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1.
J Enzyme Inhib Med Chem ; 35(1): 72-84, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31682465

RESUMO

Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC50 = 15.0 nM) and modest anti-proliferative activity (IC50 = 785.8 nM). Through two rounds of optimisation, the indazole derivative 9 u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC50 = 3.3 nM) and cellular activity (IC50 = 468.2 nM). Moreover, 9 u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1.

3.
Am J Surg Pathol ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31688139

RESUMO

Pleomorphic mantle cell lymphoma (PMCL) can closely mimic diffuse large B-cell lymphoma (DLBCL) morphologically, and expression of CD5 and cyclin D1 is helpful for differential diagnosis. To date, no cases of CD5/cyclin D1 double-negative PMCL have been reported. Four cases of B-cell lymphoma with an immunophenotype of CD5(-) cyclin D1(-) SOX11(+) and morphologic features compatible with DLBCL were included. Two were previously identified, and the other 2 were screened from 500 cases of B-cell lymphoma. We analyzed their clinicopathologic, immunophenotypic, genetic, and gene expression features. Cases of cyclin D1-positive PMCL, cyclin D1-negative PMCL, germinal center B-cell (GCB) DLBCL, and activated B cell (ABC) DLBCL were also studied for comparison. Similar to other PMCL cases, these 4 patients were mainly elderly male individuals with an aggressive clinical course. None of these tumors had detectable translocations involving CCND1, CCND2, CCND3, CCNE1, CCNE2, MYC, BCL2, or BCL6. The genome-wide copy number profile of these 4 cases was similar to that of cyclin D1-negative PMCL. None of these tumors had high expression of cyclin D1, cyclin D2, or cyclin D3. Similar to cyclin D1-negative PMCL, these cases had higher expression of cyclin E1 and cyclin E2 compared with cyclin D1-positive PMCL. The gene expression pattern of these tumors was also similar to that of cyclin D1-negative PMCL. Here we report for the first time 4 cases of CD5/cyclin D1 double-negative PMCL. SOX11 positivity is useful to identify these rare tumors, and further genetic and gene expression analysis can be used to confirm the diagnosis.

4.
Respir Care ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719192

RESUMO

BACKGROUND: We sought to evaluate the effect of an integrated prospective payment program (IPP) on knowledge of hospice care and willingness to participate in hospice care among family members of patients on prolonged mechanical ventilation (PMV). METHODS: Between November 2013 and April 2014, we used paper-based survey questionnaires from 64 institutions to evaluate knowledge, willingness, and related factors among the main caregivers of patients on PMV regarding hospice care and to determine whether their decisions for the patients were affected by the IPP. RESULTS: The average ages of the respondents and patients on PMV were 51.9 y and 70.8 y respectively; 70.6% of the respondents knew about the Hospice Palliative Care Act (HPCA), and 42.3% of the medical staff had introduced hospice care-related information to patients and caregivers in Taiwan. Among the caregiver respondents, 67.6% agreed to write a letter of intent regarding the choice of hospice care or limited life-sustaining treatment. In total, 66.2% (16.1 + 50.1%) of the respondents agreed to hospice care for their family members (ie, the patients on PMV) when the condition was terminal. The factors of greater HPCA knowledge among the patients on PMV were IPP participation, female sex, and coma status. Factors leading to higher levels of HPCA knowledge included age ≥ 65 y being married, higher income, awareness of the law, and being introduced to hospice care by medical staff. CONCLUSIONS: High levels of hospice care knowledge were unrelated to willingness to participate. HPCA knowledge was greater in the IPP group than in the non-IPP group; however, there was no significant difference in the willingness to agree to hospice care. It is recommended that individuals be encouraged to express their medical decisions.

5.
Mol Cell Proteomics ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31723016

RESUMO

We previously reported that tumor inflammasomes play a key role in tumor control and act as favorable prognostic markers in nasopharyngeal carcinoma (NPC). Activated inflammasomes frequently form distinguishable specks and govern the cellular secretion of IL-1ß. However, we know little about the biological and biochemical differences between cells with and without apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) speck formation. In this study, we used proteomic iTRAQ analysis to analyze the proteomes of NPC cells that differ in their ASC speck formation upon cisplatin treatment. We identified proteins that were differentially over-expressed in cells with specks, and found that they fell into two Gene ontology (GO) pathways: mitochondrial oxidative phosphorylation (OxPhos) and ubiquinone metabolism. We observed up-regulation of various components of the OxPhos machinery (including NDUFB3, NDUFB8 and ATP5B), and subsequently found that these changes lead to mitochondrial ROS (mtROS) production, which promotes the formation and activation of NLRP3 inflammasomes and subsequent pyroptosis. In NPC patients, better local recurrence-free survival was significantly associated with high-level expression of NDUFB8 (P=0.037) and ATP5B (P=0.029), as examined using immunohistochemistry. However, there were no significant associations between the expression of NDUFB8 and ATP5B with overall survival of NPC patients. Together, our results demonstrate that upregulated mitochondrial OxPhos components are strongly associated with NLRP3 inflammasome activation in NPC. Our findings further suggest that high-level expression of OxPhos components could be markers for local recurrence and/or promising therapeutic targets in patients with NPC.

