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BACKGROUND: Pulmonary hypertension (PH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and elevated mean pulmonary arterial pressure, resulting in right heart failure. METHODS: Here, we show that direct targeting of the endothelium to uncouple eNOS (endothelial nitric oxide synthase) with DAHP (2,4-diamino 6-hydroxypyrimidine; an inhibitor of GTP cyclohydrolase 1, the rate-limiting synthetic enzyme for the critical eNOS cofactor tetrahydrobiopterin) induces human-like, time-dependent progression of PH phenotypes in mice. RESULTS: Critical phenotypic features include progressive elevation in mean pulmonary arterial pressure, right ventricular systolic blood pressure, and right ventricle (RV)/left ventricle plus septum (LV+S) weight ratio; extensive vascular remodeling of pulmonary arterioles with increased medial thickness/perivascular collagen deposition and increased expression of PCNA (proliferative cell nuclear antigen) and alpha-actin; markedly increased total and mitochondrial superoxide production, substantially reduced tetrahydrobiopterin and nitric oxide bioavailabilities; and formation of an array of human-like vascular lesions. Intriguingly, novel in-house generated endothelial-specific dihydrofolate reductase (DHFR) transgenic mice (tg-EC-DHFR) were completely protected from the pathophysiological and molecular features of PH upon DAHP treatment or hypoxia exposure. Furthermore, DHFR overexpression with a pCMV-DHFR plasmid transfection in mice after initiation of DAHP treatment completely reversed PH phenotypes. DHFR knockout mice spontaneously developed PH at baseline and had no additional deterioration in response to hypoxia, indicating an intrinsic role of DHFR deficiency in causing PH. RNA-sequencing experiments indicated great similarity in gene regulation profiles between the DAHP model and human patients with PH. CONCLUSIONS: Taken together, these results establish a novel human-like murine model of PH that has long been lacking in the field, which can be broadly used for future mechanistic and translational studies. These data also indicate that targeting endothelial DHFR deficiency represents a novel and robust therapeutic strategy for the treatment of PH.
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Hipertensão Pulmonar , Tetra-Hidrofolato Desidrogenase , Animais , Humanos , Camundongos , Endotélio/metabolismo , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/genética , Hipóxia , Camundongos Knockout , Camundongos Transgênicos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Tetra-Hidrofolato Desidrogenase/genética , Tetra-Hidrofolato Desidrogenase/metabolismo , Tetra-Hidrofolato Desidrogenase/deficiência , Hipoxantinas , Modelos Animais de DoençasRESUMO
BACKGROUND: Pulmonary hypertension (PH) is a progressive cardiopulmonary disease with a high mortality rate. Although growing evidence has revealed the importance of dysregulated energetic metabolism in the pathogenesis of PH, the underlying cellular and molecular mechanisms are not fully understood. In this study, we focused on ME1 (malic enzyme 1), a key enzyme linking glycolysis to the tricarboxylic acid cycle. We aimed to determine the role and mechanistic action of ME1 in PH. METHODS: Global and endothelial-specific ME1 knockout mice were used to investigate the role of ME1 in hypoxia- and SU5416/hypoxia (SuHx)-induced PH. Small hairpin RNA and ME1 enzymatic inhibitor (ME1*) were used to study the mechanism of ME1 in pulmonary artery endothelial cells. Downstream key metabolic pathways and mediators of ME1 were identified by metabolomics analysis in vivo and ME1-mediated energetic alterations were examined by Seahorse metabolic analysis in vitro. The pharmacological effect of ME1* on PH treatment was evaluated in PH animal models induced by SuHx. RESULTS: We found that ME1 protein level and enzymatic activity were highly elevated in lung tissues of patients and mice with PH, primarily in vascular endothelial cells. Global knockout of ME1 protected mice from developing hypoxia- or SuHx-induced PH. Endothelial-specific ME1 deletion similarly attenuated pulmonary vascular remodeling and PH development in mice, suggesting a critical role of endothelial ME1 in PH. Mechanistic studies revealed that ME1 inhibition promoted downstream adenosine production and activated A2AR-mediated adenosine signaling, which leads to an increase in nitric oxide generation and a decrease in proinflammatory molecule expression in endothelial cells. ME1 inhibition activated adenosine production in an ATP-dependent manner through regulating malate-aspartate NADH (nicotinamide adenine dinucleotide plus hydrogen) shuttle and thereby balancing oxidative phosphorylation and glycolysis. Pharmacological inactivation of ME1 attenuated the progression of PH in both preventive and therapeutic settings by promoting adenosine production in vivo. CONCLUSIONS: Our findings indicate that ME1 upregulation in endothelial cells plays a causative role in PH development by negatively regulating adenosine production and subsequently dysregulating endothelial functions. Our findings also suggest that ME1 may represent as a novel pharmacological target for upregulating protective adenosine signaling in PH therapy.
