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1.
Front Endocrinol (Lausanne) ; 12: 719666, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777240

RESUMO

Background: Lean body mass (LBM) and fat mass (FM) have been shown to have different associations with several chronic diseases but little is known about the sex-specific association of LBM and FM with diabetic nephropathy (DN) risk among participants with diabetes. Methods: Participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was used in a post hoc analysis to examine the association of predicted LBM index (LBMI) and FM index (FMI) with incident DN risk (defined as a composite outcome of three types of predefined DN). Because of sex differences in body composition, analyses were conducted separately using sex-specific quartiles of predicted LBMI and FMI. Results: Of the 9,022 participants with type 2 diabetes (5,575 men and 3,447 women) included in this study, 5,374 individuals developed DN (3,396 in men and 1,978 in women). Higher quartiles of LBMI were associated with a reduced risk of DN while higher quartiles of FMI were associated with an increased higher risk of DN among men but not women. Compared with the lowest quartile, the fully adjusted hazard ratios (HRs) and 95% confidence intervals (CIs)for the highest quartile of predicted LBMI and FMI were respectively 0.83 (95% CI 1.71 - 0.96) and 1.23 (95% CI 1.06-1.43) among men; and 0.92 (95% CI 0.63 - 1.33) and 1.14 (95% CI 0.79 - 1.63) among women. Conclusions: Among participants with diabetes, predicted LBMI was inversely associated with risk of DN while predicted FMI was positively associated with an increased risk of incident DN among men but not women. Trial registration: ClinicalTrials.gov., no. NCT00000620.

2.
Front Endocrinol (Lausanne) ; 12: 706845, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421824

RESUMO

Background: The prevalence of diabetes is on the rise globally coupled with its associated complications, such as diabetic nephropathy (DN). Obesity has been identified as a risk factor for the development of DN but it is still unclear which obesity index is the best predictor of incident DN. Methods: Data from the participants with type 2 diabetes mellitus (T2DM) in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study were used to examine the sex-specific association between waist circumference (WC), waist-to-height ratio (WHtR), and body mass index (BMI) with incident DN risk. Results: Among the 8,887 participants with T2DM (5,489 men and 3,398 women), 5,296 participants (3,345 men and 1,951 women) developed the DN composite outcome during a follow-up period of 24302 person-years. Among men, null associations were observed between all anthropometric measures with incident DN in the multivariate analysis although the 3rd quartile of WHtR showed marginally significant results (P = 0.052). However, among women, both central and general obesity measures were associated with increased risks of incident DN. Compared with participants in the WC <88 cm category, the fully adjusted HR and 95% CI for those in the ≥88 cm of WC was 1.35 (95% CI 1.15-1.57). Compared with the lowest quartile, the fully adjusted HRs and 95% CIs for the 2nd to the 4th quartile of WHtR were 1.09 (95% CI 0.96-1.25), 1.12 (95% CI 0.98-1.28), and 1.14 (95% CI 1.00-1.30) respectively; also, compared with the normal BMI category, the fully adjusted HRs and 95% CIs for class I - class III obese were 1.36 (95% CI 1.10 - 1.67), 1.43 (95% CI 1.16 - 1.78) and 1.32 (95% CI 1.05 - 1.66) respectively. Conclusions: Among participants with T2DM, higher levels of both central and general obesity indexes were associated with DN risk among women but not in men. Women with T2DM should maintain a healthy weight targeted at reducing both central and general obesity to enhance nephroprotection. Trial registration: ClinicalTrials.gov., no. NCT00000620.

3.
Inorg Chem ; 60(17): 13434-13439, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34423965

RESUMO

Herein, a Co(II) heteroatom metal-organic framework was successfully post-modified via unsaturated coordinated S precisely capturing Ni2+ on the surface of the porous structure. The newly pristine bimetallic MOFs have increasing active edge sites (Ni(II) and S), boosting electrocatalytic activity toward oxygen evolution reaction and hydrogen evolution reaction.

