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1.
Food Chem ; 337: 127798, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32799166

RESUMO

In this study, polysaccharides (BPSs) were obtained from fresh bitter gourd (Momordica charantia L.) by room temperature extraction techniques, including three-phase partitioning (TPP) and ultrasonic-assisted extraction (UAE) performed in different solvents. The results showed that the extraction methods had significant influence on the extraction yield, chemical composition, weight-average molecular weight (Mw), monosaccharide composition, preliminary structural characterization and microstructure of the BPSs. The BPS-W sample obtained from the bitter gourd residue via UAE in distilled water had a higher uronic acid content (24.22%) and possessed stronger antioxidant capacities and α-amylase and α-glycosidase inhibitory activities than BPS-C extracted with UAE in citric acid, BPS-A extracted with UAE in 1.25 mol/L NaOH/0.05% NaBH4, and BPS-J extracted from bitter gourd juice by TPP. Moreover, BPS-A, which had the lowest Mws, showed the best bile acid-binding capacity among the four BPSs. This study had great potentials for the preparation of bioactive polysaccharides from fresh vegetables.

2.
Can J Microbiol ; 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33064956

RESUMO

Directional stress is an effective measure to evolve community structure and improve bioactivity of pit mud (PM). In this study, adding fortified Daqu in artificial PM (APM) was to disturb the microbial community and affect the metabolites furthermore. To evaluate the effect of fortified Daqu on culturing APM, microbial communities of APMs with/without adding fortified Daqu were investigated by fluorescence in situ hybridization and Illumina Miseq. These results indicated that microbes (Clostridium sp., Clostridium kluyveri, hydrogenotrophic methanogens, and acetotrophic methanogens) related to the production of key aroma compounds increased notably when fortified Daqu was added. Especially the hydrogenotrophic and acetotrophic methanogens increased by 5.19- and 4.63-fold after 30-days' culture. Then metabolites (organic acids, volatile compounds) were also analyzed by HPLC and HS-SPME-GC-MS. Results showed that the content of butyric acid and hexanoic acid was significantly higher when adding fortified Daqu. What's more, the proportion of esters and phenols were higher compared with the APM without adding fortified Daqu as well. The microbial compositions of APMs with/without adding fortified Daqu were observed in this study, which indicated the microbial community evolving in functional community in favor of liquor-brewing and suggested a novelty process was developed by disturbing the community diversity.

3.
Biochim Biophys Acta Mol Basis Dis ; : 165989, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33065235

RESUMO

We previously showed that increased epithelial sodium channel (ENaC) activity in endothelial cells induced by oxidized low-density lipoprotein (ox-LDL) contributes to vasculature dysfunction. Here, we investigated whether ENaC participates in the pathological process of atherosclerosis using LDL receptor-deficient (LDLr-/-) mice. Male C57BL/6 and LDLr-/- mice were fed a normal diet (ND) or high fat diet (HFD) for 10 weeks. Our data show that treatment of LDLr-/- mice with a specific ENaC blocker, benzamil, significantly decreased atherosclerotic lesion formation and expression of matrix metalloproteinase 2 (MMP2) and metalloproteinase 9 (MMP9) in aortic arteries. Furthermore, benzamil ameliorated HFD-induced impairment of aortic endothelium-dependent dilation by reducing expression of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6 and production of adhesion molecules including VCAM-1 and ICAM-1 in both C57BL/6 and LDLr-/- mice fed with HFD. In addition, HFD significantly increased ENaC activity and the levels of serum lipids, including ox-LDL. Our in vitro data further demonstrated that exogenous ox-LDL significantly increased the production of TNF-α, IL-1ß, IL-6, VCAM-1 and ICAM-1. This ox-LDL-induced increase in inflammatory cytokines and adhesion molecules was reversed by γ-ENaC silencing or by treatment with the cyclooxygenase-2 (COX-2) antagonist celecoxib. Benzamil inhibited HFD-induced increase in COX-2 expression in aortic tissue in both C57BL/6 and LDLr-/- mice, and γ-ENaC gene silencing attenuated ox-LDL-induced COX-2 expression in HUVECs. These data together suggest that HFD-induced activation of ENaC stimulates inflammatory signaling, thereby contributes to HFD-induced endothelial dysfunction and atherosclerotic lesion formation. Thus, targeting endothelial ENaC may be a promising strategy to halt atherogenesis.

