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Introduction: Hepatocellular carcinoma (HCC), which is closely associated with chronicinflammation, is the most common liver cancer and primarily involves dysregulated immune responses in the precancerous microenvironment. Currently, most studies have been limited to HCC incidence. However, the immunopathogenic mechanisms underlying precancerous lesions remain unknown. Methods: We obtained single-cell sequencing data (GSE136103) from two nonalcoholic fatty liver disease (NAFLD) cirrhosis samples and five healthy samples. Using pseudo-time analysis, we systematically identified five different T-cell differentiation states. Ten machine-learning algorithms were used in 81 combinations to integrate the frameworks and establish the best T-cell differentiation-related prognostic signature in a multi-cohort bulk transcriptome analysis. Results: LDHA was considered a core gene, and the results were validated using multiple external datasets. In addition, we validated LDHA expression using immunohistochemistry and flow cytometry. Conclusion: LDHA is a crucial marker gene in T cells for the progression of NAFLD cirrhosis to HCC.
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The practical applications of lithium-sulfur (Li-S) batteries have severely been hindered by notorious shuttle effect and sluggish redox kinetics of lithium polysulfide intermediates (LiPSs), which bring about rapid capacity degradation, low coulombic efficiency and poor cycling stability. In this work, 1T-rich MoS2 nanosheets are in-situ developed onto the conductive porous carbon matrix (1T-rich MoS2@PC) as efficient polysulfide promotors for high-performance Li-S batteries. The porous carbon skeleton tightly anchors MoS2 nanosheets to prevent their reaggregation and ensures accessible electrical channels, and at the same time provides a favorable confined space that promotes the generation of 1T-rich MoS2 structure. More importantly, the uniformly distributed metallic 1T-rich MoS2 nanosheets not only affords rich sulfphilic sites and high binding energy for immobilizing LiPSs, but also favors rapid electron transfer and LiPSs conversation kinetics, substantially regulating sulfur chemistry in working cells. Consequently, the Li-S cell assembled with 1T-rich MoS2@PC modified separator delivers a remarkable cycling stability with ultralow capacity decay rate of 0.067% over 500 cycles at 1C. Encouragingly, under harsh conditions (high sulfur loading of 4.78 mg cm-2 and low E/S ratio of 8 µL mg-1), a favorable electrochemical performance can still be demonstrated. This study highlights the profitable design of 1T-rich MoS2/carbon based electrocatalyst for suppressing shuttle effect and promoting catalytic conversation of LiPSs, and has the potential to be applied to in other energy storage systems.
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OBJECTIVES: Primary biliary cholangitis (PBC) is a rare disease characterized by intrahepatic cholestasis, whereas gallstone disease (GD) is common. In this study, we aimed to investigate the prevalence and impact of GD on the prognosis of PBC in China. METHODS: Medical records of the PBC patients were retrospectively reviewed and their follow-up data were obtained via regular structured, standardized telephone interviews. GD was defined as gallstones on ultrasonography or a history of cholecystectomy for gallstones. Propensity score matching (PSM) and Cox regression analysis were performed. The primary end-point was liver-related death and/or liver transplantation. RESULTS: A total of 985 ursodeoxycholic acid (UDCA)-treated PBC patients were enrolled with a median follow-up duration of 5.3 years (range 1.0-20.9 years). Among them, 258 (26.2%) had GD, including 157 (22.9%) of non-cirrhotic and 101 (33.8%) of cirrhotic patients. Compared with PBC without GD, those with GD were older, more often had type 2 diabetes mellitus, and had a more severe liver disease at baseline. After PSM (1:2), 229 PBC patients with GD were matched with 458 PBC patients without GD based on age, sex, cirrhosis, and total bilirubin level. The transplant-free survival and incidence of hepatic events were similar between the two groups. Furthermore, multivariate Cox regression analysis showed that concomitant GD was not independently associated with a worse prognosis for PBC patients. CONCLUSION: Concomitant GD was common but was not associated with long-term outcomes in patients with UDCA-treated PBC.
