, reduced the scales, and lowered the presence of inflammatory cells in the pathology in a dose-dependent manner. GE inhibited IL-23, IL-22, IL-17A, IL-12, IL-6, and TNF-α levels in psoriatic mice serum. AKT1, TNF, TLR4, MMP9, MAPK3, and EGFR were selected as the top 6 targets of GE against psoriasis via network pharmacology, and GE-TLR4 has the most robust docking score value by molecular docking. Taken together, GE significantly inhibited TLR4 and MMP9 protein expression and influenced MyD88/NF-κB p65 signaling pathway. Finally, TLR4 was verified as the critical target of GE, which engaged in immunomodulatory activities and reduced MMP9 production in LPS and TAK-242-induced HaCaT cells. GE had a medium affinity for TLR4, and the KD value was 1.06 × 10-5 M. GE is an effective treatment and preventative strategy for psoriasis since it impacts TLR4.


Assuntos
Iridoides , Metaloproteinase 9 da Matriz , Fator 88 de Diferenciação Mieloide , Psoríase , Transdução de Sinais , Receptor 4 Toll-Like , Receptor 4 Toll-Like/metabolismo , Animais , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Humanos , Psoríase/tratamento farmacológico , Psoríase/imunologia , Iridoides/farmacologia , Iridoides/uso terapêutico , Camundongos , Fator de Transcrição RelA/metabolismo , Pele/efeitos dos fármacos , Pele/patologia , Pele/imunologia , Pele/metabolismo , Citocinas/metabolismo , Masculino , Simulação de Acoplamento Molecular , Modelos Animais de Doenças , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Células HaCaT , Imiquimode , Linhagem Celular
12.
Mol Biol Rep ; 51(1): 540, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38642151

RESUMO

BACKGROUND: The MMP-9 is a known player in atherosclerosis, yet associations of the MMP-9 -1562 C/T variant (rs3918242) with various atherosclerotic phenotypes and tissue mRNA expression are still contradictory. This study aimed to investigate the MMP-9 -1562 C/T variant, its mRNA and protein expression in carotid plaque (CP) tissue, as a risk factor for CP presence and as a marker of different plaque phenotypes (hyperechoic and hypoechoic) in patients undergoing carotid endarterectomy. The MnSOD as an MMP-9 negative regulator was also studied in relation to CP phenotypes. METHODS AND RESULTS: Genotyping of 770 participants (285 controls/485 patients) was done by tetra-primer ARMS PCR. The MMP-9 mRNA expression in 88 human CP tissues was detected by TaqMan® technology. The protein levels of MMP-9 and MnSOD were assessed by Western blot analysis. The MMP-9 -1562 C/T variant was not recognized as a risk factor for plaque presence or in predisposing MMP-9 mRNA and protein levels in plaque tissue. Patients with hypoechoic plaques had significantly lower MMP-9 mRNA and protein levels than those with hyperechoic plaque (p = 0.008, p = 0.003, respectively). MnSOD protein level was significantly higher in hypoechoic plaque compared to hyperechoic (p = 0.039). MMP-9 protein expression in CP tissue was significantly affected by sex and plaque type interaction (p = 0.009). CONCLUSIONS: Considering the differences of MMP-9 mRNA and protein expression in CP tissue regarding different plaque phenotypes and the observed sex-specific effect, the role of MMP-9 in human atherosclerotic plaques should be further elucidated.


Assuntos
Aterosclerose , Doenças das Artérias Carótidas , Metaloproteinase 9 da Matriz , Placa Aterosclerótica , Feminino , Humanos , Masculino , Aterosclerose/genética , Artérias Carótidas , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
13.
Eur J Pharmacol ; 973: 176605, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38653362

