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INTRODUCTION: Osteoporotic fractures are a leading cause of disability and contribute significantly to medical care costs worldwide. Variations in bone mineral density and the risk of osteoporosis are notably influenced by altitude. This study aims to longitudinally examine individuals with osteoporosis and low bone mass at three different altitudes (low, high and very high) to understand the effects of high-altitude environments on bone density. METHODS AND ANALYSIS: This multicentre, prospective cohort study will involve 893 participants divided into three groups based on altitude: low (500-1500 m), high (2500-4500 m) and very high (4500-5500 m). Participants will undergo comprehensive diagnostic assessments, including demographic data collection, structured questionnaires, medical examinations and clinical laboratory tests. Follow-up visits will occur annually for a minimum of 5 years. The primary outcome will be changes in bone mineral density values. Secondary outcomes will include the incidence of osteoporosis and osteoporotic fractures. Cox proportional hazard models will be used to calculate the risk associated with osteoporotic events and related fractures. ETHICS AND DISSEMINATION: The study has been approved by the Institutional Review Board of the Hospital of Chengdu Office of People's Government of Tibetan Autonomous Region (No: 2024-70). The acquired insights will be disseminated via academic forums, scholarly articles and stakeholder engagement sessions. TRIAL REGISTRATIONNUMBER: ChiCTR2300078872.
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Altitude , Densidade Óssea , Osteoporose , Fraturas por Osteoporose , Humanos , Osteoporose/epidemiologia , Estudos Prospectivos , Pessoa de Meia-Idade , Feminino , Idoso , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/etiologia , Masculino , Estudos Multicêntricos como Assunto , China/epidemiologia , Fatores de Risco , Projetos de PesquisaRESUMO
The hypoxic microenvironment within the tumor microenvironment of breast cancer imposes a challenge in overcoming chemotherapy resistance. In this investigation, we designed a novel strategy utilizing a light-controlled cascade targeting nanomedicine specifically tailored for enhanced immune therapy of breast cancer. Albumin nanoparticle was achieved by crosslinking, followed by loading TPZ and Ce6, and subsequent modification to enable selective binding with CD44 hyaluronic acid to form nanomedicine. Encouragingly, it was demonstrated the remarkable ability of the nanomedicine to effectively internalize into cellular entities, thereby inducing apoptosis in 4T1 cells efficiently in vitro when exposed to light irradiation. In vivo assessments showcased the exceptional aptitude of the nanomedicine not only for preferential accumulation within tumor tissues, but also for substantial suppression of tumor growth. Immune mechanisms have shown that nanomedicine treatment promoted the maturation of DCs in vivo, enhanced the proportion of CD8+ T cells in the spleen and tumor, and simultaneously upregulated the ratio of M1 macrophages favorable for anti-tumor effects. These outcomes collectively advance a fresh perspective for the clinical breast cancer therapy.
