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1.
J Exp Med ; 218(1)2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-32991666

RESUMO

Neonatal hypoxic-ischemic encephalopathy (HIE) with the pathological characteristic of white matter injury often leads to lifelong cognitive and neurobehavioral dysfunction, but relevant therapies to promote remyelination are still unavailable. We found that histamine H2 receptor (H2R) negatively regulated the oligodendrocyte differentiation rate without affecting the oligodendrocytes at the oligodendrocyte precursor cell stage or mature stage following oxygen-glucose deprivation in vitro. Notably, selective deletion of the H2R gene (Hrh2) in differentiating oligodendrocytes (Hrh2fl/fl;CNPase-Cre) improved their differentiation, remyelination, and functional recovery following neonatal hypoxia-ischemia in mice. The regulation of oligodendrocyte differentiation by H2R is mediated by binding with Axin2, which leads to up-regulation of the Wnt/ß-catenin signaling pathway. Furthermore, H2R antagonists also promoted oligodendrocyte differentiation and remyelination and the recovery of cognition and motor functions following neonatal hypoxia-ischemia. Thus, histamine H2R in oligodendrocytes could serve as a novel and effective therapeutic target for the retard of oligodendrocyte differentiation and remyelination following neonatal hypoxia-ischemia. The H2R antagonists may have potential therapeutic value for neonatal HIE.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33036344

RESUMO

As climate change, food crises, sustainable development, and ecological conservation gain traction, the revival of traditional fishing villages has become an important governmental policy for Taiwan. To reduce cognitive bias, the choice experiment method was applied to construct an attribute function in fishing village tourism coupled with virtual reality headsets. Conditional logit and random parameter logit models were employed to estimate tourism utility functions. Moreover, a latent class model was employed to determine whether hetxerogeneous preferences regarding fishing village travel existed. The sampling sites were distributed across the Dongshi area. In total, 612 tourists and 170 local residents were interviewed. After incomplete questionnaires were removed, 816 valid questionnaires remained, representing 95.83% of the total questionnaires. Older residents and residents with shorter histories of education were inclined to increase land development and utilization by reducing natural landscapes; tourists preferred preserving landscapes and preventing land development. Residents with more education believed that local landscape imagery was essential. Tourists who were more educated, with high incomes, and those who were older believed that a selling platform incorporating local industries and products within the villages would be attractive for other tourists.

3.
J Clin Invest ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33044226

RESUMO

Influenza is a significant cause of morbidity and mortality worldwide. Here we show changes in the abundance and activation states of more than 50 immune cell subsets in 35 individuals over 11 time points during human A/California/2009 (H1N1) virus challenge monitored using mass cytometry along with other clinical assessments. Peak change in monocyte, B cell, and T cell subset frequencies coincided with peak virus shedding, followed by marked activation of T and NK cells. Results led to the identification of CD38 as a critical regulator of plasmacytoid dendritic cell function in response to influenza virus. Machine learning using study-derived clinical parameters and single-cell data effectively classified and predicted susceptibility to infection. The coordinated immune cell dynamics defined in this study provide a framework for identifying novel correlates of protection in the evaluation of future influenza therapeutics.

4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1710-1717, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067979

RESUMO

AbstractObjective: To investigate the effect of ALAS2 downregulation on the expression of BNIP3L and erythroid differentiation in K562 cells. METHODS: The expression of ALAS2 was down-regulated by transfection of lentivirus, then quantitative real-time PCR was performed to detect the transfection efficiency. Flow cytometry analysis was applied to evaluate apoptosis of cells, erythroid differentiation, mitochondrial membrane potential and reactive oxygen species (ROS) level. Western blot was used to detect the BNIP3L expression, Co-immunoprecipitation was performed to analyze the relationship between ALAS2 and BNIP3L. RESULTS: Compared with sh-NC group, knockdown of ALAS2 induced downregulation of BNIP3L mRNA and protein expression(P<0.01) and erythroid related transcription factors GATA1, Nrf2 expression, as well as reduction of ROS level(P<0.05). Mitochondrial membrane potential of control (sh-NC) group was lower than that of shALAS2 group(P<0.05), but there was no significant change of cell apoptotic rate in two groups. CD71highCD235ahigh + CD71lowCD235ahigh cells of sh-NC and shALAS2 groups were 53.5%, 92.9% at 96 h after hemin induction, respectively. No direct action between ALAS2 and BNIP3L was observed. CONCLUSION: The intracellular heme level can affect the expression of BNIP3L which may be related with the regulation of ROS and transcription factors GATA1 and Nrf2. Higher BNIP3L facilitates cell differentiation but lower BNIP3L is favorable for cells survival.


