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Cognitive dysfunction has been regarded as a complication of diabetes. Melatonin (MLT) shows a neuroprotective effect on various neurological diseases. However, its protective effect on cortical neurons in high glucose environment has not been reported. Our present study aims to observe the protective effect of melatonin on rat cortical neurons and its relationship with autophagy in high glucose environment. The rat primary cortical neurons injury model was induced by high glucose. The CCK-8, flow cytometry, Western blot and immunofluorescence methods were used to examine the cell viability, apoptosis rate and proteins expression. Our results showed that there were no differences in cell viability, apoptosis rate, and protein expression among the control, MLT and mannitol group. The cell viability of the glucose group was significantly lower than that of the control group, and the apoptosis rate of the glucose group was significantly higher than that of the control group. Compared with the glucose group, the glucose + melatonin group showed a significant increase in cell viability and a notable decrease in apoptosis rate. Melatonin concentration of 0.1-1 mmol/L can significantly alleviate the injury of cortical neurons caused by high glucose. Compared with the control group, the glucose group showed a significant reduction of B-cell lymphoma 2 (Bcl-2) protein expression, while remarkable elevations of Bcl2-associated X protein (Bax), cleaved Caspase-3, coiled-coil, myosin-like Bcl2-interacting protein (Beclin-1) and microtubule-associated protein 1 light chain-3B type II (LC3B-II) levels. The neurons pre-administered with melatonin obtained significantly reversed these changes induced by high glucose. The phosphorylation levels of protein kinase B (Akt), mechanistic target of rapamycin kinase (mTOR) and Unc-51 like autophagy activating kinase 1(ULK1) were decreased in the glucose group compared with the control group, whereas significant increase were observed in the glucose + MLT group, compared with the glucose group. These data indicated that melatonin has a neuroprotective effect on cortical neurons under high glucose environment, which may work by activating Akt/mTOR/ULK1 pathway and may be deeply associated with the downregulation of autophagy.
Assuntos
Melatonina , Fármacos Neuroprotetores , Ratos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Melatonina/farmacologia , Melatonina/metabolismo , Fármacos Neuroprotetores/farmacologia , Apoptose , Glucose/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Autofagia , Neurônios/metabolismoRESUMO
OBJECTIVE: This study examined the relationship between Cystatin C (CysC) levels and all-cause, CVD, and cancer mortality in US metabolic syndrome (MetS) patients. METHODS: The 1999-2002 National Health and Nutrition Examination Survey (NHANES) prospective cohort research included 1,980 MetS participants. To assess CysC levels and all-cause, CVD, and cancer mortality, fitted curves, Kaplan-Meier survival curves, cox regression analysis, and ROC curves were performed. RESULTS: During a mean follow-up of 15.3 ± 5.4 years, a total of 819 deaths occurred. The fitted and Kaplan-Meier survival curves revealed that greater CysC levels were linked to higher all-cause, CVD, and cancer mortality rates (P<0.05). After adjusting for variables, CysC level was associated with all-cause, CVD, and cancer mortality at 1.63 (1.42-1.88), 1.53 (1.19-1.95), and 1.53 (1â¼2.32), respectively (P<0.05). Later tertile models showed consistent results. High CysC tertile participants showed higher risk of all-cause mortality (HR 1.87; 1.43-2.45), CVD mortality (HR 1.97, 1.15â¼3.38), and cancer mortality (HR 1.72, 1.01â¼2.91) compared to those in the lowest tertile (P<0.05). Subgroup studies by sex and other characteristics confirmed the findings. CysC demonstrated the higher predictive efficacy across mortality outcomes, followed by eGFR, outperforming Urea nitrogen, Creatinine, Uric acid, and CRP. CysC alone exhibited substantial predictive value for all-cause (AUC 0.773; P<0.05) and CVD mortality (AUC 0.726; P<0.05). Combining CysC with age enhanced the predictive value for all-cause mortality to 0.861 and CVD mortality to 0.771 (P<0.05). CONCLUSION: MetS patients with elevated CysC levels have a higher risk of all-cause, CVD, and cancer death. CysC may predict MetS all-cause and CVD mortality.
