RESUMEN
Regulatory T cells (Tregs) are essential to the negative regulation of the immune system, as they avoid excessive inflammation and mediate tumor development. The abundance of Tregs in tumor tissues suggests that Tregs may be eliminated or functionally inhibited to stimulate antitumor immunity. However, immunotherapy targeting Tregs has been severely hampered by autoimmune diseases due to the systemic elimination of Tregs. Recently, emerging studies have shown that metabolic regulation can specifically target tumor-infiltrating immune cells, and lipid accumulation in TME is associated with immunosuppression. Nevertheless, how Tregs actively regulate metabolic reprogramming to outcompete effector T cells (Teffs), and how lipid metabolic reprogramming contributes to the immunomodulatory capacity of Tregs have not been fully discussed. This review will discuss the physiological processes by which lipid accumulation confers a metabolic advantage to tumor-infiltrating Tregs (TI-Tregs) and amplifies their immunosuppressive functions. Furthermore, we will provide a summary of the driving effects of various metabolic regulators on the metabolic reprogramming of Tregs. Finally, we propose that targeting the lipid metabolism of TI-Tregs could be efficacious either alone or in conjunction with immune checkpoint therapy.
RESUMEN
OBJECTIVES: This study aimed to assess the level of public trust in general practitioners (GPs) and its association with primary care contract services (PCCS) in China. STUDY DESIGN: Cross-sectional study. METHODS: Between September and December 2021, 4158 residents across eastern, central, and western China completed a structured self-administered questionnaire. Trust was assessed using the Chinese version of Wake Forest Physician Trust Scale. Multivariable linear regression models were established to identify predictors of trust. The effect size of PCCS on trust was estimated by the average treatment effect for the treated (ATT) through propensity score matching. RESULTS: The study participants had a mean Wake Forest Physician Trust Scale score of 36.82 (standard deviation = 5.45). Enrollment with PCCS (ß = 0.14, P < 0.01), Han ethnicity (ß = 0.03, P < 0.05), lower educational attainment (ß = -0.06, P < 0.01), higher individual monthly income (ß = 0.03, P < 0.05), better self-rated health (ß = 0.04, P < 0.05), chronic conditions (ß = 0.07, P < 0.01), and higher familiarity with primary care services (ß = 0.12, P < 0.01) and PCCS (ß = 0.21, P < 0.01) were associated with higher trust in GPs. The ATT of PCCS exceeded 1 (P < 0.05). CONCLUSIONS: PCCS are associated with higher levels of trust in GPs. PCCS may become an effective tool to attract public trust in GPs, although the relationship between the two may be bi-directional.
Asunto(s)
Médicos Generales , Atención Primaria de Salud , Confianza , Humanos , Estudios Transversales , China , Masculino , Femenino , Atención Primaria de Salud/estadística & datos numéricos , Persona de Mediana Edad , Adulto , Médicos Generales/psicología , Médicos Generales/estadística & datos numéricos , Encuestas y Cuestionarios , Relaciones Médico-Paciente , Servicios Contratados , Anciano , Adulto Joven , AdolescenteRESUMEN
Autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD) are caused by the body's immune response to autoantigens. The pathogenesis of autoimmune diseases is unclear. Numerous studies have demonstrated that RNA methylation plays a key role in disease progression, which is essential for post-transcriptional regulation and has gradually become a broad regulatory mechanism that controls gene expression in various physiological processes, including RNA nuclear output, translation, splicing, and noncoding RNA processing. Here, we outline the writers, erasers, and readers of RNA methylation, including N6-methyladenosine (m6A), 2'-O-methylation (Nm), 2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytidine (m5C) and N7-methylguanosine (m7G). As the role of RNA methylation modifications in the immune system and diseases is explained, the potential treatment value of these modifications has also been demonstrated. This review reports the relationship between RNA methylation and autoimmune diseases, highlighting the need for future research into the therapeutic potential of RNA modifications.
Autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD) are caused by the body's immune response to autoantigens. Numerous studies have demonstrated that RNA methylation plays a key role in disease progression, which is essential for post-transcriptional regulation and has gradually become a broad regulatory mechanism that controls gene expression in various physiological processes. Here, we outline the writers, erasers, and readers of RNA methylation, including N6-methyladenosine (m6A), 2'-O-methylation (Nm), 2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytidine (m5C) and N7-methylguanosine (m7G). This review reports the relationship between RNA methylation and autoimmune diseases, highlighting the need for future research into the therapeutic potential of RNA modifications.
RESUMEN
OBJECTIVE: We aimed to understand the current situation and contributory factors associated with professional identity, turnover intention and job burnout among general practitioners (GPs) in eastern, central and western China. METHODS: A total of 3244 GPs from community health service institutions in 12 provinces of China were recruited, from October 2017 to February 2018. Demographic information such as sex, region and mode of employment was sought, and issues regarding job burnout, professional identity and turnover intention of GPs were measured with the corresponding scale, and softwares such as SPSS and AMOS were used. T-test, analysis of variance, and covariance matrix were used for analysis. RESULTS: The average total scores of job burnout, turnover intention and professional identity of GPs in China were 44.12, 15.07 and 51.23, respectively. The results of intermediary effect analysis showed that in the GPs group, there were differences in the distribution of the three indicators. Professional identity had a significant negative effect on job burnout (ß = -0.373), while job burnout had a significant positive effect on turnover intention (ß = 0.528), and job burnout had an indirect effect in the relationship between professional identity and turnover intention. Job burnout played an intermediary role in professional identity and turnover intention. CONCLUSIONS: The turnover intention of GPs in China has improved, but it is still at a high level. Job burnout plays an intermediary role between professional identity and turnover intention.
RESUMEN
Currently, there are several treatments approaches available for lung cancer; however, patients who develop drug resistance or have poor survival rates urgently require new therapeutic strategies for lung cancer. In autophagy, damaged proteins or organelles are enclosed within autophagic vesicles with a bilayer membrane structure and transported to the lysosomes for degradation and recirculation. Autophagy is a crucial pathway involved in the clearance of reactive oxygen species (ROS) and damaged mitochondria. Meanwhile, inhibiting autophagy is a promising strategy for cancer treatment. In this study, we found for the first time that Cinchonine (Cin) can act as an autophagy suppressor and exert anti-tumor effects. Cin significantly inhibited the proliferation, migration, and invasion of cancer cells in vitro and the tumor growth and metastasis in vivo, without obvious toxic effects. We found that Cin suppressed the autophagic process by blocking autophagosome degradation through the inhibition of the maturation of lysosomal hydrolases. Cin-mediated autophagy inhibition resulted in the elevated ROS level and the accumulation of damaged mitochondria, which in turn promoted apoptosis. N-acetylcysteine, a potential ROS scavenger, significantly suppressed Cin-induced apoptosis. Additionally, Cin upregulated programmed death-ligand 1 (PD-L1) expression in lung cancer cells by inhibiting autophagy. Compared with monotherapy and control group, the combined administration of anti-PD-L1 antibody and Cin significantly reduced tumor growth. These results suggest that Cin exerts anti-tumor effects by inhibiting autophagy, and that the combination of Cin and PD-L1 blockade has synergistic anti-tumor effects. The data demonstrates the significant clinical potential of Cin in lung cancer treatment.
Asunto(s)
Autofagia , Neoplasias Pulmonares , Humanos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Pulmonares/patología , Apoptosis , Lisosomas/metabolismo , Inmunoterapia , Línea Celular TumoralRESUMEN
The mixtures of cations and anions used in hybrid halide perovskites for high-performance solar cells often undergo element and phase segregation, which limits device lifetime. We adapted Schelling's model of segregation to study individual cation migration and found that the initial film inhomogeneity accelerates materials degradation. We fabricated perovskite films (FA1-xCsxPbI3; where FA is formamidinium) through the addition of selenophene, which led to homogeneous cation distribution that retarded cation aggregation during materials processing and device operation. The resultant devices achieved enhanced efficiency and retained >91% of their initial efficiency after 3190 hours at the maximum power point under 1 sun illumination. We also observe prolonged operational lifetime in devices with initially homogeneous FACsPb(Br0.13I0.87)3 absorbers.
