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BACKGROUND: Evidence on the prevalence of smoking in China remains insufficient, with most previous studies focusing on a single region. However, smoking prevalence exhibits significant inequalities across the entire country. This study aimed to evaluate the risk of tobacco prevalence across the country, taking into account spatial inequalities. METHODS: The data used in this study were collected in 23 provinces, 5 autonomous regions, and 4 municipalities directly under the central government in 2022. Large population survey data were used, and a Bayesian geostatistical model was employed to investigate smoking prevalence rates across multiple spatial domains. FINDINGS: Significant spatial variations were observed in smokers and exposure to secondhand smoke across China. Higher levels of smokers and secondhand smoke exposure were observed in western and northeastern regions. Additionally, the autonomous region of Tibet, Shanghai municipality, and Yunnan province had the highest prevalence of smokers, while Tibet, Qinghai province, and Yunnan province had the highest prevalence of exposure to secondhand smoke. CONCLUSION: We have developed a model-based, high-resolution nationwide assessment of smoking risks and employed rigorous Bayesian geostatistical models to help visualize smoking prevalence predictions. These prediction maps provide estimates of the geographical distribution of smoking, which will serve as strong evidence for the formulation and implementation of smoking cessation policies. HIGHLIGHTS: Our study investigated the prevalence of smokers and exposure to secondhand smoke in different spatial areas of China and explored various factors influencing the smoking prevalence. For the first time, our study applied Bayesian geostatistical modeling to generate a risk prediction map of smoking prevalence, which provides a more intuitive and clear understanding of the spatial disparities in smoking prevalence across different geographical regions, economic levels, and development status. We found significant spatial variations in smokers and secondhand smoke exposure in China, with higher rates in the western and northeastern regions.
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Teorema de Bayes , Poluição por Fumaça de Tabaco , Humanos , China/epidemiologia , Estudos Transversais , Poluição por Fumaça de Tabaco/estatística & dados numéricos , Prevalência , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Fumar/epidemiologia , Fumantes/estatística & dados numéricos , Medição de Risco , Análise Espacial , Epidemias , Adulto JovemRESUMO
Alzheimer's disease (Alzheimer's disease, AD) is a progressive neurological disorder characterized by memory loss and cognitive impairment. It is characterized by the formation of tau protein neurofibrillary tangles and ß-amyloid plaques. Recent studies have found that mitochondria in neuronal cells of AD patients exhibit various dysfunctions, including reduced numbers, ultrastructural changes, reduced enzyme activity, and abnormal kinetics. These abnormal mitochondria not only lead to the loss of normal neuronal cell function, but are also a major driver of AD progression. In this review, we will focus on the advances of mitochondria and their multi-omics in AD research, with particular emphasis on how mitochondrial dysfunction in AD drives disease progression. At the same time, we will focus on summarizing how mitochondrial genomics technologies have revealed specific details of these dysfunctions and how therapeutic strategies targeting mitochondria may provide new directions for future AD treatments. By delving into the key mechanisms of mitochondria in AD related to energy metabolism, altered kinetics, regulation of cell death, and dysregulation of calcium-ion homeostasis, and how mitochondrial multi-omics technologies can be utilized to provide us with a better understanding of these processes. In the future, mitochondria-centered therapeutic strategies will be a key idea in the treatment of AD.
