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1.
Medicine (Baltimore) ; 98(43): e17607, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651869

RESUMO

BACKGROUND: This study aims to provide the best possible evidence-based information on the efficacy and safety of sifalimumab for treatment of skin injury (SI) caused by systemic lupus erythematosus (SLE). METHODS: In this study, electronic databases of MEDLINE, EMBASE, Cochrane Library, PsycINFO, CINAHL Plus, Global Health, WHO Global Index Medicus, Virtual Health Library, Social Care Online, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure will be searched comprehensively from inceptions to June 30, 2019 without language restrictions. We will include randomized controlled trials (RCTs) on evaluating the efficacy and safety of sifalimumab for SI caused by SLE. Two investigators will conduct study selection, data extraction, and risk of bias assessment independently. We will use RevMan 5.3 Software to perform statistical analysis. RESULTS: This study will lie in the exhaustive and systematic nature of the literature search and its methods for evaluating quality and analyzing RCTs data. Considering the controversial efficacy of the treatment for sifalimumab, this study is responsible for improving the existing evidence on the efficacy and safety of sifalimumab for SI caused by SLE. CONCLUSION: The results of this study will provide latest evidence for judging whether sifalimumab is an effective intervention for patients with SI caused by SLE or not. STUDY REGISTRATION: CRD42019148225.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Dermatopatias/tratamento farmacológico , Pele/lesões , Humanos , Projetos de Pesquisa , Dermatopatias/etiologia , Revisão Sistemática como Assunto , Resultado do Tratamento
2.
Sci Rep ; 9(1): 11053, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363115

RESUMO

Genitourinary tuberculosis (GUTB) accounts for up to 40% of extrapulmonary tuberculosis cases. Rapid tests for GUTB are urgently needed because it is often associated with delayed health-care seeking, leading to serious consequences. This study evaluated the performance of the Xpert MTB/RIF assay in the rapid diagnosis of urinary tract tuberculosis (UTB) and rifampicin-resistant tuberculosis with urine specimens. In all, 302 patients were included from four hospitals in China. Suspected UTB patients were tested with Xpert, smear, and MGIT 960 culture. Drug susceptibility testing (DST) was conducted for culture-positive cases. The performance of the assays was evaluated against MGIT 960 culture and a composite reference standard (CRS). Among all participants, 150 (49.7%) had CRS-positive UTB, of whom 36 (24.0%) were culture-confirmed. Against culture, Xpert and smear achieved a sensitivity of 94.4% (95% CI: 81.3-99.3%) and 22.2% (95% CI: 10.1-39.2%), respectively. Against CRS, the sensitivity of Xpert, smear and culture was 41.3% (95% CI: 33.4-49.7%), 7.3% (95% CI: 3.7-12.7%), and 24.0% (95% CI: 17.4-31.6%). Xpert had better performance than smear and culture in detecting UTB from urine samples and could be considered for the diagnosis of UTB. Moreover, Xpert showed better performance than MGIT 960-based DST using urine culture.

3.
Biotechnol J ; : e1900135, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31464064

RESUMO

Microalgae have long been considered as potential biological feedstock for the production of wide array of bioproducts, such as biofuel feedstock because of their lipid accumulating capability. However, lipid productivity of microalgae is still far below commercial viability. Here, a glucose-6-phosphate dehydrogenase from the oleaginous microalga Nannochloropsis oceanica is identified and heterologously expressed in the green microalga Chlorella pyrenoidosa to characterize its function in the pentose phosphate pathway. It is found that the G6PD enzyme activity toward NADPH production is increased by 2.19-fold in engineered microalgal strains. Lipidomic analysis reveals up to 3.09-fold increase of neutral lipid content in the engineered strains, and lipid yield is gradually increased throughout the cultivation phase and saturated at the stationary phase. Moreover, cellular physiological characteristics including photosynthesis and growth rate are not impaired. Collectively, these results reveal the pivotal role of glucose-6-phosphate dehydrogenase from N. oceanica in NADPH supply, demonstrating that provision of reducing power is crucial for microalgal lipogenesis and can be a potential target for metabolic engineering.

