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1.
Obes Rev ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32048436

RESUMO

A systematic review and meta-analysis of observational studies was performed to provide a deeper understanding of the associations between foetal and childhood exposure to famine and the risks of type 2 diabetes mellitus (T2DM), metabolic syndrome, hypertension, hyperglycaemia, dyslipidaemia, obesity, overweight, coronary heart disease, stroke, and nonalcoholic fatty liver disease (NAFLD) in adulthood. Both foetal and childhood exposure to famine were positively associated with the risks of T2DM (foetal exposure: RR 1.37, 95% CI, 1.23-1.52; childhood exposure: RR 1.33, 95% CI, 1.08-1.64), metabolic syndrome (RR 1.26, 95% CI, 1.07-1.50; RR 1.24, 95% CI, 1.13-1.35), hypertension (RR 1.30, 95% CI, 1.07-1.57; RR 1.33, 95% CI, 1.02-1.74), hyperglycaemia (RR 1.27, 95% CI, 1.11-1.45; RR 1.25, 95% CI, 1.10-1.42), dyslipidaemia (RR 1.48, 95% CI, 1.33-1.66; RR 1.27, 95% CI, 1.12-1.45), obesity (RR 1.19, 95% CI, 1.02-1.39; RR 1.13, 95% CI, 1.00-1.28), overweight (RR 1.17, 95% CI, 1.07-1.29; RR 1.07, 95% CI, 1.00-1.14), coronary heart disease (RR 1.22, 95% CI, 1.00-1.51; RR 1.21, 95% CI, 1.09-1.35), and moderate-to-severe NAFLD (RR 1.66, 95% CI, 1.07-2.57; RR 1.68, 95% CI, 1.41-1.99) in adulthood. No association was observed for the risks of stroke or mild NAFLD. Adjustments for age, alcohol, smoking, body mass index, and physical activity nullified some associations. The associations were generally stronger in women than in men. In summary, foetal and childhood exposure to famine may confer greater risks of developing certain cardiometabolic conditions in adulthood, particularly in women. The extent to which risks for cardiometabolic conditions are associated with early-life famine appears to be determined by certain factors in adulthood.

2.
Int J Biometeorol ; 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32052154

RESUMO

Although global warming is an indisputable fact, there is still uncertainty about how climate change will occur at regional levels. Kazakhstan is the largest landlocked country in the world. To best manage this country's limited water resources, socio-economic development and environmental protection, a solid understanding of regional climate change impacts is needed. In this study, tree-ring width and δ13C chronologies were established based on 99 tree-ring samples of Schrenk spruce (Picea schrenkiana Fisch. et Mey.) collected in Almaty, Kazakhstan. Climate response analysis between the tree-ring chronologies and climate data indicates that summer mean temperature is the strongest climate signal recorded by tree-ring δ13C. We reconstructed temperature change in southern Kazakhstan since 1850 C.E. using the tree-ring δ13Ccorr chronology. The results show that the temperatures in southern Kazakhstan have risen at a rate of about 0.27 °C per decade over the past 166 years. However, the rate has increased by as much as 0.44 °C per decade over the past 30 years. Analyses of temperature and precipitation data show that the climate has alternated between warm-dry and cold-humid periods over the past 166 years. The extreme droughts of 1879, 1917 and 1945 were caused by the combination of continuously high temperatures and reduced precipitation.

3.
Mol Genet Genomic Med ; : e1112, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32061057

RESUMO

BACKGROUND: Long noncoding RNA (LncRNA) XIST is one of the genes that exists in different types of cancers. Earlier researches showed that XIST can advance the progression of colorectal cancer. Nevertheless, the potential molecular mechanism of XIST in combination with miR-93-5p has not been explored in colorectal cancer. METHODS: We performed qRT-PCR to explore the level of XIST. And a serious experiments in vitro and in vivo were performed to explore the function of XIST. The relationship between XIST/HIF-1A and miR-93-5p was confirmed by RIP and dual-luciferase assays. RESULTS: In the present research, our team demonstrated the upregulation of XIST expression, which was related to tumor progression, and the downregulation of miR-93-5p in cells and tissues of colorectal cancer. XIST is the competitive endogenous RNA of miR-93-5p to promote HIF-1A, and then the upregulated AXL level facilitates the EMT process, migration, and proliferation of colorectal cancer. At last, we proved that XIST enhanced the in vivo and in vitro activities of colorectal cancer by regulating AXL signaling. CONCLUSION: In summary, the above results indicate that XIST promotes colorectal cancer tumorigenesis by regulating miR-93-5p/HIF-1A/AXL signaling pathway, which will supply a novel perspective to diagnose and treat colorectal cancer disease.