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Diabetes Mellitus Tipo 2 , Cálculos Biliares , Cirrose Hepática Biliar , Humanos , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/tratamento farmacológico , Estudos Retrospectivos , Cálculos Biliares/complicações , Colagogos e Coleréticos/uso terapêutico , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/complicações , Resultado do TratamentoRESUMO
OBJECTIVES: Drug-induced liver injury (DILI) is an increasing etiology of liver dysfunction, with various incidence worldwide. To better understand the disease burden and establish appropriate preventive and treatment strategies, a systematic review and meta-analysis was conducted. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library were searched for studies on the incidence of DILI published up to June 1, 2022. According to the predefined criteria, only population-based studies were included. Incidence was presented as cases per 100 000 person-years with 95% confidence interval (CI) using a random-effects model. RESULTS: A total of 14 studies were included. The overall incidence of DILI was 4.94 per 100 000 person-years (95% CI 4.05-5.83). Time-based cumulative meta-analysis suggested that the incidence of DILI increased over time since 2010. The incidence varied by regions, with Asia having the highest incidence of 17.82 per 100 000 person-years (95% CI 6.26-29.38), while North America having the lowest incidence of 1.72 per 100 000 person-years (95% CI 0.48-2.95). All studies reported a higher incidence of DILI in the elderly but comparable incidences between male and female (3.42 per 100 000 person-years vs 4.64 per 100 000 person-years). CONCLUSIONS: The global incidence of DILI has been increasing since 2010, with the highest incidence in Asia. Understanding the epidemiological characteristics of DILI helps establish specific strategies to deal with this emerging health problems.
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Doença Hepática Induzida por Substâncias e Drogas , Humanos , Masculino , Feminino , Idoso , Incidência , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologiaRESUMO
Background Diagnosis is particularly challenging in concealed or asymptomatic long QT syndrome (LQTS). Provocative testing, unmasking the characterization of LQTS, is a promising alternative method for the diagnosis of LQTS, but without uniform standards. Methods and Results A comprehensive search was conducted in PubMed, Embase, and the Cochrane Library through October 14, 2021. The fixed effects model was used to assess the effect of the provocative testing on QTc interval. A total of 22 studies with 1137 patients with LQTS were included. At baseline, QTc interval was 40 ms longer in patients with LQTS than in controls (mean difference [MD], 40.54 [95% CI, 37.43-43.65]; P<0.001). Compared with the control group, patients with LQTS had 28 ms longer ΔQTc upon standing (MD, 28.82 [95% CI, 23.05-34.58]; P<0.001), nearly 30 ms longer both at peak exercise (MD, 27.31 [95% CI, 21.51-33.11]; P<0.001) and recovery 4 to 5 minutes (MD, 29.85 [95% CI, 24.36-35.35]; P<0.001). With epinephrine infusion, QTc interval was prolonged both in controls and patients with QTS, most obviously in LQT1 (MD, 68.26 [95% CI, 58.91-77.60]; P<0.001) and LQT2 (MD, 60.17 [95% CI, 50.18-70.16]; P<0.001). Subgroup analysis showed QTc interval response to abrupt stand testing and exercise testing varied between LQT1, LQT2, and LQT3, named Type â , Type â ¡, and Type â ¢. Conclusions QTc trend Type â and Type â ¢ during abrupt stand testing and exercise testing can be used to propose a prospective evaluation of LQT1 and LQT3, respectively. Type â ¡ QTc trend combined epinephrine infusion testing could distinguish LQT2 from control. A preliminary diagnostic workflow was proposed but deserves further evaluation.
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Eletrocardiografia , Síndrome do QT Longo , Epinefrina , Teste de Esforço , Genótipo , Humanos , Síndrome do QT Longo/congênito , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genéticaRESUMO
BACKGROUND: Primary biliary cholangitis (PBC) patients often have concomitant extrahepatic autoimmune (EHA) diseases including Sjögren's syndrome (SS), systemic sclerosis (SSc), rheumatoid arthritis (RA), and autoimmune thyroid disease. The present study aimed to describe the prevalence of EHA diseases in PBC and explore the impact of EHA diseases on the long-term outcomes of PBC in Chinese patients. METHODS: Medical records of PBC patients diagnosed in our institute were retrospectively reviewed. Patients were followed up by a standardized telephone interview. The endpoints were defined as liver-related death and/or liver transplantation. RESULTS: Totally 247 of the 985 (25.1%) PBC patients enrolled in the study had at least one concomitant EHA disease. Sjögren's syndrome (n = 140, 14.2%) was the most frequent one, followed by rheumatoid arthritis (RA) (n = 56, 5.7%) and Hashimoto's thyroiditis (n = 45, 4.6%). Patients with EHA diseases were more common in females (P < 0.001) and in those with a family history of autoimmune disease (P = 0.017). Overall, no differences were found between PBC patients with and without EHA diseases in terms of biochemical response rates to ursodeoxycholic acid, the incidence of hepatic events, or transplant-free survival. RA and EHA ≥ 2 were protective factors for hepatic events in univariate Cox analysis, but the results became insignificant in multivariate analysis. CONCLUSIONS: Concomitant EHA diseases were common in PBC patients but did not compromise the long-term outcomes of PBC.
