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1.
Aging (Albany NY) ; 122020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33223509

RESUMO

Type 2 diabetes mellitus (T2DM) is an age-related metabolic disease that is of increasing concern. Gut microbiota might have a critical role in the pathogenesis of T2DM. Additionally, Hippo signaling has been associated strongly with the progression of T2DM and the aging process. We adopted db/db male mice as a T2DM model, and the gut microbiota of db/db and m/m mice were transplanted successfully into pseudo germ-free mice. Furthermore, Hippo signaling, including mammalian sterile 20-like protein kinases 1 (MST1), large tumor suppressors 1 (LATS1), Yes-associated protein (YAP), and phosphorylation of YAP (p-YAP) in peripheral tissues were significantly altered and highly correlated with blood glucose in db/db mice. Interestingly, the host after gut microbiota transplantation from db/db mice showed decreased MST1 and LATS1 levels, and p-YAP/YAP ratio in the heart, liver, and kidney compared to those from m/m mice. Negative correlations between fasting blood glucose and Hippo signaling levels in selected peripheral tissues also were identified. These findings suggest that alterations in Hippo signaling in selected peripheral tissues may contribute to the development of T2DM, and that therapeutic interventions improving Hippo signaling by gut microbiota transplantation might be beneficial for the treatment of T2DM and other age-related metabolic diseases.

2.
Ann Palliat Med ; 9(5): 2623-2630, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32921082

RESUMO

BACKGROUND: The impact of an overall healthy lifestyle on early-onset stroke is still unclear. Our study thus aimed to investigate the association of overall healthy lifestyle on early-onset stroke in Chinese hospitalized stroke patients. METHODS: This retrospective study included 821 hospitalized stroke patients from the First People's Hospital of Changzhou. An overall healthy lifestyle was defined as the presence of more than 2 of the following items: healthy diet, no smoking, normal body mass index (BMI <24 kg/m2 ), engaging in moderate to high physical activity (≥3 times/week, and ≥30 minutes each time). Early-onset stroke was defined as a stroke first occurring at 50 years old or younger. RESULTS: Among all participants, there were 98 early-onset stroke patients and 723 late-onset stroke patients. Early-onset patients had a lower prevalence of overall healthy lifestyles than that of late-onset patients (P<0.001). Multivariate logistic regression revealed that an overall healthy lifestyle significantly reduced the risk of early-onset stroke. In reference to those without an overall healthy lifestyle, the multivariate-adjusted odds ratios (ORs) for early-onset stroke among participants with an overall healthy lifestyle was 0.27 [95% confidence interval (CI): 0.07-0.98]. CONCLUSIONS: In Chinese stroke patients, a healthy lifestyle was significantly associated with early-onset stroke. Individuals who were adhering to an overall healthy lifestyle had a lower risk of early-onset stroke compared to those who were not.

3.
BMC Endocr Disord ; 20(1): 99, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32605653

RESUMO

BACKGROUND: Subclinical diabetic cardiomyopathy (DCM) occurs frequently in asymptomatic subjects with Type 2 diabetes mellitus (T2DM). The direct association between the immune system and DCM with effective biomarkers has been demonstrated in previous studies. METHODS: Five hundred seven subjects with T2DM were recruited from April 2018 to October 2019 and divided into T2DM with cardiac dysfunction (DCM) group and T2DM without cardiac dysfunction (non-DCM) group. The relationship between the quartiles of Neutrophil: lymphocyte ratio (NLR) and subclinical DCM was evaluated by using adjusted logistic regression models.(covariates: age, sex, BMI, duration of diabetes, and hyperlipidemia). RESULTS: Blood NLR was significantly upregulated in DCM group compared to non-DCM group (P = 0.05). Then the adjusted odds ratio (95% CI) of the highest NLR quartile was 14.32 (2.92-70.31) compared with the lowest quartile of NLR after multiple adjusted (P < 0.001). However, there was no significant relation between neutrophil and lymphocyte counts and the occurrence of DCM in T2DM patients. CONCLUSIONS: This study demonstrated that NLR was associated with the occurrence of subclinical DCM, suggesting that NLR may be a biomarker for predicting DCM with effectiveness and accuracy. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR1900027080) . Registered 30 October 2019. Retrospectively registered: www.medresman.org.

