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Glioblastoma multiforme (GBM) is the most aggressive brain cancer with a poor prognosis. Therefore, the correlative molecular markers and molecular mechanisms should be explored to assess the occurrence and treatment of glioma.WB and qPCR assays were used to detect the expression of CXCL5 in human GBM tissues. The relationship between CXCL5 expression and clinicopathological features was evaluated using logistic regression analysis, Wilcoxon symbolic rank test, and Kruskal-Wallis test. Univariate, multivariate Cox regression and Kaplan-Meier methods were used to assess CXCL5 and other prognostic factors of GBM. Gene set enrichment analysis (GSEA) was used to identify pathways associated with CXCL5. The correlation between CXCL5 and tumor immunoinfiltration was investigated using single sample gene set enrichment analysis (ssGSEA) of TCGA data. Cell experiments and mouse subcutaneous transplanted tumor models were used to evaluate the role of CXCL5 in GBM. WB, qPCR, immunofluorescence, and immunohistochemical assays showed that CXCL5 expression was increased in human GBM tissues. Furthermore, high CXCL5 expression was closely related to poor disease-specific survival and overall survival of GBM patients. The ssGSEA suggested that CXCL5 is closely related to the cell cycle and immune response through PPAR signaling pathway. GSEA also showed that CXCL5 expression was positively correlated with macrophage cell infiltration level and negatively correlated with cytotoxic cell infiltration level. CXCL5 may be associated with the prognosis and immunoinfiltration of GBM.
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Neoplasias Encefálicas , Glioblastoma , Animais , Camundongos , Humanos , Glioblastoma/patologia , Prognóstico , Processos Neoplásicos , Neoplasias Encefálicas/metabolismo , Transdução de Sinais , Quimiocina CXCL5/genéticaRESUMO
Colorectal cancer (CRC) is a significant health problem with elevated mortality rates, prompting intense exploration of its complex molecular mechanisms and innovative therapeutic avenues. Resveratrol (RSV), recognised for its anticancer effects through SIRT1 activation, is a promising candidate for CRC treatment. This study focuses on elucidating RSV's role in CRC progression, particularly its effect on autophagy-related apoptosis. Using bioinformatics, protein imprinting and immunohistochemistry, we established a direct correlation between FOXQ1 and adverse CRC prognosis. Comprehensive in vitro experiments confirmed RSV's ability to promote autophagy-related apoptosis in CRC cells. Plasmids for SIRT1 modulation were used to investigate underlying mechanisms. Molecular docking, glutathione-S-transferase pull-down experiments and immunoprecipitation highlighted RSV's direct activation of SIRT1, resulting in the inhibition of FOXQ1 expression. Downstream interventions identified ATG16L as a crucial autophagic target. In vivo and in vitro studies validated RSV's potential for CRC therapy through the SIRT1/FOXQ1/ATG16L pathway. This study establishes RSV's capacity to enhance autophagy-related cell apoptosis in CRC, positioning RSV as a prospective therapeutic agent for CRC within the SIRT1/FOXQ1/ATG16L pathway.