Assuntos
Proteínas de Transporte , Mitofagia , 5-Aminolevulinato Sintetase/metabolismo , Apoptose , Diferenciação Celular , Humanos , Células K562 , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor
5.
Food Chem ; 341(Pt 1): 128218, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-33035857

RESUMO

In this study, two polysaccharide fractions were isolated from wheat bran by sequential extraction with water and alkaline solution, DEAE Cellulose-52 chromatography and Sephacryl S-400 gel permeation chromatography, they were named as WXA-1 and AXA-1, respectively. Structural analyses indicated that both polysaccharide fractions were heteropolysaccharides, their average molecular weights were 193 kDa and 107 kDa, respectively. The backbone of WXA-1 was â†’ 4)-ß-d-Xylp-(1→, which was substituted at O-3 positions by arabinose, glucose and galactose residues, while the backbone of AXA-1 was â†’ 4)-ß-d-Xylp-(1→, which was mainly substituted at O-3 positions by arabinose. AXA-1 exerted a stronger inhibitory effect on the activities of α-amylase and α-glucosidase compared with WXA-1. Moreover, AXA-1 exhibited a competitive inhibition of α-amylase and a mixed-type noncompetitive inhibition of α-glucosidase. These results suggest that AXA-1 can be used as α-amylase and α-glucosidase inhibitors.

6.
BMJ Open ; 10(10): e036606, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051231

RESUMO

OBJECTIVES: The present nationwide population-based cohort study aims to assess the effectiveness of gamma knife radiosurgery (GKS) on ruptured and unruptured brain arteriovenous malformations (AVMs) by evaluating the haemorrhage rates. DESIGN: A nationwide, retrospective cohort study. SETTING: Taiwan National Health Insurance Research Database (NHIRD). PARTICIPANTS: An observational study of 1515 patients who were diagnosed with brain AVMs between 1997 and 2013 from the Taiwan NHIRD. PRIMARY OUTCOME AND SECONDARY OUTCOME MEASURES: We performed a survival analysis using the Kaplan-Meier method. Multivariate Cox proportional hazards regression models were used to explore the relationship between treatment modalities (GKS vs non-GKS) and haemorrhage, adjusted for age and sex. RESULTS: The GKS and non-GKS groups included 317 and 1198 patients, respectively. Patients in the GKS group (mean±SD, 33.08±15.48 years of age) tended to be younger than those in the non-GKS group (37.40±17.62) (p<0.001). The 15-year follow-up revealed that the rate of bleeding risk was lower in the GKS group than in the non-GKRS group (adjusted HR (aHR) 0.61; 95% CI 0.40 to 0.92). The bleeding risk of ruptured AVMs was significantly lower in GKS group than in the non-GKS group (aHR 0.34; 95% CI 0.19 to 0.62). On the other hand, the bleeding risk of unruptured AVMs was higher in the GKS group than in the non-GKS group (aHR 1.95; 95% CI 1.04 to 3.65). In the unruptured AVM group, the incidence of bleeding was significantly higher among patients in the GKS group that were of >40 years of age (aHR 3.21; 95% CI 1.12 to 9.14). CONCLUSIONS: GKS is safe and it reduces the risk of haemorrhage in patients with ruptured AVMs. The administration of GKS to patients with unruptured AVMs who are above the age of 40 years old male might increase the risk of haemorrhage.

7.
Cancer Cell ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-33007258

RESUMO

Although enhancers play critical roles in cancer, quantifying enhancer activities in clinical samples remains challenging, especially for super-enhancers. Enhancer activities can be inferred from enhancer RNA (eRNA) signals, which requires enhancer transcription loci definition. Only a small proportion of human eRNA loci has been precisely identified, limiting investigations of enhancer-mediated oncogenic mechanisms. Here, we characterize super-enhancer regions using aggregated RNA sequencing (RNA-seq) data from large cohorts. Super-enhancers usually contain discrete loci featuring sharp eRNA expression peaks. We identify >300,000 eRNA loci in ∼377 Mb super-enhancer regions that are regulated by evolutionarily conserved, well-positioned nucleosomes and are frequently dysregulated in cancer. The eRNAs provide explanatory power for cancer phenotypes beyond that provided by mRNA expression through resolving intratumoral heterogeneity with enhancer cell-type specificity. Our study provides a high-resolution map of eRNA loci through which super-enhancer activities can be quantified by RNA-seq and a user-friendly data portal, enabling a broad range of biomedical investigations.