4.
J Cell Mol Med ; 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32052546

RESUMO

Lung cancer is the world's leading cause of cancer-related morbidity and mortality despite advances in surgery, chemotherapy and immunotherapy; thus, there is an urgent need to find new molecules to develop novel treatment strategies. Although ncRNAs were found to account for 98% transcripts, the number of lncRNAs with distinct function in lung cancer is extremely limited. We previously demonstrated that Plasmodium infection inhibits tumour growth and metastasis, but the exact mechanisms involved have not been fully understood. In this study, we carried out RNA sequencing (RNA-Seq) of tumour tissues isolated from LLC tumour-bearing mice treated with either Plasmodium yoelli (Py)-infected red blood cells or uninfected red blood cells. We found that F630028O10Rik (abbreviated as F63) is a novel lncRNA that was significantly up-regulated in tumours isolated from mice treated with Py-infected red blood cells compared to the control. By using gene silencing technique, F63 was found to inhibit both tumour Vascular Endothelial Growth Factor A (VEGFA) secretion and endothelial cells clone formation, migration, invasion and tube formation. Injection of cholesterol-modified siRNA-F63 into mice tumour tissues produced a significant increase in tumour volume, blood vessel formation and angiogenesis 17 days after injection. We further showed that inhibiting miR-223-3p results in the down-regulation of VEGFA and VEGFR2 which are vital molecules for angiogenesis. These results reveal that F63 inhibit tumour growth and progression by modulating tumour angiogenesis suggesting F63 can be a novel lncRNA with great potential as a candidate molecule for gene therapy in lung cancer.

5.
Photodiagnosis Photodyn Ther ; : 101667, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31978564

RESUMO

BACKGROUND: Basal cell carcinoma (BCC) is the most common type of non-melanoma skin cancer worldwide. Methyl-5-aminolevulinate (MAL) photodynamic therapy (PDT) is an effective and acceptable treatment for BCC. The purpose of this analysis was to compare the benefit and tolerability of MAL-PDT with alternative modalities for the treatment of BCC. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched from inception until 5 August 2019. Eligible studies were prospective and retrospective clinical trials of MAL-PDT for superficial and nodular BCC. At least one of the following outcomes were reported: complete response (CR) at 3 months and sustained at 12 months; recurrence at 12 months and sustained at 5 years; cosmetic outcome at ≥ 3 months; adverse events. RESULTS: From 427 search results, 11 articles including seven randomized controlled trials (1339 patients; 1568 lesions) and one retrospective study (108 lesions) were eligible. CR was inferior with MAL-PDT versus surgery (3 months: Risk Ratio [RR]: 0.93, 95% confidence interval [CI] 0.89-0.97, p = 0.002; 12 months: RR: 0.90, 95% CI 0.85-0.95, p = 0.0002). Moreover, MAL-PDT had higher 12 months recurrence rate (RR: 10.43, 95% CI 1.98-55.03, p = 0.006) and more toxicities (RR: 2.12, 95% CI 1.46-3.09, p < 0.0001) in comparison with surgery. However, MAL-PDT cosmesis was superior to excisional surgery (RR: 1.99, 95% CI 1.50-2.63, p < 0.00001). Additionally, MAL-PDT was associated with similar CR in comparison with 5-aminolaevulinic acid (ALA)-PDT and ALA nanoemulsion (BF-200 ALA)-PDT, but had higher recurrence rate at 12 months and worse cosmesis compared with BF-200 ALA-PDT, even the differences were not statistically significant. CONCLUSION: MAL-PDT might not be the best first-line treatment option for BCC, although cosmetic outcome could be good-to-excellent.