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BACKGROUND: Endothelial cell injury is one of the important pathogenic mechanisms in thrombotic diseases, and also neutrophils are involved. MicroRNAs (miRNAs) have been demonstrated to act as essential players in endothelial cell injury, but the potential molecular processes are unknown. In this study, we used cellular tests to ascertain the protective effect of miR-328-3p on human umbilical vein endothelial cells (HUVECs) treated with oxygen-glucose deprivation (OGD). METHODS: In our study, an OGD-induced HUVECs model was established, and we constructed lentiviral vectors to establish stable HUVECs cell lines. miR-328-3p and Toll-like receptor 2 (TLR2) interacted, as demonstrated by the dual luciferase reporter assay. We used the CCK8, LDH release, and EdU assays to evaluate the proliferative capacity of each group of cells. To investigate the expression of TLR2, p-P65 NF-κB, P65 NF-κB, NLRP3, IL-1ß, and IL-18, we employed Western blot and ELISA. Following OGD, each group's cell supernatants were gathered and co-cultured with neutrophils. An immunofluorescence assay and Transwell assay have been performed to determine whether miR-328-3p/TLR2 interferes with neutrophil migration and neutrophil extracellular traps (NETs) formation. RESULTS: In OGD-treated HUVECs, the expression of miR-328-3p is downregulated. miR-328-3p directly targets TLR2, inhibits the NF-κB signaling pathway, and reverses the proliferative capacity of OGD-treated HUVECs, while inhibiting neutrophil migration and neutrophil extracellular trap formation. CONCLUSIONS: miR-328-3p inhibits the NF-κB signaling pathway in OGD-treated HUVECs while inhibiting neutrophil migration and NETs formation, and ameliorating endothelial cell injury, which provides new ideas for the pathogenesis of thrombotic diseases.
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Armadilhas Extracelulares , MicroRNAs , Humanos , NF-kappa B/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Armadilhas Extracelulares/metabolismo , Oxigênio/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Glucose/farmacologia , Transdução de Sinais , MicroRNAs/metabolismo , ApoptoseRESUMO
OBJECTIVE: Hip fracture and falls are significant health concerns. Handgrip strength (HGS) is closely associated with overall muscle strength and physical health. However, the longitudinal relationship between HGS and the risk of hip fractures and falls remains unclear, particularly regarding gender differences. This longitudinal study aimed to investigate the association between HGS and the risk of hip fracture and falls in individuals aged 45 years and above, considering gender-specific differences over a 4-year period. METHODS: This study included 10,092 participants (4471 men and 5621 women) aged 45 years and above from the China Health and Retirement Longitudinal Study (CHARLS). Incidents of hip fractures and falls were recorded during a 4-year follow-up, along with various demographic and clinical factors. Participants were categorized into five groups based on their HGS quintiles. Logistic regression models were employed to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationship between HGS and hip fracture/fall risk. RESULTS: During the 4-year follow-up period, 223 cases of hip fracture (2.2%) and 1831 cases of falls (18.1%) were documented. Notably, higher HGS demonstrated a strong inverse association with the risk of hip fracture in both males and females (p < 0.05). In comparison to the lowest HGS quintile, the adjusted odds ratios (ORs) for hip fracture were 0.46 (0.27-0.78) for the total population, 0.4 (0.19-0.81) for males and 0.48 (0.23-0.98) for females in the highest HGS quintile. Furthermore, a profound and statistically significant negative correlation between HGS and falls was detected (p < 0.05). The adjusted ORs for falls in the highest HGS quintile, compared to the lowest quintile, were 0.62 (0.51-0.76) in the overall population, 0.59 (0.44-0.78) in males, and 0.78 (0.62-0.99) in females. CONCLUSION: Our findings highlight the significant inverse association between HGS and the risk of hip fracture and falls in both males and females aged 45 years and above. Assessing handgrip strength may serve as a valuable tool for predicting fracture and fall risk.
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Acidentes por Quedas , Força da Mão , Fraturas do Quadril , Vida Independente , Humanos , Masculino , Acidentes por Quedas/estatística & dados numéricos , Feminino , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/fisiopatologia , Estudos Longitudinais , Idoso , Pessoa de Meia-Idade , Força da Mão/fisiologia , China/epidemiologia , Idoso de 80 Anos ou mais , Fatores de Risco , Fatores SexuaisRESUMO
Deep vein thrombosis (DVT) is a prevalent clinical venous thrombotic condition that often manifests independently or in conjunction with other ailments. Thrombi have the propensity to dislodge into the circulatory system, giving rise to complications such as pulmonary embolism, thereby posing a significant risk to the patient. Virchow proposed that blood stagnation, alterations in the vessel wall and hypercoagulation are primary factors contributing to the development of venous thrombosis. Vascular endothelial cells (VECs) constitute the initial barrier to the vascular wall and are a focal point of ongoing research. These cells exert diverse stimulatory effects on the bloodstream and secrete various regulatory factors that uphold the dynamic equilibrium between the coagulation and anticoagulation processes. MicroRNAs (miRNAs) represent a class of noncoding RNAs present in eukaryotes, characterized by significant genetic and evolutionary conservation and displaying high spatiotemporal expression specificity. Typically ranging from 20 to 25 bases in length, miRNAs can influence downstream gene transcription through RNA interference or by binding to specific mRNA sites. Consequently, advancements in understanding the molecular mechanisms of miRNAs, including their functionalities, involve modulation of vascularassociated processes such as cell proliferation, differentiation, secretion of inflammatory factors, migration, apoptosis and vascular remodeling regeneration. miRNAs play a substantial role in DVT formation via venous VECs. In the present review, the distinct functions of various miRNAs in endothelial cells are outlined and recent progress in comprehending their role in the pathogenesis and clinical application of DVT is elucidated.
