RESUMO
The prevalence of different metabolic syndromes has grown globally, and the farnesoid X receptor (FXR), a metabolic homeostat for glucose, lipid, and bile acid metabolisms, may serve an important role in the progression of metabolic disorders. Glucose intolerance by FXR deficiency was previously reported and observed in our study, but the underlying biology remained unclear. To investigate the ambiguity, we collected the nontargeted profiles of the fecal metaproteome, serum metabolome, and liver proteome in Fxr-null (Fxr-/-) and wild-type (WT) mice with LC-HRMS. FXR deficiency showed a global impact on the different molecular levels we monitored, suggesting its serious disruption in the gut microbiota, hepatic metabolism, and circulating biomolecules. The network and enrichment analyses of the dysregulated metabolites and proteins suggested the perturbation of carbohydrate and lipid metabolism by FXR deficiency. Fxr-/- mice presented lower levels of hepatic proteins involved in glycogenesis. The impairment of glycogenesis by an FXR deficiency may leave glucose to accumulate in the circulation, which may deteriorate glucose tolerance. Lipid metabolism was dysregulated by FXR deficiency in a structural-dependent manner. Fatty acid ß-oxidations were alleviated, but cholesterol metabolism was promoted by an FXR deficiency. Together, we explored the molecular events associated with glucose intolerance by impaired FXR with integrated novel multiomic data.
Assuntos
Intolerância à Glucose , Metabolismo dos Lipídeos , Fígado , Camundongos Knockout , Multiômica , Receptores Citoplasmáticos e Nucleares , Animais , Masculino , Camundongos , Fezes/química , Microbioma Gastrointestinal , Glucose/metabolismo , Intolerância à Glucose/metabolismo , Intolerância à Glucose/sangue , Intolerância à Glucose/genética , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Metaboloma , Multiômica/métodos , Proteoma/metabolismo , Proteômica/métodos , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/deficiênciaRESUMO
Glyphosate is a widely used active ingredient in agricultural herbicides, inhibiting the biosynthesis of aromatic amino acids in plants by targeting their shikimate pathway. Our gut microbiota also facilitates the shikimate pathway, making it a vulnerable target when encountering glyphosate. Dysbiosis in the gut microbiota may impair the gut-brain axis, bringing neurological outcomes. To evaluate the neurotoxicity and biochemical changes attributed to glyphosate, we exposed mice with the reference dose (RfD) set by the U.S. EPA (1.75 mg/Kg-BW/day) and its hundred-time-equivalence (175 mg/Kg-BW/day) chronically via drinking water, then compared a series of neurobehaviors and their fecal/serum metabolomic profile against the non-exposed vehicles (n = 10/dosing group). There was little alteration in the neurobehavior, including motor activities, social approach, and conditioned fear, under glyphosate exposure. Metabolomic differences attributed to glyphosate were observed in the feces, corresponding to 68 and 29 identified metabolites with dysregulation in the higher and lower dose groups, respectively, compared to the vehicle-control. There were less alterations observed in the serum metabolome. Under 175 mg/Kg-BW/day of glyphosate exposure, the aromatic amino acids (phenylalanine, tryptophan, and tyrosine) were reduced in the feces but not in the serum of mice. We further focused on how tryptophan metabolism was dysregulated based on the pathway analysis, and identified the indole-derivatives were more altered compared to the serotonin and kynurenine derivatives. Together, we obtained a three-dimensional data set that records neurobehavioral, fecal metabolic, and serum biomolecular dynamics caused by glyphosate exposure at two different doses. Our data showed that even under the high dose of glyphosate irrelevant to human exposure, there were little evidence that supported the impairment of the gut-brain axis.
