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1.
Int J Biol Sci ; 16(4): 671-681, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32025214

RESUMO

Background: Activation of macrophages and infiltration are key events in acute liver injury (ALI). Kv1.3 plays an important role in regulating immunologic functions of macrophages and is extensively recognized as a potential ion channel for immunological diseases. Objective: We hypothesized that blockage of Kv1.3 may influence ALI by inhibiting macrophages infiltration in damaged liver tissues. Methods: Margatoxin was administered into the peritoneal cavity of ALI mice. The impact of this treatment on ALI and macrophage migration in vivo and in vitro was determined using immunohistochemistry, transwell migration, and wound healing assays. Results: MgTX treatment alleviated ALI in mice, as evidenced by reduced macrophage infiltration in liver tissues and lower serum levels of liver ALT and AST. RNA-seq profiling analysis showed that the most obvious change by MgTX treatment was downregulation of δ-catenin, a protein known to be associated with macrophage migration. The effect of MgTX on macrophage migration and involvement of δ-catenin was confirmed by transwell and wound healing assays. Overexpression of δ-catenin in RAW264.7 cells promoted migration, an event that was suppressed upon silencing of δ-catenin. Mechanistically, the expression of RhoA was regulated by the overexpression or knockdown of δ-catenin. Conclusion: These findings suggest a role for blockage of Kv1.3 channel in macrophage migration and reveal a new target in the treatment of ALI.

2.
Mol Cell Biochem ; 466(1-2): 91-102, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31989367

RESUMO

Purine signaling pathway plays an important role in inflammation and tissue damage. To investigate the role of purine signaling pathway in acute alcoholic liver injury and chronic alcoholic liver fibrosis, we replicated two animal models and two cellular models. We found that body weights, liver indexes, serum biochemical parameters, serum fibrosis indexes, and pathological and immunohistochemical results had significant changes in two treatment groups compared with two control groups. In addition, gene expressions of purine receptors, inflammatory cytokines, fibrogenic cytokines, and inflammasomes increased obviously in two animal models and two cellular models. Furthermore, purine receptor inhibitors could significantly inhibit protein expressions of purine receptors and reduce protein expressions of inflammatory cytokines, fibrogenic cytokines, and inflammasomes. Besides, P2X7R small interfering ribonucleic acid (siRNA) had the same effects. Meanwhile, we detected protein expressions of inflammatory cytokines secreted by inflammasomes, and we found that purine receptor-mediated inflammasomes activation was a key event in the process of chronic alcoholic liver fibrosis. In summary, this study shows that inhibition of purine receptors can alleviate acute alcoholic liver injury and chronic alcoholic liver fibrosis in mice. Therefore, purine receptor is a potential new target for the treatment of acute alcoholic liver injury and chronic alcoholic fibrosis.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31736154

RESUMO

INTRODUCTION: This study aimed to determine the prices, availability, and affordability of national essential medicines in public primary hospitals in poverty-stricken areas of Anhui province, China. METHODS: A cross-sectional study was conducted in 143 public primary hospitals in Anhui province, eastern China. Data on access to 44 essential medicines was evaluated using the standardized methodology available in the World Health Organization and Health Action International manual. RESULTS: Median price rates show that 46.51% (21 of 44) of the lowest price generics and 100% of the originator brands were more expensive than the international reference price. The median availability of the 44 medicines was 31.47%, and 65.91% (29 of 44) of the medicines had less than 50% availability. The majority of the medicines were affordable as they would cost less than a day's income in sample areas. Suppliers could respond to 88.27% of the procuring orders raised by the 143 hospitals in the study, but this ranged from 43.96% to 99.86%. CONCLUSIONS: There is poor availability and non-ideal response rate of medicine delivery in public primary hospitals in poverty-stricken areas in eastern China. Further implementation of national essential medicine policy needs to focus on improving both availability and distribution efficiency in these areas.