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Doença de Alzheimer , Mitocôndrias , Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Humanos , Mitocôndrias/metabolismo , Animais , Genômica/métodos , Metabolismo Energético , Proteômica/métodosRESUMO
Aerobic glycolysis is involved in the pathogenesis of pulmonary hypertension (PH). The mechanisms by which glycolysis is increased and how it contributes to pulmonary vascular remodelling are not yet fully understood. In this study, we demonstrated that elevated lipocalin-2 (LCN2) in PH significantly enhances aerobic glycolysis in human pulmonary artery smooth muscle cells (PASMCs) by up-regulating LDHA expression. Knockout of Lcn2 or having heterozygous LDHA deficiency in mice significantly inhibits the progression of hypoxic PH. Our study reveals that LCN2 stimulates LDHA expression by activating Akt-HIF-1α signalling pathway. Inhibition of Akt or HIF-1α reduces LDHA expression and proliferation of PASMCs. Both Akt and HIF-1α play critical roles in the development of PH and are suppressed in the pulmonary vessels of hypoxic PH mice lacking LCN2. These findings shed light on the LCN2-Akt-HIF1α-LDHA axis in aerobic glycolysis in PH.
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BACKGROUND: There are billions of bacteria in the intestine, most of which are harmless and play important roles in humans. Although only a very small number of bacteria can cause diseases, once the pathogenic bacteria are ingested into the body and multiply in large quantities, it can lead to inflammatory diseases in the intestines and even other organs. Although polymerase chain reaction can specifically detect bacterial nucleic acid. However, the demand for temperature cycling limits its portability. Therefore, it is hoped to establish a high-throughput, highly specific and portable detection platform for directly detecting nucleic acid of intestinal pathogens. RESULTS: Herein, a one-pot chip based on RPA-CRCISPR/Cas12a platform was developed. The chip is the same size as a glass slide and allows detection at the same temperature. Multiple samples could be detected simultaneously on the one chip, achieved high-throughput detection and improved the integration of detection. The specific recognition of CRISPR/Cas12a avoided the influence of non-specific amplification of RPA and enhanced the specificity of the analysis. At the same time, the one-pot chip avoided secondary contamination when the lid was opened during the analysis process. And the bacterial concentration showed good linearity at 102-108 cfu mL-1. The limit of detection could be as low as 0.43 cfu mL-1. This method has been successfully used to detect pollution samples. It can provide a reliable platform for early screening of gastrointestinal and other inflammatory diseases. SIGNIFICANCE: The one-pot chip based on the RPA-CRISPR/Cas12a platform established can directly detect the nucleic acid of intestinal pathogens, with portability and specificity. It is worth noting that the platform has good programmability, can be used for other target detection by changing crRNA and RPA primers, it can achieve multi sample detection on the one chip.
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Sistemas CRISPR-Cas , Sistemas CRISPR-Cas/genética , Humanos , DNA Bacteriano/análise , Bactérias/isolamento & purificação , Bactérias/genética , Limite de Detecção , Microbioma Gastrointestinal , Técnicas de Amplificação de Ácido NucleicoRESUMO
BACKGROUND: BPD is a refractory disease affecting preterm infants with alveolar dysplasia and declined pulmonary function. However, the molecular mechanism underlying BPD is largely unknown. To explore the pathogenic mechanism of BPD and to facilitate better diagnosis and treatment of this disease. METHOD: The DEMs and DEGs in BPD vs. Control samples from the miRNA expression data in GSE108754 and mRNA expression data in the GSE108755 were screened, followed by the construction of the miRNA-mRNA regulatory network. DEGs PPI network and hub DEGs analysis were constructed by using the STRING database and Cytoscape software. Functional and pathway enrichment analyses were then performed for these DEGs and DEMs based on the ClusterProfiler package in the R and the miRWalk database. The k-mean algorithm is used to perform clustering analysis of DEGs. Cellular experiments (flow cytometry, western blot, RT-PCR, dual-luciferase reporter assay) were used to validate the results of bioinformatics. RESULTS: We obtained 20 DEMs and 262 DEGs. A 15 DEMs-11 DEGs regulatory network was constructed. miR-3202-RAG1 is a core sub-network. Hyperoxia induced a cell model of BPD. The upregulation of RAG1 and downregulation of miR-3202 were observed in BPD cells. Furthermore, siRNA targeting RAG1 was transfected into BEAS-2B cells to inhibit its expression and miR-3202 mimics was transfected into the cells to increase its expression. Inhibition of RAG1 and elevation of miR-3202 inhibit cell apoptosis and reduce ROS level caused by hyperoxia. A double-luciferase reporter assay revealed that miR-3202 directly targets RAG1. CONCLUSION: The miRNA-3202/RAG1 axis contributes into BPD-induced cell apoptosis and ROS production. The present study provides a probable target for the treatment of BPD.