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Apoptose , Autofagia , Neoplasias Colorretais , Fatores de Transcrição Forkhead , Resveratrol , Sirtuína 1 , Humanos , Resveratrol/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Sirtuína 1/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Animais , Linhagem Celular Tumoral , Camundongos , Camundongos Nus , Masculino , Simulação de Acoplamento Molecular , Feminino , Progressão da Doença , Camundongos Endogâmicos BALB CRESUMO
Here we present seasonal chemical characteristics, formations, sources of PM2.5 in the year 2020 in Suzhou, Yangtze River Delta, China. Expectedly, organic matter (OM) found to be the most dominant component of PM2.5, with a year-average value of 10.3 ± 5.5 µg m-3, followed by NO3- (6.7 ± 6.5 µg m-3), SO42- (3.3 ± 2.5 µg m-3), NH4+ (3.2 ± 2.8 µg m-3), EC (1.1 ± 1.3 µg m-3), Cl- (0.57 ± 0.56 µg m-3), Ca2+ (0.55 ± 0.91 µg m-3), K+ (0.2 ± 1.0 µg m-3), Na+ (0.18 ± 0.45 µg m-3), and Mg2+ (0.09 ± 0.15 µg m-3). Seasonal variations of PM2.5 showed the highest average value in spring, followed by winter, fall, and summer. Meanwhile, the formation mechanisms of the major PM2.5 species (NO3-, SO42-, and OM) varied in seasons. Interestingly, NO2 may have the highest conversion rate to NO3- in spring, which might be linked with the nighttime chemistry due to the high relative humidity. Moreover, OM in summer was mainly produced by the daytime oxidation of volatile organic compounds, while local primary organic aerosols might play a significant role in other seasons. Source apportionment showed that the more-aged PM2.5 contributed significantly to the PM2.5 mass (42%), followed by the dust-related PM2.5 (38%) and the less-aged PM2.5 (21%). Potential contribution source function (PSCF) results indicated that aged PM2.5 were less affected by transportation than dust-related PM2.5.
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Poluentes Atmosféricos , Rios , Aerossóis/análise , Poluentes Atmosféricos/análise , China , Poeira/análise , Monitoramento Ambiental/métodos , Material Particulado/análise , Rios/química , Estações do AnoRESUMO
The isatin framework is a useful template for the development of novel anticancer agents. This is exemplified by the fact that several isatin-based anticancer agents, such as semaxanib, sunitinib, nintedanib, and hesperadin, are already in use or under clinical trials for the treatment of diverse kinds of cancers. Isatin-based hybrids could be obtained by incorporating other anticancer pharmacophores into the isatin skeleton and they have the potential to overcome drug resistance with reduced side effects. Thus, isatin-based hybrids may provide attractive scaffolds for the development of novel anticancer agents. This review covers the recent advances of isatin-based hybrids with anticancer activity, covering articles published between 2001 and 2019. The anticancer activities of these molecules and the structure-activity relationships are also discussed. The purpose of this review article is to set up the direction for the design and development of isatin-based hybrids with high efficacy and low toxicity.
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Antineoplásicos/farmacologia , Isatina/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Azóis/química , Azóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Iminas/química , Iminas/farmacologia , Isatina/química , Estrutura Molecular , Neoplasias/patologia , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Postmenopausal osteoporosis (PMOP) is a major health problem affecting millions of women worldwide. PMOP patients are often accompanied by abnormal accumulation of bone marrow adipose tissue (BMAT). BMAT is a critical regulator of bone homeostasis, and an increasing BMAT volume is negatively associated with bone mass reduction or fracture. BMAT regulates bone metabolism via adipokines, cytokines and the immune system, but the specific mechanisms are largely unknown. This review emphasizes the impact of estrogen deficiency on bone homeostasis and BMAT expansion, and the mechanism by which BMAT regulates PMOP, providing a promising strategy for targeting BMAT in preventing and treating PMOP.