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BACKGROUND: The FreeStyle Libre flash glucose monitoring (FGM) system entered the Chinese market in 2017 to complement the self-monitoring of blood glucose. Due to its increased usage in clinics, the number of studies investigating its accuracy has increased. However, its accuracy has not been investigated in highland popu-lations in China. AIM: To evaluate measurements recorded using the FreeStyle Libre FGM system compared with capillary blood glucose measured using the enzyme electrode method in patients with type 2 diabetes (T2D) who had migrated within 3 mo from highlands to plains. METHODS: Overall, 68 patients with T2D, selected from those who had recently migrated from highlands to plains (within 3 mo), were hospitalized at the Department of Endocrinology from August to October 2017 and underwent continuous glucose monitoring (CGM) with the FreeStyle Libre FGM system for 14 d. Throughout the study period, fingertip capillary blood glucose was measured daily using the enzyme electrode method (Super GL, China), and blood glucose levels were read from the scanning probe during fasting and 2 h after all three meals. Moreover, the time interval between reading the data from the scanning probe and collecting fingertip capillary blood was controlled to < 5 min. The accuracy of the FGM system was evaluated according to the CGM guidelines. Subsequently, the factors influencing the mean absolute relative difference (MARD) of this system were analyzed by a multiple linear regression method. RESULTS: Pearson's correlation analysis showed that the fingertip and scanned glucose levels were positively correlated (R = 0.86, P = 0.00). The aggregated MARD of scanned glucose was 14.28 ± 13.40%. Parker's error analysis showed that 99.30% of the data pairs were located in areas A and B. According to the probe wear time of the FreeStyle Libre FGM system, MARD1 d and MARD2-14 d were 16.55% and 14.35%, respectively (t = 1.23, P = 0.22). Multiple stepwise regression analysis showed that MARD did not correlate with blood glucose when the largest amplitude of glycemic excursion (LAGE) was < 5.80 mmol/L but negatively correlated with blood glucose when the LAGE was ≥ 5.80 mmol/L. CONCLUSION: The FreeStyle Libre FGM system has good accuracy in patients with T2D who had recently migrated from highlands to plains. This system might be ideal for avoiding the effects of high hematocrit on blood glucose monitoring in populations that recently migrated to plains. MARD is mainly influenced by glucose levels and fluctuations, and the accuracy of the system is higher when the blood glucose fluctuation is small. In case of higher blood glucose level fluctuations, deviation in the scanned glucose levels is the highest at extremely low blood glucose levels.
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BACKGROUND: Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family. METHODS: The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, and a partial liver I/R operation was performed. Single-cell RNA sequencing (scRNA-seq) in the liver post I/R suggested enhanced ferroptosis by Dhx58hep-/-. The mRNAs and proteins associated with DExH-box helicase 58 (DHX58) were screened using RNA immunoprecipitation-sequencing (RIP-seq) and IP-mass spectrometry (IP-MS). RESULTS: Excessive production of reactive oxygen species (ROS) decreased the expression of the IFN-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis, while treatment using IFN-α increased DHX58 expression and prevented ferroptosis during liver I/R injury. Mechanistically, DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4 (GPX4), a central ferroptosis suppressor, and recruits the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an m6A-dependent manner, thus enhancing GPX4 protein levels and preventing hepatic ferroptosis. CONCLUSIONS: This study provides mechanistic evidence that IFN-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-α in the prevention of hepatic ferroptosis during liver I/R injury.
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Ferroptose , Traumatismo por Reperfusão , Animais , Camundongos , Diclorodifenil Dicloroetileno , Hepatócitos , Interferon-alfa , RNA , RNA MensageiroRESUMO
Hepatocarcinogenesis is initiated by repeated hepatocyte death and liver damage, and the underlying mechanisms mediating cell death and the subsequent carcinogenesis remain to be fully investigated. Immunoresponsive gene 1 (IRG1) and its enzymatic metabolite itaconate are known to suppress inflammation in myeloid cells, and its expression in liver parenchymal hepatocytes is currently determined. However, the potential roles of IRG1 in hepatocarcinogenesis are still unknown. Here, using the diethylnitrosamine (DEN)-induced hepatocarcinogenesis mouse model, we found that IRG1 expression in hepatocytes was markedly induced upon DEN administration. The DEN-induced IRG1 was then determined to promote the intrinsic mitochondrial apoptosis of hepatocytes and liver damage, thus enhancing the subsequent hepatocarcinogenesis. Mechanistically, the mitochondrial IRG1 could associate and trap anti-apoptotic MCL-1 to inhibit the interaction between MCL-1 and pro-apoptotic Bim, thus promoting Bim activation and downstream Bax mitochondrial translocation, and then releasing cytochrome c and initiating apoptosis. Thus, the inducible mitochondrial IRG1 promotes hepatocyte apoptosis and the following hepatocarcinogenesis, which provides mechanistic insight and a potential target for preventing liver injury and HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteína de Sequência 1 de Leucemia de Células Mieloides , Animais , Camundongos , Apoptose , Carcinogênese , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Hepatócitos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genéticaRESUMO
INTRODUCTION: Metabolomic signatures of type 2 diabetes mellitus (T2DM) in Tibetan Chinese population, a group with high diabetes burden, remain largely unclear. Identifying the serum metabolite profile of Tibetan T2DM (T-T2DM) individuals may provide novel insights into early T2DM diagnosis and intervention. METHODS: Hence, we conducted untargeted metabolomics analysis of plasma samples from a retrospective cohort study with 100 healthy controls and 100 T-T2DM patients by using liquid chromatography-mass spectrometry. RESULTS: The T-T2DM group had significant metabolic alterations that are distinct from known diabetes risk indicators, such as body mass index, fasting plasma glucose, and glycosylated hemoglobin levels. The optimal metabolite panels for predicting T-T2DM were selected using a tenfold cross-validation random forest classification model. Compared with the clinical features, the metabolite prediction model provided a better predictive value. We also analyzed the correlation of metabolites with clinical indices and found 10 metabolites that were independently predictive of T-T2DM. CONCLUSION: By using the metabolites identified in this study, we may provide stable and accurate biomarkers for early T-T2DM warning and diagnosis. Our study also provides a rich and open-access data resource for optimizing T-T2DM management.