RESUMEN
Hepatitis B virus (HBV) infection is a public health threat worldwide, and there is no direct treatment yet available. In the event of infection, patients may present liver cirrhosis and cancer, which threaten the patients' health globally, especially in the Asia-Pacific region and China. In 2019, Chinese hepatopathologists updated the 2015 Guidelines for the Prevention and Treatment of Chronic Hepatitis B as the clinical reference. The other versions formulated by the American Association for the Study of Liver Diseases (2018 AASLD guidelines) (AASLD, 2018), European Association for the Study of the Liver (2017 EASL guidelines) (EASL, 2017), and Asian-Pacific Association for the Study of the Liver (2015 APASL guidelines) (APASL, 2015) also provide clinical guidance. However, there are still some issues that need to be addressed. In the present study, the following aspects will be introduced successively: (1) Who should be treated in the general population according to the guidelines; (2) Treatment of specific populations infected with HBV; (3) Controversial issues in clinical practice; (4) Perspective.
RESUMEN
Chronic kidney disease is characterized by the development of renal fibrosis. The basic mechanisms of renal fibrosis have not yet been fully investigated despite significant progress in understanding the etiology of the disease. In this work, the researchers sought to identify potential diagnostic indicators for renal fibrosis. From the GEO database, we were able to acquire two gene expression profiles with publically available data (GSE22459 and GSE76882, respectively) from human renal fibrosis and control samples. 215 renal fibrosis specimens and 124 normal specimens were examined for differentially expressed genes (DEGs). The SVM-RFE and LASSO regression models were used to discover potential markers. CIBERSORT was applied to estimate the combined cohorts' immune cell fraction compositional trends in renal fibrosis. RT-PCR was used to examine the expression of ISG20 in renal fibrosis and healthy samples. In vitro experiments were applied to examine the function of ISG20 knockdown on the progression of renal fibrosis. In this study, we identified 24 DEGs. The result of LASSO and SVM-RFE identified nine critical genes. ROC assays confirmed the diagnostic value of the above nine genes for renal fibrosis. Immune cell infiltration analysis revealed that ISG20 and SERPINA3 were both found to be correlated with T cell follicular helper, neutrophils, T cell CD4 memory activated, eosinophils, T cell CD8, dendritic cell activated, B cell memory, monocytes, macrophage M2, plasma cells, T cell CD4 naïve, mast cell resting, B cell naïve, T cell regulatory, and NK cell activated. Finally, we observed that the expression of ISG20 and SERPINA3 was distinctly increased in renal fibrosis samples compared with normal samples. ISG20 siRNA significantly suppressed the progression of renal fibrosis in vitro. Overall, this study identified nine diagnostic biomarkers for renal fibrosis. ISG20 may be a novel therapeutic target of renal fibrosis.
Asunto(s)
Enfermedades Renales , Bases de Datos Factuales , Femenino , Fibrosis , Humanos , Enfermedades Renales/diagnóstico , Enfermedades Renales/genética , Recuento de Leucocitos , Aprendizaje Automático , MasculinoRESUMEN
Students' affective learning is critical for their academic success; therefore, considerable attention has been devoted to the role of various student-related and teacher-related factors as predictors of student affective learning. Notwithstanding, the impact of two important teacher-related factors, namely teacher-student rapport and teacher support, has not been adequately researched. To address this gap, the present study sought to explore the role of teacher support and teacher-student rapport in Chinese English as a foreign language (EFL) students' affective learning. To do so, three valid inventories of the variables were administered to 497 Chinese EFL students. Performing correlational analyses, favorable associations were found between teacher-student rapport, teacher support, and student affective learning. The predictive power of teacher support and teacher-student rapport was assessed using structural equation modeling (SEM). Chinese EFL students' affective learning was shown to be largely influenced by teacher-student rapport and teacher support. The pedagogical implications and future directions are also discussed.