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Tecido Adiposo , Medula Óssea , Osteoporose Pós-Menopausa , Humanos , Tecido Adiposo/metabolismo , Feminino , Densidade Óssea , Adipocinas/metabolismo , Estrogênios/metabolismo , Osso e Ossos/metabolismo , Animais , Citocinas/metabolismo , HomeostaseRESUMO
Type 2 diabetes (T2DM) significantly diminishes people's quality of life and imposes a substantial economic burden. This pathological progression is intimately linked with specific gut microbiota, such as Akkermansia muciniphila. Pasteurized A. muciniphila (P-AKK) has been defined as a novel food by the European Food Safety Authority and exhibited significant hypoglycemic activity. However, current research on the hypoglycemic activity of P-AKK is limited to the metabolic level, neglecting systematic exploration at the pathological level. Consequently, its material basis and mechanism of action for hypoglycemia remain unclear. Drawing upon this foundation, we utilized high-temperature killed A. muciniphila (H-K-AKK) with insignificant hypoglycemic activity as the control research object. Assessments were conducted at pathological levels to evaluate the hypoglycemic functions of both P-AKK and H-K-AKK separately. Our study unveiled for the first time that P-AKK ameliorated symptoms of T2DM by enhancing the generation of glucagon-Like Peptide 1 (GLP-1), with pasteurized A. muciniphila total proteins (PP) being a pivotal component responsible for this activity. Utilizing SDS-PAGE, proteomics, and molecular docking techniques, we deeply analyzed the material foundation of PP. We scientifically screened and identified a protein weighing 77.85 kDa, designated as P5. P5 enhanced GLP-1 synthesis and secretion by activating the G protein-coupled receptor (GPCR) signaling pathway, with free fatty acid receptor 2 (FFAR-2) being identified as the pivotal target protein for P5's physiological activity. These findings further promote the widespread application of P-AKK in the food industry, laying a solid theoretical foundation for its utilization as a beneficial food ingredient or functional component.
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Akkermansia , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Pasteurização , Probióticos , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Masculino , Animais , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Camundongos , Glicemia/metabolismo , Hipoglicemiantes/química , Simulação de Acoplamento MolecularRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Gui Shen Wan (GSW) stands out as a promising therapeutic approach for addressing Premature Ovarian Insufficiency (POI). With deep roots in traditional medicine, GSW highlights the ethnopharmacological significance of herbal interventions in addressing nuanced aspects of women's health, with a specific emphasis on ovarian functionality. Recognizing the importance of GSW in gynecological contexts resonates with a rich tradition of using botanical formulations to navigate the intricacies of reproductive health. Delving into GSW's potential for treating POI emphasizes the crucial role of ethnopharmacological insights in guiding modern research endeavors. AIM OF THE STUDY: GSW is extensively utilized in gynecological disorders and has recently emerged as a potential therapeutic approach for POI. The present investigation aimed to assess the efficacy of GSW in treating POI in rats and elucidate its underlying molecular mechanisms. MATERIALS AND METHODS: The study employed GSW for POI treatment in rats. GSW, prepared as pills, underwent HPLC fingerprinting for quality control. Reagents and drugs, including VCD and dehydroepiandrosterone (DHEA), were sourced from reputable providers. Eighty Sprague-Dawley rats were categorized into groups for POI induction and treatment. Ovarian tissue underwent HE staining, immunohistochemical staining, Western Blot, qRT-PCR, and vaginal secretion testing. ELISA was utilized for target molecule detection. This methodology ensures a robust and reliable experimental framework. RESULTS: The results highlight a robust collaborative improvement in POI among rats subjected to combined GSW and DHEA treatment. Particularly noteworthy is the substantial enhancement in the expression of vascular regeneration-related molecules-VDR-Klotho-VEGFR-accompanied by a significant elevation in autophagy levels. Post-GSW administration, rat ovarian morphology demonstrated increased stability, hormone levels exhibited more consistent maintenance, and there was a marked reduction in inflammatory response compared to other groups (p < 0.01). Furthermore, GSW intervention resulted in a more pronounced upregulation of ovarian autophagy (p < 0.05). CONCLUSION: By modulating VDR-Klotho signaling, GSW exerts regulatory control over ovarian autophagy and vascular regeneration, thereby mitigating the occurrence and progression of POI in rats.