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Artrite Reumatoide , Doenças Autoimunes , Colangite , Cirrose Hepática Biliar , Síndrome de Sjogren , Feminino , Humanos , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/epidemiologia , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/epidemiologia , Estudos Retrospectivos , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/epidemiologia , Artrite Reumatoide/complicações , Colangite/epidemiologiaRESUMO
BACKGROUND: ß-Blockers are first-line therapy in patients with long QT syndrome (LQTS). However, ß-blockers had genotype dependent efficacy (LQT1>LQT2>LQT3). Sodium channel blockers have been recommended as add-on therapy for LQT3 patients. However, the pooled effect of sodium channel blockers in all LQTS patients remains unknown. METHODS: We conducted a systematic electronic search of PubMed, Embase, and the Cochrane Library. Fixed effects model was used to assess the effect of sodium channel blockers on QTc, cardiac events (CEs), and the proportion of QTc ≥ 500 ms and QTc ≤ 460 ms in LQTS patients. RESULTS: Pooled analysis of 14 studies with 213 LQTS (9 LQT1 + 63 LQT2 + 135 LQT3 + 6 others) patients showed that sodium channel blockers significantly shortened QTc by nearly 50 ms (mean difference [MD], -49.43; 95% confidence interval [CI], -57.80 to -41.05, p < .001), reduced the incidence of CEs (risk ratio [RR], 0.23; 95% CI, 0.11-0.47; p < .001) and the proportion of QTc ≥ 500 ms (RR, 0.33; 95% CI, 0.24-0.47; p < .001), and increased the proportion of QTc ≤ 460 ms (RR, 10.33; 95% CI, 4.62-23.09; p < .001). Sodium channel blockers significantly shortened QTc both in LQT3 and LQT2 patients, while the QTc shortening effect in LQT3 was superior to that in LQT2 (57.39 vs. 36.61 ms). Mexiletine, flecainide, and ranolazine all significantly shortened QTc, and the QTc shortening effect by mexiletine was the best (60.70 vs. 49.08 vs. 50.10 ms). CONCLUSIONS: Sodium channel blockers can be useful both in LQT3 and LQT2 patients. Mexiletine, flecainide and ranolazine significantly shortened QTc in LQTS patients, and the QTc shortening effect by mexiletine was the best.
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Síndrome do QT Longo , Bloqueadores dos Canais de Sódio , Antagonistas Adrenérgicos beta/uso terapêutico , Eletrocardiografia , Flecainida/uso terapêutico , Humanos , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/genética , Mexiletina/uso terapêutico , Ranolazina/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêuticoRESUMO
Epilepsy is a clinical syndrome caused by the highly synchronized abnormal discharge of brain neurons. It has the characteristics of paroxysmal, transient, repetitive, and stereotyped. Circular RNAs (circRNAs) are a recently discovered type of noncoding RNA with diverse cellular functions related to their excellent stability; additionally, some circRNAs can bind and regulate microRNAs (miRNAs). The present study was designed to screen the differentially expressed circRNA in an acute seizure model of epilepsy in mice, analyze the related miRNA and mRNA, and study their participating functions and enrichment pathways. In order to obtain the differential expression of circRNA in epilepsy and infer their function, we used next-generation sequencing and found significantly different transcripts. CIRI (circRNA identifier) software was used to predict circRNA from the hippocampus cDNA, EdgeR was applied for the differential circRNA analysis between samples, and Cytoscape 3.7.2 software was used to draw the network diagram. A total of 10,388 differentially expressed circRNAs were identified, of which 34 were upregulated and 66 were downregulated. Among them, mm9_circ_008777 and mm9_circ_004424 were the key upregulated genes, and their expression in the epilepsy group was verified using Quantitative real-time PCR (QPCR). The analysis indicated that the extracted gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were closely related to several epilepsy-associated processes. This study determined that mm9_circ_008777 and mm9_circ_004424 are potential biomarkers of epilepsy, which play important roles in epilepsy-related pathways. These results could help improve the understanding of the biological mechanisms of circRNAs and epilepsy treatments.