6.
J Hum Genet ; 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980736

RESUMO

Hereditary spherocytosis (HS) is the most common inherited hemolytic anemia characterized by the presence of spherical-shaped erythrocytes on the peripheral blood smear, hemolysis, splenomegaly, jaundice, and gallstones. To date, mutations in at least five genes (ANK1, EPB42, SLC4A1, SPTA1, and SPTB) have been found to be associated with different subtypes of HS. Here, we aim to investigate the presence of novel as well as known mutations in 35 Chinese patients with clinically suspected HS. Whole-exome sequencing (WES) has identified 3 patients with SLC4A1, 16 patients with ANK1, and 16 patients with SPTB mutations, including 5 splicing, 12 nonsense, 9 frameshift, 7 missense, and 1 start-loss mutation, indicating that SPTB and ANK1 are the most frequently mutated genes in Chinese HS patients. Among 34 mutations identified, 21 were novel. Most of SPTB and ANK1 mutations were nonsense (8/16) and frameshift (6/16) mutations. By trio analysis of eight families we have confirmed six de novo mutations. In addition, genotype-phenotype analysis was also performed by comparing clinical manifestations among three groups of patients with SPTB, ANK1, and SLC4A1 mutations. It revealed that patients with ANK1 mutations had a significantly higher level of MCV and MCH but lower percentage of spherocytes compared with those carrying SPTB mutations. In conclusion, our results suggested that molecular diagnosis by next-generation sequencing (NGS) is a fast, economic, and accurate way to detect and identify pathogenic alterations of inherited diseases, highlighting the potential usage of NGS in clinical practice.

7.
J Immunol ; 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996457

RESUMO

In this study, we generated a tkl1 deletion mutant in the Toxoplasma gondii type 1 RH (RHΔtkl1) strain and tested the protective efficacies of vaccination using RHΔtkl1 tachyzoites against acute, chronic, and congenital T. gondii infections in Kunming mice. Mice vaccinated with RHΔtkl1 mounted a strong humoral and cellular response as shown by elevated levels of anti-T. gondii-specific IgG, IL-2, IL-12, IFN-γ, and IL-10. All RHΔtkl1-vaccinated mice survived a lethal challenge with 1 × 103 tachyzoites of type 1 RH or ToxoDB#9 (PYS or TgC7) strain as well as 100 cysts or oocysts of Prugniuad strain. All mock-vaccinated plus infected mice have died. Vaccination also protected against cyst- or oocyst-caused chronic infection, reduced vertical transmission caused by oocysts, increased litter size, and maintained body weight of pups born to dams challenged with 10 oocysts on day 5 of gestation. In contrast, all mock-vaccinated plus oocysts-infected dams had aborted, and no fetus has survived. Vaccinated dams remained healthy postinfection, and their brain cyst burden was significantly reduced compared with mock-vaccinated dams infected with oocysts. In vivo depletion of CD4+ T cells, CD8+ T cells, and B cells revealed that CD8+ T cells are involved in the protection of mice against T. gondii infection. Additionally, adoptive transfer of CD8+ T cells from RHΔtkl1-vaccinated mice significantly enhanced the survival of naive mice infected with the pathogenic strain. Together, these data reaffirm the importance of CD8+ T cell responses in future vaccine design for toxoplasmosis and present T. gondii tkl1 gene as a promising vaccine candidate.

8.
ACS Appl Mater Interfaces ; 12(3): 3465-3473, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31913004

RESUMO

The high-resolution technique transmission electron microscopy (TEM), with OsO4 as the traditional fixative, is an essential tool for cell biology and medicine. Although OsO4 has been extensively used, it is far from perfect because of its high volatility and toxicity. Os(II) polypyridyl complexes like [Os(phen)2(dppz)]2+ (phen = 1,10-phenanthroline; dppz = dipyridophenazine) are not only the well-known molecular DNA "light-switches" but also the potential ideal candidates for TEM studies. Here, we report that the cell-impermeable cationic [Os(phen)2(dppz)]2+ can be preferentially delivered into the live-cell nucleus through ion-pairing with chlorophenolate counter-anions, where it functions as an unparalleled enantioselective nuclear DNA imaging reagent especially suitable for correlative light and electron microscopy (CLEM) studies in both living and fixed cells, which can clearly visualize chromosome aggregation and decondensation during mitosis simultaneously. We propose that the chiral Os(II) polypyridyl complexes can be used as a distinctive group of enantioselective high-resolution CLEM imaging probes for live-cell nuclear DNA studies.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31958299