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Menopausa Precoce , Insuficiência Ovariana Primária , Humanos , Ratos , Feminino , Animais , Angiogênese , Ratos Sprague-Dawley , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/metabolismo , Desidroepiandrosterona/uso terapêutico , Receptores de CalcitriolRESUMO
Integrin ß4 (ITGB4) is a transmembrane protein that functions as a mechanosensor, mediating the bidirectional exchange of information between the intracellular and extracellular matrices. ITGB4 plays a critical role in cell adhesion, migration, and signaling. Numerous studies have implicated ITGB4 as a key facilitator of tumor migration and invasion. This review provides a foundational description of the mechanisms by which ITGB4 regulates tumor migration and invasion through pathways involving focal adhesion kinase (FAK), protein kinase B (AKT), and matrix metalloproteinases (MMPs). These mechanisms encompass epithelial-mesenchymal transition (EMT), phosphorylation, and methylation of associated molecules. Additionally, this review explores the role of ITGB4 in the migration and invasion of prevalent clinical tumors, including those of the digestive system, breast, and prostate.
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Metabolic diseases are comprehensive disease based on obesity. Numerous cumulative studies have shown a certain correlation between the fluctuating abundance of Akkermansia muciniphila and the occurrence of metabolic diseases. A. muciniphila, a potential probiotic candidate colonized in the human intestinal mucus layer, and its derivatives have various physiological functions, including treating metabolic disorders and maintaining human health. This review systematically explicates the abundance change rules of A. muciniphila in metabolic diseases. It also details the high efficacy and specific molecules mechanism of A. muciniphila and its derivatives in treating obesity, type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease.
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Diabetes Mellitus Tipo 2 , Humanos , Verrucomicrobia/metabolismo , Intestinos , Obesidade , AkkermansiaRESUMO
OBJECTIVE: To observe the therapeutic effect of electroacupuncture(EA) on obese mice, and to explore the underlying mechanism of EA in treating obesity by focusing on the balance of regulatory T cells (Treg) and T helper 17 cells (Th17) and related inflammatory factors. METHODS: C57BL/6J male mice were randomly divided into normal group, model group and EA group, with 10 mice in each group. The obesity model was established by feeding the mice with high-fat diet. Mice in the EA group was treated with EA at "Zhongwan"(CV12), "Guanyuan"(CV4), "Zusanli"(ST36) and "Fenglong"(ST40) for 20 min every time, 3 times every week, for a total of 8 weeks. The food intake and body weight of mice were observed and recorded, and Lee's index was calculated; the contents of interleukin 2(IL-2), IL-4, IL-6, IL-10, IL-17A, gamma interferon (IFN-γ) and tumor necrosis factor(TNF)-α in serum were detected by multiplex liquid chip quantitative technique; the levels of Treg and Th17 cells in mice spleen tissues were detected by flow cytometry; and the expression levels of foxhead box p3(Foxp3) and retinoic acid related orphan receptor γt(ROR-γt) mRNA in spleen were detected by real-time quantitative PCR. RESULTS: Compared with the normal group, the food intake, body weight, Lee's index, the contents of IL-2, IL-6, IL-17A, IFN-γ and TNF-α in the serum, and the percentage of Th17 and expression of ROR-γt mRNA in the spleen tissues were significantly increased (P<0.01, P<0.001), while the contents of IL-4 and IL-10 in the serum, the percentage of Treg and expression of Foxp3 mRNA in the spleen tissues were significantly decreased (P<0.001, P<0.01) in the model group. Compared with the model group, the food intake, body weight, Lee's index, the contents of IL-2, IL-6, IL-17A, IFN-γ, and TNF-α in the serum, the percentage of Th17 and expression of ROR-γt mRNA in the spleen tissues were significantly decreased (P<0.01), while the contents of IL-4 and IL-10 in serum, the percentage of Treg and expression of Foxp3 mRNA in the spleen tissues were significantly increased(P<0.01, P<0.05) in the EA group. CONCLUSION: EA may improve the obese state of mice by regulating the balance of Treg/Th17 in spleen and the expression of inflammatory factors in serum.