8.
Laryngoscope ; 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-33070361

RESUMO

OBJECTIVE: Cone-beam computed tomography (CBCT) offers three-dimensional structures in assessing upper airway of patients. This study aims to compare the cone-beam computerized tomography scan measurements between children with obstructive sleep apnea (OSA) and primary snoring. STUDY DESIGN: Case-control study. METHODS: This prospective study was conducted in a tertiary referral center. Thirty-six children with moderate-to-severe OSA (with apnea-hypopnea index [AHI] > 5 events/hour) and 36 age-, gender-, and obesity-matched children with primary snoring (AHI <1) were enrolled. The measurements in CBCT parameters were compared between children with moderate-to-severe OSA and primary snorers by conditional logistic regression model. RESULTS: A total of 72 children (mean age, 7.9 ± 2.8 years; 64% male) were included. Children with moderate-to-severe OSA had a significantly smaller nasopharyngeal (2900 ± 1400 vs. 3800 ± 1800 mm3 , P = .017) and oropharyngeal airway volume (5600 ± 2700 vs. 7400 ± 4000 mm3 , P = .026) than those with primary snoring. Children with moderate-to-severe OSA, as compared to primary snorers, also had a significantly smaller minimal airway area in nasopharynx (77.4 ± 37.7 vs. 107.7 ± 52.0 mm2 , P = .006) and oropharynx (66.6 ± 61.9 vs. 101.6 ± 65.8 mm2 , P = .023). Moreover, the airway length was not significantly different between children with moderate-to-severe OSA and primary snoring. CONCLUSIONS: The three-dimensional CBCT airway analysis could be used as a useful tool to evaluate upper airway in children with OSA. LEVEL OF EVIDENCE: 3 Laryngoscope, 2020.

9.
Am J Hum Genet ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33031748

RESUMO

Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%-54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10-10, minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEVrange = 1%-22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology.

10.
Phytopathology ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33026300

RESUMO

Phytophthora infestans, the causal agent of the Irish Potato Famine in the 1840s, is one of the most destructive crop pathogens that threaten global food security. Host resistance (R) genes may help to control the disease, but recognition by through the gene products can be evaded by newly emerging isolates. Such isolates are dangerous as they may cause disease outbreaks under favorable conditions. However, our lack of knowledge about adaptation in these isolates jeopardizes an apt response to resistance breakdown. Here we performed genome and transcriptome sequencing of HB1501 and HN1602, two field isolates from distinct Chinese geographic regions. We found extensive polymorphisms in these isolates, including gene copy number variations, nucleotide polymorphisms, and gene expression changes. Effector encoding genes, which contribute to virulence, show distinct expression landscapes in P. infestans isolates HB1501 and HN1602. In particular polymorphisms at multiple effectors required for recognition (Avr loci) enabled these isolates to overcome corresponding R gene based resistance. Although the isolates evolved multiple strategies to evade recognition, we experimentally verified that several R genes such as R8, RB, and Rpi-vnt1.1 remain effective against these isolates and are valuable to potato breeding in the future. In summary, rapid characterization of the adaptation in emerging field isolates through genomic tools inform rational agricultural management to prevent potential future epidemics.

11.
Pediatr Transplant ; : e13876, 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33098346

RESUMO

BACKGROUND: Early-onset mixed chimerism (MC) with a high proportion of residual host cells is considered a signal of graft rejection in patients undergoing allogenic hematopoietic stem cell transplantation for transfusion-dependent thalassemia. In order to prevent graft rejection and minimize the risk of treatment-related graft-versus-host disease (GVHD), we established a hierarchical management system based on chimerism analysis. METHOD: This retrospective study provides a comprehensive review of the characteristics, interventions, and outcomes of the 38 patients who developed MC after transplantation among the 144 pediatric thalassemia patients between July 2007 and January 2019 at our center. RESULTS: A sibling donor, a blood type-matched donor, conditioning regimens without fludarabine, and transplants containing <10 × 108 total nucleated cells/kg were identified to be associated with the development of MC. Among the 38 patients developing MC, only four patients rejected the grafts. The response rate to donor lymphocyte infusion (DLI, only for patients receiving sibling donor transplantation) and cytokine immunomodulation without DLI was 70.6% and 42.9%, respectively. Patients that developed GVHD after DLI or cytokine therapy had a more significant increase in donor cell chimerism (16%, range 0%-35%) than those without (8.5%, range -21% to 40%, P = .049). However, even when treatment-related GVHD was included, patients with MC had a lower cumulative incidence of total acute GVHD than patients with complete donor chimerism (29.2% vs 48.0%, P = .030). CONCLUSIONS: Interventions based on chimerism analysis were effective in preventing graft rejection and did not increase treatment-related GVHD in thalassemia patients with MC.

