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1.
Cell Death Dis ; 11(2): 97, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029701

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

2.
Chin J Integr Med ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31919749

RESUMO

OBJECTIVE: To evaluate the effects of a 48-week course of adefovir dipivoxil (ADV) plus Chinese medicine (CM) therapy, namely Tiaogan Jianpi Hexue () and Tiaogan Jiedu Huashi () fomulae, in hepatitis B e antigen (HBeAg)-positive Chinese patients. METHODS: A total of 605 HBeAg-positive Chinese CHB patients were screened and 590 eligible participants were randomly assigned to 2 groups in 1:1 ratio including experimental group (EG, received ADV plus CM) and control group (CG, received ADV plus CM-placebo) for 48 weeks. The major study outcomes were the rates of HBeAg and HBV-DNA loss on week 12, 24, 36, 48, respectively. Secondary endpoints including liver functions (enzymes and bilirubin readings) were evaluated every 4 weeks at the beginning of week 24, 36, and 48. Routine blood, urine, and stool analyses in addition to electrocardiogram and abdominal B scan were monitored as safety evaluations. Adverse events (AEs) were documented. RESULTS: The combination therapy demonstrated superior HBeAg loss at 48 weeks, without additional AEs. The full analysis population was 560 and 280 in each group. In the EG, population achieved HBeAg loss on week 12, 24, 36, and 48 were 25 (8.90%), 34 (12.14%), 52 (18.57%), and 83 (29.64%), respectively; the equivalent numbers in the CG were 20 (7.14%), 41 (14.64%), 54 (19.29%), and 50 (17.86%), respectively. There was a statistically significant difference between these group values on week 48 (P<0.01). No additional AEs were found in EG. Subgroup analysis suggested different outcomes among treatment patterns. CONCLUSION: Combination of CM and ADV therapy demonstrated superior HBeAg clearance compared with ADV monotherapy. The finding indicates that this combination therapy may provide an improved therapeutic effect and safety profile (ChiCTR-TRC-11001263).

3.
J Mol Cell Cardiol ; 139: 98-112, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31982427

RESUMO

BACKGROUND: Salvianolic acid B (Sal B) is the representative component of phenolic acids derived from the dried root and rhizome of Salvia miltiorrhiza Bge. (Labiatae), which has been widely used for the treatment of cardiovascular and cerebrovascular diseases. However, the effect of Sal B on diabetic cardiomyopathy (DCM) is still unclear. METHODS: Type 1 diabetes mellitus was induced in C57BL/6 J mice by streptozotocin (STZ) treatment, whereas meanwhile Salvianolic Acid B (Sal B (15 or 30 mg/kg/d) was intraperitoneally injected for 16 weeks. At the end of this period, cardiac function was assessed by echocardiography, and total collagen deposition was evaluated by Masson's trichrome and Picrosirius Red staining. Human umbilical vein endothelial cells exposed to hypoxia were used to investigate the effect of different doses of Sal B on angiogenesis and tube formation in vitro. Transcriptome sequencing was performed to identify potential targets of Sal B. RESULTS: Sal B ameliorated left ventricular dysfunction and remodeling, and decreased collagen deposition in the heart of diabetic mice. Administration of Sal B increased the expression of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and VEGFA in a dose-dependent manner and promoted angiogenesis both in vivo and in vitro. Furthermore, Sal B reduced HG-induced insulin-like growth factor-binding protein 3 (IGFBP3) expression, induced the phosphorylation of extracellular signal-regulated protein kinase and protein kinase B (AKT) activities, enhanced cell proliferation, and activated VEGFR2/VEGFA signaling in endothelial cells. The underlying mechanisms involve SalB that enhances IGFBP3 promoter DNA methylation and induce nuclear translocation of IGFBP3 in HUVECs under hypoxia. CONCLUSIONS: Sal B promoted angiogenesis and alleviated cardiac fibrosis and cardiac remodeling in DCM by suppressing IGFBP3.

4.
Cell Death Dis ; 11(1): 22, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924749

RESUMO

Accelerated atherosclerotic calcification is responsible for plaque burden, especially in diabetes. The regulatory mechanism for atherosclerotic calcification in diabetes is poorly characterized. Here we show that deletion of PARP-1, a main enzyme in diverse metabolic complications, attenuates diabetic atherosclerotic calcification and decreases vessel stiffening in mice through Runx2 suppression. Specifically, PARP-1 deficiency reduces diabetic arteriosclerotic calcification by regulating Stat1-mediated synthetic phenotype switching of vascular smooth muscle cells and macrophage polarization. Meanwhile, both vascular smooth muscle cells and macrophages manifested osteogenic differentiation in osteogenic media, which was attenuated by PARP-1/Stat1 inhibition. Notably, Stat1 acts as a positive transcription factor by directly binding to the promoter of Runx2 and promoting atherosclerotic calcification in diabetes. Our results identify a new function of PARP-1, in which metabolism disturbance-related stimuli activate the Runx2 expression mediated by Stat1 transcription to facilitate diabetic arteriosclerotic calcification. PARP-1 inhibition may therefore represent a useful therapy for this challenging complication.