RESUMO

The main objective of this study was to determine if the telmisartan-ameliorative effects of metabolic syndrome (MetS)-evoked nephropathy are attributed to the Hippo pathway. A secondary objective was to investigate the potential of vitamin D3 to enhance telmisartan-favourable effects. A diet composed of 24% fat and 3% salt, along with drinking water containing 10% fructose, was administered for 12 weeks to induce MetS. MetS-rats were given telmisartan (5 mg/kg/day), vitamin D3 (10 µg/kg/day) or both by gavage, starting in the sixth week of experimental diet administration. Assessments performed at closure included renal function, histological examination, catalase, malondialdehyde (MDA), nuclear factor kappa-B (NF-κB), interleukin-6 (IL-6), peroxisome proliferator-activated receptor-γ (PPAR-γ), phosphatase and tensin homolog (PTEN), and transforming growth factor-ß (TGF-ß). Matrix metalloproteinase-9 (MMP-9) immunostaining was conducted. The expression of the Hippo pathway components, as well as that of angiotensin II type 1 and type 2 (AT1 and AT2), receptors was evaluated. Telmisartan attenuated MetS-evoked nephropathy, as demonstrated by improvement of renal function and histological features, enhancement of catalase, reduction of MDA, inflammation (NF-κB, IL-6), and renal fibrosis (increased PPAR-γ and PTEN and reduced MMP-9 and TGF-ß). Telmisartan downregulated AT1-receptor, upregulated AT2-receptor and restored the Hippo pathway. Vitamin D3 replicated most of the telmisartan-elicited effects and enhanced the antifibrotic actions of telmisartan. The alleviative effects of telmisartan on MetS-evoked nephropathy may be related to the restoration of the Hippo pathway. The combination of vitamin D3 and telmisartan exerted more favourable effects on metabolic and nephropathic biomarkers compared with either one administered alone.


Assuntos
Via de Sinalização Hippo , Nefropatias , Rim , Síndrome Metabólica , Telmisartan , Animais , Telmisartan/farmacologia , Telmisartan/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Síndrome Metabólica/complicações , Síndrome Metabólica/patologia , Masculino , Ratos , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Nefropatias/patologia , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , NF-kappa B/metabolismo , Colecalciferol/farmacologia , Colecalciferol/uso terapêutico , Ratos Wistar , Metaloproteinase 9 da Matriz/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , PPAR gama/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Malondialdeído/metabolismo , Interleucina-6/metabolismo , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico
14.
Int J Mol Sci ; 25(8)2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38673967

RESUMO

Breast cancer is one of the leading causes of death in the female population because of the resistance of cancer cells to many anticancer drugs used. Curcumin has cytotoxic activities against breast cancer cells, although it has limited use due to its poor bioavailability and rapid metabolic elimination. The synthesis of metal complexes of curcumin and curcuminoids is a relevant topic in the search for more active and selective derivatives of these molecular scaffolds. However, solubility and bioavailability are concomitant disadvantages of these types of molecules. To overcome such drawbacks, the preparation of inclusion complexes offers a chemical and pharmacologically safe option for improving the aqueous solubility of organic molecules. Herein, we describe the preparation of the inclusion complex of dimethoxycurcumin magnesium complex (DiMeOC-Mg, (4)) with beta-cyclodextrin (DiMeOC-Mg-BCD, (5)) in the stoichiometric relationship 1:1. This new inclusion complex's solubility in aqueous media phosphate buffer saline (PBS) was improved by a factor of 6x over the free metal complex (4). Furthermore, 5 affects cell metabolic rate, cell morphology, cell migration, induced apoptosis, and downregulation of the matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6), and signal transducer and activator of transcription-3 (STAT3) expression levels on MD Anderson metastasis breast-231 cancer (MDA-MB-231) cell lines. Results of an antitumor assay in an in ovo model showed up to 30% inhibition of tumor growth for breast cancer (MDA-MB-231) when using (5) (0.650 mg/kg dose) and 17.29% inhibition with the free homoleptic metal complex (1.5 mg/kg dose, (4)). While the formulation of inclusion complexes from metal complexes of curcuminoids demonstrates its usefulness in improving the solubility and bioavailability of these metallodrugs, the new compound (5) exhibits excellent potential for use as a therapeutic agent in the battle against breast cancer.


Assuntos
Antineoplásicos , Curcumina , Curcumina/análogos & derivados , Magnésio , beta-Ciclodextrinas , beta-Ciclodextrinas/química , Curcumina/farmacologia , Curcumina/química , Curcumina/farmacocinética , Humanos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Magnésio/química , Apoptose/efeitos dos fármacos , Feminino , Linhagem Celular Tumoral , Fator de Transcrição STAT3/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Movimento Celular/efeitos dos fármacos , Solubilidade , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Embrião de Galinha , Metaloproteinase 9 da Matriz/metabolismo
15.
Int J Mol Sci ; 25(8)2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38674053

RESUMO

Using different three-drug immunosuppressive treatment regimens in a rat model, we aimed to determine the effects of long-term therapy on metalloproteinase-2 and metalloproteinase-9 activity and the expression of their inhibitors, as well as to assess the morphology of the animals' cardiac tissue. Our results suggest that chronic use of immunosuppressive drugs disrupts the balance between the activity of MMPs and TIMPs. Depending on the type of drug regimen used, this leads to abnormalities in the cardiac structure, collagen fiber accumulation, or cardiomyocyte hypertrophy. The information obtained in the present study allows us to conclude that the chronic treatment of rats with the most common clinical immunosuppressive regimens may contribute to abnormalities in the myocardial structure and function. The results presented in this study may serve as a prelude to more in-depth analyses and additional research into the optimal selection of an immunosuppressive treatment with the lowest possible risk of cardiovascular complications for patients receiving organ transplants.