4.
Am J Med Genet B Neuropsychiatr Genet ; 183(6): 331-340, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32657040

RESUMO

Autism (or autism spectrum disorder [ASD]) is an often disabling childhood neurologic condition of mostly unknown cause. We previously explored whether there was an association of ASD with any analyte measured in the first newborn screening blood test. Here we explore the second screen. Our matched case-control study examined data on 3-5 year-old patients with any ASD diagnosis in the Texas Medicaid system in 2010-2012. Subjects were linked to their 2007-2009 newborn screening blood test data, which included values for 36 analytes or analyte ratios. Data were available for 3,005 cases and 6,212 controls. The most compelling associations were evident for fatty acid oxidation analytes octanoylcarnitine (C8) and octanoylcarnitine/acetylcarnitine (C8/C2). Their adjusted odds ratios comparing 10th versus first analyte deciles were between 1.42 and 1.54 in total births, term births, and males. C8 was consistent with first screen results. Adipylcarnitine (C6DC), an organic acid analyte, showed opposite results in the two screens. Several other analytes exhibiting significant associations in the first screen did not in the second. Our results provide evidence that abnormal newborn blood levels of some carnitines may be associated with risk of later ASD, possibly related to their involvement with mitochondrial function in the developing brain.

5.
Mol Cell Endocrinol ; 518: 110944, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32717421

RESUMO

BACKGROUND: Diabetic cardiomyopathy (DCM) is a type of cardiac dysfunction that affects approximately 12% of diabetic patients, ultimately leading to heart failure or even death. However, there is currently no efficient or specific biomarker for DCM diagnosis. METHODS: A total of 266 subjects with type II diabetes (T2DM) were enrolled in this study and were divided into the T2DM with cardiac dysfunction (DCM) group and T2DM without cardiac dysfunction (non-DCM) group. The diagnostic efficacy of miR-21 was determined and compared with that of serum hemoglobin A1c% (HbA1c%). Db/db mice and H9c2 cells stimulated with high glucose (HG)/high fatty acid (PA) were used as in vivo and in vitro models of DCM, respectively. RESULTS: Through echocardiography and gated-myocardial perfusion imaging (gated-MPI), 49 patients were selected to be enrolled in the DCM group, with 49 matched controls in the non-DCM group. The circulating miR-21 levels were significantly decreased in the DCM group compared to the non-DCM group (P < 0.001). The diagnostic efficiency of miR-21 (area under the curve AUC = 0.899) was higher than that of other parameters, including HbA1c%. Moreover, when miR-21 was combined with the duration of diabetes, HbA1c%, and lipid profiles, the AUC was the highest (AUC = 0.939) and had the highest diagnostic efficiency. Furthermore, overexpression of miR-21 improved the impaired mitochondrial biogenesis and decreased the cardiomyocyte apoptosis induced by HG/PA, while inhibition of miR-21 exerted the opposite effects. CONCLUSIONS: Our findings identify circulating miR-21 as a novel biomarker in the diagnosis of DCM and provide an underlying mechanism for miRNA-based therapy for the treatment of DCM. TRIAL REGISTRATION: The study was approved by the Ethics Committee of the Third Affiliated Hospital of Soochow University and has been registered in the Chinese Clinical Trial Registry (ChiCTR1900027080).