4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1474-1479, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067940

RESUMO

OBJECTIVE: To investigate the value of fluorescence in situ hybridization (FISH) in the diagnosis and prognosis evaluation of patients with chronic lymphocytic leukemia (CLL). METHODS: Ninty-three patients with newly diagnosed CLL were tested by five probes including RB1 (13q14.1), D13S25 (13q14.3), p53(17p13.1), ATM( 11q22.3) and CSP12, while conventional cytogenetics (CC) was used for karyotype analysis. Then the correlation of the molecular cytogenetic abnormalities with the clinical Binet stages, Rai stages and the other related laboratory examinations was analyzed. RESULTS: The detection rate of chromosome abnormality in 93 patients was 79.6%, out of which detection rate of 13q (13q- was the highest and accounted for 45.2%), followed by trisomy 12 (+12) 26.9%, p53 deletion (17p-) 19.4% and ATM deletion (11p-) 17.2%. There were 27 cases (29.0%) with 2 or more abnormalities, including 13 cases with 13q-/17q-, 5 with 13q-/11q-, and 4 with 13q-/+12. Compared with CC test results, the positive rate of FISH detection was significantly higher (χ2=32.127, P<0.01). There was no significant correlation between FISH results and Rai stages (P>0.05), meanwhile 17p- highly correlated with later stage of the Binet stages (P=0.012). The molecular cytogenetic abnormalities significantly correlated with age, absolute value of peripheral lymphocyte count and CD38 expression level (P>0.05). The incidence of 13q- in female (65.4%) was statistically significantly higher than that in male (37.3%) (P=0.015). The unmutated IGHV rate of CLL patients with a 17p- was significantly higher than that in patients without this genetic abnormality (P=0.013). The expression of CD38 was detected among 29.0% of the patients, which significantly correlated with Binet stages (P=0.027) and unmutated IGHV (P=0.006). CONCLUSION: FISH can greatly increase the detection rate of molecular cytogenetic abnormalities in CLL patients, which, as a powerful supplement to the conventional cytogenetics, can be applied for the clinical staging and prognosis evaluation of CLL patients.

5.
J Diabetes ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33016503

RESUMO

BACKGROUND: To evaluate the efficacy and safety of dipeptidyl peptidase-4 (DPP4) inhibitors when added to insulin therapy in patients with type 2 diabetes mellitus (T2DM). METHODS: PubMed, EMBASE, the Web of Science, and the Cochrane Library were systematically searched for randomized controlled trials (RCTs) exploring the efficacy or safety of DPP4 inhibitors in T2DM patients. The quality of the included RCTs was assessed with the Cochrane risk of bias tool. For outcomes, odds ratios (ORs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated using both random- and fixed-effects models. RESULTS: A total of 16 studies were included in the meta-analysis with 5418 participants. HbA1c was significantly decreased in the DPP4 inhibitors with insulin (DPP4i/INS) group compared with insulin alone (with or without placebo) group (WMD = -0.62%; 95% CI: -0.74, -0.49; P < 0.05). Consistent with this finding, the FBG-lowering effect (WMD = -0.61 mmol/L; 95% CI: -0.77, -0.45; P < 0.05) and 2-h PPG-lowering efficacy (WMD = -2.39 mmol/L; 95% CI: -2.81, -1.97; P < 0.05) in the DPP4i/INS group was also significantly better than that in the insulin alone group. Regarding safety indicators, compared with insulin alone group, DPP4i/INS treatments had no association with the risk of adverse effects, including hypoglycemia, AEs and SAEs. CONCLUSIONS: Compared with insulin treatment alone, treatment with DPP4 inhibitors combined with insulin improved HbA1c, FBG and 2-h PPG without increasing the risk of hypoglycemia, AEs or SAEs.