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Eletroacupuntura , Baço , Ratos , Camundongos , Masculino , Animais , Ratos Wistar , Baço/metabolismo , Células Th17/metabolismo , Interleucina-2 , Camundongos Obesos , Interleucina-10 , Interleucina-17/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Fator de Necrose Tumoral alfa/metabolismo , Linfócitos T Reguladores/metabolismo , Interleucina-6 , Interleucina-4 , Camundongos Endogâmicos C57BL , Inflamação , Obesidade/genética , Obesidade/terapia , Fatores de Transcrição Forkhead/genéticaRESUMO
Colorectal cancer (CRC) is the most prevalent cancer of the digestive tract. Herba Patriniae (also known as Bai Jiang Cao, HP) have been widely used to manage diarrhea, ulcerative colitis, and several cancers, including CRC. Nonetheless, the molecular mechanisms underlying the pharmacological action of HP on CRC remain unclear. This study investigated the underlying mechanisms of HP against CRC using network pharmacology analysis and in vitro and in vivo experiments. The results revealed nine bioactive compounds of HP. Furthermore, 3460 CRC-related targets of the identified active compounds were predicted from the Gene Expression Omnibus (GEO) database. Furthermore, 65 common targets were identified through the intersection of two related targets. Moreover, ten hub genes, including CDK4, CDK2, CDK1, CCND1, CCNB1, CCNA2, MYC, E2F1, CHEK1, and CDKN1A were identified through the topological analysis. Meanwhile, the GO and KEGG pathway analysis revealed that the core target genes were majorly enriched in the p53 and HIF-1 signaling pathways. Moreover, HP promoted apoptosis and suppressed cell proliferation by activating the p53 signaling pathway in a dose-dependent manner, while a similar effect was observed for Isovitexin (the primary component of HP). Overall, this study provides valuable insights into the underlying mechanisms of HP and its component Isovitexin against CRC, providing a theoretical foundation for additional experimental verification of its clinical application.
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Neoplasias Colorretais , Medicamentos de Ervas Chinesas , Proteína Supressora de Tumor p53 , Apoptose , Pontos de Checagem do Ciclo Celular , Genes cdc , Proteína Supressora de Tumor p53/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Humanos , Medicamentos de Ervas Chinesas/farmacologia , Antineoplásicos Fitogênicos/farmacologiaRESUMO
Colorectal cancer (CRC) is one of the most common tumors of the digestive tract, with the third-highest incidence and the second-highest mortality rate among all malignant tumors worldwide. However, treatment options for CRC remain limited. As a complementary therapy, acupuncture or electro-acupuncture (EA) has been widely applied in the treatment of various inflammation-related diseases, such as obesity, ulcerative colitis and tumors. Although numerous pre-clinical and clinical studies have investigated the beneficial effects of acupuncture on CRC, the mechanism underlying the therapeutic action of EA is largely unknown. Evidence from previous studies has revealed that SIRT1 participates in CRC progression by activating autophagy-related miRNAs. Using azoxymethane/dextran sulfate sodium- (AOM/DSS-) induced colorectal cancer model in mice, we explored whether EA treatment can inhibit inflammation and promote autophagy via the SIRT1/miR-215/Atg14 axis. Our results showed that EA notably alleviated the CRC in mice, by decreasing the tumor number and DAI scores, inflammation, and increasing body weight of mice. Besides, EA increased the expression of SIRT1 and autophagy. Further experiments showed that SIRT1 overexpression downregulated miR-215, and promoted the expression of Atg14, whereas SIRT1 knockdown induced opposite results. In conclusion, EA can ameliorate AOM/DSS-induced CRC through regulating the SIRT1-mediated miR-215/Atg14 axis by suppressing inflammation and promoting autophagy in mice. These findings reveal a potential molecular mechanism underlying the anti-CRC effect of EA indicating that EA is a promising therapeutic candidate for CRC.