6.
Tumori ; 106(4): 306-311, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32366210

RESUMO

BACKGROUND: The immune checkpoint ligand, programmed cell death 1 ligand 1 (PD-L1), is expressed in various tumors and associated with response to drugs that target programmed cell death protein 1. Previous studies have estimated the level of PD-L1 expression among different stages of thymoma and thymic carcinoma to evaluate its potential use as a diagnostic factor; however, its varying expression level has been problematic. We conducted this meta-analysis of published literature to evaluate PD-L1 expression in thymomas and thymic carcinomas. METHODS: We analyzed 12 studies that included 320 patients with type A/AB/B1 thymoma, 225 patients with type B2/B3 thymoma, and 180 patients with thymic carcinoma. RESULTS: No difference in PD-L1 expression level was found between the B2/B3 vs C groups (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.26, 1.76; p = 0.42). However, the heterogeneity was very high (I2 = 78%), and a significant difference was found between groups A/AB/B1 and B2/B3 (OR, 0.22; 95% CI, 0.12, 0.41; p < 0.001), with a relatively low heterogeneity (I2 = 55%). CONCLUSION: PD-L1 positivity might be a useful factor to differentiate type A/AB/B1 thymoma from type B2/B3 and thymic carcinoma. This result might be valuable for potential anti PD-L1 treatment in thymoma and thymic carcinoma.


Assuntos
Antígeno B7-H1/genética , Timoma/genética , Neoplasias do Timo/genética , Adulto , Idoso , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Timoma/imunologia , Timoma/patologia , Timoma/terapia , Neoplasias do Timo/imunologia , Neoplasias do Timo/terapia
7.
Lung Cancer ; 142: 59-62, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32114282

RESUMO

OBJECTIVES: Transforming anaplastic lymphoma kinase (ALK) gene rearrangements are well known as a unique subset of non-small cell lung cancer (NSCLC) with mutations other than EGFR. Currently, crizotinib is the standard first-line treatment for ALK-positive NSCLC. MATERIALS AND METHODS: With advances in detection methods, more and more uncommon ALK fusion partners have been identified. Herein we present a novel SOS1-ALK fusion and the efficacy of crizotinib in an advanced NSCLC patient harboring this type of fusion. RESULTS: A 52-year-old Chinese man had left upper lobe primary NSCLC and synchronous multiple lung metastases (cT2N3M1, stage IV). The ultrasound-guided fine-needle aspiration cytology of palpable left supraclavicular lymph nodes and the results of immunohistochemistry staining supported the diagnosis of metastatic lung adenocarcinoma. Using a next-generation sequencing assay (NGS), we showed that the tumor had a SOS1-ALK fusion which the breakpoints was (S2, A20) rather than other actionable mutations. Therefore, the patient received first-line crizotinib and experienced a remarkable tumor response and has tolerated crizotinib well until this writing. CONCLUSION: Considering this rare SOS1-ALK fusion and remarkable response to an ALK-inhibitor, it is important to be aware of the presence of SOS1-ALK fusions in patients with advanced NSCLC to better guide targeted therapy. Precision methods, such as NGS for oncogenic alteration detection, should also be encouraged in clinical practice.

8.
FASEB J ; 34(2): 2173-2197, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31907983

RESUMO

Several lines of evidence have revealed the potential of microRNAs (miRNAs, miRs) as biomarkers for detecting diabetic cardiomyopathy, although their functions in hyperglycemic cardiac dysfunction are still lacking. In this study, mitochondrial biogenesis was markedly impaired induced by high glucose (HG), as evidenced by dysregulated mitochondrial structure, reduced mitochondrial DNA contents, and biogenesis-related mRNA levels, accompanied by increased cell apoptosis. MiR-144 was identified to be decreased in HG-induced cardiomyocytes and in streptozotocin (STZ)-challenged heart samples. Forced miR-144 expression enhanced mitochondrial biogenesis and suppressed cell apoptosis, while miR-144 inhibition exhibited the opposite results. Rac-1 was identified as a target gene of miR-144. Decreased Rac-1 levels activated AMPK phosphorylation and PGC-1α deacetylation, leading to increased mitochondrial biogenesis and reduced cell apoptosis. Importantly, the systemic neutralization of miR-144 attenuated mitochondrial disorder and ventricular dysfunction following STZ treatment. Additionally, plasma miR-144 decreased markedly in diabetic patients with cardiac dysfunction. The receiver-operator characteristic curve showed that plasma miR-144 could specifically predict diabetic patients developing cardiac dysfunction. In conclusion, this study provides strong evidence suggesting that miR-144 protects heart from hyperglycemia-induced injury by improving mitochondrial biogenesis and decreasing cell apoptosis via targeting Rac-1. Forced miR-144 expression might, thus, be a protective strategy for treating hyperglycemia-induced cardiac dysfunction.