4.
Int Immunopharmacol ; 77: 105915, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639617

RESUMO

Inflammation plays a central role in the progression of alcoholic liver disease. ATP-P2Y2R signaling and CD39 play an important role in various diseases, but little is known about their role in alcoholic liver steatosis and inflammation. As a transmembrane hydrolase, CD39 hydrolyzes ATP, while the mutual regulation of CD39 and ATP-P2Y2R in alcoholic steatohepatitis is poorly understood. Here, we found that the expression of ATP, P2Y2R, and CD39 is increased significantly both in the liver of alcohol-fed mice and alcohol-induced RAW264.7 cell lines. In this study, C57BL/6 mice were intrapretationally injected with P2Y2R inhibitor suramin from day 4 until day 10 during the induction of a chronic/binge drinking model. Pharmacological blockade of P2Y2R largely prevents liver damage, lipid accumulation, and inflammation, with concomitant down-expression of CD39 in liver. We found that the inhibition of P2Y2R in vitro reduces inflammation via down-expression of interleukin 6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-alpha (TNF-α), and the expression of CD39 was reduced, whereas the activation of P2Y2R showed an opposite effect. Silencing of CD39 promoted the expression of ATP and P2Y2R. These results indicate that CD39 attenuates alcohol-induced steatohepatitis by scavenging extracellular ATP to indirectly regulate the expression of P2Y2R. Interestingly, P2Y2R paradoxically boosts CD39 activity. Thus, blockade of the extracellular ATP-P2Y2R signalling represents a potential therapeutic approach against alcoholic liver disease, and CD39 is a potential therapeutic target.

5.
Alcohol Alcohol ; 54(5): 465-471, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31361816

RESUMO

AIMS: In acute alcoholic liver injury, alcohol can directly or indirectly induce endoplasmic reticulum stress (ERS) to participate in liver injury, and it is found that the expression of serum exosomal miR-122 is significantly affected. Therefore, the present study investigated the effects of endoplasmic reticulum stress inhibition on the expression of serum exosomal miR-122 and acute liver injury. METHODS: The acute alcoholic liver injury models were established by the intragastric administration of ethanol (5 g/kg) in ICR mice. Intervention group received 4-phenylbutyric acid (PBA, endoplasmic reticulum stress inhibitor; 75 mg/kg and 150 mg/kg, intraperitoneal) 12 and 24 hours before intragastric administration. Mice treated with saline were used as controls. RESULTS: The ethanol treated mice exhibited significantly elevated hepatosomatic index (liver weight/body weight) and alanine aminotransferase (ALT), compared with those in the control group (P < 0.05). The ERS inhibitor 4-phenylbutyric acid protected against ethanol induced acute liver injury and hepatocyte necrosis, and PBA 150 mg/kg significantly attenuated ethanol induced hepatic ER stress-related proteins (GRP78, pIRE1α and pIF2α) (P < 0.05). Moreover, PBA 150 mg/kg markedly alleviated ethanol induced elevation of hepatic and serum exosomal miR-122 and pri-miR-122 (P < 0.05). CONCLUSIONS: These findings suggest that ER stress inhibitor PBA attenuated ethanol induced acute liver injury and serum exosomal miR-122, and provides a potential therapy strategy for acute alcoholic liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/sangue , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Etanol/toxicidade , Exossomos/metabolismo , MicroRNAs/sangue , Fenilbutiratos/uso terapêutico , Animais , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Estresse do Retículo Endoplasmático/fisiologia , Etanol/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fenilbutiratos/farmacologia , Distribuição Aleatória
6.
Int Immunopharmacol ; 75: 105765, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31336335

RESUMO

Hepatic fibrosis is the most common pathological feature of most chronic liver diseases, and its continuous deterioration gradually develops into liver cirrhosis and eventually leads to liver cancer. At present, there are many kinds of drugs used to treat liver fibrosis. However, Western drugs tend to only target single genes/proteins and induce many adverse reactions. Most of the mechanisms and active ingredients of traditional Chinese medicine (TCM) are not clear, and there is a lack of unified diagnosis and treatment standards. Natural products, which are characterized by structural diversity, low toxicity, and origination from a wide range of sources, have unique advantages and great potential in anti-liver fibrosis. This article summarizes the work done over the previous decade, on the active ingredients in natural products that are reported to have anti-hepatic fibrosis effects. The effective anti-hepatic fibrosis ingredients identified can be generally divided into flavonoids, saponins, polysaccharides and alkaloids. Mechanisms of anti-liver fibrosis include inhibition of liver inflammation, anti-lipid peroxidation injury, inhibition of the activation and proliferation of hepatic stellate cells (HSCs), modulation of the synthesis and secretion of pro-fibrosis factors, and regulation of the synthesis and degradation of the extracellular matrix (ECM). This review provides suggestions for the development of anti-hepatic fibrosis drugs.