Assuntos
Imunossupressores , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , Miocárdio , Animais , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Imunossupressores/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Ratos , Miocárdio/patologia , Miocárdio/metabolismo , Masculino , Ratos Wistar
16.
Int J Biol Macromol ; 267(Pt 2): 131520, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38615859

RESUMO

The adverse microenvironment, including neuroinflammation, hinders the recovery of spinal cord injury (SCI). Regulating microglial polarization to alleviate neuroinflammation at the injury site is an effective strategy for SCI recovery. MG53 protein exerts obvious repair ability on multiple tissues damage, but with short half-life. In this study, we composited an innovative MG53/GMs/HA-Dex neural scaffold using gelatin microspheres (GMs), hyaluronic acid (HA), and dextran (Dex) loaded with MG53 protein. This novel neural scaffold could respond to MMP-2/9 protein and stably release MG53 protein with good physicochemical properties and biocompatibility. In addition, it significantly improved the motor function of SCI mice, suppressed M1 polarization of microglia and neuroinflammation, and promoted neurogenesis and axon regeneration. Further mechanistic experiments demonstrated that MG53/GMs/HA-Dex hydrogel inhibited the JAK2/STAT3 signaling pathway. Thus, this MG53/GMs/HA-Dex neural scaffold promotes the functional recovery of SCI mice by alleviating neuroinflammation, which provides a new intervention strategy for the neural regeneration and functional repair of SCI.


Assuntos
Gelatina , Ácido Hialurônico , Janus Quinase 2 , Doenças Neuroinflamatórias , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Animais , Camundongos , Recuperação de Função Fisiológica/efeitos dos fármacos , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Doenças Neuroinflamatórias/tratamento farmacológico , Gelatina/química , Gelatina/farmacologia , Janus Quinase 2/metabolismo , Dextranos/química , Alicerces Teciduais/química , Microesferas , Fator de Transcrição STAT3/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Regeneração Nervosa/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Modelos Animais de Doenças , Neurogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Hidrogéis/química , Hidrogéis/farmacologia
17.
Proc Natl Acad Sci U S A ; 121(18): e2314541121, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38657049

RESUMO

Recent evidence has demonstrated that the transsynaptic nanoscale organization of synaptic proteins plays a crucial role in regulating synaptic strength in excitatory synapses. However, the molecular mechanism underlying this transsynaptic nanostructure in inhibitory synapses still remains unclear and its impact on synapse function in physiological or pathological contexts has not been demonstrated. In this study, we utilized an engineered proteolysis technique to investigate the effects of acute cleavage of neuroligin-2 (NL2) on synaptic transmission. Our results show that the rapid cleavage of NL2 led to impaired synaptic transmission by reducing both neurotransmitter release probability and quantum size. These changes were attributed to the dispersion of RIM1/2 and GABAA receptors and a weakened spatial alignment between them at the subsynaptic scale, as observed through superresolution imaging and model simulations. Importantly, we found that endogenous NL2 undergoes rapid MMP9-dependent cleavage during epileptic activities, which further exacerbates the decrease in inhibitory transmission. Overall, our study demonstrates the significant impact of nanoscale structural reorganization on inhibitory transmission and unveils ongoing modulation of mature GABAergic synapses through active cleavage of NL2 in response to hyperactivity.


Assuntos
Moléculas de Adesão Celular Neuronais , Proteínas do Tecido Nervoso , Sinapses , Transmissão Sináptica , Animais , Camundongos , Moléculas de Adesão Celular Neuronais/metabolismo , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Epilepsia/patologia , Hipocampo/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Proteólise , Receptores de GABA-A/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia
18.
Molecules ; 29(8)2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38675538