4.
Bioresour Technol ; 289: 121720, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31271916

RESUMO

Haematococcus pluvialis is a main biological resource for the antioxidant astaxanthin production, however, potential modulators and molecular mechanisms underpinning astaxanthin accumulation remain largely obscured. We discovered that provision of ethanol (0.4%) significantly triggered the cellular astaxanthin content up to 3.85% on the 4th day of treatment. Amongst, 95% of the accumulated astaxanthin was esterified, particularly enriched with monoesters. Ultrastructural analysis revealed that ethanol altered cell wall structure and physiological properties. Antioxidant analyses revealed that astaxanthin accumulation offset the ethanol induced oxidative stress. Ethanol treatment reduced carbohydrates while increased lipids and jasmonic acid production. Transcriptomic analysis uncovered that ethanol orchestrated the expression of crucial genes involved in carotenogenesis, e.g. PSY, BKT and CRTR-b were significantly upregulated. Moreover, methyl jasmonic acid synthesis was induced and played a major role in regulating the carotenogenic genes. The findings uncovered the novel viewpoint in the intricate transcriptional regulatory mechanisms of astaxanthin biosynthesis.


Assuntos
Clorofíceas/metabolismo , Ciclopentanos/metabolismo , Etanol/farmacologia , Oxilipinas/metabolismo , Clorofíceas/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Xantofilas/biossíntese
5.
Medicine (Baltimore) ; 98(30): e16558, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348279

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a very tricky orthopedic condition. If it can not be treated fairly well, it may greatly affect quality of life in patients with RA, and even can cause disability. Total knee arthroplasty (TKA) has reported to treat patients with RA effectively. However, no study has systematically explored its efficacy and complications for patients with RA. METHODS: Seven databases will be searched from their inceptions to the present without any language restrictions: MEDICINE, EMBASE, Cochrane Library, Web of Science, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. Two authors will carry out all study selection, data extraction, and risk of bias assessment independently. RESULTS: The primary outcome of joint pain will be measured by any pain scales, such as visual analogue scale. The secondary outcomes will include joint function, quality of life, and postoperative adverse events. The joint function will be measured by The Western Ontario and McMaster Universities Arthritis Index, Knee Injury and Osteoarthritis Outcome Score, or other relevant scales. The quality of life will be assessed by the 36-Item Short Form Health Survey or any related tools. In addition, postoperative adverse events will also be analyzed. CONCLUSIONS: The findings of this study will summarize the latest existing evidence on the efficacy and safety of TKA for patients with RA. ETHICS AND DISSEMINATION: This study does not need ethical approval, because it will not analyze individual data. The results of this study are expected to be disseminated at peer-reviewed journals. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019133274.


Assuntos
Artrite Reumatoide/cirurgia , Artroplastia do Joelho , Artrite Reumatoide/patologia , Feminino , Humanos , Articulação do Joelho/patologia , Articulação do Joelho/cirurgia , Masculino , Medição da Dor , Período Pós-Operatório , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Revisão Sistemática como Assunto , Resultado do Tratamento
6.
Stem Cells Dev ; 28(18): 1236-1252, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311463

RESUMO

Restoring ß-cell mass by the transplantation of pancreatic islets is an effective diabetes treatment, but it is limited by the shortage of donor organs. CD133-expressing pancreatic ductal epithelial cells (PDECs) have the ability to generate insulin-producing cells. The expansion of these cells is dependent on extrinsic niche factors, but few of those signals have been identified. In this study, CD133-expressing PDECs were purified by sorting from adult wild-type C57BL/6 mice and TGFßRIInull/null mice. Furthermore, using immunofluorescence and transplantation assays, we found that the inhibition of the transforming growth factor-ß (TGF-ß) pathway promoted the expansion of CD133-expressing PDECs for many generations and maintained the ability of CD133-expressing PDECs to generate insulin-producing cells. Moreover, western blot, qRT-PCR, and dual luciferase assays using TGF-ß inhibitors were performed to identify the mechanisms by which TGF-ß signaling regulates proliferation and differentiation. The results showed that the inhibition of TGF-ß signaling enhanced Id2 binding to the promoter region of the cell proliferation repressor p16 and promoted the expansion of CD133-expressing PDECs, and the increased Id2 binding to NeuroD1 decreased the transcription of Pax6 to maintain CD133-expressing PDECs in the Pdx1-expression stage. Taken together, the effect of TGF-ß antagonists on CD133-expressing PDECs reveals a novel paradigm of signaling that explains the balance between the expansion and differentiation of pancreatic duct epithelial progenitors.