RESUMEN
Non-recurrent congestion disrupts normal traffic operations and lowers travel time (TT) reliability, which leads to many negative consequences such as difficulties in trip planning, missed appointments, loss in productivity, and driver frustration. Traffic incidents are one of the six causes of non-recurrent congestion. Early and accurate detection helps reduce incident duration, but it remains a challenge due to the limitation of current sensor technologies. In this paper, we employ a recurrence-based technique, the Quadrant Scan, to analyse time series traffic volume data for incident detection. The data is recorded by multiple sensors along a section of urban highway. The results show that the proposed method can detect incidents better by integrating data from the multiple sensors in each direction, compared to using them individually. It can also distinguish non-recurrent traffic congestion caused by incidents from recurrent congestion. The results show that the Quadrant Scan is a promising algorithm for real-time traffic incident detection with a short delay. It could also be extended to other non-recurrent congestion types.
Asunto(s)
Accidentes de Tránsito , Algoritmos , Reproducibilidad de los Resultados , Factores de Tiempo , ViajeRESUMEN
OBJECTIVE: The optimal duration of dual antiplatelet therapy (DAPT) is still controversial among East Asians. This meta-analysis was designed to evaluate the efficacy and safety of short-term (≤6 months) vs. long-term (≥12 months) DAPT in East Asians undergoing percutaneous coronary intervention (PCI) with drug-eluting stent (DES). METHODS: PubMed, Embase, Web of Science and the Cochrane Library were searched for articles published up to 30 March 2020. Then meta-analysis was performed using RevMan 5.3 software. RESULTS: Nine studies with a total of 20 177 East Asian patients were included in this meta-analysis. In East Asian patients, short-term DAPT was associated with a lower incidence of major bleeding [odds ratio (OR) = 0.70, 95% confidence interval (CI) (0.49, 0.99), P = 0.04]. In the newer-generation DES subgroup, short-term DAPT was no less effective than long-term DAPT and resulted in a lower incidence of major bleeding [OR = 0.69, 95% CI (0.49, 0.98), P = 0.04]. In the subgroup of patients with acute coronary syndrome, there was no significant difference in the incidence of cardiac death, net adverse clinical and cerebral events (NACCE) and major bleeding between short-term and long-term DAPT. It was worth noting that in the subgroup of patients with diabetes mellitus, short-term DAPT was associated with a higher incidence of myocardial infarction [OR = 2.64, 95% CI (1.19, 5.88), P = 0.02] and NACCE [OR = 1.92, 95% CI (1.07, 3.43), P = 0.03]. CONCLUSION: The short-term DAPT (≤6 months) might be a better choice for East Asian patients undergoing PCI with DES, especially the newer-generation DES. However, for high-risk patients such as diabetes, the analysis supported the longer DAPT.
Asunto(s)
Pueblo Asiatico , Aspirina/administración & dosificación , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria/administración & dosificación , Quimioterapia Combinada , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
The aim of this study was to characterize and reveal the protective effects of cinnamaldehyde (CA) against mesenteric ischemia-reperfusion- (I/R-) induced lung and liver injuries and the related mechanisms. Sprague-Dawley (SPD) rats were pretreated for three days with 10 or 40 mg/kg/d, ig of CA, and then induced with mesenteric ischemia for 1 h and reperfusion for 2 h. The results indicated that pretreatment with 10 or 40 mg/kg of CA attenuated morphological damage in both lung and liver tissues of mesenteric I/R-injured rats. CA pretreatment significantly restored the levels of aspartate transaminase (AST) and alanine transaminase (ALT) in mesenteric I/R-injured liver tissues, indicating the improvement of hepatic function. CA also significantly attenuated the inflammation via reducing myeloperoxidase (MOP) activity and downregulating the expression of inflammation-related proteins, including interleukin-6 (IL-6), interleukin-1ß (IL-1ß), cyclooxygenase-2 (Cox-2), and tumor necrosis factor receptor type-2 (TNFR-2) in both lung and liver tissues of mesenteric I/R-injured rats. Pretreatment with CA significantly downregulated nuclear factor kappa B- (NF-κB-) related protein expressions (NF-κB p65, NF-κB p50, I kappa B alpha (IK-α), and inhibitor of nuclear factor kappa-B kinase subunit beta (IKKß)) in both lung and liver tissues of mesenteric I/R-injured rats. CA also significantly downregulated the protein expression of p53 family members, including caspase-3, caspase-9, Bax, and p53, and restored Bcl-2 in both lung and liver tissues of mesenteric I/R-injured rats. CA pretreatment significantly reduced TUNEL-apoptotic cells and significantly inhibited p53 and NF-κB p65 nuclear translocation in both lung and liver tissues of mesenteric I/R-injured rats. CA neither induced pulmonary and hepatic histological alterations nor affected the parameters of inflammation and apoptosis in sham rats. We conclude that CA alleviated mesenteric I/R-induced pulmonary and hepatic injuries via attenuating apoptosis and inflammation through inhibition of NF-κB and p53 pathways in rats, suggesting the potential role of CA in remote organ ischemic injury protection.