6.
Molecules ; 24(21)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694349

RESUMO

Based upon the intramolecular charge transfer (ICT) mechanism, a novel ratiometric fluorescent probe EB was developed to detect SO32-/HSO3-. The probe displayed both colorimetric and ratiometric responses toward SO32-/HSO3-. It displayed a quick response (within 60 s), good selectivity and high sensitivity (a detection limit of 28 nM) towards SO32-/HSO3-. The SO32-/HSO3- sensing mechanism was confirmed as the Michael addition reaction by ESI-MS. Moreover, the probe could be applied to measure the level of sulfite in real samples, like sugar and chrysanthemum, and it could also be used to detect SO32-/HSO3- in HepG2 cells through confocal fluorescence microscopy, which proved its practical application in clinical diagnosis.

7.
World J Gastroenterol ; 25(40): 6107-6115, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31686766

RESUMO

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) has been widely used in pediatric patients with cholangiopancreatic diseases. AIM: To evaluate the efficacy, safety, and long-term follow-up results of ERCP in symptomatic pancreaticobiliary maljunction (PBM). METHODS: A multicenter, retrospective study was conducted on 75 pediatric patients who were diagnosed with PBM and underwent therapeutic ERCP at three endoscopy centers between January 2008 and March 2019. They were divided into four PBM groups based on the fluoroscopy in ERCP. Their clinical characteristics, specific ERCP procedures, adverse events, and long-term follow-up results were retrospectively reviewed. RESULTS: Totally, 112 ERCPs were performed on the 75 children with symptomatic PBM. Clinical manifestations included abdominal pain (62/75, 82.7%), vomiting (35/75, 46.7%), acholic stool (4/75, 5.3%), fever (3/75, 4.0%), acute pancreatitis (47/75, 62.7%), hyperbilirubinemia (13/75, 17.3%), and elevated liver enzymes (22/75, 29.3%). ERCP interventions included endoscopic sphincterotomy, endoscopic retrograde biliary or pancreatic drainage, stone extraction, etc. Procedure-related complications were observed in 12 patients and included post-ERCP pancreatitis (9/75, 12.0%), gastrointestinal bleeding (1/75, 1.3%), and infection (2/75, 2.7%). During a mean follow-up period of 46 mo (range: 2 to 134 mo), ERCP therapy alleviated the biliary obstruction and reduced the incidence of pancreatitis. The overall effective rate of ERCP therapy was 82.4%; seven patients (9.3%) were lost to follow-up, eight (11.8%) re-experienced pancreatitis, and eleven (16.2%) underwent radical surgery, known as prophylactic excision of the extrahepatic bile duct and hepaticojejunostomy. CONCLUSION: ERCP is a safe and effective treatment option to relieve biliary or pancreatic obstruction in symptomatic PBM, with the characteristics of minor trauma, fewer complications, and repeatability.

8.
Cell Mol Immunol ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754236

RESUMO

The role of the vascularized bone marrow component as a continuous source of donor-derived hematopoietic stem cells that facilitate tolerance induction of vascularized composite allografts is not completely understood. In this study, vascularized composite tissue allograft transplantation outcomes between recipients receiving either conventional bone marrow transplantation (CBMT) or vascularized bone marrow (VBM) transplantation from Balb/c (H2d) to C57BL/6 (H2b) mice were compared. Either high- or low-dose CBMT (1.5 × 108 or 3 × 107 bone marrow cells, respectively) was applied. In addition, recipients were treated with costimulation blockade (1 mg anti-CD154 and 0.5 mg CTLA4Ig on postoperative days 0 and 2, respectively) and short-term rapamycin (3 mg/kg/day for the first posttransplant week and then every other day for another 3 weeks). Similar to high-dose conventional bone marrow transplantation, 5/6 animals in the vascularized bone marrow group demonstrated long-term allograft survival (>120 days). In contrast, significantly shorter median survival was noted in the low-dose CBMT group (~64 days). Consistently high chimerism levels were observed in the VBM transplantation group. Notably, low levels of circulating CD4+ and CD8+ T cells and a higher ratio of Treg to Teff cells were maintained in VBM transplantation and high-dose CBMT recipients (>30 days) but not in low-dose VBM transplant recipients. Donor-specific hyporesponsiveness was shown in tolerant recipients in vitro. Removal of the vascularized bone marrow component after secondary donor-specific skin transplantation did not affect either primary allograft or secondary skin graft survival.