5.
Pflugers Arch ; 471(2): 347-355, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30353369

RESUMO

Our study explored the effects of lncRNA UCA1 on the proliferation and apoptosis in hypoxic human pulmonary artery smooth muscle cells (HPASMCs) and highlighted the endogenous relationship between UCA1, ING5, and hnRNP I in cell proliferation. Hypoxia-induced HPASMCs were used to simulate pulmonary arterial hypertension in vitro. Microarray assay was adopted to screen the dysregulated expressed lncRNAs in HPASMCs to find out the target gene of our study. And RT-qPCR was performed to detect the expression of lncRNA UCA1 under hypoxia and normoxia. After transfection, the relationship between UCA1 and cell proliferation in HPASMCs under hypoxia were determined by cell proliferation assay and relative expression of PCNA. Next, ELISA assays were conducted to measure the protein levels of PCNA and ING5. What's more, flow cytometry was employed to measure the apoptosis rate in differentially UCA1-expressed HPASMCs. RIP assays were conducted to further clarify the endogenous relationship between UCA1 and ING5 in hypoxic HPASMCs. Finally, the effects of ING5 to HPASMCs were detected after transfection of ING5 and UCA1 to figure out the role of ING5 in HPASMCs. Hypoxia was revealed to induce proliferation and inhibited apoptosis in HPASMCs. Besides, UCA1 was confirmed to be highly expressed under hypoxia compared with normoxia. UCA1 boosted cell proliferation under hypoxia in HPASMCs. However, the apoptosis was suppressed in the hypoxic HPASMCs transfected with pcDNA3.1-UCA1. Further, mechanism studies found that UCA1 competed with ING5 for hnRNP I, so that upregulating UCA1 inhibited the protein levels of ING5. And finally we found that ING5 restrained cell viability, but promoted cell apoptosis in hypoxic HPASMCs, which was reversed by UCA1 over-expression. In summary, our findings manifested that UCA1 promoted proliferation and restrained apoptosis by competing with ING5 for hnRNP I in HPASMCs induced by hypoxia, indicating their potential roles for the cure of hypoxic pulmonary hypertension.

6.
J Cell Physiol ; 234(6): 9535-9550, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30367500

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by the apoptosis resistance and hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Its pathogenesis has not been revealed. Here, we carried out experiments to investigate the functions of miR-140-5p and tumor necrosis factor-α (TNF-α). METHODS: We selected GSE703 from Gene Expression Omnibus (GEO) Database to conduct microarray analysis using R software and Gene Set Enrichment Analysis (GSEA). Combing bioinformatics results, the upregulation of miR-140-5p inhibited PAH progression through targeting TNF-α. RNA expression was measured by quantitative real-time polymerase chain reaction (RT-qPCR) and protein level was measured by western blot analysis and enzyme-linked immunosorbent assays (ELISA). We conducted monocrotaline (MCT) injection to rats to form PAH animal models. The lung tissues were observed by hematoxylin-eosin (HE) staining and Sirius red-picric acid staining. Right ventricular systolic pressure (RVSP) and the ratio of right ventricle (RV)-to-left ventricle (LV) plus septum (S) weight (RV/[LV + S]) were measured in MCT-induced animal models. Overexpression of miR-140-5p and TNF-α were utilized to research the proliferation, migration, and phenotypic variation of hypoxia-mediated PASMCs. The binding between miR-140-5p and TNF-α 3'-untranslated region (3'-UTR) was confirmed via luciferase reporter assay. RESULTS: Downregulation of miR-140-5p and upregulation of TNF-α were observed in PAH rat model and hypoxia-mediated PASMCs. And we proved that overexpression of miR-140-5p could suppress the proliferation, migration, and phenotypic variation of PASMCs, therefore inhibiting PAH pathogenesis. Luciferase assay verified that miR-140-5p targeted TNF-α directly. A converse correlation was also shown between miR-140-5p and TNF-α in PASMCs. CONCLUSIONS: miR-140-5p and TNF-α are important regulators in PAH pathology and may serve as a therapeutic target for PAH.