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Epilepsia/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Hipocampo/patologia , RNA Circular/genética , Animais , CamundongosRESUMO
To investigate the composition and structural characteristics of cell wall polysaccharides, three pectic fractions and two hemicellulose fractions, namely water-soluble pectin (WSP), chelator-soluble pectin (CSP), sodium carbonate-soluble pectin (NSP), 1 mol/L KOH soluble hemicellulose (KSH-1) and 4 mol/L KOH soluble hemicellulose (KSH-2), were isolated from Chinese quince fruits. The five fractions exhibited structural and compositional variation. The results showed NSP was the predominant cell wall polysaccharide fraction in the fruit. All pectic fractions had a low degree of esterification (31.7-42.4%). WSP fraction had the highest thermal stability among the five fractions. The polysaccharide chain lengths ranged from 19.4 nm to 121.4 nm. CSP had the highest molecular weight, giving it also the highest solution viscosity. NMR spectra revealed that NSP was composed of RG-I and galacturonic acid main chains, KSH-1 was composed of 1,4-ß-D-Xylp backbone attached to 1,5-α-L-Araf units. Among the five fractions, CSP has the highest DPPH radical scavenging activity while KSH-1 has the highest reducing power. This study can contribute to the applications of Chinese quince fruit polysaccharides in food and pharmaceutical industries.
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Antioxidantes/química , Parede Celular/química , Polissacarídeos/química , Rosaceae/química , Compostos de Bifenilo/química , Radicais Livres/química , Frutas/química , Ácidos Hexurônicos/química , Temperatura Alta , Microscopia de Força Atômica , Peso Molecular , Pectinas , Picratos/química , Pós/química , Reologia , Resistência ao Cisalhamento , Espectroscopia de Infravermelho com Transformada de Fourier , Estresse Mecânico , ViscosidadeRESUMO
The 70 kDa heat shock proteins function as molecular chaperones and are involved in diverse cellular processes. However, the functions of the plant mitochondrial HSP70s (mtHSC70s) remain unclear. Severe growth defects were observed in the Arabidopsis thaliana mtHSC70-1 knockout lines, mthsc70-1a and mthsc70-1b. Conversely, the introduction of the mtHSC70-1 gene into the mthsc70-1a background fully reversed the phenotypes, indicating that mtHSC70-1 is essential for plant growth. The loss of mtHSC70-1 functions resulted in abnormal mitochondria and alterations to respiration because of an inhibition of the cytochrome c oxidase (COX) pathway and the activation of the alternative respiratory pathway. Defects in COX assembly were observed in the mtHSC70-1 knockout lines, leading to decreased COX activity. The mtHSC70-1 knockout plants have increased levels of reactive oxygen species (ROS). The introduction of the Mn-superoxide dismutase 1 (MSD1) or the catalase 1 (CAT1) gene into the mthsc70-1a plants decreased ROS levels, reduced the expression of alternative oxidase, and partially rescued growth. Taken together, our data suggest that mtHSC70-1 plays important roles in the establishment of COX-dependent respiration.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Catalase/metabolismo , Regulação da Expressão Gênica de Plantas , Homeostase , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
OBJECTIVE: To explore the clinical efficacy of electroacupuncture nerve stimulation therapy (ENST) for interstitial cystitis/painful bladder syndrome (IC/PBS). METHODS: A total of 68 patients with IC/PBS were randomly divided into an observation group and a control group, 34 cases in each one. The patients in the observation group were treated with ENST; abdominal four acupoints and sacral four acupoints were connected with a pair of electrodes and treated alternately every other day. The ENST was given 50 min per times, three times a week for 3 months. The patients in the control group were treated with perfusion therapy of four-medication combination (heparin sodinm, lidocaine, sodium bicarbonate, gentamicin sulfate), twice a week for the first 6-8 weeks, followed by twice per month for 3 months. The infusion fluid remained for 1 h before discharging. The O' Leary-Sant score, including interstitial cystitis symptom index (ICSI) and interstitial cystitis problem index (ICPI), 24 h urination frequency, visual analogue scale (VAS) and maximum bladder volume were observed before treatment and treatment of 1 month, 3 months and 6 months after treatment respectively; the adverse events during the treatment were also recorded. RESULTS: Compared before treatment, the O'Leary-Sant score (ICSI, ICPI), 24 h urination frequency, VAS and maximum bladder volume in the two groups were improved after 1, 3 months treatment and 6 months after treatment (all P<0.05). The scores of ICSI, ICPI, VAS and 24 h urination frequency in the observation group were significantly lower than those in the control group (P<0.05). The maximum bladder volume in the observation group was significantly higher than that in the control group (P<0.05). Six months after treatment, the total effective rate in the observation group was 87.5% (28/32), which was higher than 69.7% (23/33) in the control group (P<0.01). No significant adverse events occurred during the treatment. CONCLUSION: ENST could effectively relieve the clinical symptoms of IC/PBS, but its long-term efficacy needs further observation.