4.
J Gerontol A Biol Sci Med Sci ; 76(11): 2062-2070, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34331763

RESUMO

BACKGROUND: To investigate the influence of diabetes duration and glycemic control, assessed by glycated hemoglobin (HbA1c) levels, on risk of incident dementia. METHODS: The present study is a prospective study of 461 563 participants from the UK Biobank. The age at diabetes diagnosis was determined by self-report. Diabetes duration was calculated as baseline age minus age at diagnosis. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidential intervals (CIs). RESULTS: During a median follow-up of 8.1 years, 2 233 dementia cases were recorded. As compared with normoglycemic individuals, individuals with diabetes had higher risk of all-cause dementia, and the risk increased with increasing duration of diabetes; compared with participants with diabetes duration of <5 years, the multivariable-adjusted HRs (95% CIs) were 1.49 (1.12-1.97), 1.71 (1.21-2.41), and 2.15 (1.60-2.90) for those with diabetes durations ≥5 to < 10, ≥10 to <15, and ≥ 15 years, respectively (p for trend < .001). Among participants with diabetes, those with both longer diabetes duration (diabetes duration ≥ 10 years) and poor glycemic control (HbA1c ≥ 8%) had the highest risk of all-cause dementia (multivariable-adjusted HR = 2.07, 95% CI 1.45, 2.94), compared with patients with shorter duration of diabetes and better glycemic control (diabetes duration < 10 years and HbA1c < 8%). CONCLUSIONS: Diabetes duration appeared to be associated with the risk of incident dementia due to factors beyond glycemic control. Clinicians should consider not only glycemic control but also diabetes duration in dementia risk assessments for patients with diabetes.

5.
NPJ Genom Med ; 6(1): 48, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127680

RESUMO

Lung adenocarcinoma is heterogeneous and hierarchically organized, with a subpopulation of stem-like cells (CSCs) that reside at the apex of the hierarchy, in which exosomes act as important mediators by transporting specific molecules among different cell populations. Although there have been numerous studies on tumor exosomes, the constituents and functional properties of CSC-derived exosomes are still poorly characterized. Here we present a detail transcriptome and proteome atlas of the exosomes released by human lung adenocarcinoma stem-like cells (LSLCs). The transcriptome analysis indicates the specific patterns of exosomal constituents, including the fragmentation of transcripts and the low-level presence of circular RNAs, and identifies multiple exosomal-enriched mRNAs and lncRNAs. Integrative analysis of transcriptome and proteome data reveals the diverse functions of exosomal-enriched RNAs and proteins, many of which are associated with tumorigenesis. Importantly, several LSLC markers we identified are highly expressed in LSLC-derived exosomes and associate with poor survival, which may serve as promising liquid biopsy biomarkers for lung adenocarcinoma diagnosis. Our study provides a resource for the future elucidation of the functions of tumor-derived exosomes and their regulatory mechanisms in mediating lung cancer development.

6.
Am J Prev Med ; 61(4): e181-e189, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34144817

RESUMO

INTRODUCTION: The relationship between variability in cardiometabolic and inflammatory parameters and cognitive changes is unknown. This study investigates the association of visit-to-visit variability in BMI, mean arterial pressure, total cholesterol, triglycerides, HbA1c, high-sensitivity C-reactive protein, ferritin, and fibrinogen with cognitive decline. METHODS: This population-based cohort study included 2,260 individuals (mean age=63.0 [SD=7.5] years) free of cognitive diseases who underwent ≥3 clinical measurements from 2004 to 2019. Variability was expressed as variability independent of the mean across visits. Participants were divided on the basis of quartiles of variability score, a scoring system generated to explore the composite effect of parameter variability (range=0-24), where 0 points were assigned for Quartile 1, 1 point was assigned for Quartile 2, 2 points were assigned for Quartile 3, and 3 points were assigned for Quartile 4, each for the variability of 8 parameters measured as variability independent of the mean. Linear mixed models evaluated the longitudinal associations with cognitive decline in memory and verbal fluency. All analyses were conducted in 2020-2021. RESULTS: Higher BMI, mean arterial pressure, total cholesterol, HbA1c, and ferritin variability were linearly associated with cognitive decline irrespective of their mean values. In addition, participants in the highest quartile of variability score had a significantly worse cognitive decline rate in memory (-0.0224 points/year, 95% CI= -0.0319, -0.0129) and verbal fluency (-0.0088 points/year, 95% CI= -0.0168, -0.0008) than those in the lowest quartile. CONCLUSIONS: A higher variability in cardiometabolic and inflammatory parameters was significantly associated with cognitive decline. Stabilizing these parameters may serve as a target to preserve cognitive functioning.