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Idiopathic pulmonary fibrosis (IPF) is a lethal progressive disease with elusive molecular mechanisms and limited therapeutic options. Aberrant activation of fibroblasts is a central hallmark of lung fibrosis. Here, we report that Golgi membrane protein 1 (GOLM1, also known as GP73 or GOLPH2) was increased in the lungs of patients with pulmonary fibrosis and mice with bleomycin (BLM)-induced pulmonary fibrosis. Loss of GOLM1 inhibited proliferation, differentiation, and extracellular matrix deposition of fibroblasts, whereas overexpression of GOLM1 exerted the opposite effects. Similarly, worsening pulmonary fibrosis after BLM treatment was observed in GOLM1-knock-in mice, whereas BLM-treated Golm1-knockout mice exhibited alleviated pulmonary fibrosis and collagen deposition. Furthermore, we identified long noncoding RNA NEAT1 downstream of GOLM1 as a potential mediator of pulmonary fibrosis through increased GOLM1 expression. Depletion of NEAT1 inhibited fibroblast proliferation and extracellular matrix production and reversed the profibrotic effects of GOLM1 overexpression. Additionally, we identified KLF4 as a downstream mediator of GOLM1 signaling to NEAT1. Our findings suggest that GOLM1 plays a pivotal role in promoting pulmonary fibrosis through the GOLM1-KLF4-NEAT1 signaling axis. Targeting GOLM1 and its downstream pathways may represent a novel therapeutic strategy for treating pulmonary fibrosis.
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Fibrose Pulmonar Idiopática , Animais , Humanos , Camundongos , Bleomicina , Matriz Extracelular , Fibroblastos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Proteínas de Membrana/genética , Camundongos Knockout , Regulação para CimaRESUMO
Matrix stiffness potently promotes the malignant phenotype in various biological contexts. Therefore, identification of gene expression to participate in mechanical force signals transduced into downstream biochemical signaling will contribute substantially to the advances in nasopharyngeal carcinoma (NPC) treatment. In the present study, we detected that cortactin (CTTN) played an indispensable role in matrix stiffness-induced cell migration, invasion, and invadopodia formation. Advances in cancer research have highlighted that dysregulated alternative splicing contributes to cancer progression as an oncogenic driver. However, whether WT-CTTN or splice variants (SV1-CTTN or SV2-CTTN) regulate matrix stiffness-induced malignant phenotype is largely unknown. We proved that alteration of WT-CTTN expression modulated matrix stiffness-induced cell migration, invasion, and invadopodia formation. Considering that splicing factors might drive cancer progression through positive feedback loops, we analyzed and showed how the splicing factor PTBP2 and TIA1 modulated the production of WT-CTTN. Moreover, we determined that high stiffness activated PTBP2 expression. Taken together, our findings showed that the PTBP2-WT-CTTN level increases upon stiffening and then promotes cell migration, invasion, and invadopodia formation in NPC.