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Cistite Intersticial , Eletroacupuntura , Doenças da Bexiga Urinária/terapia , Cistite Intersticial/terapia , Humanos , Dor , Manejo da Dor , Resultado do TratamentoRESUMO
To assess treatment response and overall survival (OS) in refractory or relapsed acute myeloid leukemia (R/R AML) patients treated by different common salvage chemotherapy regimens.Medical records data from 142 R/R AML patients were reviewed in this retrospective study. Patients were treated with regimens based on the following drugs: cytarabine, granulocyte colony-stimulating factor (G-CSF), and fludarabine (FLAG) (nâ=â46); cytarabine and G-CSF in addition to aclarubicin or daunorubicin (CAG/DAG) (nâ=â30); cytarabine, G-CSF, and cladribine (CLAG) (nâ=â27); cytarabine, etoposide, and mitoxantrone (MEA) (nâ=â17); cytarabine plus idarubicin, daunorubicin, or mitoxantrone (IA/DA/MA) (nâ=â12); and homoharringtonine, cytarabine, and aclarubicin or daunorubicin (HAA/HAD) (nâ=â10).A total of 43 (35.2%) patients achieved complete remission (CR), 60 (49.2%) patients achieved overall remission rate (ORR), and 18 (14.8%) patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CR. Median OS was 8.0 (95% CI 6.6-9.4) months with a 1-year OS rate of (29.9â±â3.9)% and 3-year OS rate of (11.1â±â3.6)%. No difference of CR (Pâ=â.621), ORR (Pâ=â.385), and allo-HSCT (Pâ=â.537) achievement was observed among different chemotherapy regimens. Interestingly, we observed that the CLAG-based regimen did not affect CR (Pâ=â.165), while it achieved a numerically higher ORR (Pâ=â.093) and was an independent factor for prolonged OS (Pâ=â.016). No other regimens were determined to be correlated with CR, ORR, or OS.FLAG-, CAG/DAG-, CLAG-, MEA-, IA/DA/MA- and HAA/HAD-based regimens were found to achieve similar CR rates, while the CLAG-based regimen achieved numerically higher ORR rates and significant favorable OS. Therefore, CLAG-based regimens should be a prioritized treatment option for R/R AML patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Salvação/métodos , Aclarubicina/efeitos adversos , Aclarubicina/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cladribina/efeitos adversos , Cladribina/uso terapêutico , Estudos de Coortes , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Daunorrubicina/efeitos adversos , Daunorrubicina/uso terapêutico , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Harringtoninas/efeitos adversos , Harringtoninas/uso terapêutico , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mitoxantrona/efeitos adversos , Mitoxantrona/uso terapêutico , Estudos Retrospectivos , Terapia de Salvação/efeitos adversos , Taxa de Sobrevida , Resultado do Tratamento , Vidarabina/efeitos adversos , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: Oppositional defiant disorder (ODD) is a behavioral disorder that mainly refers to a recurrent pattern of disobedient, defiant, negativistic and hostile behaviors toward authority figures. Previous studies have showed associations of serotonin transporter (5-HTT) and monoamine oxidase A (MAOA) with behavioral and psychiatric disorders. The purposes of this study were to investigate the potential association of 5-HTT gene promoter polymorphism (5-HTTLPR) and MAOA gene polymorphism with susceptibility to ODD in a Han Chinese school population. METHODS: The 5-HTTLPR gene polymorphism and the MAOA gene polymorphism were genotyped in a case-control study of 257 Han Chinese children (123 ODD and 134 healthy controls). RESULTS: There was significant difference in the allele distribution of 5-HTTLPR (χ2 = 7.849, P = 0.005) between the ODD and control groups. Further, there were significant differences in genotype (χ2 = 5.168, P = 0.023) and allele distributions (χ2 = 10.336, P = 0.001) of the MAOA gene polymorphism that is variable-number tandem repeat (MAOA-uVNTR) between two groups. Moreover, there were significant differences in genotype (χ2 = 4.624, P = 0.032) and allele distributions (χ2 = 9.248, P = 0.002) of MAOA-uVNTR only in the male ODD and healthy groups. CONCLUSIONS: Our results suggest that 5-HTTLPR and MAOA-uVNTR gene variants may contribute to susceptibility to ODD. Further, MAOA-uVNTR gene polymorphism may play a role in susceptibility to ODD only in male children.