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Apoptose , Displasia Broncopulmonar , Células Epiteliais , MicroRNAs , Estresse Oxidativo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Apoptose/genética , Estresse Oxidativo/genética , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Brônquios/patologia , Brônquios/metabolismo , Recém-NascidoRESUMO
Successful bone regeneration requires close cooperation between bone marrow mesenchymal stem cells (BMSCs) and macrophages, but the low osteogenic differentiation efficiency of stem cells and the excessive inflammatory response of immune cells hinder the development of bone repair. It is necessary to develop a strategy that simultaneously regulates the osteogenic differentiation of BMSCs and the anti-inflammatory polarization of macrophages for accelerating the bone regeneration. Herein, calcium-chlorogenic acid nanoparticles (Ca-CGA NPs) are synthesized by combining the small molecules of chlorogenic acid (CGA) with Ca2+. Ca-CGA NPs internalized by cells can be dissolved to release free CGA and Ca2+ under low pH conditions in lysosomes. In vitro results demonstrate that Ca-CGA NPs can not only enhance the osteogenic differentiation of BMSCs but also promote the phenotype transformation of macrophages from M1 to M2. Furthermore, in vivo experiments confirm that Ca-CGA NPs treatment facilitates the recovery of rat skull defect model through both osteoinduction and immunomodulation. This study develops a new Ca-CGA NPs-based strategy to induce the differentiation of BMSCs into osteoblasts and the polarization of macrophages into M2 phenotype, which is promising for accelerating bone repair.
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Osteoporosis-pseudoglioma syndrome (OPPG) and LRP5 high bone mass (LRP5-HBM) are two rare bone diseases with opposite clinical symptoms caused by loss-of-function and gain-of-function mutations in LRP5. Bisphosphonates are an effective treatment for OPPG patients. LRP5-HBM has a benign course, and age-related bone loss is found in one LRP5-HBM patient. PURPOSE: Low-density lipoprotein receptor-related protein 5 (LRP5) is involved in the canonical Wnt signaling pathway. The gain-of-function mutation leads to high bone mass (LRP5-HBM), while the loss-of-function mutation leads to osteoporosis-pseudoglioma syndrome (OPPG). In this study, the clinical manifestations, disease-causing mutations, treatment, and follow-up were summarized to improve the understanding of these two diseases. METHODS: Two OPPG patients and four LRP5-HBM patients were included in this study. The clinical characteristics, biochemical and radiological examinations, pathogenic mutations, and structural analysis were summarized. Furthermore, several patients were followed up to observe the treatment effect and disease progress. RESULTS: Congenital blindness, persistent bone pain, low bone mineral density (BMD), and multiple brittle fractures were the main clinical manifestations of OPPG. Complex heterozygous mutations were detected in two OPPG patients. The c.1455G > T mutation in exon 7 was first reported. During the follow-up, BMD of two patients was significantly improved after bisphosphonate treatment. On the contrary, typical clinical features of LRP5-HBM included extremely high BMD without fractures, torus palatinus and normal vision. X-ray showed diffuse osteosclerosis. Two heterozygous missense mutations were detected in four patients. In addition, age-related bone loss was found in one LRP5-HBM patient after 12-year of follow-up. CONCLUSION: This study deepened the understanding of the clinical characteristics, treatment, and follow-up of OPPG and LRP5-HBM; expanded the pathogenic gene spectrum of OPPG; and confirmed that bisphosphonates were effective for OPPG. Additionally, it was found that Ala242Thr mutation could not protect LRP5-HBM patients from age-related bone loss. This phenomenon deserves further study.