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Neoplasias Colorretais , Eletroacupuntura , MicroRNAs , Camundongos , Animais , Neoplasias Colorretais/terapia , Neoplasias Colorretais/tratamento farmacológico , Eletroacupuntura/efeitos adversos , Sirtuína 1/genética , Inflamação/complicações , MicroRNAs/genética , MicroRNAs/uso terapêutico , Autofagia , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
Central nervous system (CNS) disorders exhibit complex neurophysiological and pathological mechanisms, which seriously affect the quality of life in patients. Acupuncture, widely accepted as complementary and alternative medicine, has been proven to exert significant therapeutic effects on CNS diseases. As a part of the innate immune system, NLRP3 inflammasome contributes to the pathogenesis of CNS diseases via regulating neuroinflammation. To further explore the mechanisms of acupuncture regulating NLRP3 inflammasome in CNS diseases, our study focused on the effects of acupuncture on neuroinflammation and the NLRP3 inflammasome in vascular dementia, Alzheimer's disease, stroke, depression, and spinal cord injury. This study confirmed that the activation of NLRP3 inflammasome promotes the development of CNS diseases, and inhibiting the activation of NLRP3 inflammasome is a potential key target for the treatment of CNS diseases. In addition, it is concluded that acupuncture alleviates neuroinflammation by inhibiting the activation of the NLRP3 inflammasome pathway, thereby improving the progression of CNS diseases, which provides a theoretical basis for acupuncture to attenuate neuroinflammation and improve CNS diseases.
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To study the variation in concentration and source analysis of metal elements during COVID-19 control in Suzhou, a multi-metal online monitor was used to determine hourly online data of 14 metal elements from December 1, 2019 to March 31, 2020. This study analyzed variation in concentration and source analysis of metal elements using a PMF model before, during, and after shutdown during COVID-19 control. The results showed that the concentrations of Cr, Mn, Zn, and Fe during shutdown decreased the most, by 87.6%, 85.6%, 78.3%, and 72.2%, respectively, compared with those before shutdown. The concentrations of Mn, Cr, Zn, and Fe after shutdown increased the most, by 227.0%, 215.4%, 147.4%, and 113.4%, respectively, compared with those of the previous stage. The diurnal variation in K differed at three stages. Zn showed a single peak shape at three stages, but the peak width and peak time were different. Unlike the concentrations, the diurnal variations in Fe, Mn, Pb, Se, and Hg were not significantly changed. The daily variation characteristics of Ca, Ba, Cu, As, Cr, and Ni during and after shutdown were significantly different from those before shutdown. The results of source analysis by the PMF model showed that metal elements mainly came from dust, motor vehicle, coal burning, industrial smelting, and mixed-combustion sources. Among them, the concentration of industrial smelting sources changed greatly, with the concentration decreasing by 89.0% during shutdown and increasing by 358.0% after shutdown.
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Poluentes Atmosféricos , COVID-19 , Poluentes Atmosféricos/análise , COVID-19/epidemiologia , COVID-19/prevenção & controle , Poeira/análise , Monitoramento Ambiental , Humanos , Metais , Material Particulado/análiseRESUMO
Acupuncture is a common complementary and alternative therapy around the world, but its mechanism remains still unclear. In the past decade, some studies indicated that transient receptor potential vanilloid (TRPV) channels play a great role in the response of acupuncture stimulation. In this article, we discussed the relationship between acupuncture and TRPV channels. Different from inhibitors and agonists, the regulation of acupuncture on TRPV channels is multi-targeted and biphasic control. Acupuncture stimulation shows significant modulation on TRPV1 and TRPV4 at the autonomic nervous system (ANS) including central and peripheral nervous systems. On the contrary, the abundant expression and functional participation of TRPV1 and TRPV4 were specific to acupuncture stimulation at acupoints. The enhancement or inhibition of TRPV channels at different anatomical levels will affect the therapeutic effect of acupuncture. In conclusion, TRPV channels help to understand the principle of acupuncture stimulation, and acupuncture also provides a potential approach to TRPV-related trials.