Assuntos
Apoptose , Cardiomiopatias Diabéticas , Hiperglicemia , MicroRNAs/metabolismo , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Linhagem Celular , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/prevenção & controle , Humanos , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperglicemia/prevenção & controle , MicroRNAs/genética , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/patologia , Miocárdio/patologia , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley
9.
Metab Syndr Relat Disord ; 18(3): 128-133, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31999502

RESUMO

Background: Nonobese individuals with disproportionate body fat distribution are also vulnerable to dysglycemia. This study aimed to evaluate the association between three visceral adiposity surrogates and impaired fasting glucose (IFG) in nonobese Chinese individuals. Methods: A total of 70,200 nonobese adults without diabetes were included in this analysis. Two diagnostic criteria (IFG-ADA and IFG-WHO) were used to define IFG. The values of the visceral adiposity index, lipid accumulation product index (LAP), and cardiometabolic index (CMI) were calculated. Multivariable logistic analysis was used to evaluate the association between these surrogates and IFG. Results: Among the three indicators, only LAP and CMI were positively correlated with fasting plasma glucose (all P < 0.001). After fully adjusting for confounders, only LAP and CMI exhibited significant associations with IFG. For women, the odds ratios (ORs) for IFG-ADA in the highest quartile of the LAP and CMI were 1.967 (95% confidence interval [CI]: 1.645-2.353) and 1.594 (95% CI: 1.383-1.836), respectively; and were 2.025 (95% CI: 1.597-2.567) and 2.017 (95% CI: 1.647-2.470), respectively, for IFG-WHO (all P < 0.001). For men, the ORs for IFG-ADA of the LAP and CMI were 1.503 (95% CI: 1.233-1.833) and 2.045 (95% CI: 1.752-2.388), respectively; and were 1.534 (95% CI: 1.174-2.005) and 2.541 (95% CI: 2.025-3.188), respectively, for IFG-WHO (all P < 0.001). Conclusions: The LAP and CMI, cost-effective and simple visceral adiposity surrogates, are strongly associated with IFG in nonobese Chinese individuals. These surrogates might be potential targets to monitor for the recognition and management of excess visceral adiposity in nonobese individuals with prediabetes.

10.
Blood Coagul Fibrinolysis ; 31(1): 16-28, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31687988

RESUMO

: A zymogen-like activated factor X variant (FXa) is being developed for treating acute bleeding conditions. Activated factor V is an essential cofactor to FXa for activating prothrombin to thrombin. Thrombi/emboli formation was observed microscopically in FXa toxicity studies in animals. The objective of this research was to evaluate candidate biomarkers for FXa-induced thrombi/emboli formation to inform safety monitoring and dose-escalation decisions in FXa clinical trials. Effects of intravenous FXa administration on platelets, fibrinogen, activated partial thromboplastin time (aPTT), prothrombin time (PT), D-dimer, tissue factor pathway inhibitor, thrombin : antithrombin complex, antithrombin, and factor V, and protein C (PC) activities were evaluated in mice, rats, and monkeys. Mice had endogenous factor V activity 10× that of monkeys and were overly sensitive to FXa-induced thrombi/emboli formation. In monkeys, decreases in fibrinogen and prolongation in aPTT and PT emerged as potential biomarkers for impending FXa-induced thrombi/emboli formation, based on association of changes with microscopically observable thrombi/emboli (0-97 thrombi/emboli per monkey). PC decreases, measured by a clot-based assay, were also observed. A similar reduction in PC activity, when measured by clot-based assay, was observed in a phase 1 clinical trial. However, an in-vitro experiment with human plasma spiked with increasing concentrations of FXa indicated dose-dependent FXa-induced interference with clot-based assays and no depletion of PC or S by FXa in non-clot-based assays. Nonclinical biomarker studies identified fibrinogen, aPTT and PT as potential biomarkers for monitoring the clinical safety of FXa. Results of clot-based assays with FXa treatment should be interpreted with caution.