Assuntos
Produtos Biológicos/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Animais , Produtos Biológicos/farmacologia , Humanos , Cirrose Hepática/imunologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia
7.
Front Pharmacol ; 10: 376, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057404

RESUMO

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid loss of renal function, which may further develop into chronic kidney damage (CKD) or even end-stage renal disease (ESRD). AKI is a global health problem associated with high morbidity and costly treatments, and there is no specific or effective strategy to treat AKI. In recent years, Traditional Chinese Medicine (TCM) has attracted more attention, with lines of evidence showing that application of TCM improved AKI, and the mechanisms of action for some TCMs have been well illustrated. However, reviews summarizing the progress in this field are still lacking. In this paper, we reviewed TCM preparations and TCM monomers in the treatment of AKI over the last 10 years, describing their renal protective effects and mechanisms of action, including alleviating inflammation, programmed cell death, necrosis, and reactive oxygen species. By focusing on the mechanisms of TCMs to improve renal function, we provide effective complementary evidence to promote the development of TCMs to treat AKI. Moreover, we also summarized TCMs with nephrotoxicity, which provides a more comprehensive understanding of TCMs in the treatment of AKI. This review may provide a theoretical basis for the clinical application of TCMs in the future.

8.
Curr Drug Targets ; 20(11): 1180-1202, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947670

RESUMO

The incidence and mortality of malignant tumors are on the rise, which has become the second leading cause of death in the world. At present, anti-tumor drugs are one of the most common methods for treating cancer. In recent years, with the in-depth study of tumor biology and related disciplines, it has been gradually discovered that the essence of cell carcinogenesis is the infinite proliferation of cells caused by the disorder of cell signal transduction pathways, followed by a major shift in the concept of anti-tumor drugs research and development. The focus of research and development is shifting from traditional cytotoxic drugs to a new generation of anti-tumor drugs targeted at abnormal signaling system targets in tumor cells. In this review, we summarize the targets of anti-tumor drugs and analyse the molecular mechanisms of their effects, which lay a foundation for subsequent treatment, research and development.

9.
Int Immunopharmacol ; 66: 52-61, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30445307

RESUMO

The P2X7 receptor is an ATP-binding cation channel involved in a broad range of inflammatory diseases. However, little is known about the potential role of P2X7R in alcohol-induced steatohepatitis and intestinal injury. In our study, C57BL/6 mice were intraperitoneally injected with P2X7R antagonists Brilliant Blue G and A438079 from the 4th day to the 10th day during the induction of chronic plus binge alcohol feeding model. Our results showed that alcohol feeding induced significant steatohepatitis and liver injury, which were mitigated by P2X7R blockade as evidenced by decreased serum levels of ALT, AST, T-CHO and TG, reduced lipid accumulation, and less inflammation. The increased intestinal inflammatory cytokines production and the prominent intestinal barrier disruption caused by alcohol were also modulated by P2X7R antagonism. Interestingly, alcohol feeding increased the relative abundance of phylum Bacteroidetes while decreased the number of phylum Verrucomicrobia and genus Akkermansia in the cecal content, which were reversed by P2X7R antagonist. Importantly, the improvement of intestinal barrier function and the restoration of partial taxonomic alterations in the gut microbiota might contribute to protect the liver from gut microbiota dysbiosis-induced second hit. Furthermore, P2X7R blockade inhibited MEK1/2-ERK1/2 phosphorylation and egr-1 expression in both liver and intestine from alcohol-fed mice. Collectively, P2X7R blockade mitigates alcohol-induced steatohepatitis and intestinal injury by inhibiting MEK1/2-ERK1/2 signaling and egr-1 expression. These studies strongly suggest that P2X7R blockade may be a promising therapeutic approach for treating alcoholic liver disease.