Asunto(s)
Acroleína/análogos & derivados , Isquemia Mesentérica/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Acroleína/farmacología , Acroleína/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Citoprotección/efectos de los fármacos , Modelos Animales de Enfermedad , Inflamación/etiología , Inflamación/patología , Inflamación/prevención & control , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Riñón/patología , Hepatopatías/etiología , Hepatopatías/patología , Hepatopatías/prevención & control , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Pulmón/patología , Lesión Pulmonar/etiología , Lesión Pulmonar/patología , Lesión Pulmonar/prevención & control , Masculino , Isquemia Mesentérica/complicaciones , Isquemia Mesentérica/patología , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/etiología , Daño por Reperfusión/patologíaRESUMEN
Aging is the primary driver of various diseases, including common neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Currently there is no cure for AD and PD, and the development of novel drug candidates is demanding. Spermidine is a small anti-aging molecule with elimination of damaged mitochondria via the process of mitophagy identified as a molecular mechanism of action. Here, we show that spermidine inhibits memory loss in AD worms and improves behavioral performance, e.g., locomotor capacity, in a PD worm model, both via the PINK1-PDR1-dependent mitophagy pathway. Additionally, spermidine delays accelerated aging and improves healthspan in the DNA repair-deficient premature aging Werner syndrome (WS) worm model. While possible intertwined interactions between mitophagy/autophagy induction and DNA repair by spermidine are to be determined, our data support further translation of spermidine as a possible therapeutic intervention for such diseases.
RESUMEN
OBJECTIVES: This meta-analysis was designed to evaluate the efficacy and safety of new oral anticoagulants (NOACs) for perioperative anticoagulation of atrial fibrillation (AF) catheter ablation (CA) in Japanese patients with non-valvular atrial fibrillation (NVAF). METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched for articles published up to June 30, 2019. Two reviewers independently screened literature, extracted data, and assessed the methodological quality of the included studies according to the inclusion and exclusion criteria. Then, meta-analysis was performed using RevMan 5.3 software. RESULTS: Nineteen studies with a total of 6827 patients were included in this meta-analysis. The experimental group received dabigatran, rivaroxaban, apixaban, or edoxaban; the control group received warfarin. The safety endpoints were bleeding complications; the efficacy endpoints were thromboembolic complications. Results were as follows: Patients with NOACs had a lower risk of overall bleeding complications (OR = 0.69, 95% CI (0.54, 0.87), P = 0.002), including major bleeding complications (OR = 0.52, 95% CI (0.32, 0.84), P = 0.007) and minor bleeding complications (OR = 0.73, 95% CI (0.56, 0.94), P = 0.02). There was no significant difference in thromboembolic complications between NOACs and warfarin after CA (OR = 0.39, 95% CI (0.14, 1.10), P = 0.08). CONCLUSIONS: In Japanese NVAF patients undergoing CA, NOACs have similar effects to warfarin in the prevention of stroke and systemic embolism. Moreover, NOACs were associated with a lower incidence of bleeding complications.