Assuntos
Doenças Cardiovasculares , Disfunção Cognitiva , Doenças Cardiovasculares/epidemiologia , Disfunção Cognitiva/epidemiologia , Estudos de Coortes , Humanos , Pessoa de Meia-Idade
7.
Artigo em Inglês | MEDLINE | ID: mdl-33674815

RESUMO

BACKGROUND: Evidence regarding the associations of tooth loss and denture use with incident cognitive impairment are inconclusive in older adults, and few prospective studies have examined the potential interaction between tooth loss and denture use in these specific populations. METHODS: Data were assessed from 17,079 cognitively normal older adults aged ≥ 65 years, participating in the Chinese Longitudinal Healthy Longevity Survey (CLHLS). The outcome of interest was cognitive impairment (assessed by the Chinese version of Mini-Mental State Examination [MMSE]). The number of natural teeth and status of denture use were collected by a structural questionnaire. RESULTS: A total of 6,456 cases of cognitive impairment were recorded during 88,627 person-years of follow-up. We found that compared with participants with 20+ teeth, those with 10-19, 1-9 and 0 teeth had increased risks of incident cognitive impairment (P-trend < 0.001). Participants without dentures also had a higher risk of incident cognitive impairment, compared with those who wore dentures. Effect modification by denture use was observed (P-interaction = 0.010). Specifically, among those without dentures, the adjusted HR (95% CI) for participants with 10-19, 1-9 and 0 teeth were 1.19 (1.08,1.30), 1.28 (1.17,1.39) and 1.28 (1.16,1.41), respectively, as compared to those with 20+ teeth. In contrary, among denture users, detrimental effect was only observed among those with 0 teeth (HR 1.14, 95% CI: 1.16,1.41). CONCLUSIONS: In Chinese older adults, maintaining 20+ teeth is important for cognitive health; denture use would attenuate the detrimental effects of tooth loss, especially for partial tooth loss, on cognitive impairment.

8.
J Alzheimers Dis ; 80(4): 1591-1601, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33720888

RESUMO

BACKGROUND: Wealth and income are potential modifiable risk factors for dementia, but whether wealth status, which is composed of a combination of debt and poverty, and assessed by wealth and income, is associated with cognitive impairment among elderly adults remains unknown. OBJECTIVE: To examine the associations of different combinations of debt and poverty with the incidence of dementia and cognitive impairment without dementia (CIND) and to evaluate the mediating role of depression in these relationships. METHODS: We included 15,565 participants aged 51 years or older from the Health and Retirement Study (1992-2012) who were free of CIND and dementia at baseline. Dementia and CIND were assessed using either the modified Telephone Interview for Cognitive Status (mTICS) or a proxy assessment. Cox models with time-dependent covariates and mediation analysis were used. RESULTS: During a median of 14.4 years of follow-up, 4,484 participants experienced CIND and 1,774 were diagnosed with dementia. Both debt and poverty were independently associated with increased dementia and CIND risks, and the risks were augmented when both debt and poverty were present together (the hazard ratios [95% confidence intervals] were 1.35 [1.08-1.70] and 1.96 [1.48-2.60] for CIND and dementia, respectively). The associations between different wealth statuses and cognition were partially (mediation ratio range: 11.8-29.7%) mediated by depression. CONCLUSION: Debt and poverty were associated with an increased risk of dementia and CIND, and these associations were partially mediated by depression. Alleviating poverty and debt may be effective for improving mental health and therefore curbing the risk of cognitive impairment and dementia.


Assuntos
Disfunção Cognitiva/epidemiologia , Demência/epidemiologia , Depressão/complicações , Depressão/etiologia , Pobreza/psicologia , Idoso , China/epidemiologia , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Análise de Mediação , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Aposentadoria/psicologia , Fatores de Risco
9.
Diabetes Obes Metab ; 23(6): 1361-1370, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33620747