7.
Hypertension ; 72(5): 1189-1199, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354818

RESUMO

Abdominal aortic aneurysm (AAA) is a common vascular degenerative disease. PARP-1 (poly[ADP-ribose] polymerase 1) is a nuclear enzyme, which plays a critical role in vascular diseases. We hypothesized that PARP-1 inhibition might have protective effects on AAA. In vivo, Ang II (angiotensin II) was continuously infused by a micropump for 28 days to induce AAA in mice. In vitro, aortic endothelial cells and smooth muscle cells were stimulated by Ang II for 24 hours. Ang II infusion increased PARP-1 expression and activity and successfully induced AAA formation partly with a hemorrhage in ApoE-/- mice. Genetic deletion of PARP-1 markedly reduced the AAA incidence, abdominal aortic diameter, macrophage infiltration, ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular adhesion molecule 1) expression, and MMP (matrix metalloproteinase) expression, as well as MMP activity; but increased smooth muscle cells content and collagens expression in AAA. PARP-1 inhibition by PJ-34 also exerted a protective effect on AAA in mice. In aortic endothelial cells, Ang II-induced oxidative stress and DNA damage, resulting in increased PARP-1 expression and activity. Compared with the control, Ang II increased TNF-α (tumor necrosis factor α) and IL-6 (interleukin-6) secretions, ICAM-1 expression and THP-1 (human acute monocytic leukemia cell line) cells adhesion, while PARP-1 inhibition by siRNA reduced the inflammatory response probably through inhibition of the phosphorylation of ERK (extracellular signal-regulated kinase), NF-κB (nuclear factor-κB), and Akt signaling pathways. In smooth muscle cells, Ang II promoted cell migration, proliferation, and apoptosis, reduced collagens expression, but increased MMPs expression, while PARP-1 deletion alleviated these effects partly by reducing NF-κB-targeted MMP-9 expression. PARP-1 inhibition might be a feasible strategy for the treatment of AAA.


Assuntos
Aneurisma da Aorta Abdominal/prevenção & controle , Pressão Sanguínea/fisiologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Colágeno/metabolismo , Citocinas/metabolismo , Dano ao DNA/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/genética , RNA Interferente Pequeno , Transdução de Sinais/efeitos dos fármacos
8.
Chin J Integr Med ; 24(9): 653-660, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30209792

RESUMO

BACKGROUND: The domestic prevalence of chronic hepatitis B (CHB) in China is 7.18% in 2006, imposing great societal healthcare burdens. Nucleot(s)ide analogues (NUCs) anti-hepatitis B virus (HBV) therapies are widely applied despite the relatively low rate of seroconversion and high risk of drug-resistant mutation. More effective treatments for CHB deserve further explorations. Combined therapy of NUCs plus Chinese herbal medicine (CHM) is widely accepted in China, which is recognized as a prospective alternative approach. The study was primarily designed to confirm the hypothesis that Tiaogan-Yipi Granule (, TGYP) or Tiaogan-Jianpi-Jiedu Granule (, TGJPJD) plus entecavir tablet (ETV) was superior over ETV monotherapy in enhancing HBeAg loss rate. METHODS: The study was a nationwide, large-scale, multi-center, double-blind, randomized, placebo-controlled trial with a designed duration of 108 weeks. A total of 16 hospitals and 596 eligible Chinese HBeAg positive CHB patients were enrolled from November 2012 to September 2013 and randomly allocated into 2 groups in 1:1 ratio via central randomization system: experimental group (EG) and control group (CG). Subjects in EG received CM formulae (TGYP or TGJPJD, 50 g per dose, twice daily) plus ETV tablet (or ETV placebo) 0.5 mg per day in the first 24 weeks (stage 1), and CHM granule plus ETV tablet (0.5 mg per day) from week 25 to 108 (stage 2). Subjects in CG received CHM Granule placebo plus ETV tablet (0.5 mg per day) for 108 weeks throughout the trial. The assessments of primary outcomes (HBV serum markers and HBV-DNA) were conducted by a third-party College of American Pathologists (CAP) qualified laboratory. Adverse effects were observed in the hospitals of recruitment. DISCUSSION: The study was designed to compare the curative effect of CM plus ETV and ETV monotherapy in respect of HBeAg loss, which is recognized by the European Association for the Study of the Liver as "a valuable endpoint". We believe this trial could provide a reliable status for patients' "journey" towards durable responses after treatment discontinuation. The trial was registered before recruitment on Chinese Clinical trial registry (No. ChiCTR-TRC-12002784, Version 1.0, 2015/12/23).