Assuntos
Glifosato , Herbicidas , Humanos , Camundongos , Animais , Glicina/toxicidade , Triptofano , Ácido Chiquímico/metabolismo , Herbicidas/toxicidade , Aminoácidos AromáticosRESUMO
Microplastics and organic micropollutants are two emerging contaminants that interact with each other in environmental and engineered systems. Sorption of organic micropollutants, such as pharmaceuticals, pesticides and industrial compounds, to microplastics can modify their bioavailability and biodegradation. The present study investigated the capacity of ultra-high density polyethylene particles (125⯵m in diameter), before and after aging, to sorb 21 organic micropollutants at different environmentally relevant concentration. Furthermore, the biodegradation of these organic micropollutants by a biofilm microbial community growing on the microplastic surface was compared with the biodegradation by a microbial community originating from activated sludge. Among all tested organic micropollutants, propranolol (70%), trimethoprim (25%) and sotalol (15%) were sorbed in the presence of polyethylene particles. Growth of a biofilm on the polyethylene particles had a beneficial effect on the sorption of bromoxynil, caffeine and chloridazon and on the biodegradation of irbesartan, atenolol and benzotriazole. On the other hand, the biofilm limited the sorption of trimethoprim, propranolol, sotalol and benzotriazole and the biodegradation of 2,4-D. These results showed that ultra-high density polyethylene particles can affect both in a positive and negative way for the abiotic and biotic removal of organic micropollutants in wastewater. This project highlights the need for further investigation regarding the interaction between microplastics and organic micropollutants in the aquatic environment.
Assuntos
Biodegradação Ambiental , Biofilmes , Microplásticos , Polietileno , Propranolol , Poluentes Químicos da Água , Poluentes Químicos da Água/análise , Polietileno/química , Adsorção , Trimetoprima , Atenolol , Triazóis/química , Esgotos/química , Esgotos/microbiologiaRESUMO
INTRODUCTION: There are some problems in the quality control of Epimedii Folium (leaves of Epimedium brevicornum Maxim.), such as the mixed use of Epimedii Folium from different harvesting periods and regions, incomplete quality evaluation, and time-consuming analysis methods. OBJECTIVE: Near-infrared (NIR) spectroscopy was conducted to establish a rapid overall quality evaluation method for Epimedii Folium. MATERIALS AND METHODS: Quantitative models of the total solid, moisture, total flavonoid, and flavonol glycoside (Epimedin A, Epimedin B, Epimedin C, Icariin) contents of Epimedii Folium were established by partial least squares regression (PLSR). The root mean square error (RMSE) and correlation coefficient (R) were used to evaluate the performance of models. The qualitative models of Epimedii Folium from different geographic origins and harvest periods were established based on K-nearest neighbor (KNN), back-propagation neural network (BPNN), and random forest (RF). Accuracy and Kappa values were used to evaluate the performance of models. A new multivariable signal conversion strategy was proposed, which combines NIR spectroscopy with the PLSR model to predict the absorbance values of retention time points in the high-performance liquid chromatography (HPLC) fingerprint to obtain the predicted HPLC fingerprint. The Pearson correlation coefficient and cosine coefficient were used to evaluate the similarity between real and predicted HPLC fingerprints. RESULTS: Qualitative models, quantitative models, and the similarity between real and predicted HPLC fingerprints are satisfactory. CONCLUSION: The method serves as a fast and green analytical quality evaluation method of Epimedii Folium and can replace traditional methods to achieve the overall quality evaluation of Epimedii Folium.
Assuntos
Quimiometria , Epimedium , Flavonoides , Espectroscopia de Luz Próxima ao Infravermelho , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Epimedium/química , Flavonoides/análise , Análise dos Mínimos Quadrados , Quimiometria/métodos , Folhas de Planta/química , Controle de Qualidade , Cromatografia Líquida de Alta Pressão/métodosRESUMO
Developing clinically meaningful nanomedicines for cancer therapy requires the drugs to be effective, safe, simple, cheap, and easy to store. In the present work, we report that a simple cationic Fe(III)-rich salt of [FeIIICl(TMPPH2)][FeIIICl4]2 (Fe-TMPP) exhibits a superior anticancer performance on a broad spectrum of cancer cell lines, including breast, colorectal cancer, liver, pancreatic, prostate, and gastric cancers, with half maximal inhibitory concentration (IC50) values in the range of 0.098-3.97 µM (0.066-2.68 µg mL-1), comparable to the best-reported medicines. Fe-TMPP can form stand-alone nanoparticles in water without the need for extra surface modification or organic-solvent-assisted antisolvent precipitation. Critically, Fe-TMPP is TME-responsive (TME = tumor microenvironment), and can only elicit its function in the TME with overexpressed H2O2, converting H2O2 to the cytotoxic â¢OH to oxidize the phospholipid of the cancer cell membrane, causing ferroptosis, a programmed cell death process of cancer cells.