9.
Bioorg Med Chem Lett ; 29(24): 126772, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31711785

RESUMO

Inhibition of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) to prevent brain ß-amyloid (Aß) peptide's formation is a potential effective approach to treat Alzheimer's disease. In this report we described a structure-based optimization of a series of BACE1 inhibitors derived from an iminopyrimidinone scaffold W-41 (IC50 = 7.1 µM) by Wyeth, which had good selectivity and brain permeability but low activity. The results showed that occupying the S3 cavity of BACE1 enzyme could be an effective strategy to increase the biological activity, and five compounds exhibited stronger inhibitory activity and higher liposolubility than W-41, with L-5 was the most potent inhibitor against BACE1 (IC50 = 0.12 µM, logP = 2.49).

10.
Biomed Pharmacother ; 121: 109642, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31731191

RESUMO

BACKGROUND: Recently, a growing number of reports indicated that long non-coding RNAs (lncRNAs) were involved in the development of various cancers. However, the performance of LINC00511 is still limited in hepatocellular carcinoma (HCC). Thus, we attempted to assess the effect of LINC00511 and underlying mechanism in HCC progression. METHODS: TCGA and GEO database acted as supporters to provide us clinical samples data. Overall survival (OS) analyses were plotted using Kaplan-Meier method. Five cell lines were utilized to detect LINC00511 expression level and Cell Counting Kit-8 (CCK-8), colony formation and transwell assays were conducted to examine the effects on cell behaviors. The correlations between LINC00511 and miR-195 or eyes absent homolog 1 (EYA1) were confirmed by luciferase reporter assay. Quantitative real-time PCR and western blotting were fulfilled to ascertain the mRNA and protein expression levels. RESULTS: In this study, we found that LINC00511 was high-regulated in HCC tissue samples and cell lines, which might be linked with unfavorable prognosis of HCC patients and clinical parameters. Loss-of-function experiments determined that LINC00511 deficiency inhibited cell proliferation, colony formation and invasive activity in HepG2 cells, while gain-of-function experiments showed the counter impacts in Huh7 cells. Bioinformatics tools and luciferase reporter assays revealed that LINC00511 may act as a competing endogenous RNA (ceRNA) for miR-195 and positively correlate with EYA1, which was reinforced by rescue experiments. CONCLUSION: Taken together, these findings indicated that LINC00511 interacted with EYA1 promoted HCC development via mediating miR-195, proposing a promising therapeutic biomarker for HCC diagnosis and prognosis.

11.
BMC Palliat Care ; 18(1): 95, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690289

RESUMO

BACKGROUND: Research in Taiwan has indicated that advance care planning is rarely undertaken in long-term care facilities. The purpose of this study was to develop an advance care planning interview guideline and care model to facilitate the process of advance care planning for residents and their families in long-term care facilities. METHODS: This study follows an action research design. Cycles of planning, action, observation, and reflection were planned and modified based on the results of interviews with residents and their families as well as meetings with staff. To establish the interview guideline and care model through this action research study, residents and their families were interviewed separately. The researcher subsequently held meetings with staff members to evaluate the results and identify problems during each advance care planning process. This information was synthesised and used to modify the care model for implementation with the next resident-family pair. This process was performed a total of ten times. RESULTS: This study included residents (N = 10), their families (N = 20), and medical staff (N = 4) at a long-term care facility. The interviews and meetings were audio recorded, transcribed, and subjected to a simple thematic analysis together with the field notes and reflection logs. Four themes emerged from the data related to: opening the conversation with the interview guidelines about the life story of residents; continuing life stories to the quality of remaining years of the residents; gradually changing the topic to the end-of-life care issues; and concluding the conversation by explaining the content of advance directives and hospice care. CONCLUSIONS: The advance care planning care model was implemented following logical thinking from a Chinese perspective. This consisted of opening, developing, changing, and concluding through the views of Confucianism, Buddhism, and Taoism. The research findings indicate that the model successfully facilitated the process of advance care planning for residents and their families.