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This study aimed to determine whether there is an association between the age at menopause (AM) and diabetic microvascular complications. This cross-sectional study included 298 postmenopausal women with type 2 diabetes mellitus. They were divided into 3 groups according to AM (in years; group 1: AM < 45 years, n = 32; group 2:45 ≤ AM < 50 years, n = 102; group 3: AM ≥ 50 years, n = 164). Clinical data related to the duration of type 2 diabetes, body mass index, smoking status, hypertension status, AM, biochemical indices, and diabetic microvascular complications (retinopathy, nephropathy, and neuropathy) were collected. Logistic regression analysis was performed to identify the association between the AM and diabetic microvascular complications. No statistical differences were observed in the prevalence of diabetic retinopathy, chronic kidney disease, or diabetic peripheral neuropathy between the groups. After adjusting for possible confounders, AM did not correlate with the presence of diabetic retinopathy (ß = 1.03, 95% confidence interval [CI]: 0.94-1.14, P = .511), chronic kidney disease (ß = 1.04, 95% CI: 0.97-1.12, P = .280), and diabetic peripheral neuropathy (ß = 1.01, 95% CI: 0.93-1.09, P = .853). Our findings suggest that early menopause (age < 45 years) was not associated with microvascular diabetic complications. Further prospective studies are needed to clarify this issue.
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Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Retinopatia Diabética , Insuficiência Renal Crônica , Humanos , Feminino , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/etiologia , Estudos Transversais , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/etiologiaRESUMO
Background: Branched chain amino acids (BCAAs) have been revealed to be closely related to insulin resistance and obesity. This study aimed to investigate if BCAA levels at baseline are related to an improvement in insulin resistance after implementing a weight loss program intervention. Methods: Stored blood samples from participants in previous trials were used for BCAA evaluation. Linear regression was used to analyze the relationship between baseline amino acid levels and changes in the insulin resistance index (HOMA-IR) and blood glucose. Results: A total of 48 participants were enrolled. After the intervention, the body weight (78.29± 12.68 vs 72.06 ± 13.30 kg, p=0.020), fasting glucose (4.76 ± 0.43 vs 4.48 ± 0.39 mmol/L, p=0.001), fasting insulin (18.41±13.58 vs 12.87±10.88, p=0.028), and HOMA-IR (4.01±3.39 vs 2.62± 2.18, p=0.018) were improved significantly. BCAA levels were related to the improvement in HOMA-IR (ß=-0.006, p=0.039), and valine was found to be the most closely related to the improvement in HOMA-IR (ß=-0.013, p=0.017). Conclusion: The baseline BCAA is related to the improvement in insulin resistance among participants after a weight loss intervention.