RESUMO

OBJECTIVE: To investigate the association between hemoglobin A1c (HbA1c) 7.0%-8.0% and cardiovascular disease (CVD) risk among Chinese patients with type 2 diabetes mellitus (T2DM) with different baseline 10-year atherosclerotic CVD (ASCVD) risk stratification. RESEARCH DESIGN AND METHODS: A prospective population-based cohort of 10 060 adults aged 40-70 years in Chongming District of Shanghai was established in 2011. These participants were followed up for 3.25 years and CVD information was recorded. We investigated this association between HbA1c categories and incident CVD stratified by the 10-year ASCVD risk using multiple Cox regression analysis among 1880 patients with T2DM without CVD history. CVD events were defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. RESULTS: The corresponding incidence of CVD per 1000 person-years for the HbA1c≤6.5%, 6.6%-6.9%, 7.0%-8.0% and >8.0% groups were 12.5, 21.8, 22.9 and 28.9, respectively. The HbA1c>8.0% group was significantly associated with a higher CVD risk in patients with T2DM. The HbA1c 7.0%-8.0% group was significantly associated with a higher CVD risk in patients with T2DM with moderate baseline ASCVD risk (HR 2.48; 95% CI 1.15 to 5.32). CONCLUSION: HbA1c of 7.0%-8.0% may result in a significantly higher CVD risk among patients with T2DM with moderate baseline ASCVD risk, which support the use of HbA1c combined with baseline ASCVD risk assessment to determine future glucose-lowering treatment decisions among patients with T2DM with basic to moderate risk.

10.
Medicine (Baltimore) ; 99(2): e18739, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914091

RESUMO

Autoimmune hemolytic anemia (AIHA) is a rare disease in which autoantibodies target red blood cells (RBCs), leading to anemia that ranges from no symptoms to severe life-threatening hemolysis. Little is known about the severity of anemia, blood transfusion efficiency and risk of transfusion-related reactions among hospitalized AIHA patients, especially in those with incompatible RBC transfusions.A retrospective study was conducted among hospitalized AIHA patients from January 2009 to December 2015 in a large tertiary care medical center in southwest China.A total of 450 AIHA hospitalized patients were recruited, of whom 97.3% had warm AIHA, 30.3% had primary AIHA, and 90.7% were treated with corticosteroids. On admission, approximately 3% of patients had an hemoglobin (Hb) <30 g/L, 34% had an Hb between 30 and 59.9 g/L, and 46% had an Hb ranging from 60 to 89.9 g/L. A total of 2509.5 U RBCs were transfused to AIHA patients, and 14 transfusion-related adverse reactions were recorded, without any hemolytic transfusion reactions. With an average transfusion trigger of 52.0 ±â€Š9.3 g/L, 59.7% of the patients received RBCs, and 55.8% of the transfusions were viewed as effective. Least incompatible RBCs were given in 39% of the transfusions, but the transfusion efficiency did not significantly decrease with these incompatible blood transfusions (P = .253). Primary AIHA patients with a nadir Hb of approximately 40 to 50 g/L during their hospital stay had the highest rate of remission and did not require a different total number of RBC transfusions (P = .068) or length of hospitalization (P = .194) compared to other groups with nadir Hb values <30 g/L, ≥30 and <40 g/L, ≥50 and <60 g/L, and ≥60 g/L.One-third of AIHA patients suffered from severe anemia during hospitalization, and transfusions, even with incompatible RBCs, were safe and efficient. However, transfusion triggers between 40 and 50 g/L seemed to benefit the most patients by alleviating the RBC destruction caused by autoantibodies, and a restrictive transfusion strategy was beneficial in AIHA patients.