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Conservadores da Densidade Óssea , Densidade Óssea , Difosfonatos , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Mutação , Humanos , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Densidade Óssea/fisiologia , Densidade Óssea/genética , Feminino , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Masculino , Difosfonatos/uso terapêutico , Difosfonatos/farmacologia , Adulto , Seguimentos , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/fisiopatologia , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/complicações , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , CriançaRESUMO
BACKGROUND: There may be unexplored interactions between family health, personality, and smoking that could help provide new perspectives on tobacco control. OBJECTIVE: To examine the relationship between the health of one's family and their smoking habits, as well as investigate the potential influence of personality on this relationship. METHODS: For this cross-sectional investigation, a national survey conducted in China in 2022 recruited a total of 21,916 individuals. The Family Health Scale was utilized to assess the health of the family. The 10-item Big Five Inventory scale was utilized to assess the Big five personality traits. The relationship between big five personality, family health, and smoking were investigated using binary and linear logistic regression. The indirect effects mediated by Big five personality were analyzed using mediation analysis with Sobel tests, and the indirect effects were composited using the Karlson-Holm-Breen method. RESULTS: The overall prevalence of smoking in the study population was 14.87%, 26.19% for males and 3.54% for females. Urban and rural smoking prevalence was 13.81% and 16.10% respectively. Binary logistic regression analysis revealed a significant negative relationship between smoking and family health (odds ratio 0.964, 95% CI 0.959, 0.970, P < 0.001) with covariates controlled. The Karlson-Holm-Breen composition facilitated the connection between extraversion (47.81%) and nervousness (52.19%). CONCLUSIONS: Preventive interventions for smoking behavior should prioritize family health and the Big five personality as significant areas to focus on. According to this study, in addition to implementing various interventions for different personalities, family health should be strengthened to reduce smoking behavior.
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População do Leste Asiático , Saúde da Família , Personalidade , Masculino , Feminino , Humanos , Estudos Transversais , Fumar/epidemiologiaRESUMO
INTRODUCTION: Sepsis is a pathogenic syndrome of prolonged excessive inflammation and immunosuppression produced by invading pathogens. Programmed cell death 4 (PDCD4) may be implicated in a range of inflammatory lesions, and this study aimed to confirm the involvement of PDCD4 in septic lung injury. MATERIALS AND METHODS: Mice and bronchial epithelial 16HBE cells were separately subjected to CLP and LPS to generate in vivo and in vitro models. Following the level of PDCD4 was determined, the impacts of PDCD4 knockdown on mouse lung injury degree, inflammation, apoptosis, and pyroptosis levels were evaluated. Afterward, cells were treated with the NLRP3 agonist, and the influences of NLRP3 activation on the regulations of PDCD4 knockdown were determined. RESULTS: PDCD4 was elevated following mice developed septic lung injury, PDCD4 knockdown ameliorated septic lung injury and reduced lung inflammation and apoptosis. Moreover, PDCD4 knockdown suppressed NLRP3-mediated pyroptosis, indicating that PDCD4 also mediated pyroptosis. According to cellular models, NLRP3 activation broke the effects of PDCD4 knockdown on cells. CONCLUSIONS: The current study reveals that PDCD4 governs NLRP3-mediated pyroptosis in septic lung injury. PDCD4 is not only related to apoptosis and expands the knowledge of PDCD4 regulation of different cell death modes.