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To investigate the effect of electroacupuncture (EA) on acute lung injury (ALI), a lipopolysaccharide (LPS) induced ALI mouse model was used in this study. Before receiving intratracheal LPS instillation, mice were given EA at ST36 for 7 days as a long-term treatment or one time as a short-term treatment. Lung histopathological examination, lung injury scores, lung wet/dry (W/D) ratio, and inflammatory cytokines included proinflammation factors such as TNF-α, IL-1ß, and IL-6 and anti-inflammation factors such as IL-4 and IL-10 in serum and bronchoalveolar lavage fluid (BALF) were detected at the end of experiment. The results show that EA pretreatment ameliorated the lung damage and inflammatory response by LPS. In addition, we found that SIRT1 and its deacetylation of NF-κB were promoted after EA pretreatment in lung tissues. Meanwhile, the expression of angiotensin-converting enzyme 2 (ACE2) is also enhanced by EA pretreatment. Thus, the present findings suggest that EA could be a potential therapy of ALI.
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Colorectal cancer (CRC) is one of the most pervasive cancers in the human disease spectrum worldwide, ranked the second most common cause of cancer death by the end of 2020. Prunus mume (PM) is an essential traditional Chinese medicine for the adjuvant treatment of solid tumors, including CRC. In the current study, we utilize means of network pharmacology, molecular docking, and multilayer experimental verification to research mechanism. The five bioactive compounds and a total of eight critical differentially expressed genes are screened out using the bioinformatics approaches of Cytoscape software, String database, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathways, and molecular docking. RelA has been proven to be highly expressed in CRC. Experiments in vitro have shown that kaempferol, the main active component of PM, dramatically inhibited the growth, migration, and invasion of CRC cells, and experiments in vivo have shown that PM effectively delays CRC formation and improves the survival cycle of mice. Further analysis shows that PM inhibits the CRC progression by down-regulating the expression level of RelA, Bax, caspase 3, caspase 9, and EGFR in CRC. PM and its extract are potentially effective therapeutics for the treatment of CRC via the RelA/nuclear factor κB signaling pathway.
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OBJECTIVE: To observe the effect of electroacupuncture (EA) on tumor number, body conditions, inflammatory factors and expression levels of silent information regulator 1 (sirtuin 1, SIRT1) and autophagy-related proteins Beclin-1, P62, and LC3 in colorectal tissues in inflammatory-transformed colorectal cancer mice, so as to explore its underlying mechanisms in resisting tumor growth. METHODS: A total of 100 C57BL/6 male mice were randomly divided into normal control, model, EA, EA + SIRT1 inhibitor (EA+inhibitor) and agonist resveratrol (agonist) groups, with 20 mice in each group. EA (2 Hz, 1 mA) was applied to "Zusanli"(ST36)and "Fenglong"(ST40) for 20 min every time, 3 times a week for 11 weeks. Mice of the EA +inhibitor group received intraperitoneal injection of SIRT1 inhibitor EX527 (5 mg/kg) at the same time of EA treatment, and those of the agonist group received gavage of resveratrol (200 mg/kg, an agonist of SIRT1), 3 times a week for 11 weeks. The body mass was measured weekly. The disease activity index (DAI), colorectal length and tumor number in each group were recorded. The histopathological changes of colorectal tissues were observed by H.E. staining; the contents of interleukin 6 (IL-6), IL-10, IL-17, in the colorectal tissues were detected by enzyme-linked immunosorbent assay, and the expression levels of SITR1, Beclin-1, P62, and LC3 in colorectal tissues were detected by Western blot and real-time fluorescence quantitative PCR, respectively. RESULTS: Compared with the normal control group, the body weight, length of colorectum, the contents of IL-10, and the expression levels of SIRT1,Beclin-1 and LC3 mRNAs and proteins were significantly decreased (P<0.001), whereas the DAI score, the number of tumors, the contents of IL-6 and IL-17, and the expression levels of P62 mRNA and protein were significantly increased (P<0.000 1, P<0.001) in the model group. In comparison with the model group, the body weight, the length of colorectum, the contents of IL-10, and the expression levels of SIRT1,Beclin-1 and LC3 mRNAs and proteins were significantly increased (P<0.01,P<0.05,P<0.001), while the DAI scores, the numbers of tumors, the contents of IL-6 and IL-17, and the expression levels of P62 mRNA and protein were obviously decreased in the EA and agonist groups (P<0.01,P<0.05, P<0.001). No significant changes were found in all the above-mentioned indexes in the EA+inhibitor group in comparison with the model group (P>0.05). CONCLUSION: EA can reduce the number of tumors and inflammation reaction in colorectal tissue and improve the body condition in mice with colorectal cancer, which may be related to its functions in activating the expression of intestinal SIRT1, and then facilitating cellular autophagy.