7.
Signal Transduct Target Ther ; 5(1): 229, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028804

RESUMO

Esophageal cancer (EC) is one of the most lethal cancers in the world, and its morbidity and mortality rates rank among the top ten in China. Currently, surgical resection, radiotherapy and chemotherapy are the primary clinical treatments for esophageal cancer. However, outcomes are still unsatisfactory due to the limited efficacy and severe adverse effects of conventional treatments. As a new type of approach, targeted therapies have been confirmed to play an important role in the treatment of esophageal cancer; these include cetuximab and bevacizumab, which target epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), respectively. In addition, other drugs targeting surface antigens and signaling pathways or acting on immune checkpoints have been continuously developed. For example, trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER-2), has been approved by the Food and Drug Administration (FDA) as a first-line treatment of HER-2-positive cancer. Moreover, the PD-L1 inhibitor pembrolizumab has been approved as a highly efficient drug for patients with PD-L1-positive or advanced esophageal squamous cell carcinoma (ESCC). These novel drugs can be used alone or in combination with other treatment strategies to further improve the treatment efficacy and prognosis of cancer patients. Nevertheless, adverse events, optimal dosages and effective combinations still need further investigation. In this review, we expound an outline of the latest advances in targeted therapies of esophageal cancer and the mechanisms of relevant drugs, discuss their efficacy and safety, and provide a clinical rationale for precision medicine in esophageal cancer.

8.
Nutrition ; 79-80: 110963, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-33011471

RESUMO

OBJECTIVES: Objective nutritional indexes have been shown to predict prognosis in some clinical settings. We aimed to explore the predictive values of these indexes in patients undergoing peritoneal dialysis (PD). METHODS: This is a single-center retrospective observational study in patients undergoing PD. The controlling nutritional status (CONUT) score, prognostic nutritional index (PNI), and geriatric nutritional risk index (GNRI) were calculated at baseline. The primary outcome was all-cause mortality. The secondary outcome was new-onset cardiocerebrovascular disease (CVD) events. Univariate and multivariate Cox regressions were performed to investigate the association between confounding factors and outcomes. The optimal cutoff values were determined using a receiver operating characteristic curve analysis. We used the Kaplan-Meier curve to compare the outcomes according to the cutoff values. The area under the curve (AUC) was used to test discriminative power of these objective nutritional indexes. RESULTS: We analyzed 252 patients undergoing PD at our institution. On the Cox hazard analysis, the CONUT score, PNI, and GNRI were independently associated with all-cause mortality (CONUT: hazard ratio [HR]: 1.496; 95% confidence interval (CI), 1.241-1.804; P < 0.001; PNI: HR: 0.878; 95% CI, 0.815-0.946; P = 0.001; and GNRI: HR: 0.930; 95% CI, 0.885-0.978; P = 0.040) and CVD incidence (CONUT: HR: 1.385; 95% CI, 1.177-1.630; P < 0.001; PNI: HR: 0.885; 95% CI, 0.826-0.949; P = 0.001; and GNRI: HR: 0.936; 95% CI, 0.893-0.981; P = 0.005). In the Kaplan-Meier analysis, patients with a higher CONUT score and lower PNI had significantly higher incidence of all-cause mortality (17.7% versus 3.0%; P = 0.022; 24.3% versus 5.7%, P = 0.003, respectively). As for new-onset CVD, patients with a higher CONUT score, lower PNI, and lower GNRI had higher occurrence rates (19.4% versus 3.0%; P = 0.006; 28.7% versus 7.9%; P = 0.001; 24.4% versus 9.9%; P = 0.035, respectively). The largest AUC to predict all-cause mortality was the CONUT score (AUC: 0.733; 95% CI, 0.674-0.787). For CVD prevalence, the largest AUC was the PNI (AUC: 0.718; 95% CI, 0.658-0.773). CONCLUSIONS: Objective nutritional indexes were independently associated with all-cause mortality and CVD events in patients undergoing PD. Moreover, assessments of the CONUT score and PNI may provide more useful predictive values than GNRI.

9.
Mol Med Rep ; 22(5): 4298-4306, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33000200

RESUMO

The present study aimed to investigate the effects of sufentanil on sepsis-induced acute lung injury (ALI), and identify the potential molecular mechanisms underlying its effect. In order to achieve this, a rat sepsis model was established. Following treatment with sufentanil, the lung wet/dry (W/D) weight ratio was calculated. Histopathological analysis was performed via hematoxylin and eosin staining. Levels of inflammatory factors in bronchoalveolar lavage fluid were determined via ELISA. Furthermore, malondialdehyde (MDA) content and the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in tissue homogenates were assessed using commercial kits. Western blot analysis was performed to determine kininogen-1 (KNG1) protein expression. In addition, alveolar epithelial type II cells (AEC II) were stimulated with lipopolysaccharide (LPS) to mimic ALI. The levels of inflammation and oxidative stress were evaluated following overexpression of KNG1. Protein expression levels of nuclear factor-κB (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling were determined via western blot analysis. The results of the present study demonstrated that sufentanil alleviated histopathological injury and the W/D ratio in lung tissue. Following treatment with sufentanil, levels of inflammatory factors also decreased, accompanied by decreased concentrations of MDA, and increased activities of SOD, CAT and GSH-Px. Notably, KNG1 was decreased in lung tissues following treatment with sufentanil. Furthermore, overexpression of KNG1 attenuated the inhibitory effects of sufentanil on LPS-induced inflammation and oxidative stress in AEC II. Sufentanil markedly downregulated NF-κB expression, while upregulating Nrf2 and HO-1 expression levels, which was reversed following overexpression of KNG1. Taken together, the results of the present study suggested that sufentanil may alleviate inflammation and oxidative stress in sepsis-induced ALI by downregulating KNG1 expression.