7.
J Ethnopharmacol ; 234: 44-56, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30610932

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Chrysanthemum indicum Linne (C. indicum), a healthy food and folk medicine in China for thousands of years, has been reported to exert heat-clearing and detoxifying effects and extensively applied to treat various symptoms such as inflammation diseases, hepatitis and headache. AIM OF THIS STUDY: The purpose of the present study was to investigate the protective effect of the supercritical carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) on D-galactose-induced brain and liver damage during aging process and to illuminate the underlying mechanisms. MATERIALS AND METHODS: Mice were orally administrated with CISCFE (100, 150 and 300 mg/kg) after injection with D-galactose. 24 h after the last administration, the blood samples, whole brain and liver tissues were collected for biochemical analysis, histological examination and western blot analysis. The body weight, spleen and thymus indexes, alanine transaminase (ALT), aspartate transaminase (AST), total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), malondialdehyde (MDA) in brain and liver, interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and necrosis factor-α (TNF-α) were detected. Besides, the expressions of Bax, Bcl-2 and cleaved caspase-3 were determined by western blot assay. RESULTS: The results indicated that CISCFE effectively increased the suppressed body weight, attenuated the decline of thymus and spleen indexes, and reduced the elevated levels of ALT and AST induced by D-gal. Furthermore, CISCFE might notably alleviate D-gal-induced abnormal alterations in structure and function of brain and liver dose-dependently via renewing normal antioxidant enzymes activities (SOD, CAT, GSH-Px), reducing MDA accumulation, decreasing inflammatory cytokines productions (IL-1ß, IL-6, TNF-α), as well as attenuating the increase of Bax/Bcl-2 ratio and cleaved caspase-3 activation in the liver and brain. CONCLUSIONS: Taken together, our present results suggested that CISCFE treatment could effectively mitigate the D-gal-induced hepatic and cerebral injury, and the underlying mechanism might be tightly related to the decreased oxidative stress, inflammation and apoptosis, indicating CISCFE might be an alternative and promising agent for the treatment of aging and age-associated brain and liver diseases.


Assuntos
Chrysanthemum/química , Inflamação/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Envelhecimento/patologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Dióxido de Carbono/química , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Flores , Galactose/toxicidade , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Extratos Vegetais/administração & dosagem , Superóxido Dismutase/metabolismo
8.
Phytomedicine ; 52: 272-283, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30599908