RESUMO

AIMS: To assess the associations of diabetes duration and glycaemic control (defined by plasma glycated haemoglobin [HbA1c] level) with the risks of cardiovascular disease (CVD) and all-cause mortality and to determine whether the addition of either or both to the established CVD risk factors can improve predictions. MATERIALS AND METHODS: A total of 435 679 participants from the UK Biobank without CVD at baseline were included. Cox models adjusting for classic risk factors (sociodemographic and anthropometric characteristics, lipid profiles and medication use) were used, and predictive utility was determined by the C-index and net reclassification improvement (NRI). RESULTS: Compared with participants without diabetes, participants with longer diabetes durations and poorer glycaemic control had a higher risk of fatal/nonfatal CVD. Among participants with diabetes, the fully-adjusted hazard ratios (HRs) for diabetes durations of 5 to <10 years, 10 to <15 years and ≥15 years were 1.15 (95% confidence interval [CI] 0.99, 1.34), 1.50 (95% CI 1.26, 1.79) and 2.22 (95% CI 1.90, 2.58; P-trend <0.01), respectively, compared with participants with diabetes durations <5 years. In addition, those with the longest disease duration (≥15 years) and poorer glycaemic control (HbA1c ≥64 mmol/mol [8%]) had the highest risk of fatal/nonfatal CVD (HR 3.12, 95% CI 2.52, 3.86). Among participants with diabetes, the addition of both diabetes duration and glycaemic control levels significantly improved both the C-index (change in C-index +0.0254; 95% CI 0.0111, 0.0398) and the overall NRI for fatal/nonfatal CVD (0.0992; 95% CI 0.0085, 0.1755) beyond the use of the classic risk factors. CONCLUSIONS: Both longer diabetes duration and poorer glycaemic control were associated with elevated risks of CVD and mortality. Clinicians should consider not only glycaemic control but also diabetes duration in CVD risk assessments for participants with diabetes.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Hemoglobina A Glicada/análise , Controle Glicêmico , Humanos , Fatores de Risco
10.
J Hypertens ; 39(8): 1594-1601, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33560057

RESUMO

OBJECTIVE: The 2017 American College of Cardiology/American Heart Association blood pressure (BP) guidelines lowered the hypertension threshold from a SBP/DBP level of at least 140/90 mmHg to at least 130/80 mmHg. The cardiovascular impact of isolated systolic hypertension (ISH) and isolated diastolic hypertension (IDH) under the new definition remains unclear. METHODS: We used data from the UK Biobank study, which is a prospective population-based cohort study. Participants were categorized into five groups: normal BP, normal high BP, ISH, IDH and systolic and diastolic hypertension. The primary endpoint for this study was the composite of nonfatal myocardial infarction (MI), nonfatal ischaemic stroke, nonfatal haemorrhagic stroke and cardiovascular disease (CVD) death. We also explored the results for the above-mentioned CVD outcomes separately. Baseline BP measurements were obtained twice after the participant had been at rest for at least 5 min in a seated position. RESULTS: We included 385 955 participants who were not taking antihypertensive medications, were free of CVD at baseline and had available data on BP measurements. During a median follow-up of 8.1 years, 8959 CVD events were recorded, including 4729 nonfatal MIs, 2287 nonfatal ischaemic strokes, 813 nonfatal haemorrhagic strokes, and 1826 CVD deaths. According to the hypertension threshold of at least 130/80 mmHg by the American College of Cardiology/American Heart Association guidelines, both ISH (hazard ratio 1.39; 95% confidence interval 1.27, 1.15) and IDH (hazard ratio 1.28; 95% confidence interval 1.15, 1.43) were significantly associated with a higher overall CVD risk than normal BP. ISH was associated with most CVD risk, except for ischaemic stroke, while the excess CVD risk associated with IDH appeared to be driven mainly by MI and CVD death. We found heterogeneity by sex and age regarding the effects of IDH on overall CVD risk, with significant associations in younger adults (age <60 years) and women and null associations in men and older adults (age ≥60 years). CONCLUSION: ISH was associated with the risk of most CVD events, while the association between IDH and CVD risk was mainly driven by MI incidence and CVD death. Further research is needed to identify participants with IDH who have a particular risk for developing CVD.


Assuntos
Isquemia Encefálica , Cardiologia , Doenças Cardiovasculares , Hipertensão , Acidente Vascular Cerebral , Idoso , American Heart Association , Pressão Sanguínea , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Estados Unidos/epidemiologia
11.
J Cachexia Sarcopenia Muscle ; 12(2): 350-357, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33527771