10.
Nanoscale ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33020781

RESUMO

Multispectral detection and imaging facilitate advances in target identification; for example, the switchable functionality of sensing visible photons and sensing near-infrared photons in the eyes of some vertebrate species provide visual sensitivity beyond the range of human vision. In this work, a single sensor device is constructed with stacking solution-processed MAPbI3 and MA0.5FA0.5Pb0.5Sn0.5I3 in opposite polarity for the multispectral detection of visible and NIR photons. With applied bias modulating built-in potential, the sensing response is tunable, while the good ambipolar carrier transport and high trap tolerance in perovskite films ensure high performance. As a result, the selective sensing toward visible photons from 350-800 nm and NIR photons from 700-1000 nm is achieved in a single photodetector under -0.3V and 0.5 V, respectively, with a high on/off ratio of ∼104, a relatively low optical crosstalk of -70 dB, and specific detectivity of over 1012 Jones. Moreover, the high mode-switching rate of 1000 Hz in altering the visible and NIR sensing mode and the high -3 dB bandwidth of ∼50 kHz enable our solution-processed perovskite-based multispectral photodetector to be recognized as an advanced technique for the fast and sensitive target multispectral imaging and identification.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33023897

RESUMO

INTRODUCTION: Previous studies in mostly Western populations have yielded conflicting findings on the association of vitamin B12 with diabetes risk, in part due to differences in study design and population characteristics. This study sought to examine the vitamin B12-diabetes association in Chinese adults with hypertension by both cross-sectional and longitudinal analyses. RESEARCH DESIGN AND METHODS: This report included a total of 16 699 participants from the China Stroke Primary Prevention Trial, with pertinent baseline and follow-up data. Diabetes mellitus was defined as either physician-diagnosed diabetes, use of glucose-lowering drugs, or fasting blood glucose (FBG) ≥7.0 mmol/L. New-onset diabetes was defined as any new case of onset diabetes during the follow-up period or FBG ≥7.0 mmol/L at the exit visit. RESULTS: At baseline, there were 1872 (11.2%) patients with diabetes; less than 1.5% had clinical vitamin B12 deficiency (<148.0 pmol/L). Over a median follow-up period of 4.5 years, there were 1589 (10.7%) cases of new-onset diabetes. Cross-sectional analyses showed a positive association between baseline vitamin B12 levels and FBG levels (ß=0.18, 95% CI 0.15 to 0.21) and diabetes (OR=1.16, 95% CI 1.10 to 1.21). However, longitudinal analyses showed no association between baseline vitamin B12 and new-onset diabetes or changes in FBG levels. Among a subset of the sample (n=4366) with both baseline and exit vitamin B12 measurements, we found a positive association between an increase in vitamin B12 and an increase in FBG. CONCLUSIONS: In this large Chinese population of patients with hypertension mostly sufficient with vitamin B12, parallel cross-sectional and longitudinal analyses provided new insight into the conflicting findings of previous studies, and these results underscore the need for future studies to consider both baseline vitamin B12 and its longitudinal trajectory in order to better elucidate the role of vitamin B12 in the development of diabetes. Such findings would have important clinical and public health implications.