RESUMO

BACKGROUND: Berberine (BBR) is the most abundant and major active constituent of Rhizoma Coptidis (RC), which has been widely used to treat inflammatory diseases in traditional oriental medicine. Despite BBR has been found to exhibit pronounced anti-inflammatory effect, the anti-inflammatory activities of its natural derivatives were sparsely dissected out. PURPOSE: To comparatively investigate the anti-inflammatory potential of BBR, and its natural oxoderivative (oxyberberine, OBB) and reduced derivative (dihydroberberine, DHBB) in vitro and in vivo, and delineate the possible underlying mechanism. METHODS: LC-MS/MS was used to identify the natural derivatives of BBR in RC. The potential anti-inflammatory properties of BBR and its natural derivatives were comparatively evaluated in vitro by lipopolysaccharide (LPS)-induced RAW264.7 macrophages cells, and in vivo via three typical acute inflammation murine models. Some important inflammation-related molecules were analyzed by ELISA, qRT-PCR and Western blotting. RESULTS: LC-MS/MS led to the identification of BBR, OBB and DHBB in RC ethyl acetate extract. The in vitro assay indicated that BBR, OBB and DHBB (1.25, 2.5 and 5 µM) pretreatment significantly decreased the levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), prostaglandinE2 (PGE2) and nitricoxide (NO), and inhibited the mRNA expressions of cyclooxygenase-2 (COX-2) and inducible nitricoxide synthase (iNOS) in a dose-dependent manner, with relative efficiency of OBB > BBR > DHBB. Furthermore, OBB, BBR and DHBB remarkably inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 and inhibitory kappa Bα (IκBα). In vivo, BBR (20 mg/kg) and OBB (5, 10, and 20 mg/kg) pretreatment significantly ameliorated the xylene-induced ear edema, carrageenan-stimulated paw edema, and acetic acid-elicited vascular permeability in mice in a dose-dependent manner, with OBB exhibiting superior anti-inflammatory effect at the same dose (20 mg/kg). Histopathological analysis indicated that OBB and BBR could markedly attenuate the inflammatory deterioration and decrease the cellular infiltration in paw tissues. Additionally, the carrageenan-induced increases in TNF-α, IL-6, IL-1ß, PGE2 and NO productions, and COX-2 and iNOS mRNA expressions were effectually and concentration-dependently suppressed by OBB and BBR pretreatment. CONCLUSION: The anti-inflammatory activity of BBR and its natural derivatives was in the order of OBB > BBR > DHBB. OBB was for the first time found to be endowed with pronounced anti-inflammatory property, which was probably associated with suppressing the activation of NF-κB signaling pathway, and the subsequent gene expressions and productions of pro-inflammatory mediators. The results might contribute to illuminating the pharmacodynamic underpinnings of RC and provide evidence for developing OBB as a safe and promising natural lead compound in inflammation treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Berberina/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Animais , Berberina/análogos & derivados , Carragenina/efeitos adversos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Feminino , Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Inibidor de NF-kappaB alfa/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
J Pathol ; 248(1): 103-115, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30666650

RESUMO

Liver metastasis is the main cause of death in patients with colorectal cancer (CRC). Here, we searched for CRC metastasis-associated circular RNA in a mouse model of liver metastasis of CRC by using RNA (transcriptome)-sequencing. We identified a novel and conserved circular RNA, circ-NSD2, functioning as a promoter of CRC metastasis. Circ-NSD2 expression was elevated in CRC tissues and was markedly increased in advanced stages or metastatic tumours of CRC patients. Gain-of-function and loss-of-function experiments demonstrated that circ-NSD2 promoted migration and metastasis of CRC in vitro and in vivo. Mechanistically, circ-NSD2 acted as a sponge for the tumour suppressor miR-199b-5p and activated DDR1 (discoidin domain receptor tyrosine kinase 1) and JAG1 (Jagged 1) genes, which synergistically helped with cell-matrix interaction, migration and metastasis of CRC cells. Taken together, our findings highlight a novel oncogenic function of circ-NSD2 and uncover a key mechanism for the circ-NSD2/miR-199b-5p/DDR1/JAG1 axis in CRC metastasis, which may serve as a prognostic factor and therapeutic target for antimetastatic therapy in CRC patients. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

10.
Front Pharmacol ; 9: 1181, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386242

RESUMO

Curcumin (CUR), a promising naturally occurring dietary compound, is commonly recognized as the potential anti-inflammatory agent. While the application of CUR was hampered by its low stability and poor systemic bioavailability, it has been suggested that the biological activities of CUR are intimately related to its metabolites. In the current investigation, we aimed to comparatively explore the anti-inflammatory effects of tetrahydrocurcumin (THC), octahydrocurcumin (OHC), and CUR, and to elucidate the underlying action mechanisms on experimental mice models of acute inflammation, i.e., xylene-induced ear edema, acetic acid-induced vascular permeability, and carrageenan-induced paw edema. The results showed that THC and OHC exerted significant and dose-dependent inhibitions on the formation of ear edema induced by xylene and paw edema provoked by carrageenan and inhibited the Evans blue dye leakage in peritoneal cavity elicited by acetic acid. Moreover, THC and OHC treatments were more effective than CUR in selectively inhibiting the expression of cyclooxygenase 2 (COX-2) and suppressing nuclear factor-κB (NF-κB) pathways via transforming growth factor ß activated kinase-1 (TAK1) inactivation in the carrageenan-induced mouse paw edema model.