12.
Genet Epidemiol ; 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32864785

RESUMO

Complex human diseases are affected by genetic and environmental risk factors and their interactions. Gene-environment interaction (GEI) tests for aggregate genetic variant sets have been developed in recent years. However, existing statistical methods become rate limiting for large biobank-scale sequencing studies with correlated samples. We propose efficient Mixed-model Association tests for GEne-Environment interactions (MAGEE), for testing GEI between an aggregate variant set and environmental exposures on quantitative and binary traits in large-scale sequencing studies with related individuals. Joint tests for the aggregate genetic main effects and GEI effects are also developed. A null generalized linear mixed model adjusting for covariates but without any genetic effects is fit only once in a whole genome GEI analysis, thereby vastly reducing the overall computational burden. Score tests for variant sets are performed as a combination of genetic burden and variance component tests by accounting for the genetic main effects using matrix projections. The computational complexity is dramatically reduced in a whole genome GEI analysis, which makes MAGEE scalable to hundreds of thousands of individuals. We applied MAGEE to the exome sequencing data of 41,144 related individuals from the UK Biobank, and the analysis of 18,970 protein coding genes finished within 10.4 CPU hours.

13.
BMC Cancer ; 20(1): 853, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32891122

RESUMO

BACKGROUND: Excision Repair Cross-Complementation group 6-like (ERCC6L) has been shown to exhibit carcinogenic effect in several malignant tumors. However, the function and molecular mechanism of the ERCC6L in hepatocellular carcinoma (HCC) have not been investigated extensively. METHODS: Immunohistochemistry analyses were used to detect ERCC6L expression in a HCC tissue microarray, and the Chi-square test was used to assess the correlation between ERCC6L expression and patients' clinicopathological features. shRNA was used to down-regulation ERCC6L expression in HCC cell lines. MTT assay, plate clone formation assay, flow cytometry, caspase 3/7 activity and migration assays were performed to evaluate the impact of ERCC6L on HCC cells in vitro. Nude mice xenograft models were used to assess the role of ERCC6L in vivo. The regulatory of mechanism of PI3K/AKT pathway was evaluated by western blotting. RESULTS: ERCC6L was highly expressed in HCC tissue compared with tumor adjacent tissues in 90 paired samples. ERCC6L expression positively correlated with gender, tumor encapsulation, and pathological stage. Patients with low ERCC6L expression had significantly longer OS than those with high ERCC6L expression. Knockdown of ERCC6L expression significantly inhibited proliferation, invasion and metastasis in vitro and tumor growth in vivo, and it promoted cell cycle arrest and apoptosis. Mechanistic analyses revealed that PI3K/AKT and NF-κB signaling pathway were inhibited by silencing ERCC6L. CONCLUSION: These results demonstrate that ERCC6L plays a critical role in HCC progression, and thereby might be a potential therapeutic target for HCC patients.

14.
Pathobiology ; : 1-9, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32950981

RESUMO

Since the outbreak of coronavirus disease 2019 (COVID-19), there has been a debate whether pregnant women are at a specific risk for COVID-19 and whether it might be vertically transmittable through the placenta. We present a series of five placentas of SARS coronavirus 2 (SARS-CoV-2)-positive women who had been diagnosed with mild symptoms of COVID-19 or had been asymptomatic before birth. We provide a detailed histopathologic description of morphological changes accompanied by an analysis of presence of SARS-CoV-2 in the placental tissue. All placentas were term deliveries (40th and 41st gestational weeks). One SARS-CoV-2-positive patient presented with cough and dyspnoea. This placenta showed prominent lymphohistiocytic villitis and intervillositis and signs of maternal and foetal malperfusion. Viral RNA was present in both placenta tissue and the umbilical cord and could be visualized by in situ hybridization in the decidua. SARS-CoV-2 tests were negative at the time of delivery of 3/5 women, and their placentas did not show increased inflammatory infiltrates. Signs of maternal and/or foetal malperfusion were present in 100% and 40% of cases, respectively. There was no transplacental transmission to the infants. In our cohort, we can document different time points regarding SARS-CoV-2 infection. In acute COVID-19, prominent lymphohistiocytic villitis may occur and might potentially be attributable to SARS-CoV-2 infection of the placenta. Furthermore, there are histopathological signs of maternal and foetal malperfusion, which might have a relationship to an altered coagulative or microangiopathic state induced by SARS-CoV-2, yet this cannot be proven considering a plethora of confounding factors.