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During the past decade, the characterization of microbial community in soil of contaminated sites was primarily done by high-throughput short-read amplicon sequencing. However, due to the similarity of 16S rRNA and ITS genes amplicon sequences, the short-read approach often limits the microbial composition analysis at the species level. Here, we simultaneously performed full-length and short-read amplicon sequencing to clarify the community composition and ecological status of different microbial taxa in contaminated soil from a high-resolution perspective. We found that (1) full-length 16S rRNA gene sequencing gave better resolution for bacterial identification at all levels, while there were no significant differences between the two sequencing platforms for fungal identification in some samples. (2) Abundant taxa were vital for microbial co-occurrences network constructed by both full-length and short-read sequencing data, and abundant fungal species such as Mortierella alpine, Fusarium solani, Mrakia frigida, and Chaetomium homopilatum served as the keystone species. (3) Heavy metal correlated with the microbial community significantly, and bacterial community and its abundant taxa were assembled by deterministic process, while the other taxa were dominated by stochastic process. These findings contribute to the understanding of the ecological mechanisms and microbial interactions in site soil ecosystems and demonstrate that full-length sequencing has the potential to provide more details of microbial community.
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Microbiota , Solo , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Filogenia , Microbiota/genéticaRESUMO
BACKGROUND AND AIMS: Hepatocarcinogenesis goes through HCC progenitor cells (HcPCs) to fully established HCC, and the mechanisms driving the development of HcPCs are still largely unknown. APPROACH AND RESULTS: Proteomic analysis in nonaggregated hepatocytes and aggregates containing HcPCs from a diethylnitrosamine-induced HCC mouse model was screened using a quantitative mass spectrometry-based approach to elucidate the dysregulated proteins in HcPCs. The heterotrimeric G stimulating protein α subunit (GαS) protein level was significantly increased in liver cancer progenitor HcPCs, which promotes their response to oncogenic and proinflammatory cytokine IL-6 and drives premalignant HcPCs to fully established HCC. Mechanistically, GαS was located at the membrane inside of hepatocytes and acetylated at K28 by acetyltransferase lysine acetyltransferase 7 (KAT7) under IL-6 in HcPCs, causing the acyl protein thioesterase 1-mediated depalmitoylation of GαS and its cytoplasmic translocation, which were determined by GαS K28A mimicking deacetylation or K28Q mimicking acetylation mutant mice and hepatic Kat7 knockout mouse. Then, cytoplasmic acetylated GαS associated with signal transducer and activator of transcription 3 (STAT3) to impede its interaction with suppressor of cytokine signaling 3, thus promoting in a feedforward manner STAT3 phosphorylation and the response to IL-6 in HcPCs. Clinically, GαS, especially K28-acetylated GαS, was determined to be increased in human hepatic premalignant dysplastic nodules and positively correlated with the enhanced STAT3 phosphorylation, which were in accordance with the data obtained in mouse models. CONCLUSIONS: Malignant progression of HcPCs requires increased K28-acetylated and cytoplasm-translocated GαS, causing enhanced response to IL-6 and driving premalignant HcPCs to fully established HCC, which provides mechanistic insight and a potential target for preventing hepatocarcinogenesis.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Lisina Acetiltransferases , Humanos , Camundongos , Animais , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/patologia , Interleucina-6/metabolismo , Proteômica , Citoplasma/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Lisina Acetiltransferases/metabolismo , Fator de Transcrição STAT3/metabolismo , Histona Acetiltransferases/metabolismoRESUMO
The long-term dismantling of electronic waste (E-waste) has contaminated the soil environment considerably. In spite of this, it is unknown if it affects the depth-resolved microbial communities. In the present research, six soil profiles (dismantling sites and the surrounding farmland) were collected from one of the largest Chinese E-waste disposal centers to identify depth-resolved microbiota and assess how heavy metal contamination affects microbial adaptation. Results suggested that cadmium (0.12-7.22 mg kg-1) and copper (18.99-11282.03 mg kg-1) were the main pollutants in the test soil profiles, and their concentrations gradually decreased with depth. The surrounding contaminated farmland has a more complex interaction and higher modularity (0.77-0.85) among microbes, indicating a stronger niche differentiation to enhance functional diversity. The proportion of positive interactions between taxa decreased with depth, as high heavy metals contamination in the topsoil results in the co-occurrence of microorganisms with the same ecological niche that collaborated to face environmental stress. Soil physicochemical properties, heavy metals concentration, and soil depth critically affect microbial communities. Microbial community assembly processes in the topsoil were affected by environmental filtering, i.e., by deterministic processes (NST: 13-52%), while were more stochastic (NST: 46-72%) in the subsoil due to the environment of soil becoming more homogeneous as soil depth increased.