11.
Front Genet ; 10: 1149, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803236

RESUMO

Dilated cardiomyopathy (DCM) is an important cause of sudden death and heart failure with an unknown etiology. Recent studies have suggested that long non-coding RNA (lncRNA) can interact with microRNA (miRNA) and indirectly interact with mRNA through competitive endogenous RNA (ceRNA) activities. However, the mechanism of ceRNA in DCM remains unclear. In this study, a miRNA array was first performed using heart samples from DCM patients and healthy controls. For further validation, we conducted real-time quantitative reverse transcription (RT)-PCR using samples from DCM patients and a doxorubicin-induced rodent model of cardiomyopathy, revealing that miR-144-3p and miR-451a were down-regulated, and miR-21-5p was up-regulated. Based on the ceRNA theory, we constructed a global triple network using data from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI-GEO) and our miRNA array. The lncRNA-miRNA-mRNA network comprised 22 lncRNA nodes, 32 mRNA nodes, and 11 miRNA nodes. Hub nodes and the number of relationship pairs were then analyzed, and the results showed that two lncRNAs (NONHSAT001691 and NONHSAT006358) targeting miR-144/451 were highly related to DCM. Then, cluster module and random walk with restart for the ceRNA network were analyzed and identified four lncRNAs (NONHSAT026953/NONHSAT006250/NONHSAT133928/NONHSAT041662) targeting miR-21 that were significantly related to DCM. This study provides a new strategy for research on DCM or other diseases. Furthermore, lncRNA-miRNA pairs may be regarded as candidate diagnostic biomarkers or potential therapeutic targets of DCM.

12.
Med Sci Monit ; 25: 9207-9215, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31793519

RESUMO

BACKGROUND Cystatin C is a protease inhibitor that is increased in the serum of patients with chronic kidney disease (CKD) and is associated with an increased risk of developing cardiovascular disease (CVD). This study aimed to evaluate the association between serum levels of cystatin C and arterial stiffness, associated with dyslipidemia, obesity, and increased pulse pressure, in middle-aged and elderly individuals without CKD in a population in China. MATERIAL AND METHODS A cross-sectional population-based study included 1,138 patients aged ≥40 years without CKD, defined as an estimated glomerular filtration rate measured by serum creatinine (eGFRSCr) ≥60 ml/min/1.73 m². Study participants provided clinical details, including height and weight, and blood samples for serum measurements of cystatin C and lipid profiles and completed a clinical questionnaire. Pulse pressure was calculated as the mean systolic pressure (SBP) minus the diastolic pressure (DBP). Data underwent multivariate logistic regression analysis. RESULTS An increase in serum levels of cystatin C was associated with an increased risk of arterial stiffness. Each standard deviation in the increase of cystatin C resulted in a 22% increased risk of dyslipidemia, a 27% increased risk of obesity, and a 24% increased risk of increased pulse pressure, after adjusting for confounders. These associations were further confirmed in a sensitivity analysis by excluding participants with hypertension, diabetes, and patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). CONCLUSIONS In middle-aged and elderly individuals without CKD, arterial stiffness determined by obesity, dyslipidemia and increased pulse pressure, was significantly associated with increased serum levels of cystatin C.


Assuntos
Cistatina C/análise , Insuficiência Renal Crônica/metabolismo , Rigidez Vascular/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea , China , Creatinina/sangue , Estudos Transversais , Cistatina C/sangue , Dislipidemias/complicações , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Insuficiência Renal Crônica/sangue , Apneia Obstrutiva do Sono/complicações
13.
Transl Oncol ; 13(2): 329-335, 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31881505