16.
Infect Dis Poverty ; 9(1): 125, 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32867841

RESUMO

BACKGROUND: Visceral leishmaniasis (VL) was one of the most important parasitic diseases in China, caused by Leishmania protozoans and transmitted by sand flies. Recently VL cases have reappeared in China, including the extension region of the Loess Plateau. The purpose of this study was to collect fundamental data on the host-vector VL system in the Loess Plateau to assist in the development of prevention and control measures. METHODS: Sand flies were collected by light traps from rural areas in Shanxian, Henan, China in 2015, as well as in Wuxiang and Yangquan, Shanxi, China in 2017. The blood sources of sand flies were analyzed by PCR detecting the host-specific mitochondrial cytochrome b (mtDNA cyt b) gene fragments. Leishmania infection in sand flies was detected by amplifying and sequencing ribosomal DNA internal transcribed spacer 1 (ITS1). The Leishmania specific antibodies in the sera of local dogs were detected by ELISA kit. RESULTS: Blood sources showed diversity in the extension region of the Loess Plateau, including human, chicken, dog, cattle, pig and goat. Multiple blood sources within a sand fly were observed in samples from Yangquan (17/118, 14.4%) and Wuxiang (12/108, 11.1%). Leishmania DNA was detected in sand flies collected from Yangquan with minimum infection rate of 1.00%. The ITS1 sequences were conserved with the Leishmania donovani complex. The positive rate of Leishmania specific antibodies in dogs was 5.97%. CONCLUSIONS: This study detected the blood sources and Leishmania parasites infection of sand flies by molecular methods in the extension region of Loess Plateau, China. A high epidemic risk of leishmaniasis is currently indicated by the results as the infection of Leishmania in sand flies, the extensive blood sources of sand flies including humans, and positive antibody of Leishmania in local dog sera. Given the recent increase of VL cases, asymptomatic patients, dogs and other potential infected animals should be screened and treated. Furthermore, the density of sand flies needs to be controlled and personal protection should be strengthened.

17.
Artigo em Inglês | MEDLINE | ID: mdl-32989694

RESUMO

As prime coastal recreational areas, beaches attract an increasing number of users worldwide. However, current studies have shown that beaches are subject to plastic pollution, one of the most significant global environmental threats. Considering the health of tourists and ecological environmental management of beaches, microplastics on recreational beaches are urgently being studied. This paper first focused on microplastics on the recreational beaches of Haichow Bay, which is located on the central coast of China and faces the Yellow Sea. The microplastic pollution level, occurrence, and distribution were investigated. Our study demonstrated that microplastics were consistently found on all studied beaches, which emphasized their extensive distribution throughout recreational beaches. The average microplastic abundance was 106.50 ± 34.41 items/kg, demonstrating that the microplastic pollution level on the studied beaches tended to be in the middle-to-low position compared with previous studies. In total, eight colors were found, more than 90% of microplastics were less than 1 mm in size, and fiber and fragments were the dominant shapes. Resort beaches contained the highest number of microplastics, indicating that the microplastic pollution level on recreational beaches was directly related to the tourism intensity. Five types of plastic were found in the samples, i.e., polyethylene (PE), polypropylene (PP), PS (polystyrene (PS), polyethylene terephthalate (PET) and nylon. Land inputs were the main source of pollution. This study provided baseline information on microplastic pollution that can be used for effective and comprehensive management of recreational beaches and suggests that the management of plastic use and recycling on beaches should be integrated into China's'coastal zone management practices.