11.
Appl Microbiol Biotechnol ; 102(24): 10803-10815, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30349933

RESUMO

Commercial production of biofuel from oleaginous microalgae is often impeded by their slow growth rate than other fast-growing algal species. A promising strategy is to genetically engineer the fast-growing algae to accumulate lipids by expressing key lipogenic genes from oleaginous microalgae. However, lacking of strong expression cassette to transform most of the algal species and potential metabolic target to engineer lipid metabolism has hindered its biotechnological applications. In this study, we engineered the oxidative pentose phosphate pathway (PPP) of green microalga Chlorella pyrenoidosa for lipid enhancement by expressing a glucose-6-phosphate dehydrogenase (G6PD) from oleaginous diatom Phaeodactylum tricornutum. Molecular characterization of transformed lines revealed that heterologous PtG6PD was transcribed and expressed successfully. Interestingly, subcellular localization analyses revealed that PtG6PD was targeted to chloroplasts of C. pyrenoidosa. PtG6PD expression remarkably elevated NADPH content and consequently enhanced the lipid content without affecting growth rate. Collectively, this report represents a promising candidate to engineer lipid biosynthesis in heterologous hosts with notable commercial significance, and it highlights the potential role of plastidial PPP in supplying lipogenic NADPH in microalgae.

12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(5): 1294-1300, 2018 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-30295241

RESUMO

OBJECTIVE: To investigate the mutation rate and mutation characteristics of FBXW7 and NOTCH1 in adult T-ALL, and to study the effect of these 2 mutations on the clinical features and prognosis of patients with adult T-ALL. METHODS: The mutations of FBXW7 and NOTCH1 in 106 adult T-ALL patients were determined by gene sequencing of FBXW7 and NOTCH1 genes. and the clinical characteristics and prognosis were compared. RESULTS: Among the 106 cases of adult T-ALL, there were 21 cases (19.8%) of FBXW7 mutation, 66 cases (62.3%) of NOTCH1 mutation and 18 cases (17.0%) of FBXW7 / NOTCH1 double mutations. The 2-year cumulative overall survival rate and event-free survival rate of the patiants in FBXW7 / NOTCH1 double mutant group were lower than those without mutations (27.8% vs 70.3%)(P<0.01) and (16.7% vs 48.6%) ( P<0.01) respectivly, but the FBXW7 or NOTCH1 mutations had a little effect on the prognosis. The recurrence rate at mutant group was higher than that of the non - mutant group (77.8% vs 43.2%) (P<0.05). CONCLUSION: FBXW7 or NOTCH1 mutations can not be as the prognostic factors, but the FBXW7 / NOTCH1 double mutations may indicate poor prognosis.

13.
Food Funct ; 9(11): 5891-5902, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30375606

RESUMO

Acetaminophen (APAP) is commonly used to relieve pain and fever in a clinical setting, but its excessive use can lead to serious hepatotoxicity. Our previous study demonstrated that polydatin (PD) can effectively attenuate d-galactose- and alcohol-induced hepatotoxicity, however, its effect on APAP-induced hepatotoxicity is still unknown. In this study, we explore the protective effect and potential mechanism of PD against APAP-induced hepatotoxicity in mice. The results indicate that PD effectively improves the survival of mice with APAP-induced hepatotoxicity, significantly alleviating histopathologic alterations in the liver, and decreasing the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). PD significantly and dose-dependently reduces oxidative stress by lowering the content of oxidized glutathione (GSSG), reactive oxygen species (ROS), nitric oxide (NO) and malonaldehyde (MDA), while enhancing the hepatic activities of glutathione (GSH), glutathione peroxidase (GSH-Px) and the GSH/GSSG ratio. Meanwhile, PD also substantially inhibits the levels and mRNA expressions of inducible nitric oxide synthase (iNOS) and NADPH oxidase 2 (NOX2). Additionally, PD markedly arrests apoptosis by assuaging TUNEL-positive hepatocytes and the apoptotic index, decreasing the levels and expression of cytochrome c (CytC), cleaved-caspase-9, apoptotic protease activating factor 1 (Apaf-1), cleaved-caspase-3, and Bax and increasing the level and expression of Bcl-2. Overall, PD pretreatment shows a potent protective effect against APAP-induced hepatotoxicity by relieving oxidative stress and inhibiting apoptosis.