Assuntos
Fígado Gorduroso Alcoólico/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/tratamento farmacológico , Intestinos/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Piridinas/uso terapêutico , Corantes de Rosanilina/uso terapêutico , Tetrazóis/uso terapêutico , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Microbioma Gastrointestinal/fisiologia , Humanos , Intestinos/patologia , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Oncogene ; 37(47): 6119-6135, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29993036

RESUMO

Macrophages play a crucial role in the progression of hepatic fibrosis (HF). In macrophages, epigenetic mechanisms are increasingly being recognized as crucial controllers of their phenotype. However, the functions of macrophage DNA methylation in experimental models of hepatic fibrosis have not been fully addressed. Here, we analyzed isolated hepatic macrophages DNA methylation from CCL4-induced (4 weeks) mice using reduced representation bisulfite sequencing (RRBS). We identified and validated the methylation status of 26 gene promoter regions associated with CpG islands. We further investigated the function of PSTPIP2 in HF by hepatic-adeno-associated virus (AAV9)-PSTPIP2 overexpression. The molecular mechanisms underlying PSTPIPS2-regulated HF were further explored in mice and RAW264.7 cell line. RRBS results show hypermethylation of PSTPIP2 (chr18: 77,843,840-77,843,968) in the 5'-UTR region. PSTPIP2 expression was significantly decreased in isolated hepatic macrophages from CCL4-induced mice. PSTPIP2 hypermethylation is mediated by the methyltransferases DNMT3a and DNMT3b in LPS-induced RAW264.7 cell line. Further investigation indicated that specific overexpression of PSTPIP2 in C57BL/6 mice reduced the inflammatory response and ameliorated liver fibrosis. These data indicated that hypermethylation of PSTPIP2 caused a mixed induction of hepatic classical macrophage (M1) and alternative macrophage (M2) biomarkers in CCL4-induced HF mice. Furthermore, overexpression of PSTPIP2 inhibited the expression of M1 markers by suppressing STAT1 activity, and enhanced the expression of M2 markers by promoting STAT6 activity. In contrast, knockdown of PSTPIP2 promoted M1 polarization and suppressed M2 polarization in vitro. Adding PSTPIP2 expression alleviates liver fibrosis and hepatic inflammation in mice by regulating macrophage polarization.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas do Citoesqueleto/genética , Metilação de DNA/genética , Cirrose Hepática/genética , Macrófagos/metabolismo , Regiões 5' não Traduzidas/genética , Animais , Biomarcadores/metabolismo , Tetracloreto de Carbono/farmacologia , Linhagem Celular , Ilhas de CpG/genética , Modelos Animais de Doenças , Epigênese Genética/genética , Inflamação/genética , Inflamação/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Células RAW 264.7 , Fator de Transcrição STAT1/genética
11.
Alcohol ; 71: 1-4, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29864674

RESUMO

BACKGROUND: An increase in alcohol consumption and related harmful effects has been reported among the elderly population in Asia. Of note, it is important to monitor patterns of alcohol use, and to establish a valid and reliable evaluation system when screening for risky consumption in this age group. OBJECTIVE: The aim of the current study was to evaluate the possible alcoholic liver disease (ALD) risk factors of a local population in elderly Chinese adults. METHODS: A questionnaire was sent to 3393 Chinese adults over 40 years old in Hefei. Alcohol consumption was determined based on the AUDIT questionnaire. ALD was defined by ALD diagnostic standards. Adjusted odds ratios and 95% confidence intervals (95% CI) derived from multiple logistic regression models were used to assess the relationship between ALD and sociodemographic variables. RESULTS: Among 2545 total interviewees, 448 (17.6%) reported a history of alcohol consumption in the previous 12 months. Of these drinkers, 46.7% were male and 53.3% were female. The overall Cronbach's alpha coefficient for AUDIT was 0.648. The rate of ALD was 6.83%. Alcohol abuse was significantly associated with ALD. In the logistical model, alcohol abuse was independently associated with ALD (OR = 6.17, 95% CI: 3.69-15.24; p < 0.01). CONCLUSIONS: Alcohol use, sex, age, and facial flushing were risk factors for ALD. These results provide important evidence for the prevention and therapy of ALD.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Alcoolismo/epidemiologia , Hepatopatias Alcoólicas/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Comorbidade , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Inquéritos e Questionários
12.
Int J Pharm Pract ; 26(4): 291-301, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29693291