RESUMO

BACKGROUND: KRAS gene mutations are well known as a key driver of advanced non-small cell lung cancer (NSCLC). The impact of KRAS-mutant subtypes on the survival benefit from salvage chemotherapy is controversial. Here, we present a real-world study in patients across China with advanced NSCLC with KRAS mutations using a website-based patient self-report system. METHODS: We identified a total of 75 patients diagnosed with KRAS-mutant (determined by molecular sequencing) advanced NSCLC between 2014/5/9 and 2019/5/30. KRAS mutation subtypes were divided into G12C and non-G12C groups for statistical analysis. The clinicopathological characteristics and treatment survival benefit in all patients with a KRAS mutation were evaluated. Programmed death-ligand 1 (PD-L1) expression data were collected from 30 patients in the same cohort. RESULTS: In this study, 23 patients with stage IIIB NSCLC and 52 patients with stage IV NSCLC were enrolled with 58 men and 17 women; the median age was 60 years (39-84). All patients received regular chemotherapy/radiotherapy/targeted therapy/immune therapy as per the disease condition. Four main KRAS mutation subtypes were detected: G12C (33%), G12V (19%), G12A (12%), and G12D (12%). Three predominant KRAS comutations were detected: TP53-KRAS (31%), EGFR-KRAS (11%), and STK11-KRAS (8%). Compared with the KRAS non-G12C mutation subtype, patients with the KRAS G12C mutation had potentially longer progression-free survival (PFS) after first-line chemotherapy (4.7 vs. 2.5 months, p < 0.05). Pemetrexed-based chemotherapy appeared to be superior to taxanes- and gemcitabine-based chemotherapies in all patients (PFS: 5.0 vs. 1.5 and 2.3 months, respectively, p > 0.05). Cox regression analysis showed that the KRAS G12C mutation and pemetrexed-based first-line chemotherapy were positive influencers for PFS after first-line (hazard ratios = 0.31 and 0.55, respectively, P < 0.05), but not second-line chemotherapies. CONCLUSION: The KRAS G12C mutation could be a predictive biomarker for better survival benefit from first-line chemotherapy in patients with advanced NSCLC and KRAS mutations. The first-line chemotherapy regimen could possibly influence the outcome in patients with KRAS mutations. Larger and prospective clinical trials are warranted to confirm our conclusions.

14.
Aging (Albany NY) ; 11(22): 10454-10467, 2019 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-31760385

RESUMO

It is well recognized that type 2 diabetes mellitus (T2DM) is an age-related metabolic disease, emerging gradually as a major global health burden that has gained public attention. Meanwhile, increasing attention is paid to the crucial role of gut microbiota in the pathogenesis and therapeutic mechanisms of metabolic disorders, especially T2DM. In this study, we used C57 BL/KS db/db male mice as a T2DM murine model. We found that the ß-diversity and relative abundances of gut bacteria were obviously altered in db/db mice, associated with a significant increase in Verrucomicrobia at six levels (phylum, class, order, etc.) and family S24-7 and a significant decrease in Bacteroidaceae at family, genus, and species levels, as well as Prevotellaceae at family and genus levels. Furthermore, fecal bacteria from db/db and m/m mice transplanted into pseudo-germ-free mice showed a significant change in the metabolic parameters, including the body weight, fasting blood glucose, fluid and food intake, and alterations in the composition of the gut microbiota. Taken together, these findings suggest that abnormalities in the composition of the gut microbiota might contribute to the development of T2DM and that potential therapeutic strategies improving gut microbiota might provide beneficial effects for individuals with T2DM and age-related glucose intolerance.