Assuntos
Corticosteroides/uso terapêutico , Anemia Hemolítica Autoimune/fisiopatologia , Anemia Hemolítica Autoimune/terapia , Transfusão de Eritrócitos/métodos , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Adulto , Anemia Hemolítica Autoimune/epidemiologia , Transfusão de Eritrócitos/efeitos adversos , Feminino , Hemoglobinas , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Reação Transfusional/epidemiologia
11.
FASEB J ; 34(2): 3165-3178, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31908049

RESUMO

Dense granule protein 12 (GRA12) is implicated in a range of processes related to the establishment of Toxoplasma gondii infection, such as the formation of the intravacuolar network (IVN) within the parasitophorous vacuole (PV). This protein is also thought to be important for T. gondii-host interaction, pathogenesis, and immune evasion, but their exact roles remain unknown. In this study, the contributions of GRA12 to the molecular pathogenesis of T. gondii infection were examined in vitro and in vivo. Deletion of GRA12 in type I RH and type II Pru T. gondii strains did not affect the parasite growth and replication in vitro, however, it caused a significant reduction in the parasite virulence and tissue cyst burden in vivo. T. gondii Δgra12 mutants were more vulnerable to be eliminated by host immunity, without the accumulation of immunity-related GTPase a6 (Irga6) onto the PV membrane. The ultrastructure of IVN in Δgra12 mutants appeared normal, suggesting that GRA12 is not required for biogenesis of the IVN. Combined deletion of GRA12 and ROP18 induced more severe attenuation of virulence compared to single Δgra12 or Δrop18 mutant strains. These data suggest a functional association between GRA12 and ROP18 that is revealed by the severe attenuation of virulence in a double mutant relative to the single individual mutations. Future studies are needed to define the molecular basis of this putative association. Collectively these findings indicate that although GRA12 is not essential for the parasite growth and replication in vitro, it contributes to the virulence and growth of T. gondii in mice.

12.
JAMA Oncol ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31971541

RESUMO

Importance: Patients with advanced sarcoma have limited treatment options. Talimogene laherparepvec (T-VEC) has been shown to increase tumor-specific immune activation via augmenting antigen presentation and T-cell priming. Objective: To examine whether T-VEC in combination with pembrolizumab is associated with increased tumor-infiltrating lymphocyte infiltration and programmed death-ligand 1 expression and thus with increased antitumor activity in patients with locally advanced or metastatic sarcoma. Design, Setting, and Participants: This open-label, single-institution phase 2 interventional trial of T-VEC plus pembrolizumab enrolled 20 patients with locally advanced or metastatic sarcoma between March 16 and December 4, 2017, for whom at least 1 standard systemic therapy had failed. The median duration of therapy was 16 weeks (range, 7-67 weeks). Reported analyses include data through December 14, 2018. Intervention: Patients received pembrolizumab (200-mg flat dose) intravenously and T-VEC (first dose, ≤4 mL × 106 plaque-forming units [PFU]/mL; second and subsequent doses, ≤4 mL × 108 PFU/mL) injected into palpable tumor site(s) on day 1 of each 21-day cycle. Main Outcomes and Measures: The primary end point was objective response rate (ORR; complete response and partial response) at 24 weeks determined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, criteria. Secondary end points included best ORR by immune-related RECIST criteria, progression-free survival rate at 24 weeks, overall survival, and safety. Results: All 20 patients (12 women [60%]; median age, 63.5 years [range, 24-90 years]) were evaluable for response. The study met its primary end point of evaluating the best ORR at 24 weeks determined by RECIST, version 1.1, criteria; the best ORR was 30% (95% CI, 12%-54%; n = 6). The ORR overall was 35% (95% CI, 15%-59%; n = 7). The incidence of grade 3 treatment-related adverse events was low (4 patients [20%]). There were no grade 4 treatment-related adverse events or treatment-related deaths. Conclusions and Relevance: In this phase 2 clinical trial, treatment with T-VEC plus pembrolizumab was associated with antitumor activity in advanced sarcoma across a range of sarcoma histologic subtypes, with a manageable safety profile. This combination therapy met its predefined primary study end point; further evaluation of T-VEC in combination with pembrolizumab for patients with select sarcoma subtypes is planned. Trial Registration: ClinicalTrials.gov identifier: NCT03069378.