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Neoplasias Nasofaríngeas , Podossomos , Humanos , Cortactina/genética , Cortactina/metabolismo , Carcinoma Nasofaríngeo/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Nasofaríngeas/genética , Invasividade NeoplásicaRESUMO
Heat stress induces testicular oxidative stress, impairs spermatogenesis, and increases the risk of male infertility. Recent studies have highlighted the antioxidative properties of the Sestrins family in reducing cellular oxidative damage. However, the role of Sestrins (Sestrin1, 2, and 3) in the testicular response to heat stress remains unclear. Here, we found that Sestrin2 and 3 were highly expressed in the testis relative to Sestrin1. Then, the Sestrin2-/- and Sestrin3-/- mice were generated by CRISPR/Cas9 to investigate the role of them on spermatogenesis after heat stress. Our data showed that Sestrin2-/- and Sestrin3-/- mice testes exhibited more severe damage manifested by exacerbated loss of germ cells and higher levels of oxidative stress as compared to wild-type counterparts after heat stress. Notably, Sestrin2-/- and Sestrin3-/- mice underwent a remarkable increase in heat-induced spermatocyte apoptosis than that of controls. Furthermore, the transcriptome landscape of spermatocytes and chromosome spreading showed that loss of Sestrin2 and Sestrin3 exacerbated meiotic failure by compromising DNA double-strand breaks repair after heat stress. Taken together, our work demonstrated a critical protective function of Sestrin2 and Sestrin3 in mitigating the impairments of spermatogenesis against heat stress.
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Resposta ao Choque Térmico , Meiose , Camundongos Knockout , Espermatogênese , Animais , Masculino , Espermatogênese/fisiologia , Espermatogênese/genética , Camundongos , Meiose/fisiologia , Resposta ao Choque Térmico/fisiologia , Sestrinas/genética , Sestrinas/metabolismo , Estresse Oxidativo/fisiologia , Testículo/metabolismo , Espermatócitos/metabolismo , Apoptose/fisiologiaRESUMO
BACKGROUND: Lung transplant recipients (LTRs) have a higher risk of hospitalization and mortality due to COVID-19 compared with the immunocompetent population. The use of nirmatrelvir/ritonavir (NR), an effective oral treatment for COVID-19, is quite challenging due to its potent drug-drug interactions with immunosuppressants and azole antifungals. As there are few clinical reports of the use of NR in LTRs, we measured tacrolimus levels in patients receiving NR in our hospital to improve safety when prescribing NR. METHODS: In total, 48 adult LTRs who received NR between November 19, 2022, and January 19, 2023, at China-Japan Friendship Hospital were retrospectively included and followed for 20 days after initiating NR. Tacrolimus was held at least 12 h before initiating NR and re-administered based on the trough levels after completing NR treatment. All concomitant medications, drug concentrations, laboratory results, and genotypes were recorded and analyzed. RESULTS: Most patients showed stable tacrolimus trough levels despite high individual variability. Four patients exhibited supratherapeutic trough levels of tacrolimus (more than 15 ng/mL). Two patients who received 0.5 mg of tacrolimus during NR treatment had trough levels below 3.0 ng/mL. In addition, we found that in 13 patients, the trough levels were 130% of baseline after cessation of tacrolimus, and logistic regression revealed that increased trough level was significantly associated with age more than 60 years. CONCLUSIONS: NR can be safely used in LTRs with close monitoring of tacrolimus levels and appropriate dose adjustments. However, more attention should be paid to elderly patients, as NR may more severely affect their drug metabolism. Due to the limited sample size, further studies are needed to guide the optimal use of tacrolimus following treatment with NR and explore the risk factors significantly affecting the interactions between NR and tacrolimus.