Assuntos
Antineoplásicos , Ferroptose , Nanomedicina , Humanos , Ferroptose/efeitos dos fármacos , Linhagem Celular Tumoral , Nanomedicina/métodos , Antineoplásicos/farmacologia , Antineoplásicos/química , Nanopartículas/química , Compostos Férricos/química , Microambiente Tumoral/efeitos dos fármacos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/patologiaRESUMO
BACKGROUND: As the incidence of colorectal cancer tends to be younger, early-onset colorectal cancer (EOCRC) has attracted more attention in recent years. We aimed to assess the optimal lymph node staging system among EOCRC patients, and then, establish informative assessment models for prognosis prediction. METHODS: Data of EOCRC were retrieved from the Surveillance, Epidemiology, and End Results database. Survival prediction ability of three lymph node staging systems including N stage of the tumor node metastasis (TNM) staging system, lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) was assessed and compared using Akaike information criterion (AIC), Harrell's concordance index (C-index), and likelihood ratio (LR) test. Univariate and multivariate Cox regression analyses were conducted to identify the prognostic predictors for overall survival (OS) and cancer-specific survival (CSS). Effectiveness of the model was demonstrated by receiver operative curve and decision curve analysis. RESULTS: A total of 17,535 cases were finally included in this study. All three lymph node staging systems showed significant performance in survival prediction (p < 0.001). Comparatively, LODDS presented a better ability of prognosis prediction with lower AIC (OS: 70,510.99; CSS: 60,925.34), higher C-index (OS: 0.6617; CSS: 0.6799), and higher LR test score (OS: 998.65; CSS: 1103.09). Based on independent factors identified from Cox regression analysis, OS and CSS nomograms for EOCRC were established and validated. CONCLUSIONS: LODDS shows better predictive performance than N stage or LNR among patients with EOCRC. Novel validated nomograms based on LODDS could effectively provide more prognostic information than the TNM staging system.
Assuntos
Neoplasias Colorretais , Segunda Neoplasia Primária , Humanos , Prognóstico , Nomogramas , LinfonodosRESUMO
Near-infrared (NIR) phosphors with high thermal stability are significant for NIR light-emitting diodes (LEDs). For a decade, Debye temperature has been a successful indicator of structural rigidity and thermal stability for phosphors, but some exceptions exist due to its dependence on atomic mass. Inspired by the Debye temperature model that relates the elastic properties of solids, our density functional theory calculations revealed that the Vickers hardness of Cr3+-doped NIR phosphors was negatively correlated with Stokes shifts (Pearson's R = -0.81) and positively correlated with thermal stabilities (Pearson's R = 0.85) within a set of 13 distinct material types. Highlighting the predictive power of Vickers hardness, two new NIR phosphors were investigated: KMg(PO3)3:Cr3+ showed low thermal stability, correlating with its lower Vickers hardness, in contrast to the high thermal stability and correspondingly higher Vickers hardness of La2MgSnO6:Cr3+. Vickers hardness can be used to screen potential hosts for Cr3+-doped NIR phosphors with high thermal stabilities, due to the advantages of the predictable feature by density functional theory calculation and low independence on atomic mass.
RESUMO
Ischemic stroke is one of the leading causes of death and disability worldwide. The severe sequelae caused by ischemic thrombolysis and the narrow time window are now the main clinical challenges. Our previous study has reported 4-Trifluoromethyl-(E)-cinnamoyl]-L-4-F-phenylalanine Acid (AE-18) was a promising candidate for Parkinson's Disease. In this study, the preventive and therapeutic effects of AE-18 on focal cerebral ischemia-reperfusion injury and the mechanisms are explored. In oxygen glucose deprivation/reoxygenation (OGD/R)-induced well-differentiated PC12 cells model, AE-18 (10 or 20 µM) can significantly reduce nerve damage when administered before or after molding. In middle cerebral artery occlusion-reperfusion (MCAO/R) rat model, pre-modelling, or post-modelling administration of AE-18 (5 or 10 mg/kg) was effective in reducing neurological damage, decreasing infarct volume and improving motor disturbances. In addition, AE-18 (5 mg/kg) given by intravenous injection immediately after occlusion significantly reduce the infarct volume caused by reperfusion for different durations, indicating that AE-18 could extend the time window of thrombolytic therapy. Further studies demonstrate that AE-18 exerts the effects in the prevention, treatment, and prolongation of the time window of cerebral ischemic injury mainly through inhibiting excitotoxicity and improving BBB permeability, VEGF and BDNF. These results suggest that AE-18 is a good candidate for the treatment of ischemic stroke.