RESUMO

BACKGROUND: Candidate genes of neuromuscular junction (NMJ) pathway increased risk of frailty, but the extent and whether can be offset by exercises was unclear. The aim of this study was to investigate the association between aerobic exercises and incident frailty regardless of NMJ pathway-related genetic risk. METHODS: A cohort study on participants from Chinese Longitudinal Healthy Longevity Survey was conducted from 2008 to 2011. A total of 7006 participants (mean age of 80.6 ± 10.3 years) without frailty at baseline were interviewed to record aerobic exercise status, and 4053 individuals among them submitted saliva samples. NMJ pathway-related genes were genotyped and weighted genetic risk scores were constructed. RESULTS: During a median follow-up of 3.1 years (19 634 person-years), there were 1345 cases (19.2%) of incident frailty. Persistent aerobic exercises were associated with a 26% lesser frailty risk [adjusted hazard ratio (HR) = 0.74, 95% confidence interval (CI) = 0.64-0.85]. This association was stronger in a subgroup of 1552 longevous participants (age between 90 and 111 years, adjusted HR = 0.72, 95% CI = 0.60-0.87). High genetic risk was associated with a 35% increased risk of frailty (adjusted HR = 1.35, 95% CI = 1.16-1.58). Of the participants with high genetic risk and no persistent aerobic exercises, there was a 59% increased risk of frailty (adjusted HR = 1.59, 95% CI = 1.20-2.09). HRs for the risk of frailty increased from the low genetic risk with persistent aerobic exercise to high genetic risk without persistent aerobic exercise (P trend <0.001). CONCLUSIONS: Both aerobic exercises and NMJ pathway-related genetic risk were significantly associated with frailty. Persistent aerobic exercises can partly offset NMJ pathway-related genetic risk to frailty in elderly people.


Assuntos
Exercício Físico , Fragilidade , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Estudos de Coortes , Idoso Fragilizado , Fragilidade/epidemiologia , Fragilidade/genética , Humanos , Incidência , Junção Neuromuscular
12.
J Am Med Dir Assoc ; 22(9): 1946-1952.e3, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33249058

RESUMO

OBJECTIVES: A few studies of Western populations have found inconsistent results regarding the associations between vitamin D status and physical function. We explored the association between circulating vitamin D status [plasma 25-hydroxyvitamin D, 25(OH)D] and incident activities of daily living (ADL) disability among Chinese older adults. DESIGN: Community-based longitudinal cohort study. SETTING AND PARTICIPANTS: A total of 2453 men and women (median age 84.0 years) in 7 Chinese longevity areas were included. MEASURES: Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for incident ADL, with adjustments for potential sociodemographic, and lifestyle confounders and biomarkers. Because there was a statistically significant interaction between plasma 25(OH)D and sex in relation to incident ADL, men and women were analyzed separately. RESULTS: The median concentrations of plasma 25(OH)D were 46.6 nmol/L and 36.4 nmol/L for men and women, respectively. Compared with the lowest quartile in the fully adjusted model, the HR for incident ADL disability for the highest quartile was 0.55 (95% CI 0.36-0.85) for women; for men, a null association was indicated (HRhighest vs lowest 0.61, 95% CI 0.37-1.00). However, when using the recommended circulating 25(OH)D thresholds by the US Institute of Medicine, those with vitamin D sufficiency (≥50 nmol/L) had better ADL disability prognoses than those with vitamin D deficiency (<30 nmol/L) in both sexes (men HR 0.45, 95% CI 0.28-0.72; women HR 0.58, 95% CI 0.37-0.90). CONCLUSIONS AND IMPLICATIONS: The relationship between plasma 25(OH)D concentration and incident ADL disability was sex-specific among Chinese older adults. However, participants with recommended vitamin D sufficiency may have better disability prognoses in both sexes, suggesting that the recommended 25(OH)D concentration for bone health may extend to functional outcomes such as ADL disability in Chinese older adults.

13.
Am J Transl Res ; 12(11): 7275-7286, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33312366

RESUMO

In animal models, hepatocytes can be reprogrammed into insulin-producing cells (IPCs) for a novel antidiabetic treatment. However, the potential for an immunologic reaction and issues with gene integration of the viral vehicle hamper system efficacy. Here, we adopted an Ultrasound Targeted Microbubble Destruction (UTMD) enhanced hydrodynamic gene delivery system in a streptozotocin induced mouse diabetic model to examine its treatment effect. After transfection by combining UTMD and hydrodynamic injection, accumulated luciferase signal was only found in the liver with optimal signal intensity. Liver function tests showed an increase in alanine aminotransferase level followed by a decrease to normal levels. Then this new gene delivery system was used to deliver Pdx1, Neurog3, and MafA plasmids into diabetic mice. We found that glucose levels gradually decreased, and insulin levels increased in transfected diabetic mice compared to controls. Glucose intolerance in transfected mice was alleviated. Gene expression assay confirmed the reprogramming of hepatocytes. We demonstrated the feasibility of repeated plasmid transfection in vivo by UTMD enhanced hydrodynamic gene delivery system.