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Povo Asiático/genética , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/genética , Monoaminoxidase/genética , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Povo Asiático/etnologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/diagnóstico , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/etnologia , Estudos de Casos e Controles , Criança , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Vigilância da População/métodosRESUMO
The study explores whether miR-139-5p targeting LPAR4 affects epithelial-mesenchymal transition (EMT) and fibrosis in post-menopausal women with interstitial cystitis (IC) via the PI3K/Akt signaling pathway. Bladder tissues of IC and normal bladder tissues were collected. The pathology of bladder tissues was observed by HE, Masson and Picrosirius red staining. LPAR4 positive expression rate were determined by IHC. ELISA was performed to detect the levels of IL-6, IL-8, IL-10, and TNF-α. Rat IC models were randomized into seven different groups. miR-139-5p, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, P13K, Akt, E-cadherin, N-cadherin, Vimentin, TGF-ß1, and CTGF expression were determined by RT-qPCR and Western blotting. Dual luciferase reporter gene assay verified that LPAR4 is a target gene of miR-139-5p. Fibrosis was a pathological manifestation of IC. The IC group showed higher LPAR4, PI3K, Akt, p-PI3K, p-Akt, N-cadherin, Vimentin, TGF-ß1, and CTGF expression but lower miR-139-5p and E-cadherin expression than the normal group. The levels of IL-6, IL-8, IL-10, and TNF-α expression decreased while HB-EGF increased in the IC group in comparison of the normal group. Compared with the blank and NC groups, E-cadherin expression was increased in the miR-139-5p mimic and siRNA-LPAR4 groups, while LPAR4, PI3K, Akt, p-P13K, p-Akt, N-cadherin, Vimentin, TGF-ß1, and CTGF expression were decreased. An opposite trend was found in the miR-139-5p inhibitor group. The miR-139-5p decreased in the miR-139-5p inhibitor + siRNA-LPAR4 and miR-139-5p inhibitor + wortmannin groups. Conclusively, miR-139-5p targeting LPAR4 inhibits EMT and fibrosis in post-menopausal IC women through the PI3K/Akt signaling pathway.
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Cistite Intersticial/metabolismo , Transição Epitelial-Mesenquimal , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Pós-Menopausa/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Purinérgicos P2/metabolismo , Transdução de Sinais , Idoso , Idoso de 80 Anos ou mais , Animais , Cistite Intersticial/genética , Cistite Intersticial/patologia , Feminino , Fibrose , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Pós-Menopausa/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2/genéticaRESUMO
Effects of enriched environment (EE) combined with fluoxetine in a chronic unpredictable stress (CUS) rat model were examined in our study. Thirty male Sprague-Dawley rats were randomly divided into control group, CUS group, CUS+EE group, CUS+fluoxetine group, and CUS+EE+fluoxetine group (n=six per group). Rats in the CUS group were bred under conditions of CUS and separation for 6 weeks; Control group animals were bred in group cages (three rats per cage) under standard laboratory conditions for 6 weeks; Rats in CUS+EE group, CUS+fluoxetine group, and CUS+EE+fluoxetine groups were bred under the conditions of CUS and separation for 6 weeks and had an intervention of EE, an oral gavage of fluoxetine, and an intervention of EE+oral gavage of fluoxetine, respectively, every day for the final 3 weeks. Every rat underwent a behavioral assessment at the beginning of the 1st week, at the end of the 3rd week and at the end of the 6th week. Behavioral assessments included sucrose water consumption, weight measurement, and an open field test (measuring horizontal moving distance, rearing behavior, and defecation). Finally, the level of synaptophysin expressed in the hippocampus was measured with immunohistochemistry. We found that EE, fluoxetine, and EE+fluoxetine all reversed the depression-like behaviors of CUS rats. The effect of EE+fluoxetine appeared to be superior to EE or fluoxetine alone; the expression level of synaptophysin in CA1, CA3, and DG of the hippocampus was decreased in CUS rats, however, exposure to EE, fluoxetine, and EE+fluoxetine all reversed this decrease.