Assuntos
Isquemia Encefálica , AVC Isquêmico , Fármacos Neuroprotetores , Fenilalanina , Traumatismo por Reperfusão , Animais , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Isquemia/complicações , Fármacos Neuroprotetores/uso terapêutico , Fenilalanina/farmacologia , Fenilalanina/uso terapêutico , Ratos , Reperfusão/efeitos adversos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controleRESUMO
Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90-Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a-2d, 3a-3g, and 4a-4t, were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f, with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC50 = 1.9 µM), and antiproliferative activity against MDA-MB-231 cells (IC50 = 0.2 µM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Chaperoninas/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Triterpenos Pentacíclicos/farmacologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-ZebraRESUMO
Celastrol, a friedelane-type triterpenoid isolated from the genus Triperygium, possesses antitumor, anti-inflammatory, and immunosuppressive activities. A total of 42 celastrol derivatives (1a-1t, 2a-2l, and 3a-3j) were synthesized and evaluated for their immunosuppressive activities. Compounds 2a-2e showed immunosuppressive effects, with IC50 values ranging from 25 to 83 nM, and weak cytotoxicity (CC50 > 1 µM). Compound 2a, with a selectivity index value 31 times higher than that of celastrol, was selected as a lead compound. Further research showed that 2a exerted its immunosuppressive effects by inducing apoptosis and inhibiting cytokine secretion via Lck- and ZAP-70-mediated signaling pathways.
Assuntos
Imunossupressores/síntese química , Imunossupressores/farmacologia , Triterpenos Pentacíclicos/síntese química , Triterpenos Pentacíclicos/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Proteína-Tirosina Quinase ZAP-70/efeitos dos fármacosRESUMO
Previous studies have shown that κ-opioid receptor activation possesses cardioprotection against myocardial ischemia and reperfusion (MI/R) injury. The current study was designed to investigate whether mitochondrial dysfunction after MI/R is regulated by the κ-opioid receptor and to further explore the underlying mechanisms involved. MI/R rat model was established in vivo, and a hypoxia and reoxygenation cardiomyocytes model was used in vitro. Mitochondrial morphology and function as well as myocardial apoptosis were determined. Our data indicated that treatment with U50,488H (a selective κ-opioid receptor agonist) not only reduced apoptosis but also significantly improved mitochondrial morphology and function. These effects were blocked by nor-binaltorphimine (nor-BNI, a selective κ-opioid receptor antagonist), Compound C (an AMPK inhibitor), and AR-A014418 (a GSK3ß inhibitor). Moreover, in cardiomyocytes, treatment with U50,488H significantly increased the expression in phosphorylation of AMPK and the phosphorylation of GSK3ß. Treatment of cardiomyocytes with AMPKα siRNA decreased the phosphorylation of AMPK and GSK3ß. Moreover, AMPK activation resulted in the phosphorylation of GSK3ß. Our findings suggested that U50,488H exerted cardioprotective effects by improving mitochondrial morphology and function against MI/R injury through activation of the κ-opioid receptor-mediated AMPK/GSK3ß pathway.
Assuntos
(trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Receptores Opioides kappa/agonistas , Proteínas Quinases Ativadas por AMP/genética , Animais , Linhagem Celular , Modelos Animais de Doenças , Masculino , Mitocôndrias Cardíacas/enzimologia , Mitocôndrias Cardíacas/ultraestrutura , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/ultraestrutura , Fosforilação , Ratos Sprague-Dawley , Receptores Opioides kappa/metabolismo , Transdução de SinaisRESUMO
Cynaroside is a flavonoid compound proved to possess antioxidant activity, but its protective effect on age-related macular degeneration still remains unclear. In this study, the protective effects of cynaroside on oxidative stress and apoptosis in retinal pigment epithelial (RPE) cells induced by hydrogen peroxide (H2 O2 ) were investigated. Results showed that cynaroside effectively attenuated the decrease of cell activity induced by H2 O2 . The total reactive oxygen species can be remitted by decreasing malondialdehyde level, as well as increasing glutathione level, and superoxide dismutase and catalase activities. In addition, Western blot analysis indicated that cynaroside protected ARPE-19 cells from apoptosis through downregulation of caspase-3 protein activation which was controlled by the upstream proteins Bcl-2 and Bax. It was finally proved that cynaroside could enhance the antioxidant and antiapoptotic ability in ARPE-19 cells by promoting the expression of p-Akt.