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Resíduo Eletrônico , Microbiota , Eliminação de Resíduos , Solo , FazendasRESUMO
BACKGROUND: Hepatocarcinogenesis is driven by necroinflammation or metabolic disorders, and the underlying mechanisms remain largely elusive. We previously found that retinoic acid-inducible gene-I (RIG-I), a sensor for recognizing RNA virus in innate immune cells, is mainly expressed by parenchymal hepatocytes in the liver. However, its roles in hepatocarcinogenesis are unknown, which is intensively investigated in this study. METHODS: DEN-induced necroinflammation-driven hepatocarcinogenesis and STAM NASH-hepatocarcinogenesis were carried out in hepatocyte-specific RIG-I knockout mice. The post-translational modification of RIG-I was determined by mass spectrometry, and specific antibodies against methylated lysine sites and the RIG-I lysine mutant mice were constructed to identify the functions of RIG-I methylation. RESULTS: We interestingly found that DEN-induced hepatocarcinogenesis was enhanced, while NASH-induced hepatocarcinogenesis was suppressed by hepatocyte-specific RIG-I deficiency. Further, IL-6 decreased RIG-I expression in HCC progenitor cells (HcPCs), which then viciously promoted IL-6 effector signaling and drove HcPCs to fully established HCC. RIG-I expression was increased by HFD, which then enhanced cholesterol synthesis and steatosis, and the in-turn NASH and NASH-induced hepatocarcinogenesis. Mechanistically, RIG-I was constitutively mono-methylated at K18 and K146, and demethylase JMJD4-mediated RIG-I demethylation suppressed IL-6-STAT3 signaling. The constitutive methylated RIG-I associated with AMPKα to inhibit HMGCR phosphorylation, thus promoting HMGCR enzymatic activity and cholesterol synthesis. Clinically, RIG-I was decreased in human hepatic precancerous dysplastic nodules while increased in NAFLD livers, which were in accordance with the data in mouse models. CONCLUSIONS: Decreased RIG-I in HcPCs promotes necroinflammation-induced hepatocarcinogenesis, while increased constitutive methylated RIG-I enhances steatosis and NASH-induced hepatocarcinogenesis. JMJD4-demethylated RIG-I prevents both necroinflammation and NASH-induced hepatocarcinogenesis, which provides mechanistic insight and potential target for preventing HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Camundongos , Humanos , Animais , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Hepatopatia Gordurosa não Alcoólica/complicações , Interleucina-6 , Lisina , Carcinogênese , Camundongos Knockout , Colesterol/efeitos adversosRESUMO
INTRODUCTION: Obesity is a global health issue that impacts quality of life. A calorie-restricted diet with high-intensity consultation provided via the internet may be an effective way to lose weight. The objective of this study was to assess the effectiveness of a practitioner-guided, mobile internet-based low-energy dietary intervention in overweight and obese populations in China. METHODS AND ANALYSIS: This open-label randomised controlled trial enrolled 220 overweight and obese adults aged 18-70 years who met the inclusion criteria. Participants were assigned to the control group (n=110) or trial group (n=110). The trial group will be enrolled in the MetaWell programme, a weight loss programme using diet replacement products, wireless scales and a mobile phone app. Participants in the control group will receive paper material containing a sample diet for weight loss. The follow-up period will be 1 year, and measurements will occur at 3, 6 and 12 months. Dual-emission X-ray absorptiometry and abdominal quantitative CT will be performed to estimate the percentage of overall body fat and areas of visceral and subcutaneous fat, alongside several cardiometabolic measurements. The primary outcome of this study is the change in body mas index (BMI) at 6 months after enrolment. A mixed-effects model will be used to compare BMI and body fat changes between the two groups. ETHICS AND DISSEMINATION: This study was approved by the ethics committee of the Hospital of Chengdu Office of the People's Government of the Tibetan Autonomous Region. Advertisements for recruitment will be sent via official accounts using WeChat. The results will be disseminated via publications in academic journals and our clinic. Our study group will maintain contact with the participants to inform them of the study findings. TRIAL REGISTRATION NUMBER: ChiCTR1900021630.