12.
Clin Cardiol ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33026120

RESUMO

BACKGROUD: The association between underlying comorbidities and cardiac injury and the prognosis in coronavirus disease 2019 (COVID-19) patients was assessed in this study. HYPOTHESIS: The underlying comorbidities and cardiac injury may be associated with the prognosis in COVID-19 patients. METHODS: A systematic search was conducted in PubMed, EMBASE, Web of science, and The Cochrane library from December 2019 to July 2020. The odds ratio (OR) and 95% confidence intervals (95% CI) were used to estimate the probability of comorbidities and cardiac injury in COVID-19 patients with or without severe type, or in survivors vs nonsurvivors of COVID-19 patients. RESULTS: A total of 124 studies were included in this analysis. A higher risk for severity was observed in COVID-19 patients with comorbidities. The pooled result in patients with hypertension (OR 2.57, 95% CI: 2.12-3.11), diabetes (OR 2.54, 95% CI: 1.89-3.41), cardiovascular diseases (OR 3.86, 95% CI: 2.70-5.52), chronic obstractive pulmonary disease (OR 2.71, 95% CI: 1.98-3.70), chronic kidney disease (OR 2.20, 95% CI: 1.27-3.80), and cancer (OR 2.42, 95% CI: 1.81-3.22) respectively. All the comorbidities presented a higher risk of mortality. Moreover, the prevalence of acute cardiac injury is higher in severe group than in nonsevere group, and acute cardiac injury is associated with an increased risk for in-hospital mortality. CONCLUSION: Comorbidities and acute cardiac injury are closely associated with poor prognosis in COVID-19 patients. It is necessary to continuously monitor related clinical indicators of organs injury and concern comorbidities in COVID-19 patients.

13.
Clin Cancer Res ; 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32998963

RESUMO

PURPOSE: T-cells engineered to express a chimeric antigen receptor (CAR T-cells) are a promising cancer immunotherapy. Such targeted therapies have shown long-term relapse-free survival in patients with B-cell leukemia and lymphoma. However, cytokine release syndrome (CRS) represents a serious, potentially life-threatening side effect often associated with CAR T-cell therapy. CRS manifests as a rapid (hyper)immune reaction driven by excessive inflammatory cytokine release, including interferon-g and interleukin-6. EXPERIMENTAL DESIGN: Many cytokines implicated in CRS are known to signal through the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway. Here we study the effect of blocking JAK pathway signaling on CAR T-cell proliferation, anti-tumor activity and cytokine levels in in vitro and in vivo models. RESULTS: We report that itacitinib, a potent, selective JAK1 inhibitor, was able to significantly and dose-dependently reduce levels of multiple cytokines implicated in CRS in several in vitro and in vivo models. Importantly, we also report that at clinically relevant doses that mimic human JAK1 pharmacologic inhibition, itacitinib did not significantly inhibit proliferation or antitumor killing capacity of three different human CAR T-cell constructs (GD2, EGFR, and CD19). Finally, in an in vivo model, antitumor activity of CD19-CAR T-cells adoptively transferred into CD19+ tumor bearing immuno-deficient animals was unabated by oral itacitinib treatment. CONCLUSIONS: Together, these data suggest that itacitinib has potential as a prophylactic agent for the prevention of CAR T-cell-induced CRS, and a phase II clinical trial of itacitinib for prevention of CRS induced by CAR T-cell therapy has been initiated (NCT04071366).

14.
Food Chem ; 341(Pt 1): 128216, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-33032253

RESUMO

Ultrasonic degradation has become a promising strategy for producing modified pectin (MP). In this study, the impact of ultrasonic treatment at various pH values (4.0, 7.0, and 10.0) on the macromolecular, structural and rheological characteristics of citrus pectin was investigated. Results demonstrated that ultrasonic irradiation at the higher pH led to larger reductions in the intrinsic viscosity and weight-average molecular weight of pectin. The degradation kinetics of pectin at different pH values under ultrasound well fitted to a second-order reaction kinetics model. Acoustic cavitation, ß-elimination, and demethylation led to the breakage of glycosidic linkages of side chains and methoxyl groups of pectin, but did not have noticeable influences on the main chain of pectin. The ultrasonic treatment at a high pH led to an apparent change in the rheological characteristics of pectin. Therefore, ultrasonic treatment at various pH values can be developed as a viable means to prepare desirable MP.