18.
Biomed Pharmacother ; 131: 110669, 2020 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-32937246

RESUMO

OBJECTIVE: Berberine (BBR), which is extracted from traditional Chinese herb, is abundant in Coptis chinensis and Berberis vulgaris, with a treatment on type 2 diabetes mellitus (T2DM). However, its oral bioavailability is poor. Therefore, the ability of BBR to regulate gut microbiota and intestinal metabolites might exist. This study aimed to investigate changes in gut microbiota and intestinal metabolites, and to reveal the potential mechanism of BBR. METHODS: To observe the role of gut microbiota in the treatment of T2DM by BBR, antibiotics intervened gut microbiota was used in this study, and the therapeutic effects of BBR were evaluated. A 16S rRNA gene sequencing approach was utilized to analyze gut microbiota alterations, and UHPLC-QTOF/MS-based untargeted metabolomics analysis of colon contents was used to identity differential intestinal metabolites. Finally, serum aromatic amino acids (AAAs) were absolutely quantified using LC/MS. RESULTS: Inhibition of the blood glucose levels, and improvements in glucose tolerance and serum lipid parameters were observed in the BBR treated group. Type 2 diabetic symptoms in rats in the BA group (treated with antibotics and BBR) were alleviated. However, the therapeutical effects are weaker in the BA group compared with the BBR group, indicating that BBR can be used to treat type 2 diabetic rats immediately, and modulation of gut microbiota is related to the mechanism of BBR in the treatment of T2DM. The community richness and diversity of the gut microbiota were significantly increased by BBR, and the relative abundance of Bacteroidetes was increased in the BBR group, which was accompanied by a decreased relative abundance of Proteobacteria and Verrucomicrobia at the phylum level. At the family level, a probiotic Lactobacillaceae was significantly upregulated not only in the BBR group but also in the BA group and was negatively associated with the risk of T2DM. Metabolomic analysis of colon contents identified 55 differential intestinal metabolites between the BBR group and the model group. AAAs, including tyrosine, tryptophan and phenylalanine, were obviously decreased in the BBR group not only in the colon contents but also in the serum. CONCLUSIONS: These results demonstrated that BBR could alleviate symptoms in type 2 diabetic rats by affecting gut microbiota composition and reducing the concentration of AAAs.

19.
Cancers (Basel) ; 12(9)2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32961945

RESUMO

Epidemiology studies suggest that Human Immunodeficiency Virus (HIV)-infected patients on highly active anti-retroviral therapy (HAART) may be at increased risk of acquiring opportunistic Human Papillomavirus (HPV) infections and developing oral and cervical cancers. Effective HAART usage has improved survival but increased the risk for HPV-associated cancers. In this manuscript, we report that Protease Inhibitors (PI) treatment of three-dimensional tissues derived from primary human gingiva and cervical epithelial cells compromised cell-cell junctions within stratified epithelium and enhanced paracellular permeability of HPV16 to the basal layer for infection, culminating in de novo biosynthesis of progeny HPV16 as determined using 5-Bromo-2'-deoxyuridine (BrdU) labeling of newly synthesized genomes. We propose that HAART/PI represent a novel class of co-factors that modulate HPV infection of the target epithelium. Our in vitro tissue culture model is an important tool to study the mechanistic role of anti-retroviral drugs in promoting HPV infections in HAART-naïve primary epithelium. Changes in subsequent viral load could promote new infections, create HPV reservoirs that increase virus persistence, and increase the risk of oral and cervical cancer development in HIV-positive patients undergoing long-term HAART treatment.

20.
Circ Res ; 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32912104

RESUMO

Rationale: Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular remodeling, accompanied by varying degrees of perivascular inflammation. Niacin, a commonly used lipid-lowering drug, possesses vasodilating and pro-resolution effects by promoting the release of prostaglandin D2 (PGD2). However, whether or not niacin confers protection against PAH pathogenesis is still unknown. Objective: This study aimed to determine whether or not niacin attenuates the development of PAH and, if so, to elucidate the molecular mechanisms underlying its effects. Methods and Results: Vascular endothelial growth factor receptor inhibitor SU5416 and hypoxic exposure were used to induce pulmonary hypertension (PH) in rodents. We found that niacin attenuated the development of this hypoxia/SU5416 (HySu) -induced PH in mice and suppressed progression of monocrotaline- and HySu -induced PH in rats through the reduction of pulmonary artery remodeling. Niacin boosted PGD2 generation in lung tissue, mainly through hematopoietic PGD2 synthases (H-PGDS). Deletion of H-PGDS, but not lipocalin-type PGDS, exacerbated the HySu -induced PH in mice and abolished the protective effects of niacin against PAH. Moreover, H-PGDS was expressed dominantly in infiltrated macrophages in lungs of PH mice and idiopathic PAH patients. Macrophage-specific deletion of H-PGDS markedly decreased PGD2 generation in lungs, aggravated HySu -induced PH in mice and attenuated the therapeutic effect of niacin on PAH. Conclusions: Niacin treatment ameliorates the progression of PAH through the suppression of vascular remodeling by stimulating H-PGDS-derived PGD2 release from macrophages.

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