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Sobrepeso , Qualidade de Vida , Adolescente , Adulto , Idoso , China , Exercício Físico , Humanos , Internet , Pessoa de Meia-Idade , Obesidade/terapia , Sobrepeso/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Redução de Peso , Adulto JovemRESUMO
OBJECTIVE: In this study, we focused on the interaction between SARS-CoV-2 and host Type I Interferon (IFN) response, so as to identify whether IFN effects could be influenced by the products of SARS-CoV-2. METHODS: All the structural and non-structural proteins of SARS-CoV-2 were transfected and overexpressed in the bronchial epithelial cell line BEAS-2B respectively, and typical antiviral IFN-stimulated gene (ISG) ISG15 expression was detected by qRT-PCR. RNA-seq based transcriptome analysis was performed between control and Spike (S) protein-overexpressed BEAS-2B cells. The expression of ACE2 and IFN effector JAK-STAT signaling activation were detected in control and S protein-overexpressed BEAS-2B cells by qRT-PCR or/and Western blot respectively. The interaction between S protein with STAT1 and STAT2, and the association between JAK1 with downstream STAT1 and STAT2 were measured in BEAS-2B cells by co-immunoprecipitation (co-IP). RESULTS: S protein could activate IFN effects and downstream ISGs expression. By transcriptome analysis, overexpression of S protein induced a set of genes expression, including series of ISGs and the SARS-CoV-2 receptor ACE2. Mechanistically, S protein enhanced the association between the upstream JAK1 and downstream STAT1 and STAT2, so as to promote STAT1 and STAT2 phosphorylation and ACE2 expression. CONCLUSION: SARS-CoV-2 S protein enhances ACE2 expression via facilitating IFN effects, which may help its infection.
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Enzima de Conversão de Angiotensina 2/metabolismo , Brônquios/efeitos dos fármacos , COVID-19/virologia , Células Epiteliais/efeitos dos fármacos , Interferon alfa-2/farmacologia , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Brônquios/enzimologia , Brônquios/virologia , COVID-19/enzimologia , Citocinas/genética , Citocinas/metabolismo , Células Epiteliais/enzimologia , Células Epiteliais/virologia , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Janus Quinase 1/metabolismo , Fosforilação , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT2/metabolismo , Transdução de Sinais , Glicoproteína da Espícula de Coronavírus/genética , Ubiquitinas/genética , Ubiquitinas/metabolismo , Regulação para CimaRESUMO
Hepatic apoptosis and the initiated liver inflammation play the initial roles in inflammation-induced hepatocarcinogenesis. Molecular mechanisms underlying the regulation of hepatocyte apoptosis and their roles in hepatocarcinogenesis have attracted much attention. A set of microRNAs (miRNAs) have been determined to be dysregulated in hepatocellular carcinoma (HCC) and participated in cancer progression, however, the roles of these dysregulated miRNAs in carcinogenesis are still poorly understood. We previously analyzed the dysregulated miRNAs in HCC using high-throughput sequencing, and found that miR-199a/b-3p was abundantly expressed in human normal liver while markedly decreased in HCC, which promotes HCC progression. Whether miR-199a/b-3p participates in HCC carcinogenesis is still unknown up to now. Hence, we focused on the role and mechanism of miR-199a/b-3p in hepatocarcinogenesis in this study. Hepatic miR-199a/b-3p was determined to be expressed by miR-199a-2 gene in mice, and we constructed miR-199a-2 knockout and hepatocyte-specific miR-199a-2 knockout mice. Diethylnitrosamine (DEN)-induced hepatocarcinogenesis were markedly increased by hepatocyte-specific miR-199a-3p knockout, which is mediated by the enhanced hepatocyte apoptosis and hepatic injury by DEN administration. In acetaminophen (APAP)-induced acute hepatic injury model, hepatocyte-specific miR-199a-3p knockout also aggravated hepatic apoptosis. By proteomic screening and reporter gene validation, we identified and verified that hepatic programed cell death 4 (PDCD4), which promotes apoptosis, was directly targeted by miR-199a-3p. Furthermore, we confirmed that miR-199a-3p-suppressed hepatocyte apoptosis and hepatic injury by targeting and suppressing PDCD4. Thus, hepatic miR-199a-3p inhibits hepatocyte apoptosis and hepatocarcinogenesis, and decreased miR-199a-3p in hepatocytes may aggravate hepatic injury and HCC development.