RESUMO

Polyphenols, the main antioxidants of diet, have shown anti-inflammatory, antioxidant and anticarcinogenic activities. Here, we compared the effects of four polyphenolic compounds on ROS production and on the levels of matrix metalloproteinase (MMP)-2 and -9, which represent important pathogenetic factors of breast cancer. THP-1 differentiated macrophages were activated by LPS and simultaneously treated with different doses of a green tea extract (GTE), resveratrol (RSV), curcumin (CRC) and an olive fruit extract (oliplus). By using the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, we found that all of the tested compounds showed antioxidant activity in vitro. In addition, GTE, RSV and CRC were able to counteract ROS production induced by H2O2 in THP-1 cells. As assessed by a zymographic analysis of THP-1 supernatants and by an "in-gel zymography" of a pool of sera from patients with breast cancer, the antioxidant compounds used in this study inhibited both the activity and expression of MMP-2 and MMP-9 through different mechanisms related to their structures and to their ability to scavenge ROS. The results of this study suggest that the used antioxidants could be promising agents for the prevention and complementary treatment of breast cancer and other diseases in which MMPs play a pivotal role.


Assuntos
Antioxidantes , Neoplasias da Mama , Macrófagos , Feminino , Humanos , Antioxidantes/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Curcumina/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/farmacologia , Células THP-1
19.
Cells ; 13(7)2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38606999

RESUMO

Cervical cancer (CC) is the fourth leading cancer among women and is one of the principal gynecological malignancies. In the tumor microenvironment, cancer-associated fibroblasts (CAFs) play a crucial role during malignant progression, exhibiting a variety of heterogeneous phenotypes. CAFs express phenotypic markers like fibroblast activation protein (FAP), vimentin, S100A4, α-smooth muscle actin (αSMA), and functional markers such as MMP9. This study aimed to evaluate the protein expression of vimentin, S100A4, αSMA, FAP, and MMP9 in mesenchymal stem cells (MSC)-CAF cells, as well as in cervical cancer samples. MSC cells were stimulated with HeLa and SiHa tumor cell supernatants, followed by protein evaluation and cytokine profile to confirm differentiation towards a CAF phenotype. In addition, automated immunohistochemistry (IHQa) was performed to evaluate the expression of these proteins in CC samples at different stages. Our findings revealed a high expression of FAP in stimulated MSC cells, accompanied by the secretion of pro/anti-inflammatory cytokines. In the other hand, CC samples were observed to have high expression of FAP, vimentin, αSMA, and MMP9. Most importantly, there was a high expression of their activation proteins αSMA and FAP during the different stages. In the early stages, a myofibroblast-like phenotype (CAFs αSMA+ FAP+), and in the late stages a protumoral phenotype (CAF αSMA- FAP+). In summary, FAP has a crucial role in the activation of CAFs during cervical cancer progression.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias do Colo do Útero , Humanos , Feminino , Fibroblastos Associados a Câncer/metabolismo , Vimentina/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias do Colo do Útero/metabolismo , Processos Neoplásicos , Fenótipo , Microambiente Tumoral
20.
Nutrients ; 16(7)2024 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-38612961

RESUMO

Sodium, although essential for life, is a key factor in changes in vascular function and cardiovascular disease when consumed in excess. Sarcocornia spp., a halophyte plant with many nutritional benefits, presents itself as a promising substitute for the consumption of purified salt. Matrix metalloproteinases (MMPs) 2 and 9 are widely studied due to their action in physiological processes and as biomarkers at the diagnostic level due to their increased expression in inflammatory processes. This study aimed to evaluate whether replacing salt with Sarcocornia perennis (S. perennis) powder in healthy young people leads to an improvement in biochemical profiles and the attenuation of MMP-2 and MMP-9 activity. In the present study, 30 participants were randomized into a control group that consumed salt and an intervention group that replaced salt with powdered S. perennis. The evaluation of the biochemical parameters was carried out by the spectrophotometry method, and the evaluation of MMP activity was carried out by zymography. A significant decrease was observed in the intervention group in total cholesterol, high-density lipoprotein cholesterol (HDL-c), and creatinine (p-value ≤ 0.05), along with lower but not significantly different mean values of triglycerides. Regarding MMP activity after the intervention, a lower mean value was observed for MMP-9 activity, with there being higher mean values for MMP-2 activity, both with p-values ≥ 0.05. The results confirmed that the consumption of S. perennis is a beneficial choice for health regarding the lipid profile. The evaluation of MMP activity indicated the potential of S. perennis in the regulation of MMP-9 activity in healthy individuals, along with the need for the further study of these proteases in individuals with pathologies.


Assuntos
Gelatinases , Metaloproteinase 9 da Matriz , Humanos , Adolescente , Metaloproteinase 2 da Matriz , Cloreto de Sódio , Cloreto de Sódio na Dieta , HDL-Colesterol , Endopeptidases
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...