Assuntos
Glucosídeos/farmacologia , Luteolina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Apoptose , Catalase/metabolismo , Linhagem Celular , Ativação Enzimática , Glutationa/metabolismo , Humanos , Malondialdeído/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/enzimologia , Epitélio Pigmentado da Retina/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Five new phloroglucinol derivatives, eucalyptins C-G (1-5), together with 13 known analogues (6-18) were isolated from the fruits of Eucalyptus globulus. The structures and absolute configurations of 1-5 were established by means of spectroscopic data analysis, computational calculation methods, and single-crystal X-ray diffraction. Compounds 1-18 were investigated for their immunosuppressive effects in vitro, and 1, 2, 6, and 7 displayed moderate inhibitory activities with IC50 values of 11.8, 10.2, 18.2, and 19.1 µM, respectively. The stimulation index (SI) of 1 was 64.2 and was compared to that of cyclosporine A (SI = 149.57). Further study demonstrated that 1 exhibited an immunosuppressive effect through inducing apoptosis and inhibiting cytokine secretion.
Assuntos
Eucalyptus/química , Imunossupressores/farmacologia , Floroglucinol/farmacologia , Animais , Células Cultivadas , Cristalografia por Raios X , Citocinas/metabolismo , Humanos , Imunossupressores/química , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Floroglucinol/químicaRESUMO
Abrus pulchellus subsp. mollis (Hance) Verdc. (Leguminosae) is a well-known edible plant usually added to soups and beverages. In this study, vicenin-2 (1: ), isoschaftoside (2: ), schaftoside (3: ), and their enrichment fraction, total flavonoid C-glycosides, derived from the extracts of A. mollis, were firstly found to prevent nonalcoholic fatty liver disease both in vitro and in vivo. In the in vitro study, total flavonoid C-glycosides decreased the lipid accumulation in oleic acid-treated HepG2 cells. The mechanisms of total flavonoid C-glycosides are involved in the regulation of peroxisome proliferator-activated receptor α and its downstream, and the reduction of proinflammatory cytokines. In high-fat diet-induced fatty liver rats, total flavonoid C-glycosides decreased the levels of glutamic-oxalacetic transaminease and glutamic-pyruvic transaminase, and decreased the lipid accumulation both in the liver and blood without affecting food intake. In addition, total flavonoid C-glycosides also increased the activities of the antioxidant enzyme system in vivo. In conclusion, total flavonoid C-glycosides are active components of A. mollis on nonalcoholic fatty liver disease, and can be used in functional food and supplements for nonalcoholic fatty liver disease prevention and treatment.