12.
Inorg Chem ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31710209

RESUMO

Inorganic CuSCN and organic tetrathiafulvalene derivatives (TTFs) have been exploited as hole-transport materials (HTM) in hybrid perovskite solar cells. To develop new HTM, we herein report two hybrid materials incorporating redox-active TTFs with CuSCN framework (TTFs-CuSCN). Single-crystal analysis showed that compound [Cu2(py-TTF-py)(SCN)2] (1) is three-dimensional (3D) and compound [Cu(py-TTF-py)(SCN)] (2) is two-dimensional (2D) (py-TTF-py = 2,6-bis(4'-pyridyl)tetrathiafulvalene). There are covalent coordination interactions between CuSCN and py-TTF-py and short S···S contacts between the py-TTF-py ligands for both compounds. Besides, C···S contacts exist between py-TTF-py ligands of the neighboring 2D networks in 2, which facilitate the charge transfer and supply efficient multidimensional pathways for carrier migration. As a result, 2 presented better semiconductor performance in comparison with that of 1. The performance of 2 related to the HTMs could be significantly improved by modulating the electronic state of the TTFs-CuSCN framework via oxidative doping. The iodine-doped 2D material (2-I2) gives the most excellent conductivity and carrier mobility, which might be a potential new HTM.

13.
Curr Diab Rep ; 19(11): 138, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31749022

RESUMO

PURPOSE OF REVIEW: Obesity is a major risk factor for type 2 diabetes. Although adipose tissue allows storage of excess calories in periods of overnutrition, in obesity, adipose tissue metabolism becomes dysregulated and can promote metabolic diseases. This review discusses recent advances in understandings how adipocyte metabolism impacts metabolic homeostasis. RECENT FINDINGS: The ability of adipocytes to synthesize lipids from glucose is a marker of metabolic fitness, e.g., low de novo lipogenesis (DNL) in adipocytes correlates with insulin resistance in obesity. Adipocyte DNL may promote synthesis of special "insulin sensitizing" signaling lipids that act hormonally. However, each metabolic intermediate in the DNL pathway (i.e., citrate, acetyl-CoA, malonyl-CoA, and palmitate) also has second messenger functions. Mounting evidence suggests these signaling functions may also be important for maintaining healthy adipocytes. While adipocyte DNL contributes to lipid storage, lipid precursors may have additional second messenger functions critical for maintaining adipocyte health, and thus systemic metabolic homeostasis.

14.
Biomaterials ; : 119629, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31767446

RESUMO

Most cancer vaccines under development are associated with defined tumor antigens rather than with all antigens of whole tumor cells, limiting the anti-tumor immune responses that they elicit. This work proposes an immunomodulator (R848)-loaded nanoparticle system (R848@NPs) that can absorb near-infrared light (+NIR) to cause low-temperature hyperthermia that interacts synergistically with its loaded R848 to relieve the tumor-mediated immunosuppressive microenvironment, generating robust anti-tumor memory immunity. In vitro results reveal that the R848@NPs could be effectively internalized by dendritic cells, causing their maturation and the subsequent regulation of their anti-tumor immune responses. Post-treatment observations in mice in which tumors were heat-treated at high temperatures reveal that tumor growth was significantly inhibited initially but not in the longer term, while low-temperature hyperthermia or immunotherapy alone simply delayed tumor growth. In contrast, a combined therapy that involved low-temperature hyperthermia and immunotherapy using R848@NPs/+NIR induced a long-lasting immunologic memory and consequently inhibited tumor growth and prevented cancer recurrence and metastasis. These results suggest that the method that is proposed herein is promising for generating cancer vaccines in situ, by using the tumor itself as the antigen source and the introduced R848@NPs/+NIR to generate a long-term anti-tumor immunity, for personalized immunotherapy.