13.
Br J Nutr ; : 1-20, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31964442

RESUMO

The association between milk consumption and metabolic syndrome remains inconclusive, and the data from Chinese populations are scarce. We conducted a cross-sectional study to investigate the association between milk consumption and metabolic syndrome and its components among the residents of Suzhou Industrial Park, Suzhou, China. A total of 5149 participants were included in the final analysis. A logistic regression model was applied to estimate the odds ratios (OR) and 95% confidence intervals (CIs) for the prevalence of metabolic syndrome and its components according to milk consumption. In addition, the results of our study were further meta-analyzed with other published observational studies to quantify the association between the highest versus lowest categories of milk consumption and metabolic syndrome and its components. There was no significant difference in the odds of having metabolic syndrome between milk consumers and non-milk consumers (OR 0.86, 95% CI 0.73, 1.01). However, milk consumers had lower odds of having elevated waist circumference (OR 0.78, 95% CI 0.67, 0.92), elevated triglyceride (OR 0.83, 95% CI 0.70, 0.99), and elevated blood pressure (OR 0.85, 95% CI 0.73, 0.99). When the results were pooled together with other published studies, higher milk consumption was inversely associated with the risk of metabolic syndrome (relative risk 0.80, 95% CI 0.72, 0.88) and its components (except elevated fasting blood glucose); however, these results should be treated with caution as high heterogeneity observed. In summary, the currently available evidence from observational studies suggests that higher milk consumption may be inversely associated with metabolic syndrome.

14.
Fitoterapia ; 141: 104477, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31927015

RESUMO

Extensive phytochemical investigation from the roots of Aconitum kirinense Nakai led to the identification of fifteen new compounds, including four ranaconitine type C18-diterpenoid alkaloids (kirisines A-D, 1-4), one lappaconitine type C18-diterpenoid alkaloid (kirisine E, 5), seven denudatine type C20-diterpenoid alkaloids (kirisines F-L, 6-12), and three napelline type C20-diterpenoid alkaloids (kirisines M-O, 13-15), together with 25 known ones. Their structures were elucidated by extensive spectroscopic analyses. Among them, compounds 1 and 2 are rare diterpenoid alkaloid with 9,14-methylenedioxy group, and the latter also has a rare chloro-substituent. The diterpenoid alkaloids isolated were C18, C19 and C20-category, which might provide further clues for understanding the chemotaxonomic significance of this plant. The isolated compounds were tested for neuroprotective activity and acetylcholinesterase inhibitory activity. Compounds 7, 18, 30 and 40 which exhibited moderate activity at 80 µM against acetylcholinesterase.

15.
Food Funct ; 11(1): 347-357, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31799533

RESUMO

Hypotaurine, an important sulfur-containing and nonpeptidic amino acid, is a precursor of taurine and an antioxidant. Our previous study indicated that hypotaurine levels are associated with the ageing of Caenorhabditis elegans (C. elegans). However, whether hypotaurine plays a role in the lifespan regulation of C. elegans and the mechanism remains undetermined. Here, we found that hypotaurine enhances oxidative stress resistance and ameliorates ageing in C. elegans. Our results show that hypotaurine regulates a variety of pathways and leads to the upregulation of some age-related genes to extend lifespan. We also found that the stress response-related transcription factors DAF-16/FOXO and SKN-1/NRF2 contribute to the beneficial longevity conferred by hypotaurine. Moreover, our results demonstrate that hypotaurine induced lifespan extension by regulating the insulin/IGF-1 signaling (IIS) pathway, the reproductive signaling pathway and DR-like mechanisms. Additionally, our results also indicated that mitochondrial function also plays a crucial role in the lifespan extension induced by hypotaurine. Taken together, these data indicate that hypotaurine delays the ageing of C. elegans, due, at least in part, to its antioxidant activity, which in turn regulates IIS, and reproductive and DR-related pathways, thereby inducing the activity of the transcription factors DAF-16 and SKN-1.