Assuntos
Depressão/metabolismo , Fluoxetina/farmacologia , Sinaptofisina/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Meio Ambiente , Fluoxetina/metabolismo , Regulação da Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo , Sinaptofisina/genética , Sinaptofisina/metabolismoRESUMO
Our study aims to investigate the roles that microRNA-214 (miR-214) plays in the epithelial mesenchymal transition (EMT) process and the development of interstitial cystitis (IC) in postmenopausal women by targeting Mitofusin 2 (Mfn2). IC bladder tissues and adjacent normal bladder tissues were collected from postmenopausal women. Immunohistochemistry (IHC) staining was conducted. The target relationship between miR-214 and Mfn2 was determined by a dual luciferase reporter gene assay. Adipose-derived mesenchymal stem cells (ADMSCs) were extracted from postmenopausal rats and assigned to the blank, mimics, miR-214 inhibitors, mimics negative control (NC), inhibitors NC, Mfn2 siRNA, miR-214 inhibitors and Mfn2 siRNA groups. Exosomes secreted by transfected ADMSCs were instilled into the bladders of postmenopausal rats. The expression of miR-214 and Mfn2 mRNA and EMT markers was assessed by qRT-PCR and western blotting. It was confirmed that Mfn2 was the target gene of miR-214 in IC. Compared with the normal bladder tissues, miR-214 decreased, but Mfn2 increased in IC bladder tissues. Compared with the blank group, the expression of miR-214 and the expression levels of N-cadherin, Fibronectin, Twist1, Snail and Vimentin mRNA and protein increased, whereas the expression levels of Mfn2, E-cadherin and ZO-1 mRNA and protein decreased in the miR-214 mimics and Mfn2 groups. The expression of MiR-214 and the expression levels of N-cadherin, Fibronectin, Twist1, Snail and Vimentin mRNA and protein decreased, whereas the expression levels of Mfn2, E-cadherin and ZO-1 mRNA and protein increased in the miR-214 inhibitors group. Our findings indicate that the inhibition of miR-214 promotes the EMT process and contributes to bladder wall fibrosis by up-regulating Mfn2, thus leading to the occurrence of IC in postmenopausal women.
Assuntos
Cistite Intersticial/metabolismo , Transição Epitelial-Mesenquimal , GTP Fosfo-Hidrolases/metabolismo , MicroRNAs/fisiologia , Proteínas Mitocondriais/metabolismo , Pós-Menopausa/metabolismo , Bexiga Urinária/patologia , Tecido Adiposo/citologia , Animais , Biomarcadores/análise , Cistite Intersticial/patologia , Modelos Animais de Doenças , Exossomos/metabolismo , Feminino , Fibrose , GTP Fosfo-Hidrolases/genética , Humanos , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/antagonistas & inibidores , Proteínas Mitocondriais/genética , Inibidores da Síntese de Ácido Nucleico/farmacologia , Ratos , Ratos Sprague-Dawley , Regulação para CimaRESUMO
The role of CD147 in regulation of rheumatoid arthritis (RA) is not fully elucidated. The aim of this study was to investigate the effect of cell-to-cell contact of activated CD14+ monocytes with CD4+ T cells, and the modulatory role of CD147 on T-helper 17 (Th17) cells differentiation in patients with RA. Twenty confirmed active RA patients and twenty normal controls were enrolled. CD4+ T cells and CD14+ monocytes were purified by magnetic beads cell sorting. Cells were cultured under different conditions in CD4+ T cells alone, direct cell-to-cell contact co-culture of CD4+ and CD14+ cells, or indirect transwell co-culture of CD4+ /CD14+ cells in response to LPS and anti-CD3 stimulation with or without anti-CD147 antibody pretreatments. The proportion of IL-17-producing CD4+ T cells (defined as Th17 cells) was determined by flow cytometry. The levels of interleukin (IL)-17, IL-6, and IL-1ß in the supernatants of cultured cells were measured by ELISA. The optimal condition for in vitro induction of Th17 cells differentiation was co-stimulation with 0.1 µg/mL of LPS and 100 ng/mL of anti-CD3 for 3 days under direct cell-to-cell contact co-culture of CD4+ and CD14+ cells. Anti-CD147 antibody reduced the proportion of Th17 cells, and also inhibited the productions of IL-17, IL-6, and IL-1ß in PBMC culture from RA patients. The current results revealed that Th17 differentiation required cell-to-cell contact with activated monocytes. CD147 promoted the differentiation of Th17 cells by regulation of cytokine production, which provided the evidence for pathogenesis and potential therapeutic targets for RA.