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Lesão Pulmonar , Piroptose , Animais , Camundongos , Apoptose , Inflamação , Pulmão , Proteína 3 que Contém Domínio de Pirina da Família NLR/genéticaRESUMO
The inactivated whole-virion severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine has been widely used in a two-dose schedule, but with insufficient data on the immunogenicity of homologous BBIBP-CorV/CoronaVac boosting vaccination and too little follow-up to assess the duration of the immunogenic response. We prospectively evaluated the immunogenicity of a third-dose BBIBP-CorV/CoronaVac boosting vaccination, with neutralizing titers against wild type and Omicron assessed at the baseline (immediately before the booster dose), and days 14, 28, 98, and 174 post the third-booster. Of 182 volunteers screened, 165 were assessed eligible for enrolment. No moderate/severe adverse events were observed during the term of the study. From the baseline to day 174 post the third booster, neutralizing titers against wild type and Omicron peaked by approximately sixfold increase (up to 811.83 and 33.40, respectively) at day 14 and slowly decreased over time. The geometric mean titers against Omicron were lower than against type with a 19.8-39. Sixfold reduction at all time points. The seropositivity against Omicron at the baseline, days 14, 28, 98, and 174 after the booster dose was 12.6%, 50.0%, 37.8%, 38.6%, and 22.8%, respectively. Data presented herein indicated that the BBIBP-CorV/CoronaVac booster significantly enhances the neutralizing potency against wild-type strain but elicited weaker neutralizing activity to Omicron. Our findings suggest that individuals receiving booster inactivated vaccine remain at risk for Omicron infection, which is crucial to inform ongoing and future vaccination strategies to combat coronavirus disease 2019.
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Vacinas contra COVID-19 , COVID-19 , Vacinação , Vacinas de Produtos Inativados , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Imunogenicidade da Vacina , Estudos Prospectivos , SARS-CoV-2RESUMO
We propose a novel silicon carbide (SiC) self-aligned N-type ion implanted trench MOSFET (NITMOS) device. The maximum electric field in the gate oxide could be effectively reduced to below 3 MV/cm with the introduction of the P-epi layer below the trench. The P-epi layer is partially counter-doped by a self-aligned N-type ion implantation process, resulting in a relatively low specific on-resistance (Ron,sp). The lateral spacing between the trench sidewall and N-implanted region (Wsp) plays a crucial role in determining the performance of the SiC NITMOS device, which is comprehensively studied through the numerical simulation. With the Wsp increasing, the SiC NITMOS device demonstrates a better short-circuit capability owing to the reduced saturation current. The gate-to-drain capacitance (Cgd) and gate-to-drain charge (Qgd) are also investigated. It is observed that both Cgd and Qgd decrease as the Wsp increases, owing to the enhanced screen effect. Compared to the SiC double-trench MOSFET device, the optimal SiC NITMOS device exhibits a 79% reduction in Cgd, a 38% decrease in Qgd, and a 41% reduction in Qgd × Ron,sp. A higher switching speed and a lower switching loss can be achieved using the proposed structure.
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As an important biomarker, microRNAs (miRNAs) play an important role in gene expression, and their detection has attracted increasing attention. In this study, a DNAzyme walker that could provide power to perform autonomous movement was designed. Based on the continuous mechanical motion characteristics of DNAzyme walker, a miRNA detection strategy for the self-assembly of AuNPs induced by the hairpin probe-guided DNAzyme walker "enzyme cleavage and walk" was established. In this strategy, DNAzyme walker continuously cleaved and walked on the hairpin probe on the surface of AuNPs to induce the continuous shedding of some segments of the hairpin probe. The remaining hairpin sequences on the surface of the AuNP pair with each other, causing the nanoparticles to self-assemble. This strategy uses the autonomous movement mechanism of DNAzyme walker to improve reaction efficiency and avoid the problem of using expensive and easily degradable proteases. Secondly, using dynamic light scattering technology as the signal output system, ultra-sensitive detection with a detection limit of 3.6 fM is achieved. In addition, this strategy has been successfully used to analyze target miRNAs in cancer cell samples.