16.
Int Immunopharmacol ; 78: 105790, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31813830

RESUMO

Acute lung injury (ALI) is a complex clinical syndrome with high morbidity and mortality rates. Autophagy is an adaptive process that plays a complex role in ALI. The aim of this study was to investigate the effects of autophagy on lipopolysaccharide (LPS)-induced lung injury by establishing a rat ALI model and to further explore the possible mechanisms involved. Rats were pretreated with the autophagy inhibitor 3-methyladenine (3-MA) or the autophagy activator rapamycin before they were challenged with the intratracheal instillation of LPS (5 mg/kg). The level of autophagy in the lung tissue was detected. Lung injury and vascular permeability were assessed. The role of the mechanistic target of rapamycin (mTOR)-mediated Unc-51-like kinase 1 (ULK1) and the class III PI3 kinase VPS34 in autophagy regulation was examined. LPS challenge induced autophagy and rapamycin pretreatment enhanced autophagy activity in LPS-induced ALI rats. LPS caused severe lung injury and high pulmonary vascular permeability, which could be alleviated by enhancing autophagy. In addition, the inhibition of mTOR upregulated the expression of ULK1 and VPS34 and thus increased LPS-induced autophagy. Autophagy plays a protective role in LPS-induced ALI, and enhancing autophagy via the inhibition of mTOR alleviates lung injury and pulmonary barrier function. Moreover, mTOR negatively mediates ULK1 and VPS34 to regulate LPS-induced autophagy in rats.

17.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1865(2): 158547, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31678514

RESUMO

Atherosclerosis (AS) is characterized by lipids metabolism disorder and inflammatory response. Accumulating evidence has demonstrated that Wingless type 5a (Wnt5a) is implicated in cardiovascular diseases through non-canonical Wnt cascades. However, its precise role during the pathogenesis of AS is still unclear. Therefore, the present study aims to investigate the role and the underlying mechanism of Wnt5a/receptor tyrosine kinase-like orphan receptor 2 (Ror2) pathways in the promotion of AS process through affecting lipid accumulation and inflammation. In atherosclerotic clinical samples, Wnt5a levels were measured by using enzyme-linked immunosorbent assay (ELISA) assay. In vivo experiments were conducted by using apolipoprotein E knockout (apoE-/-) mice model. Vascular smooth muscle cells (VSMCs) were applied for in vitro studies. Wnt5a was highly expressed in both of atherosclerotic clinical samples and apoE-/- mice. The knockdown of Wnt5a significantly inhibited cholesterol accumulation and inflammatory response. Additionally, the lipopolysaccharide (LPS)-induced inflammation aggravated the cholesterol accumulation and decreased adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) expression in VSMCs. Depletion of intracellular cholesterol by ß-cyclodextrin (ß-CD) led to the upregulation of ABCA1 and the inhibition of inflammation. Conversely, the overexpression of Wnt5a inhibited ABCA1 expression, facilitated cholesterol accumulation, impared cholesterol efflux, promoted NF-κB nuclear translocation and the inflammatory cytokines secretion. Moreover, the knockdown of Ror2 increased ABCA1 expression and reduced Wnt5a-induced cholesterol accumulation and inflammatory responses. Furthermore, the knockdown of ABCA1 enhanced cholesterol accumulation and inflammatory response. Therefore, Wnt5a/Ror2 pathway was critical in regulating cholesterol homeostasis and inflammatory response, which might be a promising therapeutic target for AS therapy.