Assuntos
Antivirais/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Guanina/análogos & derivados , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Duplo-Cego , Quimioterapia Combinada , Guanina/administração & dosagem , Hepatite B Crônica/imunologia , Humanos , Estudos Multicêntricos como Assunto , Estudos Prospectivos
9.
World J Gastroenterol ; 24(29): 3273-3280, 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30090007

RESUMO

AIM: To detect the expression of type I inositol 1,4,5-trisphosphate receptor (IP3RI) in the kidney of rats with hepatorenal syndrome (HRS). METHODS: One hundred and twenty-five Sprague-Dawley rats were randomly divided into four groups to receive an intravenous injection of D-galactosamine (D-GalN) plus lipopolysaccharide (LPS; group G/L, n = 50), D-GalN alone (group G, n = 25), LPS alone (group L, n = 25), and normal saline (group NS, n = 25), respectively. At 3, 6, 9, 12, and 24 h after injection, blood, liver, and kidney samples were collected. Hematoxylin-eosin staining of liver tissue was performed to assess hepatocyte necrosis. Electron microscopy was used to observe ultrastructural changes in the kidney. Western blot analysis and real-time PCR were performed to detect the expression of IP3RI protein and mRNA in the kidney, respectively. RESULTS: Hepatocyte necrosis was aggravated gradually, which was most significant at 12 h after treatment with D-galactosamine/lipopolysaccharide, and was characterized by massive hepatocyte necrosis. At the same time, serum levels of biochemical indicators including liver and kidney function indexes were all significantly changed. The structure of the renal glomerulus and tubules was normal at all time points. Western blot analysis indicated that IP3RI protein expression began to rise at 3 h (P < 0.05) and peaked at 12 h (P < 0.01). Real-time PCR demonstrated that IP3RI mRNA expression began to rise at 3 h (P < 0.05) and peaked at 9 h (P < 0.01). CONCLUSION: IP3RI protein expression is increased in the kidney of HRS rats, and may be regulated at the transcriptional level.


Assuntos
Síndrome Hepatorrenal/patologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Rim/patologia , Animais , Modelos Animais de Doenças , Galactosamina/toxicidade , Hepatócitos/patologia , Síndrome Hepatorrenal/induzido quimicamente , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Rim/irrigação sanguínea , Rim/citologia , Rim/ultraestrutura , Lipopolissacarídeos/toxicidade , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Microscopia Eletrônica , Músculo Liso Vascular/citologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/ultraestrutura , Necrose , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Organismos Livres de Patógenos Específicos
10.
World J Gastroenterol ; 24(12): 1361-1372, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29599611

RESUMO

AIM: To assess daclatasvir plus asunaprevir (DUAL) in treatment-naïve patients from mainland China, Russia and South Korea with hepatitis C virus (HCV) genotype 1b infection. METHODS: Patients were randomly assigned (3:1) to receive 24 wk of treatment with DUAL (daclatasvir 60 mg once daily and asunaprevir 100 mg twice daily) beginning on day 1 of the treatment period (immediate treatment arm) or following 12 wk of matching placebo (placebo-deferred treatment arm). The primary endpoint was a comparison of sustained virologic response at posttreatment week 12 (SVR12) compared with the historical SVR rate for peg-interferon plus ribavirin (70%) among patients in the immediate treatment arm. The first 12 wk of the study were blinded. Safety was assessed in DUAL-treated patients compared with placebo patients during the first 12 wk (double-blind phase), and during 24 wk of DUAL in both arms combined. RESULTS: In total, 207 patients were randomly assigned to immediate (n = 155) or placebo-deferred (n = 52) treatment. Most patients were Asian (86%), female (59%) and aged < 65 years (90%). Among them, 13% had cirrhosis, 32% had IL28B non-CC genotypes and 53% had baseline HCV RNA levels of ≥ 6 million IU/mL. Among patients in the immediate treatment arm, SVR12 was achieved by 92% (95% confidence interval: 87.2-96.0), which was significantly higher than the historical comparator rate (70%). SVR12 was largely unaffected by cirrhosis (89%), age ≥ 65 years (92%), male sex (90%), baseline HCV RNA ≥ 6 million (89%) or IL28B non-CC genotypes (96%), although SVR12 was higher among patients without (96%) than among those with (53%) baseline NS5A resistance-associated polymorphisms (at L31 or Y93H). During the double-blind phase, aminotransferase elevations were more common among placebo recipients than among patients receiving DUAL. During 24 wk of DUAL therapy (combined arms), the most common adverse events (≥ 10%) were elevated alanine aminotransferase and upper respiratory tract infection; emergent grade 3-4 laboratory abnormalities were infrequently observed, and all grade 3-4 aminotransferase abnormalities (alanine aminotransferase, n = 9; aspartate transaminase, n = 6) reversed within 8-11 d. Two patients discontinued DUAL treatment; one due to aminotransferase elevations, nausea, and jaundice and the other due to a fatal adverse event unrelated to treatment. There were no treatment-related deaths. CONCLUSION: DUAL was well-tolerated during this phase 3 study, and SVR12 with DUAL treatment (92%) exceeded the historical SVR rate for peg-interferon plus ribavirin of 70%.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Adulto , Idoso , China , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Imidazóis/uso terapêutico , Isoquinolinas/uso terapêutico , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Placebos , República da Coreia , Federação Russa , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada , Falha de Tratamento , Adulto Jovem
11.
J Cell Mol Med ; 22(2): 808-822, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29063670