Assuntos
Abrus/química , Glicosídeos/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , PPAR alfa/metabolismo , Fitoterapia , Extratos Vegetais/uso terapêutico , Animais , Dieta , Glicosídeos/química , Glicosídeos/isolamento & purificação , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Células RAW 264.7 , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Myocardial contractile dysfunction is associated with an increase in mitochondrial fission in patients with diabetes. However, whether mitochondrial fission directly promotes diabetes-induced cardiac dysfunction is still unknown. Melatonin exerts a substantial influence on the regulation of mitochondrial fission/fusion. This study investigated whether melatonin protects against diabetes-induced cardiac dysfunction via regulation of mitochondrial fission/fusion and explored its underlying mechanisms. Here, we show that melatonin prevented diabetes-induced cardiac dysfunction by inhibiting dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Melatonin treatment decreased Drp1 expression, inhibited mitochondrial fragmentation, suppressed oxidative stress, reduced cardiomyocyte apoptosis, improved mitochondrial function and cardiac function in streptozotocin (STZ)-induced diabetic mice, but not in SIRT1-/- diabetic mice. In high glucose-exposed H9c2 cells, melatonin treatment increased the expression of SIRT1 and PGC-1α and inhibited Drp1-mediated mitochondrial fission and mitochondria-derived superoxide production. In contrast, SIRT1 or PGC-1α siRNA knockdown blunted the inhibitory effects of melatonin on Drp1 expression and mitochondrial fission. These data indicated that melatonin exerted its cardioprotective effects by reducing Drp1-mediated mitochondrial fission in a SIRT1/PGC-1α-dependent manner. Moreover, chromatin immunoprecipitation analysis revealed that PGC-1α directly regulated the expression of Drp1 by binding to its promoter. Inhibition of mitochondrial fission with Drp1 inhibitor mdivi-1 suppressed oxidative stress, alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. These findings show that melatonin attenuates the development of diabetes-induced cardiac dysfunction by preventing mitochondrial fission through SIRT1-PGC1α pathway, which negatively regulates the expression of Drp1 directly. Inhibition of mitochondrial fission may be a potential target for delaying cardiac complications in patients with diabetes.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Dinaminas/metabolismo , Melatonina/farmacocinética , Mitocôndrias Cardíacas/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Dinaminas/genética , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/patologia , Dinâmica Mitocondrial/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Transdução de Sinais/genética , Sirtuína 1/genéticaRESUMO
BACKGROUND: Pioglitazone (PIO), a thiazolidinediones drug, is a well-known anti-diabetic medicine, but its anti-atherosclerotic effects remain controversial. Thus it is important to investigate the effects of PIO on atherogenesis and the relevant mechanisms. METHODS: For in vitro studies, primary cultured or AMP-activated protein kinase (AMPK) inhibited splenocytes were treated with oxidized low density lipoprotein (ox-LDL) or ox-LDL plus PIO. Percentage of T helper 17 (Th17) and regulatory T (Treg) cells were determined by flow cytometry. Expression of AMPK, interleukin-17 (IL-17) and forkhead box P3 (FoxP3) were detected by Western blots. For in vivo studies, apolipoprotein E-deficient (apoE-/-) mice fed with western diet were treated with PIO or vehicle for 8 weeks respectively. Percentage of Th17 and Treg cells in spleen were measured by immunohistochemical analysis. The atherosclerotic lesions were analyzed using oil red O staining, and collagen types I and III in atherosclerotic lesions were stained by Sirius red. Expression of IL-17 and FoxP3 were determined by quantitative polymerase chain reaction. RESULTS: In cultured primary splenocytes, PIO dramatically inhibited Th17 and raised Treg. Intriguingly, pharmacological and genetic AMPK inhibitions abolished PIO-induced Treg elevation and Th17 inhibition. Moreover, PIO significantly induced AMPK phosphorylation, decreased IL-17+ and increased FoxP3+ cells in spleen of apoE-/- mice. Finally, PIO did not alter plaque area, but intriguingly, stabilized atherosclerotic plaque through collagen induction in apoE-/- mice. PIO treatment also improved Th17/Treg balance in atherosclerotic lesions. CONCLUSIONS: PIO exhibits anti-atherosclerotic effects for stabilization of atherosclerotic plaque through regulating the Th17/Treg balance in an AMPK-dependent manner.
Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/enzimologia , Proteínas Quinases/biossíntese , Linfócitos T Reguladores/fisiologia , Células Th17/fisiologia , Tiazolidinedionas/uso terapêutico , Quinases Proteína-Quinases Ativadas por AMP , Animais , Aterosclerose/fisiopatologia , Células Cultivadas , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Pioglitazona , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Tiazolidinedionas/farmacologiaAssuntos
Catecóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Tirosina/análogos & derivados , Apoptose/efeitos dos fármacos , Catecóis/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Relação Estrutura-Atividade , Tirosina/síntese química , Tirosina/química , Tirosina/farmacologiaRESUMO
The expression levels and prognostic role of AP3M2 in colorectal adenocarcinoma (CRAC) have yet to be fully unveiled. Our study comprehensively investigated the clinical significance of AP3M2 in colorectal cancer through an extensive bioinformatics data mining process (TCGA, GEO, GEPIA, Timer, Ualcan, ROCPLOT, and David), followed by experimental validation. We found AP3M2 is a cancer gene, which can be used to distinguish between colorectal cancer and colorectal adenomas, liver metastasis, lung metastasis, colorectal polyp. Higher AP3M2 expression levels were associated with longer overall survival in colon adenocarcinoma. AP3M2 might be the primary biomarker for oxaliplatin in colon cancer and an acquired resistance biomarker for oxaliplatin and 5-fu. AP3M2 was positively associated with CD274, CTLA4. AP3M2 might be associated with T-cell, NF-kappaB transcription factor activity, and response to hypoxia. AP3M2 could predict chemotherapy effectiveness and prognosis for colon cancer patients. AP3M2 might inhibit tumor growth via influencing tumor-infiltrating immune cells in the context of Tumor microenvironment. AP3M2 plays as an oncogene in CRAC and is suggested as a new potential biotarget for therapy.