Assuntos
Artrite Reumatoide/patologia , Basigina/metabolismo , Diferenciação Celular , Células Th17/fisiologia , Adolescente , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Técnicas de Cocultura , Meios de Cultura/química , Citocinas/análise , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Adulto JovemRESUMO
BACKGROUND: Oppositional defiant disorder (ODD) is a behavioral disorder of school-age population. It is well known that 5-HT dysfunction is correlated with impulsivity, which is one of the common characteristics of ODD. The enzyme tryptophan hydroxylase-2 (TPH-2) synthesizes 5-HT in serotonergic neurons of the midbrain raphe. The purposes of this study were to investigate the potential association of TPH-2 polymorphisms with susceptibility to ODD in a Han Chinese school population. METHODS: Four polymorphisms (rs4570625, rs11178997, rs1386494 and rs7305115) of the TPH-2 gene were analyzed by using polymerase chain reaction and DNA microarray hybridization in a case-control study of 276 Han Chinese individuals (124 ODD and 152 controls). RESULTS: In single marker analyses,there was a significant difference in the genotype (χ 2 = 4.163, P = 0.041) and allele frequency (χ 2 = 3.930, P = 0.047) of rs1386494 between ODD and control groups. Haplotype analyses revealed higher frequencies of haplotypes TA (rs4570625-rs11178997), TAG (rs4570625-rs11178997-rs1386494), TAA (rs4570625-rs11178997-rs7305115) and TAGA (rs4570625-rs11178997-rs1386494-rs7305115), but lower frequencies of haplotypes GA (rs4570625-rs11178997) and GAG (rs4570625-rs11178997-rs1386494) in ODD compared to control groups. CONCLUSIONS: These findings suggest the role of these TPH-2 gene variants in susceptibility to ODD. Some haplotypes might be the risk factors for Chinese Han children with ODD, while others might be preventable factors.
Assuntos
Transtornos de Deficit da Atenção e do Comportamento Disruptivo/enzimologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/genética , Triptofano Hidroxilase/genética , Adolescente , Povo Asiático/genética , Estudos de Casos e Controles , Criança , China , Etnicidade/genética , Feminino , Frequência do Gene , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Triptofano Hidroxilase/metabolismoRESUMO
AtDjB1 is a mitochondria-located J-protein in Arabidopsis thaliana It is involved in the regulation of plant growth and development; however, the exact mechanisms remain to be determined. We performed comparison analyses of phenotypes, auxin signalling, redox status, mitochondrial structure and function using wild-type plants, AtDjB1 mutants, rescued AtDjB1 mutants by AtDjB1 or YUCCA2 (an auxin synthesis gene), and AtDjB1 overexpression plants. AtDjB1 mutants (atj1-1 or atj1-4) exhibited inhibition of growth and development and reductions in the level of IAA and the expression of YUCCA genes compared to wild-type plants. The introduction of AtDjB1 or YUCCA2 into atj1-1 largely rescued phenotypic defects and the IAA level, indicating that AtDjB1 probably regulates growth and development via auxin. Furthermore, atj1-1 plants displayed a significant reduction in amount/activity of mitochondrial complex I compared to wild-type plants; this resulted in the accumulation of reactive oxygen species (ROS). Moreover, exogenous H2O2 markedly inhibited the expression of YUCCA genes in wild-type plants. In contrast, the reducing agent ascorbate increased the expression of YUCCA genes and IAA level in atj1-1 plants, indicating that the low auxin level observed in atj1-1 was probably due to the high oxidation status. Overall, the data presented here suggest that AtDjB1 is required for mitochondrial complex I activity and regulates growth and development through ROS-mediated auxin signalling in Arabidopsis.