15.
Lung Cancer ; 150: 9-11, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-33035779

RESUMO

EGFR mutations, primarily sensitizing mutations such as exon 19 deletion and exon 21 point mutations, have been proven to act as predictive biomarkers for the response to tyrosine kinase inhibitors (TKIs). How patients harboring EGFR L747 P (a rare mutation located in exon 19) respond to EGFR-TKI is controversial. Some studies have described EGFR L747 P as providing intrinsic resistance to EGFR-TKIs, but others support this rare mutation as a sensitive mutation. Hence, we reported a patient with advanced lung adenocarcinoma harboring an EGFR L747 P who benefited from first-line treatment with gefitinib. This patient achieved stable disease (SD) and had a progression-free survival (PFS) of 18 months. After disease progression, this patient was subsequently administered osimertinib and responded, as evidenced by a significant reduction in nodular lesions. This case revealed that EGFR L747 P rendered both gefitinib and osimertinib therapeutically efficacious.

16.
Int Immunopharmacol ; 89(Pt A): 106999, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33045563

RESUMO

Cisplatin is widely used as a chemotherapeutic agent for treating patients with solid tumors. The most common side effect of cisplatin treatment is nephrotoxicity. Recent studies have shown that mitochondrial apoptotic pathways are involved in cisplatin-induced acute kidney injury (Cis-AKI). LIGHT, the 14th member of the tumor necrosis factor superfamily (TNFSF14), was found to induce apoptosis of certain types of tumor cells. So far, a link between LIGHT and Cis-AKI has not been reported. In this study, we observed that expression of LIGHT and its receptors HVEM and LTßR was increased in kidney tissues of mice after cisplatin treatment. LIGHT deficiency aggravated kidney injury, as evidenced by more severe tubular injury; remarkably increased levels of serum creatinine (Scr), blood urea nitrogen (BUN), and both kidney injury molecule-1 (KIM-1) and inflammatory cytokine mRNAs in renal tissues. Moreover, in the renal tissues of LIGHT KO mice, cisplatin-induced mitochondrion injury and the levels of the pro-apoptotic molecules Bax, Cytochrome C (Cyt C), cleaved caspase-3, and cleaved caspase-9 were dramatically increased; in contrast, the expression of anti-apoptotic molecule Bcl-2 was markedly reduced, compared to those in WT mice, suggesting that LIGHT deficiency accelerated cisplatin-induced mitochondrial apoptosis of renal tubular cells in these mice. Accordingly, treatment with recombinant human LIGHT (rLIGHT) was shown to alleviate cisplatin-induced kidney injury in vivo. Similar results were observed after the human renal tubular epithelial cell line HK-2 cells exposure to rLIGHT stimulation, evidenced by the reduction in the mitochondrion dysfunction (as confirmed by the significant reduced oxidative stress and membrane potential changes) and in the percentage of cells apoptosis. While blocking LIGHT with the soluble fusion protein LTßR-Ig or HVEM-Ig accelerated the HK-2 cells apoptosis. In conclusion, LIGHT deficiency aggravates Cis-AKI by promoting mitochondrial apoptosis pathways.

17.
Diabetes Obes Metab ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33016522

RESUMO

AIMS: To quantitatively analyse the association between the durability of glycaemic control and body weight changes during treatment. METHODS: This study adhered to an appropriate methodology according to Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Studies with follow-ups longer than 12 months and final and intermediate assessments of haemoglobin A1c (HbA1c) and body weight were included. Four outcomes assessing therapeutic durability were extracted and synthesized using Stata statistical software, including changes in HbA1c, the goal-achievement rate, the failure rate, and the coefficient of failure (CoF). RESULT: After 8.9 months of treatment, HbA1c levels declined from 8.03% (95% confidence interval (CI), 7.91 to 8.15; I2 = 99.2%) to 7.15% (95% CI, 7.02 to 7.27; I2 = 99.4%) and then gradually increased up to 7.72% (95% CI, 7.50 to 7.94; I2 = 99.0%) five years later. The goal-achievement rate decreased from 54.8% (after one year of treatment) to 19.4% five years later. The CoF was 0.123±0.022 %/year (P < 0.001). After stratification, the CoFs were 0.224 ± 0.025%/y (p < 0.001) for weight gain, 0.137 ±0.034%/y (p <0.001) for neutral weight and -0.024 ± 0.032%/y (p = 0.450) for weight loss. After stratification by treatment approaches, the CoFs were 0.45%/y for insulin, 0.43%/y for sulfonylurea, 0.34%/y for thiazolidinediones, 0.29%/y for metformin, 0.16% for glucagon-like polypeptide-1 receptor agonists, 0.12% for surgery, -0.03% for sodium-glucose cotransporter-2 inhibitors and -0.21% for dipeptidyl peptidase-IV inhibitors. CONCLUSION: Modest weight loss with a goal of 2-3% of body weight should be recommended to improve therapeutic durability and prevent beta-cell deterioration.