Asunto(s)
Fibrilación Atrial , Ablación por Catéter , Accidente Cerebrovascular , Administración Oral , Anticoagulantes/efectos adversos , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/cirugía , Dabigatrán , Humanos , Japón/epidemiología , Rivaroxabán , Warfarina/efectos adversosRESUMEN
Our preliminary study shows that cinnamaldehyde (CA) could protect against intestinal ischemia/reperfusion (I/R) injuries, in which p53 and NF-κB p65 play a synergistic role. In this study, we conducted in vivo and in vitro experiments to verify this proposal. SD rats were pretreated with CA (10 or 40 mg · kg-1 · d-1, ig) for 3 days, then subjected to 1 h mesenteric ischemia followed by 2 h reperfusion. CA pretreatment dose-dependently ameliorated morphological damage and reduced inflammation evidenced by decreased TNF-α, IL-1ß, and IL-6 levels and MPO activity in I/R-treated intestinal tissues. CA pretreatment also attenuated oxidative stress through restoring SOD, GSH, LDH, and MDA levels in I/R-treated intestinal tissues. Furthermore, CA pretreatment significantly reduced the expression of inflammation/apoptosis-related NF-κB p65, IKKß, IK-α, and NF-κB p50, and downregulated apoptotic protein expression including p53, Bax, caspase-9 and caspase-3, and restoring Bcl-2, in I/R-treated intestinal tissues. We pretreated IEC-6 cells in vitro with CA for 24 h, followed by 4 h hypoxia and 3 h reoxygenation (H/R) incubation. Pretreatment with CA (3.125, 6.25, and 12.5 µmol · L-1) significantly reversed H/R-induced reduction of IEC-6 cell viability. CA pretreatment significantly suppressed oxidative stress, NF-κB activation and apoptosis in H/R-treated IEC-6 cells. Moreover, CA pretreatment significantly reversed mitochondrial dysfunction in H/R-treated IEC-6 cells. CA pretreatment inhibited the nuclear translocation of p53 and NF-κB p65 in H/R-treated IEC-6 cells. Double knockdown or overexpression of p53 and NF-κB p65 caused a synergistic reduction or elevation of p53 compared with knockdown or overexpression of p53 or NF-κB p65 alone. In H/R-treated IEC-6 cells with double knockdown or overexpression of NF-κB p65 and p53, CA pretreatment caused neither further decrease nor increase of NF-κB p65 or p53 expression, suggesting that CA-induced synergistic inhibition on both NF-κB and p53 played a key role in ameliorating intestinal I/R injuries. Finally, we used immunoprecipitation assay to demonstrate an interaction between p53 and NF-κB p65, showing the basis for CA-induced synergistic inhibition. Our results provide valuable information for further studies.
Asunto(s)
Acroleína/análogos & derivados , Intestinos/efectos de los fármacos , Sustancias Protectoras/uso terapéutico , Daño por Reperfusión/prevención & control , Factor de Transcripción ReIA/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Acroleína/uso terapéutico , Animales , Línea Celular , Inflamación/prevención & control , Intestinos/patología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Isquemia Mesentérica/complicaciones , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Daño por Reperfusión/epidemiologíaRESUMEN
Intestinal ischemia-reperfusion (I/R) injury is a common pathological process with high clinical morbidity and mortality. Paeoniflorin, a monoterpene glucoside, is found to have diverse health beneficial effects including autophagy modulation, anti-inflammatory, anti-apoptotic, and anti-oxidative effects. Based on our pre-experiments, we proposed that paeoniflorin could ameliorate intestinal I/R injury and restore autophagy through activating LKB1/AMPK signal pathway. Our proposal was verified using rat intestinal I/R model in vivo and intestinal epithelial cell line (IEC-6 cells) hypoxia/reoxygenation (H/R) model in vitro. Our results showed that paeoniflorin pretreatment exerted protective effects in rat intestinal I/R injury by reducing intestinal morphological damage, inflammation, oxidative stress, and apoptosis. Paeoniflorin restored H/R-impaired autophagy flux by up-regulating autophagy-related protein p62/SQSTM1 degradation, LC3II and beclin-1 expression, and autophagosomes synthesis without significantly affecting control IEC-6 cells. Paeoniflorin pretreatment significantly activated LKB1/AMPK signaling pathway by reversing the decreased LKB1 and AMPK phosphorylation without affecting total LKB1 both in vivo and in vitro. LKB1 knockdown reduced AMPK phosphorylation, suppressed LC3II and Beclin-1 level, and decreased the degradation of SQSTM/p62, and the knockdown weakened the effects of paeoniflorin in restoring the impaired autophagy flux in H/R injured IEC-6 cells, suggesting that paeoniflorin mitigated the intestinal I/R-impaired autophagy flux by activating LKB1/AMPK signaling pathway. Our study may provide valuable information for further studies.