RESUMO

OBJECTIVE: A systematic review and meta-analysis of randomized controlled trials (RCTs) were performed to understand the effectiveness of medication adherence (MA) interventions among Chinese patients with hypertension. METHODS: A literature search was conducted with three English databases (PubMed, Web of Science and Embase) and three Chinese databases (China National Knowledge Infrastructure, Wanfang and VIP Database for Chinese Technical Periodicals) for the period from 1970 to October 2017. Only both RCTs with a minimum of 10 participants in each intervention group and Chinese patients with hypertension as participants were included. A random-effects model was applied to calculate pooled effect sizes with 95% CI. Subgroup analysis was conducted to identify potential sources of heterogeneity from duration of intervention, type of intervener, methods of intervention and sites of intervention. Funnel plots and Egger's test were used to evaluate for publication bias. KEY FINDINGS: A total of 48 studies met criteria for the meta-analysis, including 14 568 participants, testing 57 independent comparisons. Overall, the effect size revealed that interventions significantly improved MA (pooled relative risk = 1.59, 95% CI: 1.43 to 1.78; pooled Cohen's d = 1.42, 95% CI: 0.976 to 1.876). Interventions were found to significantly reduce blood pressure (BP) (systolic BP: Cohen's d = -0.85, 95% CI: -1.11 to -0.60 and diastolic BP: Cohen's d = -0.73, 95% CI: -1.00 to -0.46). Longer duration of intervention gave better effectiveness. Physician as interventionist, regular follow-up visits and interventions conducted at a hospital were associated with better effectiveness. CONCLUSION: Adherence interventions improve MA and reduce uncontrolled BP among Chinese patients with hypertension. In the future, investigators should adopt a skill set to address the problem of poor MA.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , China , Humanos , Avaliação de Programas e Projetos de Saúde , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Int J Mol Med ; 41(6): 3527-3536, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29512759

RESUMO

Investigations of hepatic gene expression are crucial for determining the molecular factors involved in acute alcoholic liver injury. The results of liver molecular investigations may reveal etiologically important genomic alterations. Therefore, it is necessary to normalize gene expression data to identify stable genes, which may be used as a reference under different experimental conditions. The aim of the present study was to apply reverse transcription­quantitative polymerase chain reaction analysis and use analysis software to investigate the expression stability of candidate reference genes in hepatic tissues from mice with acute alcoholic liver injury. The acute alcoholic liver injury models were established by the intragastric administration of alcohol (5 mg/kg) in Imprinting Control Region mice. Total RNA was isolated from the mouse livers, following which the expression levels of seven reference genes, ß-actin, glyceraldehyde 3-phosphate dehydrogenase (Gadph), glucuronidase ß, hypoxanthine phosphoribosyltransferase 1 (Hprt1), 18S ribosomal RNA, TATA binding protein and ß­2 microglobulin, were examined, and gene expression stability was assessed using the geNorm, NormFinder and BestKeeper tools. The geNorm analysis revealed that the gene with the lowest variability was Hprt1. Hprt1 and Gapdh were validated as the optimal reference gene pair in all samples from all groups. The NormFinder and BestKeeper results showed that Hprt1 was the most stable gene in all samples. Alcohol induces endoplasmic reticulum (ER) stress, causing changes in the expression levels of ER stress­associated genes. The stability of Hprt1 was verified by the expression analysis of ER stress­associated genes, and gene expression levels in the ethanol groups were upregulated, with a significant difference in expression, compared with those in the control group. Therefore, Hprt1 was selected as the most stable gene, and Hprt1 and Gapdh were determined to be the optimum gene pair in mouse models of acute alcoholic liver injury. The reliability of the Hprt1 gene was confirmed by expression analysis of ER stress­associated genes.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Perfilação da Expressão Gênica/métodos , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Animais , Estresse do Retículo Endoplasmático/genética , Gliceraldeído-3-Fosfato Desidrogenases/genética , Camundongos , Monoéster Fosfórico Hidrolases/genética , RNA Ribossômico 18S/genética , Proteína de Ligação a TATA-Box/genética , Proteína de Ligação a TATA-Box/fisiologia
14.
Lab Invest ; 98(1): 79-94, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29200200