RESUMO

Emerging evidence indicates that irisin provides beneficial effects in diabetes. However, whether irisin influences the development of diabetic cardiomyopathy (DCM) remains unclear. Therefore, we investigated the potential role and mechanism of action of irisin in diabetes-induced myocardial dysfunction in mice. Type 1 diabetes was induced in mice by injecting streptozotocin, and the diabetic mice were administered recombinant r-irisin (low or high dose: 0.5 or 1.5 µg/g body weight/day, I.P.) or PBS for 16 weeks. Irisin treatment did not alter blood glucose levels in the diabetic mice. However, the results of echocardiographical and histopathological assays indicated that low-dose irisin treatment alleviated cardiac fibrosis and left ventricular function in the diabetic mice, whereas high-dose irisin failed to mitigate the ventricular function impairment and increased collagen deposition. The potential mechanism underlying the effect of low-dose irisin involved irisin-mediated inhibition of high glucose-induced endothelial-to-mesenchymal transition (EndMT); conversely, high-dose irisin treatment enhanced high glucose-induced MMP expression by stimulating MAPK (p38 and ERK) signalling and cardiac fibroblast proliferation and migration. Low-dose irisin alleviated DCM development by inhibiting high glucose-induced EndMT. By contrast, high-dose irisin disrupted normal MMP expression and induced cardiac fibroblast proliferation and migration, which results in excess collagen deposition. Thus, irisin can inhibit high glucose-induced EndMT and exert a dose-dependent bidirectional effect on DCM.


Assuntos
Cardiomiopatias Diabéticas/patologia , Fibronectinas/farmacologia , Glucose/toxicidade , Células Endoteliais da Veia Umbilical Humana/patologia , Mesoderma/patologia , Animais , Glicemia/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Cardiomiopatias Diabéticas/sangue , Cardiomiopatias Diabéticas/fisiopatologia , Ativação Enzimática/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mesoderma/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Estreptozocina , Fator de Crescimento Transformador beta/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Mol Med Rep ; 16(5): 7513-7519, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28944890

RESUMO

Paeonol (Pae) is an herbal extract that has attracted extensive attention for its anti­cancer effects demonstrated by a number of studies, which have predominantly demonstrated inhibition of cell proliferation and induction of apoptosis. The influence of Pae on cancer cell metastasis has been less widely reported. The present study aimed to investigate the under­reported effects of Pae on the growth, invasion and migration of poorly differentiated BGC823 gastric cancer cells with strong invasive and metastatic abilities. The anti­proliferative and pro­apoptotic effects of Pae on BGC823 cells were verified by Cell Counting kit­8 and Annexin V­fluorescein isothiocyanate/propidium iodide assays. Cell scratch­wound healing and Transwell methods were applied, and it was demonstrated that Pae could exert inhibitory activities on the invasion and migration of BGC823 cells. Furthermore, it was indicated by western blot analysis that Pae could downregulate the protein expression levels of matrix metalloproteinase (MMP)­2 and ­9 in a concentration­dependent manner, which may support a novel potential mechanism accounting for its anti­cancer effects on gastric cancer.