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia/efectos de los fármacos , Glucósidos/farmacología , Intestinos/efectos de los fármacos , Monoterpenos/farmacología , Sustancias Protectoras/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Apoptosis/efectos de los fármacos , Beclina-1/metabolismo , Línea Celular , Masculino , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
N6-Methyladenosine (m6A) is the most abundant and important internal modification site of RNA methylation in viruses and eukaryotic. m6A RNA methylation plays key roles in the regulation of post-transcriptional gene expression, including messenger RNA (mRNA), microRNA (miRNA) and long noncoding RNA (lncRNA). And m6A methylation regulates the various aspects of RNA metabolism, including structure, maturation, stability, splicing, export, translation and decay. Liver is a vital metabolic and digestive organ in the pathophysiological processes. Recent studies suggested that m6A RNA modification highly regulates hepatic function and development of liver diseases. Here, we aim to summarize the biological and clinical significance of m6A modification in hepatic growth and hepatic disease including viral hepatitis, non-alcoholic fatty liver disease (NAFLD), and liver cancer.
Asunto(s)
Adenosina/análogos & derivados , Hepatopatías/metabolismo , Hígado/metabolismo , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , ARN Mensajero/metabolismo , Adenosina/metabolismo , Eucariontes/metabolismo , Metilación , Procesamiento Postranscripcional del ARN , Virus/metabolismoRESUMEN
Intestinal ischemia reperfusion (I/R) may cause inflammation-, oxidative stress-, and apoptosis-related tissue injuries and facilitate bacterial infection, leading to multiple organ failure. Myricetin, a flavonoid, is found to have diverse biological effects including anti-inflammatory, anti-oxidative, and anti-bacterial effects. Based on our pre-experiment, we proposed that myricetin pretreatment (25, 50mg/kg) could ameliorate intestinal I/R injury and myricetin-induced modulation on MKK7/JNK signal pathway might play a key role in the amelioration. The present study was designed to verify the proposal by using both rat intestinal I/R model in vivo and hypoxia/reoxygenation (H/R)-injured intestinal epithelial cell line (IEC-6 cells) model in vitro. The results confirmed our proposal. Myricetin selectively ameliorated I/R- and H/R-induced injuries in vivo and in vitro respectively without significantly affecting the corresponding normal controls. Myricetin significantly alleviated I/R-induced rat intestinal injury by reducing the generation of pro-inflammatory cytokines including TNF-α, IL-1ß, and IL-6 and by reducing MPO activity. Myricetin significantly reduced oxidative stress through decreasing MDA level and increasing the levels of SOD and GSH in the intestinal tissues compared with I/R control rats. Myricetin significantly decreased apoptosis by selectively down-regulating the expression of p-MKK7 and p-JNK without affecting MKK7 and JNK, inhibiting Bax, caspase-3 protein expression, and up-regulating Bcl-2 protein expression in I/R-injured jejunum of rats. In vitro study indicated that MKK7 siRNA transfection significantly decreased both MKK7 and p-MKK7 and other apoptosis-related proteins, partially simulating myricetin-induced anti-apoptotic effects. MKK7 siRNA transfection+myricetin could not further decrease MKK7, p-MKK7, and other apoptosis-related proteins, suggesting that inhibition of MKK7/JNK pathway plays a key role in myricetin-induced protection against intestinal I/R. MKK7 overexpression by cDNA transfection abrogated myricetin-reduced apoptosis-related protein expression, confirming that the MKK7/JNK signal pathway is the key target for myricetin-induced amelioration. The present study indicated that pretreatment of myricetin induced selective protection against intestinal I/R injury without significantly affecting corresponding normal controls and p-MKK7 was the key target, suggesting that myricetin is worth further translational studies.