15.
Neuroscience ; 421: 48-58, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31682826

RESUMO

Increasing studies have revealed that metabolic disorders, especially diabetes, are high risk factors for the development of Alzheimer's disease (AD) and other neurodegenerative diseases. It has been reported that patients with diabetes are prone to suffer from cognitive dysfunction (CD). Although abnormal glucose metabolism and deposition of amyloid ß (Aß) are proven to have a closely relationship with diabetes-induced CD, its exact mechanism is still undetermined. In this study, a total of 14 mice were intraperitoneally injected with streptozotocin for 5 consecutive days to mimic diabetic models, and then hierarchical cluster analysis was adopted to classify the diabetic mice into CD and Non-CD phenotypes by the results of Morris water maze test (MWMT). Furthermore, we detected Hippo signaling including mammalian sterile 20-like protein kinases1 (MST1), large tumor suppressors 1 (LATS1), Yes-associated protein (YAP) and phosphorylation of YAP (p-YAP) in brain and peripheral tissues. As compared with control mice, the levels of MST1, LATS1 and p-YAP/YAP ratio were increased in medial prefrontal cortex (mPFC), striatum and hippocampus of CD mice, while these proteins were decreased in gut tissue of CD mice. Additionally, there were significant positive correlations between escape latency and p-YAP/YAP ratio in mPFC, anterior cingulate cortex (ACC) and hippocampus, as well as the level of LATS1 in liver, kidney and gut tissues. In conclusion, alterations in Hippo signaling may contribute to CD induced by diabetes. Therefore, therapeutic interventions improving Hippo signaling might be beneficial to the treatment of diabetes-induced CD and other neurodegenerative diseases.

16.
J Transl Med ; 17(1): 341, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601236

RESUMO

BACKGROUND: The role of body fat distribution in uric acid metabolism is still ambiguity. We aimed to investigate the independent contribution of visceral adipose measured by visceral adiposity index and lipid accumulation product and liver fat assessed by fatty liver index to the risk of hyperuricemia. METHODS: We conducted a cross-sectional study involving 1284 participants aged ≥ 40 years old recruited from communities in Zhonglou district, Changzhou. Each participant completed a standard questionnaire, and provided blood samples for biochemical measurements. Visceral adiposity index, fatty liver index and lipid accumulation product were calculated by simple anthropometric and functional parameters. Hyperuricemia was defined as serum uric acid ≥ 420 µmol/l for males and ≥ 360 µmol/l for females. RESULTS: The prevalence of hyperuricemia was 15.9% and gradually increased across tertiles of adiposity-based indices. The visceral adipose-based measurements (visceral adiposity index, fatty liver index, lipid accumulation product) had better power to discriminate hyperuricemia than body mass index (BMI), waist circumference and neck circumference, and visceral adiposity index exhibited the highest power, with the area under the receiver operating characteristics curve (AUROC) of 0.662 (0.636-0.688). Multivariate logistic regression found 1.49-fold, 2.21-fold and 2.12-fold increased risk of hyperuricemia with 1-unit increment of visceral adiposity index, fatty liver index, and lipid accumulation product, respectively. Compared to tertile 1, the odds ratios of hyperuricemia for the second tertile and the third tertile of visceral adiposity index were 1.57 (1.00-2.50) and 3.11 (1.96-4.94), those of fatty liver index were 1.64 (1.05-2.68) and 3.58 (1.94-6.01), and those of lipid accumulation product were 1.93 (1.19-3.15) and 3.53 (2.05-6.09), respectively. However, no significant associations of BMI, waist circumference and neck circumference with hyperuricemia were observed. CONCLUSIONS: Visceral adipose accumulation increased the risk of hyperuricemia, independently of BMI, waist circumference and neck circumference, among middle-aged and elderly Chinese adults.

17.
Stem Cell Res Ther ; 10(1): 295, 2019 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547872

RESUMO

BACKGROUND: Interleukin 33 is known to have an important influence in the process of myocardial infarction, and the immunoregulatory function of MSCs could be influenced by cell factors. In this study, we evaluated the therapeutic efficacy of IL-33-overexpressing bone marrow mesenchymal stem cells (IL33-MSCs) on myocardial infarction (MI) and detected the inflammatory level and cardiac function in rats. METHODS AND RESULTS: First, we evaluated the proliferation of T cells and polarization of macrophages that had been co-cultured with Vector-MSCs or IL33-MSCs. Co-culture experiments indicated that IL33-MSCs reduced T cell proliferation and enhanced CD206+ macrophage polarization. Second, we determined the inflammation level and cardiac function of PBS-, Vector-MSC-, and IL33-MSC-injected rats. Echocardiography indicated that left ventricular ejection fraction (LVEF) was enhanced in IL33-MSC-injected rats compared with Vector-MSC-injected rats. Postmortem analysis of rat heart tissue showed reduced fibrosis and less inflammation in IL33-MSC-injected rats. CONCLUSION: These studies indicated that the IL33-MSC injection improved heart function and reduces inflammation in rats with MI compared with PBS or Vector-MSC injections. IL-33 overexpression enhances the immunomodulatory function and therapeutic effects of MSCs on acute MI via enhancing the polarization of macrophages toward M2, enhancing the differentiation of CD4+ T cells toward CD4+IL4+Th2 cells, and finally, reducing heart inflammation and enhancing heart function.