Assuntos
Adenocarcinoma , Neoplasias do Colo , Neoplasias Colorretais , Humanos , Neoplasias do Colo/genética , Prognóstico , Complexo 3 de Proteínas Adaptadoras , Oxaliplatina , Neoplasias Colorretais/genética , Oligonucleotídeos , Microambiente Tumoral/genéticaRESUMO
The cerebral cortex is a pivotal structure integral to advanced brain functions within the mammalian central nervous system. DNA methylation and hydroxymethylation play important roles in regulating cerebral cortex development. However, it remains unclear whether abnormal cerebral cortex development, such as microcephaly, could rescale the epigenetic landscape, potentially contributing to dysregulated gene expression during brain development. In this study, we characterize and compare the DNA methylome/hydroxymethylome and transcriptome profiles of the cerebral cortex across several developmental stages in wild-type (WT) mice and Mcph1 knockout (Mcph1-del) mice with severe microcephaly. Intriguingly, we discover a global reduction of 5'-hydroxymethylcytosine (5hmC) level, primarily in TET1-binding regions, in Mcph1-del mice compared to WT mice during juvenile and adult stages. Notably, genes exhibiting diminished 5hmC levels and concurrently decreased expression are essential for neurodevelopment and brain functions. Additionally, genes displaying a delayed accumulation of 5hmC in Mcph1-del mice are significantly associated with the establishment and maintenance of the nervous system during the adult stage. These findings reveal that aberrant cerebral cortex development in the early stages profoundly alters the epigenetic regulation program, which provides unique insights into the molecular mechanisms underpinning diseases related to cerebral cortex development.
RESUMO
OBJECTIVE: The purpose of this study was to evaluate the effectiveness of Governor vessel acupuncture (GV Ac) in treating post-stroke cognitive impairment (PSCI). METHODS: There was a total of seven databases examined. Four English databases (Cochrane Library, PubMed, Embase, and Medline) and three Chinese databases (Chinese National Knowledge Infrastructure (CNKI), Chinese Science and Technology Periodical Databases (VIP), and Wan Fang Database) contain all randomized controlled trials (RCTs) comparing Governor vessel acupuncture to other treatments or none acupuncture for PSCI. The exact dates for the search period are from January 1, 2000, to January 1, 2023.Two researchers independently reviewed the literature, gathered RCT data, and performed statistical analysis. All data were analyzed using Review Manager software (Rev Man) 5.3. RESULTS: This meta-analysis includes a total of 39 trials with 2044 patients. There were 1022 participants in each of the test and control groups. Following 12-120 days of acupuncture treatment, a meta-analysis revealed that the treatment groups (GV Ac combined with conventional treatment groups) significantly increased their scores on the Curative ratio (OR = 3.00, 95â¯%CI = 2.37-3.79, P = 0.98, I² = 0â¯%), Montreal Cognitive Assessment (MoCA)(MD = 1.82, 95â¯%CI = 1.60-2.03, P = 0.11, I² = 25â¯%), Mini-Mental State Examination (MMSE)(MD = 2.18, 95â¯%CI = 1.64-2.72, P<0.005, I² = 92â¯%), and Activity of Daily Living (ADL)(MD = 5.99, 95â¯%CI = 5.33-6.64, P = 0.19, I² = 26â¯%). CONCLUSION: The results suggested that acupuncture on points of the Governor vessel enhanced cognitive function in stroke survivors.