Asunto(s)
Flavonoides/farmacología , MAP Quinasa Quinasa 7/metabolismo , Sustancias Protectoras/farmacología , Daño por Reperfusión/metabolismo , Animales , Línea Celular , Flavonoides/uso terapéutico , Intestino Delgado/patología , MAP Quinasa Quinasa 7/genética , Masculino , Sustancias Protectoras/uso terapéutico , ARN Interferente Pequeño/genética , Ratas Sprague-Dawley , Daño por Reperfusión/tratamiento farmacológicoRESUMEN
Zero-valent iron/activated carbon (Fe/C) particles can degrade persistent organic pollutants via micro-electrolysis and therefore, they may be used to develop materials for permeable reactive barriers (PRBs). In this study, surfactant-enhanced electrokinetics (EK) was coupled with a Fe/C-PRB to treat phenanthrene (PHE) and 2,4,6-trichlorophenol (TCP) co-contaminated clay soil. An environment-friendly biosurfactant, rhamnolipid, was selected as the solubility-enhancing agent. Five bench-scale tests were conducted to investigate the performance of EK-PRB on PHE and TCP removal from soil as well as the impact of pH and rhamnolipid concentration. The results show that both PHE and TCP, driven by electro-osmotic flow (EOF), moved toward the cathode and reacted with the Fe/C-PRB. Catholyte acidification and rhamnolipid concentration increase improved the removal efficiencies of PHE and TCP. The highest removal efficiency of PHE in soil column was five times the efficiency of the control group on which only EK was applied (49.89 versus 9.40%). The highest removal efficiency of TCP in soil column was 4.5 times the efficiency of the control group (64.60 versus 14.30%). Desorption and mobility of PHE and TCP improved with the increase of rhamnolipid concentration when this exceeded the critical micelle concentration. This study indicates that the combination of EK and a Fe/C-PRB is efficient and promising for removing persistent organic pollutants (POPs) from contaminated soil with the enhancement of rhamnolipid.
Asunto(s)
Carbón Orgánico , Clorofenoles/química , Restauración y Remediación Ambiental , Glucolípidos/química , Hierro/química , Contaminantes del Suelo/química , Tensoactivos , Electroquímica , Contaminación Ambiental , Fenantrenos/química , Suelo/químicaRESUMEN
Intestinal ischemia reperfusion (I/R) injury caused by severe trauma, intestinal obstruction, and operation is one of the tough challenges in clinic. 6-Gingerol (6G), a main active ingredient of ginger, is found to have anti-microbial, anti-inflammatory, anti-oxidative, and anti-cancer activities. The present study was designed to characterize the potential protective effects of 6G on rat intestinal I/R injury and reveal the correlated mechanisms. Rat intestinal I/R model was established with clamping the superior mesenteric artery (SMA) and 6G was intragastrically administered for three consecutive days before I/R injury. Caco-2 and IEC-6 cells were incubated under hypoxia/reoxygenation (H/R) conditions to simulate I/R injury in vitro. The results showed that 6G significantly alleviated intestinal injury in I/R injured rats by reducing the generation of oxidative stress and inhibiting p38 MAPK signaling pathway. 6G significantly reduced MDA level and increased the levels of SOD, GSH, and GSH-Px in I/R injured intestinal tissues. 6G significantly decreased the production of proinflammatory cytokines including TNF-α, IL-1ß, and IL-6, and inhibited the expression of inflammatory mediators iNOS/NO in I/R injured intestinal tissues. The impaired intestinal barrier function was restored by using 6G in I/R injured rats and in both Caco-2 and IEC-6 cells characterized by inhibiting p38 MAPK phosphorylation, nuclear translocation of NF-κB, and expression of myosin light chain kinase (MLCK) protein. 6G also reduced the generation of reactive oxygen species (ROS) in both Caco-2 and IEC-6 cells. In vitro transfection of p38 MAPK siRNA mitigated the impact of 6G on NF-κB and MLCK expression, and the results further corroborated the protective effects of 6G on intestinal I/R injury by repressing p38 MAPK signaling. In conclusion, the present study suggests that 6G exerts protective effects against I/R-induced intestinal mucosa injury by inhibiting the formation of ROS and p38 MAPK activation, providing novel insights into the mechanisms of this therapeutic candidate for the treatment of intestinal injury.