14.
Org Lett ; 22(13): 5145-5150, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32610932

RESUMO

The first intermolecular ring-opening hydroacylation of alkylidenecyclopropanes with chelating aldehydes through a rhodium-catalyzed acrylamide-promoted protocol is reported. This highly efficient catalytic system enables the direct synthesis of a diverse range of linear γ,δ-unsaturated ketones. Good functional group compatibility is demonstrated for the completely atom-economical and remarkably selective proximal C-C bond cleavage process. Mechanistic studies reveal that the bidentate coordination of N,N-dimethylmethacrylamide (L1) to the acylrhodium intermediates might facilitate the cyclopropane ring fragmentation and isomerization.

15.
Medicine (Baltimore) ; 99(22): e20413, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481435

RESUMO

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is an autosomal recessive hepatorenal fibrocystic syndrome. The majority of ARPKD patients progress to end-stage renal disease. Precise molecular diagnosis of ARPKD has proven valuable for understanding its mechanism and selecting optimal therapy. METHODS: A Chinese family with ARPKD was recruited in current study. The clinical characteristics of ARPKD patient were collected from medical records and the potential responsible genes were studied by the whole exome sequencing (WES). Candidate pathogenic variants were validated by Sanger sequencing. RESULTS: Both renal manifestation and hepatobiliary phenotype were observed. WES revealed compound heterozygous mutations of polycystic kidney and hepatic disease 1 genes, NM_138694: c.751G>T, (p.Asp251Tyr) and c.3998_4004delACCTGAA (p.Asn1333Thr fs × 13), which were confirmed by Sanger sequencing. Moreover, the mutations in the proband and its affected sib were co-segregated with the phenotype. CONCLUSIONS: The novel mutation in polycystic kidney and hepatic disease 1 gene identified by WES might be molecular pathogenic basis of this disorder.


Assuntos
Rim Policístico Autossômico Recessivo/genética , Sequenciamento Completo do Exoma , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Criança , China , Feminino , Predisposição Genética para Doença/genética , Humanos , Mutação de Sentido Incorreto/genética , Receptores de Superfície Celular/genética , Deleção de Sequência/genética , Sequenciamento Completo do Exoma/métodos
16.
Int J Nanomedicine ; 15: 2859-2872, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368058

RESUMO

Purpose: The topical application of exosomes secreted by mesenchymal stem cells (MSC-Exos) on the skin is a very new and interesting topic in the medical field. In this study, we aimed to investigate whether marine sponge Haliclona sp. spicules (SHSs) could effectively enhance the skin delivery of human umbilical cord-derived MSC-Exos (hucMSC-Exos), and further evaluate the topical application of hucMSC-Exos combined with SHSs in rejuvenating photoaged mouse skin. Materials and Methods: SHSs were isolated from the explants of sponge Haliclona sp. with our proprietary method, and hucMSC-Exos were prepared from the conditioned medium of hucMSCs using ultracentrifugation. The effects of SHSs on the skin penetration of fluorescently labeled hucMSC-Exos were determined using confocal microscopy in vitro (porcine skin) and in vivo (mouse skin). The therapeutic effects of hucMSC-Exos coupled with SHSs against UV-induced photoaging in mice were assessed by using microwrinkles analysis, pathohistological examination and real-time RT-PCR. We also tested the skin irritation caused by the combination of hucMSC-Exos and SHSs in guinea pigs. Results: In vitro results showed that hucMSC-Exos could not readily penetrate through porcine skin by themselves. However, SHSs increased the skin absorption of exosomes by a factor of 5.87 through creating microchannels. Similar penetration enhancement of hucMSC-Exos was observed after SHSs treatment in mice. The combined use of hucMSC-Exos and SHSs showed significant anti-photoaging effects in mice, including reducing microwrinkles, alleviating histopathological changes, and promoting the expression of extracellular matrix constituents, whereas hucMSC-Exos alone produced considerably weaker effects. Skin irritation test showed that the combination of hucMSC-Exos and SHSs caused slight irritation, and the skin recovered shortly. Conclusion: SHSs provide a safe and effective way to enhance the skin delivery of MSC-Exos. Moreover, the combination of MSC-Exos and SHSs may be of much use in the treatment of photoaging.