RESUMO

Acute kidney injury (AKI), characterized by aggressive inflammatory responses and destruction of renal resident cells, can cause abrupt kidney dysfunction. To date, effective therapy for AKI is lacking. In this study, we evaluated the renoprotective effect of wogonin, an herbal active compound, using a cisplatin-induced AKI mouse model. In vivo results show that wogonin substantially suppressed the increased levels of serum creatinine and blood urea nitrogen (BUN) almost to the normal level. Wogonin also attenuated tubular damage, shown by PAS staining, electron microscopy and molecular analysis of KIM-1. In addition, wogonin suppressed kidney inflammation as indicated by a >60% decrease in macrophage infiltration, a >50% reduction in inflammatory cytokine production and inhibited NF-κB activation in the injured kidney. Mechanistically, molecular docking results show that wogonin effectively inhibited RIPK1 by occupying the ATP-binding pocket of the enzyme, which is a key regulator of necroptosis. Moreover, inhibition of RIPK1, or RIPK3, reversed the protective effects of wogonin in cisplatin-treated HK2 cells, indicating wogonin works in a RIPK1/RIPK3-dependent manner. Surprisingly, wogonin enhanced the anti-proliferative effect of cisplatin on human hepatoma HepG2 cells. Thus, our findings suggest wogonin may be a renoprotective adjuvant for cisplatin-based anticancer therapy.


Assuntos
Lesão Renal Aguda/prevenção & controle , Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Cisplatino/efeitos adversos , Flavanonas/uso terapêutico , Rim/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Biomarcadores/sangue , Biomarcadores/metabolismo , Domínio Catalítico , Linhagem Celular Transformada , Linhagem Celular Tumoral , Cisplatino/antagonistas & inibidores , Cisplatino/farmacologia , Flavanonas/química , Flavanonas/metabolismo , Flavanonas/farmacologia , Humanos , Rim/imunologia , Rim/metabolismo , Rim/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/imunologia , Túbulos Renais/metabolismo , Túbulos Renais/ultraestrutura , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Simulação de Acoplamento Molecular , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Interferência de RNA , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Proteína Serina-Treonina Quinases de Interação com Receptores/química , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
15.
Lab Invest ; 98(1): 63-78, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29106395

RESUMO

The goal of this study was to elucidate the functional role of Nox4 during acute kidney injury (AKI). NADPH oxidases are a major source of reactive oxygen species (ROS) in the kidney in normal and pathological conditions. Among NADPH oxidase isoforms, NADPH oxidase4 (Nox4) is highly expressed in the kidney and has an important role in kidney diseases, such as diabetic nephropathy and renal carcinoma. We previously found that Nox4 expression significantly increased in the toxic AKI model. However, its functional role and mechanism of action in AKI are still unknown. We scavenged ROS with apocynin in vitro and in vivo and found it attenuated cisplatin-triggered renal function decline. It also alleviated programmed cell death and renal inflammation, indicating a critical role for ROS in mediating AKI. Nox4 protein and mRNA levels were substantially upregulated by cisplatin in vivo and in vitro. Nox4 knockdown alleviated cisplatin-induced cell death and inflammatory response, while Nox4 overexpression aggravated them. Moreover, N-acetyl-L-cysteine (NAC)-mediated inhibition of ROS suppressed cell injury led by Nox4 overexpression, indicating Nox4-mediated ROS generation may be the key mediator in cisplatin-induced nephrotoxicity. Mechanistically, excessive expression of Nox4 induced programmed cell death, especially RIP-mediated necroptosis. Finally, we tested whether Nox4 is a potential therapeutic target using an AKI mouse model by injecting a lentivirus-packaged Nox4 shRNA plasmid through tail vein. Disruption of Nox4 led to renal function recovery, kidney damage relief and reduced inflammation. We conclude that Nox4 aggravates cisplatin-induced nephrotoxicity by promoting ROS-mediated programmed cell death and inflammation. Thus Nox4 may serve as a potential therapeutic target in the treatment of AKI.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Modelos Animais de Doenças , Rim/efeitos dos fármacos , NADPH Oxidase 4/metabolismo , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Lesão Renal Aguda/prevenção & controle , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Transformada , Células Cultivadas , Cisplatino/antagonistas & inibidores , Cisplatino/farmacologia , Depuradores de Radicais Livres/farmacologia , Depuradores de Radicais Livres/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Rim/imunologia , Rim/metabolismo , Rim/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/imunologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/genética , Estresse Oxidativo/efeitos dos fármacos , Interferência de RNA , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo
16.
Biomark Med ; 11(6): 491-501, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28598214

RESUMO

Liver disease is a primary cause of liver-related morbidity and mortality worldwide. Currently, histological examination is the gold standard for diagnosis and classification of liver disease; however, due to its several drawbacks, including the risk of complications and sampling variability, noninvasive diagnostic options are favorable. Exosomal miRNAs have recently been considered as an important source of medical biomarkers due to being widely distributed in body fluids. This review summarizes existing concepts related to the origin, mode of transportation and possible functions of exosomal miRNAs, and recent findings on the role of exosomal miRNAs in liver diseases and development of exosomal miRNA-based diagnostic biomarkers in the primary forms of liver diseases.