14.
J Hematol Oncol ; 11(1): 95, 2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-30016968

RESUMO

BACKGROUND: Ubiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin-proteasome system. However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study aimed to investigate the role of Ube2v1, one of the ubiquitin-conjugating E2 enzyme variant proteins (Ube2v) but without the conserved cysteine residue required for the catalytic activity of E2s, in CRC. METHODS: Immunohistochemistry and real-time RT-PCR were used to study the expressions of Ube2v1 at protein and mRNA levels in CRC, respectively. Western blotting and immunofluorescence, transmission electron microscopy, and in vivo rescue experiments were used to study the functional effects of Ube2v1 on autophagy and EMT program. Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, western blotting, and real-time RT-PCR were used to analyze the effects of Ube2v1 on histone H4 lysine 16 acetylation, interaction with Sirt1, ubiquitination of Sirt1, and autophagy-related gene expression. RESULTS: Ube2v1 was elevated in CRC samples, and its increased expression was correlated with poorer survival of CRC patients. Ube2v1 promoted migration and invasion of CRC cells in vitro and tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1suppressed autophagy program and promoted epithelial mesenchymal transition (EMT) and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, both rapamycin and trehalose attenuated the enhanced Ube2v1-mediated lung metastasis by inducing the autophagy pathway in an orthotropic mouse xenograft model of lung metastasis. Mechanistically, Ube2v1 promoted Ubc13-mediated ubiquitination and degradation of Sirt1 and inhibited histone H4 lysine 16 acetylation, and finally epigenetically suppressed autophagy gene expression in CRC. CONCLUSIONS: Our study functionally links Ube2v1, an E2 member in the ubiquitin-proteasome system, to autophagy program, thereby shedding light on developing Ube2v1 targeted therapy for CRC patients.

15.
Oncotarget ; 9(15): 12035-12049, 2018 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-29552291

RESUMO

The pathogenesis and key functional molecules involved in inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) remain unclear. Here, we reported that Erbin, a protein required for the polarity of epithelial cells, is conserved across species and highly expressed in the intestinal mucosa in mice and zebrafish. Pathologically, Erbin expression in the intestinal mucosa was significantly decreased in DSS induced acute colitis mice, IL-10 deficient mice and clinical biopsy specimens from patients with ulcerative colitis. Moreover, Erbin deficient mice are more susceptible to experimental colitis, exhibiting more severe intestinal barrier disruption, with increased histological scores and excessive production of proinflammatory cytokines. Mechanistically, Erbin deficiency or knockdown significantly exacerbated activation of autophagic program and autophagic cell death in vivo and in vitro. And, inhibition of autophagy by Chloroquine attenuates excessive inflammatory response in the DSS-induced colitis mouse model of Erbin deletion. Generally, our study uncovers a crucial role of Erbin in autophagic cell death and IBD, giving rise to a new strategy for IBD therapy by inhibiting excessive activation of autophagy and autophagic cell death.