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BACKGROUND: We investigated the associations between low-density lipoprotein cholesterol (LDL-C) to high-density cholesterol (HDL-C) ratio (LDL-C/HDL-C) with structural and functional early atherosclerosis vascular changes in patients with type 2 diabetes mellitus (T2DM). METHODS: This hospital-based cross-sectional study included 814 patients with T2DM. Structural atherosclerotic parameters included carotid intima-media thickness (CIMT) and carotid plaque, the cardio-ankle vascular index (CAVI) was considered as the functional parameter. Multiple linear regression and logistic regression models were preformed to identify the associations between LDL-C/HDL-C with atherosclerotic parameters. RESULTS: Increased LDL-C/HDL-C corresponded with the increase levels in CIMT and percentage of carotid plaque. LDL-C/HDL-C was found to be positively associated with CIMT both in female and male patients in unadjusted model. This association persisted in male patients but not in female patients after adjusted for other related factors. No association was found between LDL-C/HDL-C with CAVI both in female and male patients. LDL-C/HDL-C was positively associated with the presence of carotid plaque in male patients. However, this association was not found in female patients. CONCLUSION: LDL-C/HDL-C was positively associated with CIMT and presence of carotid plaque though not with CAVI in male T2DM patients. However, these associations were not observed in female patients.
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Espessura Intima-Media Carotídea , Diabetes Mellitus Tipo 2 , HDL-Colesterol , LDL-Colesterol , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Fatores de RiscoRESUMO
OBJECTIVE: To explore the possible etiological factors of iron overload through detecting plasma hepcidin level of adult males at Tibet plateau. METHODS: 81 Tibetan male adult patients hospitalized in our department during January 2017 - December 2018 were selected, and divided into iron overload group and non-iron overload group. The difference in serum ferritin, serum iron, total iron binding capacity, hemoglobin, HBSAg, ALT, AST, albumin, creatinine and hepcidin of patients in each group were tested. To analyze the differences between groups. The regression analysis was applied to analyze the relationship between laboratory index and hepcidin. RESULTS: The plasma hepcidin of iron overload group was significantly higher than that of the non-iron overload group [93.69 (65.57-133.92) ng/ml vs 63.93 (40.01-90.65) ng/ml] (P=0.005). And there was a positive correlation between plasma hepcidin and ferritin (ß=0.03 ng/mlï¼95%CI 0.01-0.05) (P<0.01) and BMI (ß=5.71 ng/mlï¼95%CI 0.54-10.88) (P<0.05ï¼. CONCLUSION: Iron overload at Tibet plateau can not be attributed to hepcidin deficiency in Tibetan adult male patients. Iron metabolism disorders in Tibetan population may be associated with metabolic syndrome.