18.
Free Radic Biol Med ; 146: 70-78, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31626947

RESUMO

We found recently that benzohydroxamic acid (BHA) could detoxify the chlorinated quinoid carcinogens via an unusual Lossen rearrangement reaction. However, it is not clear what would happen when the nitrogen hydrogen of BHA was substituted with methyl and other alkyl groups. Here we show that N-methyl benzohydroxamic acid (N-MeBHA, a simple model compound for the classic iron-chelator deferoxamine, which is a typical N-alkyl trihydroxamic acid) could react with 2,5-dichloro-1,4-benzoquinone (DCBQ) to form a relatively stable initial carbon-oxygen bonding conjugation intermediate CBQ-O-N-MeBHA. However, the major final product was identified, unexpectedly, as a carbon-nitrogen bonding conjugate CBQ(OH)-N(CH3)-COAr, which is the rearranged isomer of CBQ-O-N-MeBHA. Interestingly, a new 18-line nitrogen-centered radical and a carbon-centered quinone ketoxy radical were observed by the ESR spin-trapping method, which was further confirmed by HPLC-MS and 15N-isotope labeling methods. We further found that both new DNA adducts and DNA strand breaks could be produced by the reactive nitrogen-centered radical. Taken together, we propose that the reaction between DCBQ and N-MeBHA was not via the Lossen rearrangement, but rather through a novel radical homolysis and recoupling pathway. Analogous results were observed for other chlorinated quinones and N-alkyl hydroxamic acids including the widely-used trihydroxamate iron-chelating drug deferoxamine. This represents the first report of unexpected radical pathway for the reaction between chlorinated quinones and N-alkyl hydroxamic acids under normal physiological conditions, which may have broad biological and environmental significance for future study of carcinogenic chloroquinones and hydroxamic acid drugs.

19.
Kaohsiung J Med Sci ; 36(1): 27-34, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31631531

RESUMO

Multiple microRNAs (miRs) have also been implicated in ischemic brain injury. This research intended to probe the regulatory function and the mechanism of miR-15a on the ischemic brain injury induced by oxygen-glucose deprivation/reoxygenation (OGD/R) in neurons of rats. The OGD/R model was established with the cortical neurons separated from rats. After transfection with miR-15a mimic negative control (NC), miR-15a mimic, miR-15a inhibitor NC and miR-15a inhibitor, the OGD/R-induced apoptosis were detected. Using bioinformatic softwares including TargetScan, miRanda, and miRWalk to predict the underlying targets of miR-15a, and the binding of miR-15a with brain-derived neurotrophic factor (BDNF) were validated with double-fluorescein reporter assay system. The expression levels of BDNF mRNA and protein were detected with qRT-PCR and western blot. The effect of miR-15a on PI3K/AKT pathway in neurons submitted to OGD/R was also investigated. The findings showed that miR-15a may mediate the apoptosis of neurons submitted to OGD/R, and lower expression of Bcl-2 and higher expression of Bax and cleaved caspase-3 were observed. BDNF was screened as the candidate target, and the direct binding of miR-15a with 3'-UTR of BDNF were verified. Further research showed that miR-15a downregulated the expression of BDNF mRNA and protein, thus exerted negative regulatory effect on the OGD/R injury. PI3K/AKT pathway may be related to the regulatory effect of miR-15a. Our findings contribute to uncovering novel pathogenesis for ischemic brain injury.

20.
Phytopathology ; 110(1): 80-84, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31631804

RESUMO

The pepper cultivar Yellow Lantern, one of the spiciest pepper varieties, is a local germplasm of Capsicum chinense, cultivated exclusively on Hainan Island, China. However, this variety is susceptible to viral diseases that severely affect its production. In this study, we report that pepper veinal mottle virus (PVMV) is associated with foliar chlorosis and rugosity symptoms in Yellow Lantern. To verify this correlation, we constructed a full-length cDNA clone of a PVMV isolate named HNu. The virus progeny derived from the cDNA clone replicated and moved systemically in the pepper, inducing the same symptoms as those induced by PVMV-HNu in Yellow Lantern peppers in the field. The results support that PVMV-HNu is the causal agent of foliar chlorosis and rugosity disease in Yellow Lantern. This knowledge will help in the diagnosis and prevention of disease caused by PVMV. Furthermore, the cDNA clone serves as a reverse genetic tool to study the molecular pathogenesis of PVMV.


Assuntos
Capsicum , Doenças das Plantas , Potyvirus/genética , Capsicum/virologia , China , Clonagem de Organismos , DNA Complementar/genética , Doenças das Plantas/virologia , Potyvirus/fisiologia
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