16.
Phytomedicine ; 39: 111-118, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29433672

RESUMO

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are most widely used as effective anti-inflammatory agents. However, their clinical application brings about inevasible gastrointestinal side effects. Pogostemon cablin is a traditional herbal medicine used for the treatment of gastrointestinal diseases in China. One of its representative components, the tricyclic triterpenoid ß-patchoulone (ß-PAE) has demonstrated great anti-inflammatory activity and gastroprotective effect against ethanol-induced gastric injury, but its protective effect against gastric ulcer induced by indomethacin is still unknown. PURPOSE: To assess the protective effect of ß-PAE against ulcer produced by indomethacin and reveal the underlying pharmacological mechanism. STUDY DESIGN: We used an indomethacin-induced gastric ulcer model of rats in vivo. METHODS: Gastroprotective activity of ß-PAE (10, 20, 40 mg/kg, i.g.) was estimated via indomethacin-induced gastric ulcer model in rats. Histopathological and histochemical assessment of ulcerated tissues were performed. Protein and mRNA expression were determined by Elisa, Western blotting and qRT-PCR. RESULTS: ß-PAE could inhibit ulcer formation. Histopathological and histochemical assessment macroscopically demonstrated that ß-PAE alleviates indomethacin-induced gastric ulceration in dose-dependent manner. After administration of ß-PAE, elevated tumor necrosis factor -α level was significantly decreased and the phosphorylation of JNK and IκB was markedly inhibited. ß-PAE suppressed the levels of E-selectin, P-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule and monocyte chemoattractant protein 1, as well as myeloperoxidase. Meanwhile, ß-PAE increased cyclooxygenase enzyme activities (COX-1 and COX-2) to enhance the production of prostaglandin E2. Proangiogenic protein, vascular endothelial growth factor and its receptor fms-like tyrosine kinase-1 mRNA expression were promoted while anti-angiogenic protein, endostatin-1 and its receptor ETAR mRNA expression were decreased. CONCLUSION: ß-PAE may provide gastroprotection in indomethacin-induced gastric ulcer in rats by reducing inflammatory response and improving angiogenesis.


Assuntos
Indometacina/efeitos adversos , Substâncias Protetoras/farmacologia , Sesquiterpenos/farmacologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Indutores da Angiogênese/farmacologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Antiulcerosos/farmacologia , Dinoprostona/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Masculino , Pogostemon/química , Ratos Sprague-Dawley , Úlcera Gástrica/patologia , Fator de Necrose Tumoral alfa/metabolismo
17.
J Cell Biochem ; 119(2): 1538-1547, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28777475

RESUMO

The current study was conducted for investigating the mechanism by which GIT2 gene deletion affects the functional recovery and chondrocyte differentiation in rats with rheumatoid arthritis (RA). Thirty-two rats were randomly divided into normal, model, GIT2 gene knockout (GIT2-KO), and model + GIT2-KO groups. Hematoxylin-eosin (HE) staining was performed for the observation of synovial tissues. Immunohistochemistry examinations were conducted to determine type II collagen expression as well as identify chondrocyte differentiation. qRT-PCR and Western blotting techniques were adopted in order to expressions of interleukin-1ß (1L-1ß), tumor necrosis factor-α (TNF-α), Aggrecan, and Sry-related HMG box 9 (Sox9). A tape measure and Vernier caliper were used to measure the degree of swelling. Compared with synovial tissues in the model group, those in the model + GIT2-KO group, were thicker and comprised of a mass of inflammatory cells (P < 0.05). Compared with the model group, the type II collagen expressions of the cartilage tissues of the rats decreased in the model + GIT2-KO group (P < 0.05). In terms of the degree of swelling in cartilage tissues, the model group displayed a lesser degree of swelling than in that of the model + GIT2-KO group (P < 0.05). When compared with the model + GIT2-KO group, the mRNA expressions of 1L-1ß, TNF-α, Aggrecan, Sox9 and the relevant protein expressions were lower in the model group (all P < 0.05). GIT2 gene deletion might weaken chondrocyte differentiation in rats with RA, as a result acting to ultimately prolong the functional recovery of RA.