19.
J Pharmacokinet Pharmacodyn ; 46(5): 485-498, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432345

RESUMO

We developed a mathematical model of colon physiology driven by serotonin signaling in the enteric nervous system. No such models are currently available to assist drug discovery and development for GI motility disorders. Model parameterization was informed by published preclinical and clinical data. Our simulations provide clinically relevant readouts of bowel movement frequency and stool consistency. The model recapitulates healthy and slow transit constipation phenotypes, and the effect of a 5-HT4 receptor agonist in healthy volunteers. Using the calibrated model, we predicted the agonist dose to normalize defecation frequency in slow transit constipation while avoiding the onset of diarrhea. Model sensitivity analysis predicted that changes in HAPC frequency and liquid secretion have the greatest impact on colonic motility. However, exclusively increasing the liquid secretion can lead to diarrhea. In contrast, increasing HAPC frequency alone can enhance bowel frequency without leading to diarrhea. The quantitative systems pharmacology approach used here demonstrates how mechanistic modeling of disease pathophysiology expands our understanding of biology and supports judicious hypothesis generation for therapeutic intervention.


Assuntos
Colo/fisiologia , Desenvolvimento de Medicamentos/métodos , Motilidade Gastrointestinal/fisiologia , Modelos Biológicos , Constipação Intestinal/complicações , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/fisiopatologia , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Agonistas do Receptor de Serotonina/farmacocinética , Agonistas do Receptor de Serotonina/uso terapêutico
20.
Thromb Res ; 182: 56-63, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31450009

RESUMO

INTRODUCTION: Endotoxemia often results in systemic inflammatory response syndrome (SIRS), coagulation disturbance and acute lung injury (ALI), and such a condition is associated with the activation of platelets, leukocytes and vascular endothelial cells (VECs). P-selectin glycoprotein ligand 1 (PSGL-1) is a key regulatory molecule in the activation of platelets, leukocytes and VECs. However, it still remains largely unexplored whether PSGL-1 plays an important role in SIRS, coagulation dysfunction and ALI of endotoxemia. In the present study, we aimed to study the role of PSGL-1 in above-mentioned situations using endotoxemic mice. MATERIALS AND METHODS: An endotoxemia model was established in BALB/c mice via lipopolysaccharide (LPS) administration. Moreover, the mice were simultaneously injected with PSGL-1 antibody for intervention. The survival rate, morphologic changes of lung tissues, platelet-leukocyte adhesion, tissue factor expression on leukocytes, fibrinogen deposition in lung tissues, serum levels of inflammatory factors and the activation of VECs were determined. RESULTS: The results showed that the aggregation and recruitment of platelets and leukocytes in lung tissues, the expression of tissue factor on leukocytes, the serum levels of inflammatory factors, the activation of VECs, and the fibrinogen deposition in lung tissues were increased in endotoxemic mice, which were significantly alleviated by administration of PSGL-1 antibody. Moreover, blockade of PSGL-1 markedly increased survival rate, and alleviated coagulation disturbance and lung injury in endotoxemic mice. CONCLUSIONS: Taken together, PSGL-1 played an important role in pathogenesis of SIRS and coagulation dysfunction and ALI in endotoxemic mice.


Assuntos
Transtornos da Coagulação Sanguínea/imunologia , Endotoxemia/imunologia , Glicoproteínas de Membrana/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/imunologia , Animais , Coagulação Sanguínea , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/complicações , Endotélio Vascular/imunologia , Endotoxemia/sangue , Endotoxemia/complicações , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Agregação Plaquetária , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/complicações
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