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Neoplasias Colorretais , Eletroacupuntura , Pontos de Acupuntura , Animais , Autofagia/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Inflamação/genética , Inflamação/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sirtuína 1/genéticaRESUMO
INTRODUCTION: Endothelial nitric oxide synthase (eNOS) polymorphisms might influence predisposition to hemorrhagic cerebral vascular diseases, but the results of already published studies regarding relationship between eNOS polymorphisms and hemorrhagic cerebral vascular diseases were still controversial. METHODS: The authors performed this meta-analysis to estimate relationship between eNOS polymorphisms and hemorrhagic cerebral vascular diseases in a larger pooled population by combing the results of already published related studies. The authors searched Pubmed, Embase, Web of Science, and CNKI for already published studies. RESULTS: Eighteen already published studies were pooled analyzed in this meta-analysis. The pooled meta-analyses results showed that eNOS rs2070744 polymorphism was significantly associated with predisposition to hemorrhagic cerebral vascular diseases in East Asians (dominant comparison: OR = 0.77, p = .01; overdominant comparison: OR = 1.24, p = .04; allele comparison: OR = 0.78, p = .006) Nevertheless, the pooled meta-analyses did not reveal any positive results for eNOS rs1799983 and rs869109213 polymorphisms. CONCLUSIONS: This meta-analysis suggested that eNOS rs2070744 polymorphism, but not rs1799983 and rs869109213 polymorphisms, might influence predisposition to hemorrhagic cerebral vascular diseases in East Asians.
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Transtornos Cerebrovasculares , Óxido Nítrico Sintase Tipo III , Povo Asiático/genética , Predisposição Genética para Doença , Humanos , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo Genético , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Lycorine is a powerful anti-cancer agent against various cancer cell lines with minor side effects. However, the detailed mechanisms of its effects in colorectal cancer (CRC) remain unclear. In this study, we investigated the function and mechanism of lycorine against CRC both in vitro and in vivo. Molecular docking modeling was used to identify potential inhibitory targets of lycorine in CRC. Cell viability was measured using the Cell Counting Kit-8 assay, and apoptosis was measured using flow cytometry. Autophagosomes were examined using transmission electron microscopy and confocal microscopy. HCT116-derived xenografts were constructed to analyze the effect of lycorine in CRC in vivo. Using the CDOCKER algorithm, we determined that lycorine has four interactions with the conserved domain of mitogen-activated protein kinase kinase 2 (MEK2). This prediction was further confirmed by the degradation of phosphorylated MEK2 and its downstream targets after lycorine treatment, and MEK2 overexpression abolished lycorine-induced autophagy-associated apoptosis. Additionally, we revealed that the combination of vemurafenib and lycorine had better effects in CRC models in vitro and in vivo than monotherapy. Our findings identified lycorine as an effective MEK2 inhibitor and suggested that the combination of lycorine and vemurafenib could be used to treat CRC.