Assuntos
Acetofenonas/toxicidade , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
13.
World J Gastroenterol ; 23(2): 306-317, 2017 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-28127204

RESUMO

AIM: To assess the efficacy and safety of in vivo electroporation (EP)-mediated dual-plasmid hepatitis B virus (HBV) DNA vaccine vs placebo for sequential combination therapy with lamivudine (LAM) in patients with chronic hepatitis B. METHODS: Two hundred and twenty-five patients were randomized to receive either LAM + vaccine (vaccine group, n = 109) or LAM + placebo (control group, n = 116). LAM treatment lasted 72 wk. Patients received the DNA vaccine or placebo by intramuscular injection mediated by EP at weeks 12 (start of treatment with vaccine or placebo, SOT), 16, 24, and 36 (end of treatment with vaccine or placebo, EOT). RESULTS: In the modified intent-to-treat population, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 after EOT compared with the control group. A trend toward a difference in the number of patients with undetectable HBV DNA at week 28 after EOT was obtained. Adverse events were similar. In the dynamic per-protocol set, which excluded adefovir (ADV) add-on cases at each time point instantly after ADV administration due to LAM antiviral failure, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 and 28 after EOT compared with the control group. More patients with undetectable HBV DNA at week 28 after EOT in the vaccine group were also observed. Among patients with a viral load < 1000 copies/mL at week 12, more patients achieved HBeAg seroconversion in the vaccine group than among controls at week 36 after EOT, as well as less virological breakthrough and YMDD mutations. CONCLUSION: The primary endpoint was not achieved using the HBV DNA vaccine. The HBV DNA vaccine could only be beneficial in subjects that have achieved initial virological response under LAM chemotherapy.


Assuntos
DNA Viral/uso terapêutico , Eletroporação/métodos , Vacinas contra Hepatite B/uso terapêutico , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Vacinas de DNA/uso terapêutico , Adulto , DNA Viral/administração & dosagem , DNA Viral/efeitos adversos , DNA Viral/isolamento & purificação , Método Duplo-Cego , Farmacorresistência Viral/efeitos dos fármacos , Feminino , Vacinas contra Hepatite B/administração & dosagem , Vacinas contra Hepatite B/efeitos adversos , Vírus da Hepatite B/isolamento & purificação , Humanos , Injeções Intramusculares , Lamivudina/administração & dosagem , Masculino , Plasmídeos , Inibidores da Transcriptase Reversa/administração & dosagem , Resultado do Tratamento , Vacinas de DNA/administração & dosagem , Vacinas de DNA/efeitos adversos , Carga Viral , Adulto Jovem
14.
Front Plant Sci ; 8: 2253, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29379514

RESUMO

Hydrological conditions determine the distribution of plant species in wetlands, where conditions such as water depth and hydrological fluctuations are expected to affect the interspecific interactions among emergent wetland species. To test such effects, we conducted a greenhouse experiment with three treatment categories, interspecific interaction (mixed culture or monoculture), water depth (10 or 30 cm depth), and hydrological fluctuation (static or fluctuating water level), and two common emergent wetland plant species, Scirpus planiculumis Fr. (Cyperaceae) and Phragmites australis var. baiyangdiansis (Gramineae). An increase in the water depth significantly restrained the growth of both S. planiculumis and P. australis, while hydrological fluctuations did not obviously alter the growth of either species. In addition, both water depth and hydrological fluctuations significantly affected the interspecific interaction between these two wetland species. P. australis benefited from interspecific interaction under increasing water depth and hydrological fluctuations, and the RII values were clearly positive for plants grown at a water depth that fluctuated around 30 cm. The results may have some implications for understanding how S. planiculumis and P. australis, as well as wetland communities, respond to the natural variation or human modification of hydrological conditions.

15.
Clin Exp Pharmacol Physiol ; 44(1): 114-122, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27757983

RESUMO

Poly (ADP-ribose) polymerase (PARP) plays an important role in endothelial dysfunction, leading to atherogenesis and vascular-related diseases. However, whether PARP regulates nitric oxide (NO), a key regulator of endothelial function, is unclear so far. We investigated whether inhibition of PARP-1, the most abundant PARP isoform, prevents atherogenesis by regulating NO production and tried to elucidate the possible mechanisms involved in this phenomenon. In apolipoprotein E-deficient (apoE-/- ) mice fed a high-cholesterol diet for 12 weeks, PARP-1 inhibition via treatment with 3,4-dihydro-54-(1-piperindinyl) butoxy-1(2H)-isoquinoline (DPQ) or PARP-1 gene knockout reduced aortic atherosclerotic plaque areas (49% and 46%, respectively). Both the groups showed restored NO production in mouse aortas with reduced arginase II (Arg II) expression compared to that in the controls. In mouse peritoneal macrophages and aortic endothelial cells (MAECs), PARP-1 knockout resulted in lowered Arg II expression. Moreover, phosphorylation of endothelial NO synthase (eNOS) was preserved in the aortas and MAECs when PARP-1 was inhibited. Reduced NO production in vitro due to PARP-1 deficiency could be restored by treating the MAECs with oxidized low-density lipoprotein treatment, but this effect could not be achieved with peritoneal macrophages, which was likely due to a reduction in the expression of induced NOS expression. Our findings indicate that PARP-1 inhibition may attenuate atherogenesis by restoring NO production in endothelial cells and thus by reducing Arg II expression and consequently arginase the activity.