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MicroRNAs , Embolia Pulmonar , Trombose Venosa , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Células Endoteliais/metabolismo , Trombose Venosa/metabolismo , Coagulação SanguíneaRESUMO
Deep venous thrombosis (DVT) is a part of venous thromboembolism (VTE) that clinically manifests as swelling and pain in the lower limbs. The most serious clinical complication of DVT is pulmonary embolism (PE), which has a high mortality rate. To date, its underlying mechanisms are not fully understood, and patients usually present with clinical symptoms only after the formation of the thrombus. Thus, it is essential to understand the underlying mechanisms of deep vein thrombosis for an early diagnosis and treatment of DVT. In recent years, many studies have concluded that Neutrophil Extracellular Traps (NETs) are closely associated with DVT. These are released by neutrophils and, in addition to trapping pathogens, can mediate the formation of deep vein thrombi, thereby blocking blood vessels and leading to the development of disease. Therefore, this paper describes the occurrence and development of NETs and discusses the mechanism of action of NETs on deep vein thrombosis. It aims to provide a direction for improved diagnosis and treatment of deep vein thrombosis in the near future.
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Armadilhas Extracelulares , Trombose Venosa , Humanos , Neutrófilos , Extremidade Inferior , Dor , Trombose Venosa/terapiaRESUMO
Venous thromboembolism is a very common and costly health problem. Deep-vein thrombosis (DVT) can cause permanent damage to the venous system and lead to swelling, ulceration, gangrene, and other symptoms in the affected limb. In addition, more than half of the embolus of pulmonary embolism comes from venous thrombosis, which is the most serious cause of death, second only to ischemic heart disease and stroke patients. It can be seen that deep-vein thrombosis has become a serious disease affecting human health. In recent years, with the deepening of research, inflammatory response is considered to be an important pathway to trigger venous thromboembolism, in which the transcription factor NF-κB is the central medium of inflammation, and the NF-κB signaling pathway can regulate the pro-inflammatory and coagulation response. Thus, to explore the mechanism and make use of it may provide new solutions for the prevention and treatment of thrombosis.
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Trombose , Tromboembolia Venosa , Trombose Venosa , Humanos , NF-kappa B , Tromboembolia Venosa/prevenção & controle , Trombose/etiologia , Transdução de SinaisRESUMO
BACKGROUND: The relationship between leukocyte telomere length (LTL) and mortality risk in individuals with metabolic syndrome (MetS) remains poorly understood. This study aimed to investigate the association between telomere length and long-term all-cause mortality, and cardiovascular disease (CVD) mortality, in individuals with MetS in the United States. METHODS: A total of 1980 participants with MetS aged 18 years or older from the National Health and Nutrition Examination Survey (NHANES) prospective cohort study (1999-2002) were included in this cohort study. Medical records review was used to identify the cause of deaths as of December 2018. We employed Kaplan-Meier curves, fitted curves, and Cox proportional hazards regression models to estimate hazard ratios (HRs) for all-cause and CVD mortality, stratified by tertiles of LTL. RESULTS: Over a median follow-up of 17.75 years of participants with metabolic syndrome, 819 deaths occurred, including 231 cardiovascular deaths. After adjusting for multiple covariates, participants with shorter telomere length had a significantly higher risk of all-cause mortality (HR, 1.33; 95% CI, 1.11-1.6) and CVD mortality (HR, 1.36; 95% CI, 0.96-1.93) compared with those in the highest tertile of telomere length. All-cause mortality (P < 0.001) and cardiovascular disease mortality (P = 0.028) followed a similar pattern across tertiles of telomere length. CONCLUSION: In individuals with MetS, shorter telomere length is associated with increased risks of death from cardiovascular disease and all causes. The underlying mechanisms and clinical implications of these findings require additional investigation.