Assuntos
Exossomos , Poríferos/anatomia & histologia , Envelhecimento da Pele/efeitos dos fármacos , Cordão Umbilical/citologia , Administração Tópica , Animais , Exossomos/metabolismo , Feminino , Cobaias , Humanos , Células-Tronco Mesenquimais/citologia , Camundongos , Envelhecimento da Pele/fisiologia , Testes de Irritação da Pele/métodos , Suínos
17.
Stem Cell Res Ther ; 11(1): 185, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32430053

RESUMO

BACKGROUND: Human induced pluripotent stem cells (hiPSCs) represent a potentially unlimited source of pancreatic endocrine lineage cells. Although insulin-producing ß cells derived from hiPSCs have been successfully induced, much work remains to be done to achieve mature ß cells. Lysine-specific demethylase 1 (LSD1) plays an important role in the regulation of hiPSC self-renewal and differentiation. We propose a new strategy to acquire insulin-producing cells (IPCs) from hiPSCs by knocking down LSD1. METHODS: Knockdown of LSD1 in hiPSCs with five shRNA. Assessment of the effects of shRNA on hiPSC proliferation, cell cycle, and apoptosis. Using knockdown hiPSCs with 31.33% LSD1 activity, we achieved a four-step differentiation into IPCs and test its differentiation efficiency, morphology, and marker genes and proteins. We implanted the IPCs into the renal subcapsular of SCID-Beige diabetic mice to evaluate the hypoglycemic effect in vivo. We tested LSD1 and HDAC1 whether they are present in the CoREST complex through IP-WB, and analyzed LSD1, CoREST, HDAC1, H3K4me2/me3, and H3K27me3 protein expression before and after knockdown of LSD1. RESULTS: Differentiated hiPSCs were 38.32% ± 3.54% insulin-positive cells and released insulin/C-peptide in response to glucose stimulus in a manner comparable to adult human islets. Most of the IPCs co-expressed mature ß cell-specific markers. When transplanted under the left renal capsule of SCID-Beige diabetic mice, these IPCs reversed hyperglycemia, leading to a significant increase in the definitive endoderm cells. IP-WB results showed that LSD1, HDAC1, and CoREST formed a complex in hiPSCs. Chip-PCR results showed that LSD1, HDAC1, and CoREST were enriched in the same district during the SOX17 and FOXA2 promoter region. Inhibition of LSD1 would not affect the level of CoREST but decreased the HDAC1 expressions. The H3K4me2/me3 and H3K9act level of SOX17 and FOXA2 promoter region increased after inhibited of LSD1, and promoted transcriptional activation. The H3K4me2/me3 and H3K9act level of OCT4 and SOX2 promoter region decreased with the transcriptional repressed. CONCLUSIONS: LSD1 regulated histone methylation and acetylation in promoter regions of pluripotent or endodermal genes. Our results suggest a highly efficient approach to producing IPCs from hiPSCs.


Assuntos
Diabetes Mellitus Experimental , Células-Tronco Pluripotentes Induzidas , Células Secretoras de Insulina , Animais , Diferenciação Celular , Histona Desmetilases/genética , Humanos , Insulina , Camundongos , Camundongos SCID
18.
Ann Rheum Dis ; 79(6): 829-836, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32253185

RESUMO

OBJECTIVES: To evaluate the associations of regular glucosamine use with all-cause and cause-specific mortality in a large prospective cohort. METHODS: This population-based prospective cohort study included 495 077 women and men (mean (SD) age, 56.6 (8.1) years) from the UK Biobank study. Participants were recruited from 2006 to 2010 and were followed up through 2018. We evaluated all-cause mortality and mortality due to cardiovascular disease (CVD), cancer, respiratory and digestive disease. HRs and 95% CIs for all-cause and cause-specific mortality were calculated using Cox proportional hazards models with adjustment for potential confounding variables. RESULTS: At baseline, 19.1% of the participants reported regular use of glucosamine supplements. During a median follow-up of 8.9 years (IQR 8.3-9.7 years), 19 882 all-cause deaths were recorded, including 3802 CVD deaths, 8090 cancer deaths, 3380 respiratory disease deaths and 1061 digestive disease deaths. In multivariable adjusted analyses, the HRs associated with glucosamine use were 0.85 (95% CI 0.82 to 0.89) for all-cause mortality, 0.82 (95% CI 0.74 to 0.90) for CVD mortality, 0.94 (95% CI 0.88 to 0.99) for cancer mortality, 0.73 (95% CI 0.66 to 0.81) for respiratory mortality and 0.74 (95% CI 0.62 to 0.90) for digestive mortality. The inverse associations of glucosamine use with all-cause mortality seemed to be somewhat stronger among current than non-current smokers (p for interaction=0.00080). CONCLUSIONS: Regular glucosamine supplementation was associated with lower mortality due to all causes, cancer, CVD, respiratory and digestive diseases.