Assuntos
Artrite Reumatoide/genética , Proteínas de Ciclo Celular/genética , Condrócitos/citologia , Deleção de Genes , Fosfoproteínas/genética , Animais , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Condrócitos/metabolismo , Colágeno Tipo II/metabolismo , Modelos Animais de Doenças , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Fosfoproteínas/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
18.
Artigo em Inglês | MEDLINE | ID: mdl-29250126

RESUMO

Excessive alcohol consumption leads to serious liver injury, associating with oxidative stress and inflammatory response. Previous study has demonstrated that polydatin (PD) exerted antioxidant and anti-inflammatory effects and attenuated ethanol-induced liver damage, but the research remained insufficient. Hence, this experiment aimed to evaluate the hepatoprotective effect and potential mechanisms of PD on ethanol-induced hepatotoxicity. Our results showed that PD pretreatment dramatically decreased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) in the serum, suppressed the malonaldehyde (MDA) and triglyceride (TG) content and the production of reactive oxygen species (ROS), and enhanced the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), andalcohol dehydrogenase (ADH), and aldehyde dehydrogenase (ALDH), paralleled by an improvement of histopathology alterations. The protective effect of PD against oxidative stress was probably associated with downregulation of cytochrome P450 2E1 (CYP2E1) and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target gene haem oxygenase-1 (HO-1). Moreover, PD inhibited the release of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) via downregulating toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) p65. To conclude, PD pretreatment protects against ethanol-induced liver injury via suppressing oxidative stress and inflammation.

19.
Biomed Environ Sci ; 30(9): 671-675, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29081342

RESUMO

We assessed the role of diabetes mellitus (DM) on treatment effects in drug-susceptible initial pulmonary tuberculosis (PTB) patients. A prospective study was conducted in eight provinces of China from October 2008 to December 2010. We enrolled 1,313 confirmed drug-susceptible initial PTB patients, and all subjects received the treatment regimen (2H3R3E3Z3/4H3R3) as recommended by the national guidelines. Of the 1,313 PTB patients, 157 (11.9%) had DM; these patients had more sputum smear-positive rates at the end of the second month [adjusted odds ratios (aOR) 2.829, 95% confidence intervals (CI) 1.783-4.490], and higher treatment failure (aOR 2.120, 95% CI 1.565-3.477) and death rates (aOR 1.536, 95% CI 1.011-2.628). DM was a contributing factor for culture-positive rates at the end of the second month and treatment failure and death of PTB patients, thus playing an unfavorable role in treatment effects of PTB.


Assuntos
Antituberculosos/uso terapêutico , Diabetes Mellitus/terapia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , China/epidemiologia , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Masculino , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/epidemiologia
20.
Oncotarget ; 8(34): 55776-55789, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28915552

RESUMO

Emerging evidence indicates that microRNAs, a class of small and well-conserved noncoding RNAs, participate in many physiological and pathological processes. RNase III endonuclease DICER is one of the key enzymes for microRNA biogenesis. Here, we found that DICER was downregulated in tumor samples of colorectal cancer (CRC) patients at both mRNA and protein levels. Importantly, intestinal epithelial cell (IEC)-specific deletion of Dicer mice got more tumors after azoxymethane and dextran sulfate sodium (DSS) administration. Interestingly, IEC-specific deletion of Dicer led to severe chronic inflammation and epithelium layer remodeling in mice with or without DSS administration. Microarray analysis of 3 paired Dicer deletion CRC cell lines showed that miR-324-5p was one of the most significantly decreased miRNAs. In the intestinal epithelium of IEC-specific deletion of Dicer mice, miR-324-5p was also found to be markedly reduced. Mechanistically, miR-324-5p directly bound to the 3'untranslated regions (3'UTRs) of HMG-box containing 3 (HMGXB3) and WAS protein family member 2 (WASF-2), two key proteins participated in cell motility and cytoskeleton remodeling, to suppress their expressions. Intraperitoneal injection of miR-324-5p AgomiR (an agonist of miR-324-5p) curtailed chronic inflammation and cytoskeleton remodeling of colorectal epithelium and restored intestinal barrier function in IEC-specific deletion of Dicer mice induced by DSS. Therefore, our study reveals a key role of a DICER/miR-324-5p/HMGXB3/WASF-2 axis in tumorigenesis of CRC by regulation of cytoskeleton remodeling and maintaining integrity of intestinal barriers.

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