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Background: Sarcopenia has been linked to adverse health outcomes, including an increased risk of mortality. This study aimed to assess the 7-year mortality risk of sarcopenia in a community-based population in China and explore the causal relationship between components of sarcopenia and any death. Methods: Data were sourced from the China Health and Retirement Longitudinal Study (CHARLS) conducted between 2011 and 2018. Sarcopenia was diagnosed using the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Logistic regression, Kaplan-Meier (KM) survival analysis, and propensity score matching with inverse probability of treatment weighting were used. Mendelian randomization (MR) analyses, conducted using European population data, were utilized to assess causality between sarcopenia and any death. Results: The study included 9,006 participants: 3,892 had no sarcopenia, 3,570 had possible sarcopenia, 1,125 had sarcopenia, and 419 had severe sarcopenia. Over 7 years of follow-up, there were 871 deaths, including 196 with sarcopenia and 133 with severe sarcopenia. The KM curves showed that sarcopenia had a higher risk of mortality. Compared to those of no sarcopenia, the odds ratios (ORs) of sarcopenia for 7-year mortality were 1.41 (95% CI, 1.06-1.87) after adjusting for confounding variables (p < 0.05). The ORs of severe sarcopenia were 2.11 (95% CI, 1.51-2.95). Propensity score matching analysis and inverse probability of treatment weighting analysis confirmed these findings. The adjusted ORs of sarcopenia and 7-year mortality were 2.94 (95% CI, 1.6-5.39) in the 45-60 age group, 1.72 (95% CI, 1.11-2.68) in the 60-80 age group, and 5.03 (95% CI, 0.48-52.65) in the ≥80 age group. The ORs of severe sarcopenia and 7-year mortality were 6.92 (95% CI, 1.95-24.5) in the 45-60 age group, 2.59 (95% CI, 1.61-4.17) in the 60-80 age group, and 12.52 (95% CI, 1.18-133.18) in the ≥80 age group. The MR analyses, leveraging the inverse variance weighted (IVW) method, unveiled substantial causal links between low hand grip strength in individuals aged 60 and older, the usual walking pace, and mortality risk. Conclusion: This study underscores the significant impact of sarcopenia and its components on mortality risk within the Chinese population. Particularly, low hand grip strength and usual walking pace emerged as noteworthy contributors to mortality risk.
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População do Leste Asiático , Sarcopenia , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Estudos de Coortes , Pontuação de Propensão , Estudos Longitudinais , Força da Mão , Vida Independente , Análise da Randomização Mendeliana , Sarcopenia/epidemiologiaRESUMO
PURPOSE: MicroRNAs play an important role in osteosarcoma (OS) development and progress. Although miR-1253 was considered as a tumor-inhibitor in some cancers, it's function in the OS is not clear. METHODS: In our study, we examined the expression of miR-1253 in OS cells and osteoblast cells using quantitative real-time PCR. The proliferation of OS cells was measured by BrdU assay, and we performed transwell to detect migration and invasion of OS cells. Meanwhile, EMT proteins were tested by western blot. We used Bioinformatics to predict the target genes of miR-1253 and found out Matrix metalloproteinases9 (MMP9) was one of that. The direct combination between miR-1253 and MMP9 was verified by double luciferase reporting experiment. Quantitative real-time PCR and western blot were used to detect the expression of MMP9. RESULTS: We found that the expression level of miR-1253 in OS cells was significantly lower than that in osteoblast cells. Overexpression of miR-1253 could significantly inhibit OS cell proliferation, migration, invasion and EMT. And then, MMP9 was predicted as a downstream target of miR-1253 by Bioinformatics analysis. Further experiments showed that miR-1253 could reduce the protein level of MMP9 by directly binding to the 3'-UTR of MMP9. Afterward, we performed a rescue experiment, in which both MMP9 and miR-1253 were overexpressed. Compared with the groups overexpressed miR-1253 alone, cell proliferation, migration and invasion in co-overexpression groups were improved. CONCLUSIONS: In summary, these results suggested that miR-1253 down-regulated in OS cells, and could suppress the proliferation, migration and invasion of OS cells. Its molecular regulatory mechanism was that inhibits the expression of the downstream target gene MMP9 by directly binding, thus affect OS cell functions. Therefore, miR-1253 has the potential to become a biomarker and therapeutic target for OS therapy.