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Técnicas Biossensoriais , DNA Catalítico , Nanopartículas Metálicas , MicroRNAs , DNA Catalítico/metabolismo , Ouro , Difusão Dinâmica da Luz , Limite de DetecçãoRESUMO
Two-dimensional (2D) materials with simultaneous magnetic semiconducting properties and a negative Poisson's ratio are crucial for fabricating multifunctional electronic devices. However, progress in this area has been generally constrained. Based on first-principles calculations, we engineered a 2D Ni-based oxyhalide with a honeycomb lattice structure. It was observed that the NiCl2O8 monolayer exhibits both high- and low-buckling states in its geometry, along with intrinsic magnetic semiconductor properties in its electronic structure. Importantly, we demonstrated that the magnetic ordering of the NiCl2O8 lattice is susceptible to applied strain, which resulted in a phase transition from paramagnetic to ferromagnetic under biaxial strain. The Curie temperature was also evaluated using Monte Carlo simulations within the Ising model. Additionally, our research uncovered that the 2D NiCl2O8 lattice chain displays a negative Poisson's ratio (NPR) along the z-direction. The triangular hinge structure in its centrosymmetric configuration was identified as the origin of this unique phenomenon. The coexistence of NPR and magnetic phase transition properties in the NiCl2O8 lattice makes it quite promising for applications in nanoelectronic and spintronic devices.
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The prognosis of a gastric cancer (GC) diagnosis is poor due to the current lack of effective early diagnostic methods. Extracellular vesicle (EV) biomarkers have previously demonstrated strong diagnostic efficiency for certain types of cancer, including pancreatic and lung cancer. The present review aimed to summarize the diagnostic value of circulating EV biomarkers for early stage GC. The PubMed, Medline and Web of Science databases were searched from May 1983 to September 18, 2022. All studies that reported the diagnostic performance of EV biomarkers for GC were included for analysis. Overall, 27 studies were selected containing 2,831 patients with GC and 2,117 controls. A total of 58 EV RNAs were reported in 26 studies, including 39 microRNAs (miRNAs), 10 long non-coding RNAs (lncRNAs), five circular RNAs, three PIWI-interacting RNAs and one mRNA, in addition to one protein in the remaining study. Meta-analysis of the aforementioned studies demonstrated that the pooled sensitivity, specificity and AUC value of the total RNAs were 84, 67% and 0.822, respectively. The diagnostic values of miRNAs were consistent with the total RNA, as the pooled sensitivity, specificity and AUC value were 84, 67% and 0.808, respectively. The pooled sensitivity, specificity and AUC values of lncRNAs were 89, 69% and 0.872, respectively, markedly higher compared with that of miRNAs. A total of five studies reported the diagnostic performance of EV RNA panels for early stage GC and reported powerful diagnostic values with a pooled sensitivity, specificity and AUC value of 80, 77% and 0.879, respectively. Circulating EV RNAs could have the potential to be used in the future as effective, noninvasive biomarkers for early GC diagnosis. Further research in this field is necessary to translate these findings into clinical practice.
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BACKGROUND: Selenium profile has been related with humoral immune response after vaccination, but evidence with regard to inactivated SARS-CoV-2 vaccine is lacking. OBJECTIVE: The current study aimed to examine the relationship between selenium profile and neutralizing antibody response to inactivated SARS-CoV-2 vaccine. METHODS: Plasma selenium and selenoprotein P concentrations, neutralizing antibody against the wild-type and Omicron variant were measured at baseline and at 14 days, 98 days after the third dose of inactivated SARS-CoV-2 vaccine. RESULTS: Neutralizing antibody against the wild-type and Omicron variant increased significantly after the third vaccination dose. Both higher plasma selenium and selenoprotein P were associated with increased neutralizing antibody against the wild-type strain at baseline. Moreover, higher plasma selenoprotein P was associated with increased neutralizing antibody against Omicron variant at baseline. However, nonsignificant association were observed after the third vaccine dose. CONCLUSION: Higher selenium profile was associated with neutralizing antibody response before the third dose of inactivated SARS-CoV-2 vaccine, but not after the third dose. Further prospective cohort studies are warranted to confirm our findings.