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Sobrecarga de Ferro , Ferro , Adulto , Ferritinas , Hepcidinas , Humanos , Masculino , TibetRESUMO
AIM: To explore the association between the atherosclerosis and diabetic retinopathy (DR) in Chinese patients with type 2 diabetes mellitus (T2DM). METHODS: This hospital-based cross-sectional study included 949 patients (700 males and 249 females) with T2DM. The atherosclerotic parameters were assessed using the cardio-ankle vascular index (CAVI), ankle-brachial index (ABI), and carotid plaque. DR was assessed and graded using digital retinal photography and fundus fluorescein angiography as either nonproliferative DR (NPDR) or proliferative DR (PDR). Multiple logistic regression analysis was performed to identify the associations between the atherosclerotic parameters and DR status. RESULTS: The prevalence of DR was 23.6% in total patients, including 167 (17.6%) patients with NPDR and 57 (6.0%) patients with PDR. Patients with NPDR and PDR were more likely to have higher prevalence of increased CAVI, increased ABI, and carotid plaque than those without DR. In multivariable adjusted logistic regression analysis, patients with NPDR showed an odds ratio (OR) of 2.59 [95% confidence interval (CI), 1.61-4.19] for increased CAVI, 1.99 (0.62-6.34) for increased ABI, and 1.75 (1.13-2.71) for carotid plaque. Patients with PDR showed an OR of 7.83 (3.52-17.41) for increased CAVI, 10.65 (3.33-34.04) for increased ABI, and 11.40 (2.67-48.63) for carotid plaque. CONCLUSION: Both NPDR and PDR were independently associated with increased CAVI and presence of carotid plaque in Chinese patients with T2DM.
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The aim of the study is to investigate the diffusion characteristics of Alzheimer's disease (AD) patients using an ultra-high b-values apparent diffusion coefficient (ADC_uh) and diffusion kurtosis imaging (DKI). A total of 31 AD patients and 20 healthy controls (HC) who underwent both MRI examination and clinical assessment were included in this study. Diffusion weighted imaging (DWI) was acquired with 14 b-values in the range of 0 and 5000 s/mm2. Diffusivity was analyzed in selected regions, including the amygdala (AMY), hippocampus (HIP), thalamus (THA), caudate (CAU), globus pallidus (GPA), lateral ventricles (LVe), white matter (WM) of the frontal lobe (FL), WM of the temporal lobe (TL), WM of the parietal lobe (PL) and centrum semiovale (CS). The mean, median, skewness and kurtosis of the conventional apparent diffusion coefficient (ADC), DKI (including two variables, Dapp and Kapp) and ADC_uh values were calculated for these selected regions. Compared to the HC group, the ADC values of AD group were significantly higher in the right HIP and right PL (WM), while the ADC_uh values of the AD group increased significantly in the WM of the bilateral TL and right CS. In the AD group, the Kapp values in the bilateral LVe, bilateral PL/left TL (WM) and right CS were lower than those in the HC group, while the Dapp value of the right PL (WM) increased. The ADC_uh value of the right TL was negatively correlated with MMSE (mean, r=-0.420, p=0.019). The ADC value and Dapp value have the same regions correlated with MMSE. Compared with the ADC_uh, combining ADC_uh and ADC parameters will result in a higher AUC (0.894, 95%CI=0.803-0.984, p=0.022). Comparing to ADC or DKI, ADC_uh has no significant difference in the detectability of AD, but ADC_uh can better reflect characteristic alternation in unconventional brain regions of AD patients.
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A high-quality Ge0.88Si0.08Sn0.04/Ge0.94Sn0.06 multiple quantum well (MQW) structure was grown on a Ge (001) substrate by sputtering epitaxy. The MQW structure was characterized by high-resolution x-ray diffraction and transmission electron microscopy. Surface-illuminated Ge0.88Si0.08Sn0.04/Ge0.94Sn0.06 MQW pin photodetectors were fabricated with cutoff wavelengths of up to 2140 nm. The analysis of transitions from spectral response was fitted well with the theoretical calculations. Results suggest that sputtering epitaxy is a promising method for preparing high-quality low-dimensional Sn-based group IV materials and that Ge1-x-ySiySnx/Ge1-xSnx MQWs have potential applications in the development of efficient Si-based photonic devices.