15.
Acta Pharmacol Sin ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729469

RESUMO

Dengue fever is an acute infectious disease caused by dengue virus (DENV) and transmitted by Aedes mosquitoes. There is no effective vaccine or antiviral drug available to date to prevent or treat dengue disease. Recently, RNA-dependent RNA polymerase (RdRp), a class of polymerases involved in the synthesis of complementary RNA strands using single-stranded RNA, has been proposed as a promising drug target. Hence, we screened new molecules against DENV RdRp using our previously constructed virtual screening method. Mol-5, [1,2,4]triazolo[1,5-a]pyrimidine derivative, was screened out from an antiviral compound library (~8000 molecules). Using biophysical methods, we confirmed the direct interactions between mol-5 and purified DENV RdRp protein. In luciferase assay, mol-5 inhibited NS5-RdRp activity with an IC50 value of 1.28 ± 0.2 µM. In the cell-based cytopathic effect (CPE) assay, mol-5 inhibited DENV2 infectivity with an EC50 value of 4.5 ± 0.08 µM. Mol-5 also potently inhibited DENV2 RNA replication as observed in immunofluorescence assay and qRT-PCR. Both the viral structural (E) and non-structural (NS1) proteins of DENV2 were dose-dependently decreased by treatment with mol-5 (2.5-10 µM). Mol-5 treatment suppressed DENV2-induced inflammation in host cells, but had no direct effect on host defense (JAK/STAT-signaling pathway). These results demonstrate that mol-5 could be a novel RdRp inhibitor amenable for further research and development.

16.
Clin Sci (Lond) ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31755934

RESUMO

G protein-coupled receptors (GPCRs) are important drug targets. Blocking angiotensin II (Ang II) type 1 receptor signaling alleviates hypertension and improves outcomes in patients with heart failure. Changes in structure and trafficking of GPCR, and desensitization of GPCR signaling induce pathophysiological processes. We investigated whether Ang II, via induction of AT1R and µ-opioid receptor (µOR) dimerization in the nucleus tractus solitarius (NTS), leads to progressive hypertension. Ang II signaling increased µOR and adrenergic receptor α2A (α2A-AR) heterodimer levels and decreased expression of extracellular signal-regulated kinases 1/2T202/Y204, ribosomal protein S6 kinaseT359/S363, and nNOSS1416 phosphorylation. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) expression was abolished in the NTS of adult spontaneously hypertensive rats (SHRs). Endomorphin-2 was overexpressed in NTS of adult SHRs compared with that in 6-week-old Wistar-Kyoto rats (WKY). Administration of µOR agonist into the NTS of WKY increased blood pressure (BP), decreased nitric oxide (NO) production, and decreased DDAH1 activity. µOR agonist significantly reduced the activity of DDAH1 and decreased neuronal NO synthase (nNOS) phosphorylation. The AT1R II inhibitor, losartan, significantly decreased BP and abolished AT1R-induced formation of AT1R and µOR, and α2A-AR and µOR, heterodimers. Losartan also significantly increased the levels of nNOSS1416 phosphorylation and DDAH1 expression. These results show that Ang II may induce expression of endomorphin-2 and abolished DDAH1 activity by enhancing the formation of AT1R and µOR heterodimers in the NTS, leading to progressive hypertension.

17.
Exp Dermatol ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31571275

RESUMO

Alopecia areata (AA) is thought to be an autoimmune process. In other autoimmune diseases, the innate immune system and Toll-like receptors (TLRs) can play a significant role. Expression of TLR7, TLR9 and associated inducible genes was evaluated by quantitative PCR in peripheral blood mononuclear cells (PBMCs) from 10 healthy individuals and 19 AA patients, categorized according to disease duration, activity and hair loss extent. Microdissected scalp biopsies from five patients and four controls were also assessed by quantitative PCR and immunohistology. TLR9 was significantly upregulated 2.37 fold in AA PBMCs. Notably, TLR9 was most significantly upregulated in patients with active AA, as shown by a positive hair pull test, compared to stable AA patients. In hair follicle bulbs from AA patients, IFNG and TLR7 exhibited statistically significant 3.85 and 2.70 fold increases in mRNA, respectively. Immunohistology revealed TLR7 present in lesional follicles, while TLR9 positive cells were primarily observed peri-bulbar to AA affected hair follicles. The increased expression of TLR7 and TLR9 suggest components of the innate immune system may be active in AA pathogenesis.