Assuntos
Aorta/metabolismo , Arginase/metabolismo , Aterosclerose/metabolismo , Regulação para Baixo/fisiologia , Óxido Nítrico/biossíntese , Poli(ADP-Ribose) Polimerase-1/deficiência , Animais , Aterosclerose/induzido quimicamente , Aterosclerose/prevenção & controle , Células Cultivadas , Colesterol na Dieta/efeitos adversos , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
16.
Oncotarget ; 7(24): 35562-35576, 2016 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-27191745

RESUMO

Previous studies demonstrated that aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which eliminates ALDH2 activity down to 1%-6%, is a susceptibility gene for coronary disease. Here we investigated the underlying mechanisms based on our prior clinical and experimental studies. Male apoE-/- mice were transfected with GFP, ALDH2-overexpression and ALDH2-RNAi lentivirus respectively (n=20 each) after constrictive collars were placed around the right common carotid arteries. Consequently, ALDH2 gene silencing led to an increased en face plaque area, more unstable plaque with heavier accumulation of lipids, more macrophages, less smooth muscle cells and collagen, which were associated with aggravated inflammation. However, ALDH2 overexpression displayed opposing effects. We also found that ALDH2 activity decreased in atherosclerotic plaques of human and aged apoE-/- mice. Moreover, in vitro experiments with human umbilical vein endothelial cells further illustrated that, inhibition of ALDH2 activity resulted in elevating inflammatory molecules, an increase of nuclear translocation of NF-κB, and enhanced phosphorylation of NF-κB p65, AP-1 c-Jun, Jun-N terminal kinase and p38 MAPK, while ALDH2 activation could trigger contrary effects. These findings suggested that ALDH2 can influence plaque development and vulnerability, and inflammation via MAPK, NF-κB and AP-1 signaling pathways.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Doença das Coronárias/patologia , Inflamação/metabolismo , Placa Aterosclerótica/patologia , Fatores Etários , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Células Cultivadas , Doença das Coronárias/sangue , Vasos Coronários/patologia , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , Humanos , Lentivirus/genética , Lipídeos/sangue , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout para ApoE , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo , Fator de Transcrição RelA/metabolismo , Transfecção , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Mol Med Rep ; 14(1): 649-54, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27221044

RESUMO

The aim of the present study was to identify the genetic defect responsible for familial coronary artery disease/myocardial infarction (CAD/MI), which exhibited an autosomal dominant pattern of inheritance, in an extended Chinese Han pedigree containing 34 members. Using exome and Sanger sequencing, a novel 6­base pair (bp) 'CAGCCG' deletion in exon 11 of the myocyte enhancer factor 2A (MEF2A) gene was identified, which cosegregated with CAD/MI cases in this family. This 6­bp deletion was not detected in 311 sporadic cases of premature CAD/MI or in 323 unrelated healthy controls. Determination of a genetic risk profile has a key role in understanding the pathogenesis of CAD and MI. Among the reported risk­conferring genes and their variants, mutations in MEF2A have been reported to segregate with CAD/MI in Caucasian families. Causative missense mutations have also been detected in sporadic CAD/MI cases. However, this suggested genetic linkage is controversial, since it could not be confirmed by ensuing studies. The discovery of a novel MEF2A mutation in a Chinese family with premature CAD/MI suggests that MEF2A may have a significant role in the pathogenesis of premature CAD/MI. To better understand this association, further in vitro and in vivo studies are required.