Assuntos
Exossomos/genética , Hepatopatias/diagnóstico , Hepatopatias/genética , MicroRNAs/metabolismo , Animais , Biomarcadores/metabolismo , Humanos , Hepatopatias/patologia
17.
Burns ; 43(4): 839-845, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28041753

RESUMO

OBJECTIVE: Challenges persist in the reconstruction of the ankle and the foot with exposed tendons, joints, and bones as a result of severe burns and trauma. In flap elevation involving the sensitive superficial nerve, the local nerve was always sacrificed to obtain an anesthetic donor site; however, such a procedure introduced the possibility of painful neuromas. In this study, we present a desired clinical application of a modified reversed superficial peroneal artery flap, in which the superficial peroneal nerve is preserved. METHODS: From 2008 to 2015, 12 patients with ankle or foot defects were treated with the modified reversed superficial peroneal artery flap. The defects of the patients were caused by hot liquid scald (one patient), electrical injury (five patients), and trauma (six patients). The flap was utilized for covering defects on the ankle (seven patients) and the foot (five patients). The size of the flaps ranged from 4.0cm×6.0cm to 18.0cm×10.0cm. The superficial peroneal artery was involved in the flap, whereas the superficial peroneal nerve was spared by dedicate dissection. The reverse-flow flap was nourished by the superficial peroneal artery through the terminal peroneal artery perforator. RESULTS: The obtained outcomes were satisfactory functionally and aesthetically. The flaps in 11 patients survived completely without complications, whereas partial necrosis occurred in a 78-year-old patient when the flap survived a week later during follow up. CT angiography revealed the stenosis of the popliteal artery. The wound healed after interventional treatment involving placing a stent and changing the dressings. Basic functions and configurations were salvaged in all cases. All patients were completely satisfied with the proposed flap and suffered no paresthesia in their lower leg. CONCLUSION: Exhibiting beneficial characteristics such as reliable blood supply, favorable thickness, wide rotating arc, and retention of major vessels and the superficial peroneal nerve, the modified reversed superficial peroneal artery flap is useful in the reconstruction of ankle and foot defects that would not cause any hypoesthesia of the foot.


Assuntos
Traumatismos do Tornozelo/cirurgia , Queimaduras/cirurgia , Traumatismos do Pé/cirurgia , Procedimentos Cirúrgicos Reconstrutivos/métodos , Retalhos Cirúrgicos , Adolescente , Adulto , Idoso , Artérias , Criança , Feminino , Humanos , Hipestesia/prevenção & controle , Masculino , Pessoa de Meia-Idade , Nervo Fibular , Complicações Pós-Operatórias/prevenção & controle , Lesões dos Tecidos Moles/cirurgia , Ferimentos e Lesões/cirurgia , Adulto Jovem
18.
Int J Biol Macromol ; 96: 578-588, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28041914

RESUMO

Pulmonary fibrosis (PF) is a severe inflammatory disease with limited effective treatments. It is known that the transdifferentiation of human embryo lung fibroblast (HELF) cells from pulmonary fibroblasts into myofibroblasts, contributes to the progression of pulmonary fibrogenesis. The tuberous sclerosis proteins TSC1 and TSC2 are two key signaling factors which can suppress cell growth and proliferation. However, the roles of TSC1 and TSC2 in lung fibroblast are unclear. Here, we developed a PF model with bleomycin (BLM) in mice and conducted several simulation experiments in HELF cells. Our study shows that the expression of TSC1 and TSC2 in fibrotic mice lung was reduced and stimulation of HELF cells with TGF-ß1 resulted in a down-regulation of TSC1 and TSC2. In addition, overexpression of TSC1 or TSC2 decreased cell proliferation and differentiation. Furthermore, we found that reduced expression of TSC1 and TSC2 caused by TGF-ß1 is associated with the promoter methylation status of TSC1 and TSC2. MeCP2, controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. We found that expression of TSC1 and TSC2 can be repressed by MeCP2, which regulates HELF cell differentiation and proliferation as myofibroblasts and lead to PF ultimately.