18.
Curr Med Sci ; 39(5): 719-726, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31612388

RESUMO

Hepatitis E virus (HEV) infection is a major cause of morbidity in endemic areas. Its consequences among chronic hepatitis B (CHB) patients have been under-reported. The aim of this study was to assess the impact of superinfective HEV infection (acute and past) on virological and clinical features of patients with CHB infection. Clinical, biochemical, virological and immunological data of 153 CHB patients including 98 with hepatitis B virus (HBV) monoinfection and 55 with HBV-HEV superinfection with both HEV and HBV infection was retrospectively investigated and analyzed in this study conducted in Wuhan, China. An overall anti-HEV IgG seroprevalence was found to be 35.9% in CHB patients. HBV-HEV superinfection patients showed significantly higher rate of complications (ascites, hepato-renal syndrome & encephalopathy) (all with P=0.04), cirrhosis (P<0.001) and acute-on-chronic liver failure (P<0.001) than HBV monoinfection patients. They also displayed elevated ALTs (P<0.001) and total serum bilirubin (P<0.001) with diminished albumin (P<0.001) and HBV viral load (P<0.001). Cytokines assay revealed increased expression of IL-6 (P=0.02), IL-10 (P=0.009) and TNF-α (P=0.003) in HBV-HEV superinfection patients compared to HBV monoinfection patients. Our study demonstrated that HEV superinfection in CHB patients was associated with progressive clinical manifestation, which is likely due to the enhanced expression of cytokines related with hepatocytes necrosis. HEV was also associated with repressed HBV replication, but the underlying mechanism requires further investigation.

19.
Curr Med Sci ; 39(5): 784-793, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31612397

RESUMO

Huai Qi Huang (HQH) exerts great effects in clinic, such as anti-inflammation, immune-regulation, anti-cancer, and so on. However, the mechanism by which HQH protects juvenile idiopathic arthritis (JIA) is obscure. Thus, we explored deeply the protective mechanisms in juvenile collagen-induced arthritis (CIA) rat model. Pyroptosis is Gasdermin D (GSDMD)-dependent programmed cell death, involved in many diseases, such as sepsis. We investigated whether GSDMD-induced pyroptosis take part in mechanisms of juvenile CIA arthritis. Juvenile Wistar rats (3-4 weeks) were injected intradermally with fully emulsified bovine type II collagen and complete Freund's adjuvant to establish CIA rat models. Later, the CIA rats received oral administration of HQH (4.16 g/kg) once a day from the day 21 of modeling, with the treatment lasting for 28 days. Varieties of indicators were measured for evaluation of anti-inflammation effect of HQH, including hind paw swelling, arthritis scores, micro CT, and histopathological changes and the level of pro-inflammatory cytokines in the serum, including tumor necrosis factor alpha (TNF-±) and interleukin-18 (IL-18). The expression of GSDMD and caspase-1 in the joint synovial tissues was detected. The results demonstrated that the expression of the pyroptotic protein GSDMD and its upstream caspase-1 was significantly increased in the synovial tissues of CIA rats. The treatment of HQH ameliorated the symptoms in CIA rats, reduced levels of pro-inflammatory cytokines and hind paw swelling, down-regulated the expression of GDSMD and caspase-1. GSDMD-induced pyroptosis participated in the pathogenesis of CIA rats. The study supported that HQH can effectively improve joints inflammation of juvenile collagen-induced arthritis rats by inhibiting pyroptosis pathway in the joint synovial tissues.

20.
BMJ Open ; 9(10): e026626, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619415

RESUMO

OBJECTIVES: A pay-for-performance (P4P) programme is a management strategy that encourages healthcare providers to deliver high quality of care. In Taiwan, the P4P programme has been implemented for diabetes, and certified diabetes physicians voluntarily enrol patients with diabetes into the P4P programme. The objectives of this study were to compare the risk of stroke and its related factors in patients with type 2 diabetes who were enrolled in a P4P programme compared with those who were not. STUDY DESIGN: This study is a natural experiment in Taiwan. A retrospective cohort investigation was conducted from 2002 to 2013, which included 459 726 patients with type 2 diabetes, who were grouped according to P4P enrolment status following a propensity score matching process. METHODS: We reviewed patients ≥45 years of age newly diagnosed with type 2 diabetes mellitus (DM) from the National Health Insurance Research Database in Taiwan. A Cox proportional hazards model was used to compare the relative risk of stroke between patients with type 2 DM enrolled in the P4P programme and those who were not enrolled. RESULTS: Compared with the patients not enrolled, there was a significantly lower stroke risk in P4P participants (HR=0.97, 95% CI 0.95 to 0.99). Although a significantly lower risk of haemorrhagic stroke was observed (HR=0.87, 95% CI 0.82 to 0.93) in P4P participants, no statistically significant difference for the risk of ischaemic stroke between P4P and non-P4P patients (HR=0.99, 95% CI 0.97 to 1.02) was found. Following stratification analysis, a significantly reduced stroke risk was observed in male patients with type 2 diabetes, but not in women. CONCLUSIONS: Participants in Taiwan's Diabetes P4P programme displayed a significantly reduced stroke risk, especially haemorrhagic stroke. We recommend the continual promotion of this programme to the general public and to physicians.

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