Assuntos
Doenças Cardiovasculares/mortalidade , Doenças do Sistema Digestório/mortalidade , Glucosamina/uso terapêutico , Neoplasias/mortalidade , Doenças Respiratórias/mortalidade , Suplementos Nutricionais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Reino Unido/epidemiologia
19.
Stem Cell Res Ther ; 11(1): 163, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345350

RESUMO

BACKGROUND: Human embryonic stem cells represent a potentially unlimited source of insulin-producing cells for diabetes therapy. While tremendous progress has been made in directed differentiation of human embryonic stem cells into IPCs in vitro, the mechanisms controlling its differentiation and function are not fully understood. Previous studies revealed that lysine-specific demethylase 1(LSD1) balanced the self-renewal and differentiation in human induced pluripotent stem cells and human embryonic stem cells. This study aims to explore the role of LSD1 in directed differentiation of human embryonic stem cells into insulin-producing cells. METHODS: Human embryonic stem cell line H9 was induced into insulin-producing cells by a four-step differentiation protocol. Lentivirus transfection was applied to knockdown LSD1 expression. Immunofluorescence assay and flow cytometry were utilized to check differentiation efficiency. Western blot was used to examine signaling pathway proteins and differentiation-associated proteins. Insulin/C-peptide release was assayed by ELISA. Statistical analysis between groups was carried out with one-way ANOVA tests or a student's t test when appropriate. RESULTS: Inhibition or silencing LSD1 promotes the specification of pancreatic progenitors and finally the commitment of functional insulin-producing ß cells; Moreover, inhibition or silencing LSD1 activated ERK signaling and upregulated pancreatic progenitor associated genes, accelerating pre-maturation of pancreatic progenitors, and conferred the NKX6.1+ population with better proliferation ability. IPCs with LSD1 inhibitor tranylcypromine treatment displayed enhanced insulin secretion in response to glucose stimulation. CONCLUSIONS: We identify a novel role of LSD1 inhibition in promoting IPCs differentiation from hESCs, which would be emerged as potential intervention for generation of functional pancreatic ß cells to cure diabetes.


Assuntos
Células-Tronco Embrionárias Humanas , Células-Tronco Pluripotentes Induzidas , Células Secretoras de Insulina , Diferenciação Celular , Histona Desmetilases/genética , Humanos , Insulina
20.
J Transl Med ; 18(1): 108, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32122370

RESUMO

BACKGROUND: Commonly used miRNA detection methods cannot be applied for high-throughput analyses. However, this study was aimed to performed a liquid bead array detection system (LBAS) to detect tissue 6 miRNAs in non-small cell lung cancer (NSCLC). METHODS: In this study, evaluation of LBAS was performed to observe the precision, specificity, limitation and stability. Then, a total of 52 primary NSCLC patients who received resection operation without preoperative radiotherapy and chemotherapy between June 2013 and March 2014 were selected, and then the total RNA of the tissues were extracted. We prepared six NSCLC-related miRNAs for LBAS. After optimization and evaluation, LBAS was verified by detecting the relative expression levels of 6 microRNAs in the pathological tissues and corresponding normal tissues of 52 NSCLC patients. RESULTS: The results of evaluation of LBAS showed that the Mean Fluorescence Intensity (MFI) of the reaction only added with chimeric probes and beads showed no significant change after 180 days (P > 0.05). And the intra-assay Coefficient of Variation (CV) was between 1.57 and 3.5%, while the inter-assay CV was between 4.24 and 11.27%, indicating this system was ideal for diagnostic reagents. In addition, only the beads corresponding to the additional miRNAs showed high MFIs from 8426 to 18,769, whereas the fluorescence values of the other beads were under background levels (MFIs = 20 to 55) in each reaction, indicating no cross reactivity among the miRNAs. The limit of detection of miR-21, miR-210, miR-125b, miR-155, miR-375, and miR-31 were 5.27, 1.39, 1.85, 2.01, 1.34, and 2.73 amol/µL, respectively, showing that the lowest detection limit of miRNA by this system was under pM level. Then, the relative expression levels of miR-21, miR-210, miR-125b, miR-155, miR-375, and miR-31 by using this system were significantly correlated with NSCLC (P < 0.05). And the results of AUC method indicated that specific of the LBAS system was 94.2%. CONCLUSIONS: Our findings suggest that LBAS was simple, high-throughput, and freely combined with absolute quantification. Thus, this system could be applied for tumor miRNAs detection.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , MicroRNAs/genética
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