Assuntos
Diferenciação Celular , Regulação para Baixo , Fibroblastos/citologia , Pulmão/citologia , Proteína 2 de Ligação a Metil-CpG/metabolismo , Proteínas Supressoras de Tumor/genética , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Embrião de Mamíferos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose , Humanos , Pulmão/patologia , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Regiões Promotoras Genéticas/genética , Fator de Crescimento Transformador beta1/farmacologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa
19.
Int Immunopharmacol ; 43: 164-171, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28061416

RESUMO

The activation of hepatic stellate cells (HSCs) is an essential part in the development of alcoholic liver fibrosis (ALF). In this study, stimulated HSCs with 200µM acetaldehyde for 48h was used to imitate alcoholic liver fibrosis in vitro. The western blot and qRT-PCR results showed that P2X7R expression was significantly increased in the activation of HSCs after acetaldehyde treatment. Interestingly, activation of P2X7R by stimulating with P2X7R agonist BzATP significantly promoted acetaldehyde-induced CyclinD1 expression, cell proportion in S phase, inflammatory response, and the protein and mRNA levels of α-SMA, collagen I. In contrast, blockage of P2X7R by stimulating with the inhibitor A438079 or transfecting with specific siRNA dramatically suppressed acetaldehyde-induced HSCs activation. Furthermore, PKC activation treated with PMA could obviously up-regulate the expression of α-SMA and collagen I and the phosphorylation of GSK3ß, while inhibition of PKC significantly reduced GSK3ß activation. Moreover, GSK3ß inhibition harvested a dramatic decrease of the mRNA and protein levels of α-SMA and collagen I by suppressing GSK3ß phosphorylation. Taken together, these results suggested that purinergic P2X7R mediated acetaldehyde-induced activation of HSCs via PKC-dependent GSK3ß pathway, which maybe a novel target for limiting HSCs activation.


Assuntos
Células Estreladas do Fígado/fisiologia , Hepatopatias Alcoólicas/metabolismo , Fígado/patologia , Receptores Purinérgicos P2X7/metabolismo , Acetaldeído/metabolismo , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Animais , Células Cultivadas , Fibrose , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Hepatopatias Alcoólicas/patologia , Proteína Quinase C/metabolismo , Agonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/farmacologia , RNA Interferente Pequeno/genética , Ratos , Receptores Purinérgicos P2X7/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tetrazóis/farmacologia
20.
Biochim Biophys Acta Mol Basis Dis ; 1863(3): 674-686, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27979710

RESUMO

Long non-coding RNAs (lncRNAs) are increasingly recognized as major players in regulating various biological processes. LncRNA HOX transcript antisense RNA (Hotair) has been extensively studied in cancer. However, the role of Hotair in liver fibrosis remains unknown. Here we observed that Hotair expression was significantly increased in CCl4-induced mouse liver fibrosis models, human fibrotic livers and activated hepatic stellate cells (HSCs) by TGF-ß1 stimulation. Enforced expression of Hotair in LX-2 cells promoted cell proliferation and activation while inhibition of its expression had an opposite effect. Furthermore, we found that Hotair may act as an endogenous 'sponge' of miR-148b, which regulates expression of the DNMT1/MEG3/p53 pathways in HSCs. Intriguingly, Hotair enhanced polycomb repressive complex 2 (PRC2) occupancy and histone H3K27me3 repressive marks, specifically at the MEG3 promoter region. Finally, we found that Hotair forms an RNA/DNA hybrid and recruits PRC2 to MEG3 promoter. These data suggest that Hotair inhibition may represent a promising therapeutic option for suppressing liver fibrosis.


Assuntos
Células Estreladas do Fígado/metabolismo , Cirrose Hepática/genética , RNA Longo não Codificante/genética , Regulação para Cima , Animais , Linhagem Celular , DNA (Citosina-5-)-Metiltransferase 1/genética , Epigênese Genética , Regulação da Expressão Gênica , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética
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