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COVID-19 , Selênio , Humanos , Vacinas contra COVID-19 , SARS-CoV-2 , Selenoproteína P , COVID-19/prevenção & controle , Vacinação , Anticorpos NeutralizantesRESUMO
Zoledronic acid (ZOL) is a potent antiresorptive agent that increases bone mineral density (BMD) and reduces fracture risk in postmenopausal osteoporosis (PMOP). The anti-osteoporotic effect of ZOL is determined by annual BMD measurement. In most cases, bone turnover markers function as early indicators of therapeutic response, but they fail to reflect long-term effects. We used untargeted metabolomics to characterize time-dependent metabolic shifts in response to ZOL and to screen potential therapeutic markers. In addition, bone marrow RNA-seq was performed to support plasma metabolic profiling. Sixty rats were assigned to sham-operated group (SHAM, n = 21) and ovariectomy group (OVX, n = 39) and received sham operation or bilateral ovariectomy, respectively. After modeling and verification, rats in the OVX group were further divided into normal saline group (NS, n = 15) and ZOL group (ZA, n = 18). Three doses of 100 µg/kg ZOL were administrated to the ZA group every 2 weeks to simulate 3-year ZOL therapy in PMOP. An equal volume of saline was administered to the SHAM and NS groups. Plasma samples were collected at five time points for metabolic profiling. At the end of the study, selected rats were euthanatized for bone marrow RNA-seq. A total number of 163 compound were identified as differential metabolites between the ZA and NS groups, including mevalonate, a critical molecule in target pathway of ZOL. In addition, prolyl hydroxyproline (PHP), leucyl hydroxyproline (LHP), 4-vinylphenol sulfate (4-VPS) were identified as differential metabolites throughout the study. Moreover, 4-VPS negatively correlated with increased vertebral BMD after ZOL administration as time-series analysis revealed. Bone marrow RNA-seq showed that the PI3K-AKT signaling pathway was significantly associated with ZOL-mediated changes in expression (adjusted-p = 0.018). In conclusion, mevalonate, PHP, LHP, and 4-VPS are candidate therapeutic markers of ZOL. The pharmacological effect of ZOL likely occurs through inhibition of the PI3K-AKT signaling pathway.
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Hypophosphatasia (HPP) is an inherited disease caused by ALPL mutation, resulting in decreased alkaline phosphatase (ALP) activity and damage to bone and tooth mineralization. The clinical symptoms of adult HPP are variable, making diagnosis challenging. This study aims to clarify the clinical and genetic characteristics of HPP in Chinese adults. There were 19 patients, including 1 with childhood-onset and 18 with adult-onset HPP. The median age was 62 (32-74) years and 16 female patients were involved. Common symptoms included musculoskeletal symptoms (12/19), dental problems (8/19), fractures (7/19), and fatigue (6/19). Nine patients (47.4%) were misdiagnosed with osteoporosis and six received anti-resorptive treatment. The average serum ALP level was 29.1 (14-53) U/L and 94.7% (18/19) of patients had ALP levels below 40 U/L. Genetic analysis found 14 ALPL mutations, including three novel mutations-c.511C>G (p.His171Ala), c.782C>A (p.Pro261Gln), and 1399A>G (p.Met467Val). The symptoms of two patients with compound heterozygous mutations were more severe than those with heterozygous mutations. Our study summarized the clinical characteristics of adult HPP patients in the Chinese population, expanded the spectrum of pathogenic mutations, and deepened clinicians' understanding of this neglected disease.