18.
Nat Commun ; 11(1): 4810, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968061

RESUMO

Chimeric antigen receptor (CAR) therapy is a promising immunotherapeutic strategy for treating multiple refractory blood cancers, but further advances are required for solid tumor CAR therapy. One challenge is identifying a safe and effective tumor antigen. Here, we devise a strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest malignancies). We report that T and NK cells transduced with a CAR that recognizes the surface marker, CD147, also known as Basigin, can effectively kill various malignant HCC cell lines in vitro, and HCC tumors in xenograft and patient-derived xenograft mouse models. To minimize any on-target/off-tumor toxicity, we use logic-gated (log) GPC3-synNotch-inducible CD147-CAR to target HCC. LogCD147-CAR selectively kills dual antigen (GPC3+CD147+), but not single antigen (GPC3-CD147+) positive HCC cells and does not cause severe on-target/off-tumor toxicity in a human CD147 transgenic mouse model. In conclusion, these findings support the therapeutic potential of CD147-CAR-modified immune cells for HCC patients.


Assuntos
Basigina/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Imunoterapia Adotiva/métodos , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Antígenos Quiméricos/efeitos dos fármacos , Animais , Basigina/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Células Hep G2 , Humanos , Células Matadoras Naturais , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Proc Natl Acad Sci U S A ; 117(38): 23707-23716, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32878999

RESUMO

Trafficking of toll-like receptor 3 (TLR3) from the endoplasmic reticulum (ER) to endolysosomes and its subsequent proteolytic cleavage are required for it to sense viral double-stranded RNA (dsRNA) and trigger antiviral response, yet the underlying mechanisms remain enigmatic. We show that the E3 ubiquitin ligase TRIM3 is mainly located in the Golgi apparatus and transported to the early endosomes upon stimulation with the dsRNA analog poly(I:C). TRIM3 mediates K63-linked polyubiquitination of TLR3 at K831, which is enhanced following poly(I:C) stimulation. The polyubiquitinated TLR3 is recognized and sorted by the ESCRT (endosomal sorting complex required for transport) complexes to endolysosomes. Deficiency of TRIM3 impairs TLR3 trafficking from the Golgi apparatus to endosomes and its subsequent activation. Trim3 -/- cells and mice express lower levels of antiviral genes and show lower levels of inflammatory response following poly(I:C) but not lipopolysaccharide (LPS) stimulation. These findings suggest that TRIM3-mediated polyubiquitination of TLR3 represents a feedback-positive regulatory mechanism for TLR3-mediated innate immune and inflammatory responses.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32900569

RESUMO

BACKGROUND AND AIMS: The aim of this study was to evaluate the association between body mass index (BMI) and mortality in atrial fibrillation (AF) patients with and without diabetes mellitus (DM). METHODS AND RESULTS: A total of 1991 AF patients were enrolled and divided into two groups according to whether they have DM at recruitment. Baseline information was collected and a mean follow-up of 1 year was carried out. The primary outcome was defined as all-cause mortality with the secondary outcomes including cardiovascular mortality, stroke and major adverse events (MAEs). Univariable and multivariable Cox regression were performed to estimate the association between BMI and 1-year outcomes in AF patients with and without DM. 309 patients with AF (15.5%) had comorbid DM at baseline. Patients with DM were more likely to have cardiovascular comorbidities, receive relevant medications but carry worse 1-year outcomes. Multivariable Cox regressions indicated that elevated BMI was related with reduced risk of all-cause mortality, cardiovascular mortality and major adverse events. Compared to normal weight, overweight [HR (95% CI): 0.548 (0.405-0.741), p < 0.001] and obesity [HR (95% CI): 0.541 (0.326-0.898), p = 0.018] were significantly related with decreased all-cause mortality for the entire cohort. Remarkably reduced all-cause mortality in the overweight [HR (95% CI): 0.497 (0.347-0.711), p < 0.001] and obesity groups [HR (95% CI): 0.405 (0.205-0.800), p = 0.009] could also be detected in AF patients without DM, but not in those with DM. CONCLUSION: Elevated BMI was associated with reduced mortality in patients with AF. This association was modified by DM. The obesity paradox confined to AF patients without DM, but could not be generalized to those with DM.

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