Assuntos
Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/genética , Fatores de Transcrição MEF2/genética , Deleção de Sequência , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Grupo com Ancestrais do Continente Asiático , Biomarcadores , Criança , China , Mapeamento Cromossômico , Angiografia Coronária , Exoma , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto Jovem
18.
Oncotarget ; 7(21): 31053-66, 2016 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-27105518

RESUMO

Cardiac fibrosis is an important pathological process of diabetic cardiomyopathy, the underlying mechanism remains elusive. This study sought to identify whether inhibition of Myocyte enhancer factor 2A (MEF2A) alleviates cardiac fibrosis by partially regulating Endothelial-to-mesenchymal transition (EndMT). We induced type 1 diabetes mellitus using the toxin streptozotocin (STZ) in mice and injected with lentivirus-mediated short-hairpin RNA (shRNA) in myocardium to inhibit MEF2A expression. Protein expression, histological and functional parameters were examined twenty-one weeks post-STZ injection. We found that Diabetes mellitus increased cardiac MEF2A expression, aggravated cardiac dysfunction and myocardial fibrosis through the accumulation of fibroblasts via EndMT. All of these features were abolished by MEF2A inhibition. MEF2A gene silencing by shRNA in cultured human umbilical vein endothelial cells (HUVECs) ameliorated high glucose-induced phenotypic transition and acquisition of mesenchymal markers through interaction with p38MAPK and Smad2. We conclude that inhibition of endothelial cell-derived MEF2A might be beneficial in the prevention of diabetes mellitus-induced cardiac fibrosis by partially inhibiting EndMT through interaction with p38MAPK and Smad2.


Assuntos
Diabetes Mellitus Experimental/terapia , Fibrose/terapia , Fatores de Transcrição MEF2/antagonistas & inibidores , Miocárdio/patologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Transição Epitelial-Mesenquimal , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Fatores de Transcrição MEF2/biossíntese , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Transdução de Sinais , Transfecção
19.
Oncotarget ; 7(24): 35618-35631, 2016 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-27027354

RESUMO

Diabetic cardiomyopathy (DCM) is characterized by structural alterations such as cardiomyocyte hypertrophy, necrosis and focal fibrosis. Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme which can be activated by DNA damage and plays a critical role in various diseases. We hypothesized that PARP-1 may play an important role in DCM and that its inhibition may protect cardiomyocytes from inflammation and apoptosis in DCM. H9c2 cardiomyocytes were treated with normal glucose, mannitol or high glucose (HG). Male C57BL/6 mice or PARP-1-/- mice were treated with streptozotocin (STZ) by intraperitoneal injection for 5 consecutive days to induce diabetes. In vitro, HG stimulation induced oxidative stress and DNA damage and increased PARP-1 expression and activity. Compared with the control, pretreatment with PARP-1 siRNA significantly reduced HG-induced inflammatory response, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 secretion, and intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) expression. PARP-1 inhibition reduced HG-induced cardiomyocyte apoptosis through downregulation of cleaved caspases and activation of IGF-1R/Akt pathway. In vivo, hyperglycemia increased the protein expression of nitrotyrosine and PARP-1 as well as PARP-1 activity. PARP-1 gene deletion significantly improved cardiac dysfunction and reduced inflammatory response and apoptosis. This work demonstrated the critical role of PARP-1 in diabetic heart injury, and suggested that PARP-1 inhibition may be a feasible strategy for the treatment of DCM.


Assuntos
Apoptose , Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/patologia , Inflamação/patologia , Miócitos Cardíacos/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Animais , Caspases/metabolismo , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Regulação para Baixo , Técnicas de Inativação de Genes , Hiperglicemia/complicações , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/enzimologia , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno , Receptores de Somatomedina/metabolismo , Transdução de Sinais , Estreptozocina/toxicidade , Fator de Necrose Tumoral alfa/metabolismo
20.
Int J Infect Dis ; 45: 36-42, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26899955

RESUMO

OBJECTIVES: In this study, we studied the N and H genes from wild type measles viruses (MeVs) isolated during the 2013-2014 outbreak. METHODS: Clinical samples were collected, and the genotyping, phylogenetic analysis were performed. RESULTS: The vaccination rate of the study population was 4%. Genotype H1a was the predominant genotype. Wild type viruses were classified into clusters A and B, C and may have different origins. N-450 sequences from wild type viruses were highly homologous with, and likely evolved from MeVs circulating in Tianjing and Henan in 2012. MVs/Shenyang.CHN/18.14/3 could have evolved from MeVs from Liaoning, Beijing, Hebei, Heilongjiang, Henan, Jilin, and Tianjin. Our data suggested that one or more of the same viruses circulated between Beijing, Shenyang, Hong Kong, Taiwan and Berlin. CONCLUSIONS: Important factors contributing to outbreaks could include weak vaccination coverage, poor vaccination strategies, and migration of adult workers between cities, countries, and from rural areas to urban areas.


Assuntos
Vírus do Sarampo/genética , Sarampo/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Feminino , Genótipo , Humanos , Masculino , Sarampo/epidemiologia , Sarampo/prevenção & controle , Vírus do Sarampo/classificação , Pessoa de Meia-Idade , Vacinação
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