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Hipofosfatasia , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Fosfatase Alcalina/genética , População do Leste Asiático , Hipofosfatasia/epidemiologia , Hipofosfatasia/genética , Hipofosfatasia/diagnóstico , Mutação , Idoso , MasculinoRESUMO
Cardiovascular disease is a leading cause of disability and death worldwide. Although the survival rate of patients with heart diseases can be improved with contemporary pharmacological treatments and surgical procedures, none of these therapies provide a significant improvement in cardiac repair and regeneration. Stem cell-based therapies are a promising approach for functional recovery of damaged myocardium. However, the available stem cells are difficult to differentiate into cardiomyocytes, which result in the extremely low transplantation efficiency. Nanomaterials are widely used to regulate the myocardial differentiation of stem cells, and play a very important role in cardiac tissue engineering. This study discusses the current status and limitations of stem cells and cell-derived exosomes/micro RNAs based cardiac therapy, describes the cardiac repair mechanism of nanomaterials, summarizes the recent advances in nanomaterials used in cardiac repair and regeneration, and evaluates the advantages and disadvantages of the relevant nanomaterials. Besides discussing the potential clinical applications of nanomaterials in cardiac therapy, the perspectives and challenges of nanomaterials used in stem cell-based cardiac repair and regeneration are also considered. Finally, new research directions in this field are proposed, and future research trends are highlighted.
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Miocárdio , Nanoestruturas , Humanos , Miócitos Cardíacos , Células-Tronco , RegeneraçãoRESUMO
Diabetes mellitus is a prevalent chronic disease characterized by hyperglycemia. Diabetic peripheral neuropathy (DPN) is one of the complications of diabetes mellitus and is caused by neuron injury induced by hyperglycemic circumstances. The incidence of DPN varies among different countries and regions, ranging from nearly 20% to over 70%. Patients with DPN may encounter symmetric pain or discomfort of the extremes, leading to reduced quality of life and even amputation. The pharmacological management for painful DPN mainly includes antidepressants due to their analgesic effects. Nevertheless, effective therapies to impact the pathogenesis and progression of DPN are lacking. Glucagon-like peptide-1 receptor (GLP-1R) agonists show efficacy in controlling blood glucose and serve as a treatment modality for diabetes mellitus. In recent years, evidence has been proposed that GLP-1R agonists exert neuroprotective effects through modulating inflammation, oxidative stress, and mitochondrial dysfunction. On the other hand, clinical evidence on the potential of GLP-1R agonists for treating DPN is still controversial and limited. This narrative review summarizes the preclinical and clinical studies investigating the capacity of GLP-1R agonists as therapeutic agents for DPN.
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Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Qualidade de VidaRESUMO
Renal fibrosis is increasingly recognized as a global public health problem. Acute kidney injury (AKI) and chronic kidney disease (CKD) both result in renal fibrosis. Oxidative stress and inflammation play central roles in progressive renal fibrosis. Oxidative stress and inflammation are closely linked and form a vicious cycle in which oxidative stress induces inflammation through various molecular mechanisms. Ample evidence has indicated that a hyperactive nuclear factor kappa B (NF-ÆB) signaling pathway plays a pivotal role in renal fibrosis. Hyperactive NF-ÆB causes the activation and recruitment of immune cells. Inflammation, in turn, triggers oxidative stress through the production of reactive oxygen species and nitrogen species by activating leukocytes and resident cells. These events mediate organ injury through apoptosis, necrosis, and fibrosis. Therefore, developing a strategy to target the NF-ÆB signaling pathway is important for the effective treatment of renal fibrosis. This Review summarizes the effect of the NF-ÆB signaling pathway on renal fibrosis in the context of AKI and CKD (immunoglobulin A nephropathy, membranous nephropathy, diabetic nephropathy, hypertensive nephropathy, and kidney transplantation). Therapies targeting the NF-ÆB signaling pathway, including natural products, are also discussed. In addition, NF-ÆB-dependent non-coding RNAs are involved in renal inflammation and fibrosis and are crucial targets in the development of effective treatments for kidney disease. This Review provides a clear pathophysiological rationale and specific concept-driven therapeutic strategy for the treatment of renal fibrosis by targeting the NF-ÆB signaling pathway.