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COVID-19 , Lactamas , Leucina , Nitrilas , Prolina , Tacrolimo , Adulto , Humanos , Idoso , Pessoa de Meia-Idade , Tacrolimo/efeitos adversos , Estudos Retrospectivos , Ritonavir/uso terapêutico , Transplantados , ImunossupressoresRESUMO
Obesity may lead to cognitive impairment and psychiatric disorders, which are associated with alterations in the brain cortical structure. However, the exact causality remains inconclusive. We aimed to conduct two-sample Mendelian randomization (MR) analysis to identify the causal associations of obesity [body mass index (BMI), waist-hip ratio (WHR), and waist-hip ratio adjusted for BMI ((WHRadjBMI)) and brain cortical structure (cortical thickness and cortical surface area). Inverse-variance weighted (IVW) method was used as the main analysis, whereas a series of sensitivity analyses were employed to assess heterogeneity and pleiotropy. The main MR results showed that higher BMI significantly increased the cortical surface area of the transverse temporal (ß = 5.13 mm2, 95% confidence interval [CI]: 2.55-7.71, P = 9.9 × 10-5); higher WHR significantly decreased cortical surface area of the inferior temporal (ß = -38.60, 95% CI: -56.67- -20.54, P = 1.2 × 10-5), but significantly increased cortical surface area of the isthmus cingulate (ß = 14.25, 95% CI: 6.97-21.54, P = 1.2 × 10-4). No significant evidence of pleiotropy was found in the MR analyses. This study supports that obesity has a causal effect on the brain cortical structure. Further studies are warranted to understand the clinical outcomes caused by these effects.
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Disfunção Cognitiva , Análise da Randomização Mendeliana , Humanos , Encéfalo , Obesidade/genética , Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVE: Previous research has primarily focused on the incidence and mortality rates of Merkel cell carcinoma (MCC), neglecting the examination of cardiovascular mortality (CVM) risk among survivors, particularly older patients. This study aims to assess the risk of CVM in older individuals diagnosed with MCC. METHODS: Data pertaining to older MCC patients were obtained from the Surveillance, Epidemiology, and End Results database (SEER). CVM risk was measured using standardized mortality ratio (SMR) and cumulative mortality. Multivariate Fine-Gray's competing risk model was utilized to evaluate the risk factors contributing to CVM. RESULTS: Among the study population of 2,899 MCC patients, 465 (16.0%) experienced CVM during the follow-up period. With the prolongation of the follow-up duration, the cumulative mortality rate for CVM reached 27.36%, indicating that cardiovascular disease (CVD) became the second most common cause of death. MCC patients exhibited a higher CVM risk compared to the general population (SMR: 1.69; 95% CI: 1.54-1.86, p < 0.05). Notably, the SMR for other diseases of arteries, arterioles, and capillaries displayed the most significant elevation (SMR: 2.69; 95% CI: 1.16-5.29, p < 0.05). Furthermore, age at diagnosis and disease stage were identified as primary risk factors for CVM, whereas undergoing chemotherapy or radiation demonstrated a protective effect. CONCLUSION: This study emphasizes the significance of CVM as a competing cause of death in older individuals with MCC. MCC patients face a heightened risk of CVM compared to the general population. It is crucial to prioritize cardiovascular health starting from the time of diagnosis and implement personalized CVD monitoring and supportive interventions for MCC patients at high risk. These measures are essential for enhancing survival outcomes.
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Carcinoma de Célula de Merkel , Doenças Cardiovasculares , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/mortalidade , Carcinoma de Célula de Merkel/epidemiologia , Masculino , Idoso , Feminino , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/epidemiologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/epidemiologia , Idoso de 80 Anos ou mais , Fatores de Risco , Programa de SEER/tendências , Estados Unidos/epidemiologia , Medição de Risco/métodosRESUMO
Pedestrian trajectory prediction is crucial for developing collision avoidance algorithms in autonomous driving systems, aiming to predict the future movement of the detected pedestrians based on their past trajectories. The traditional methods for pedestrian trajectory prediction involve a sequence of tasks, including detection and tracking to gather the historical movement of the observed pedestrians. Consequently, the accuracy of trajectory prediction heavily relies on the accuracy of the detection and tracking models, making it susceptible to their performance. The prior research in trajectory prediction has mainly assessed the model performance using public datasets, which often overlook the errors originating from detection and tracking models. This oversight fails to capture the real-world scenario of inevitable detection and tracking inaccuracies. In this study, we investigate the cumulative effect of errors within integrated detection, tracking, and trajectory prediction pipelines. Through empirical analysis, we examine the errors introduced at each stage of the pipeline and assess their collective impact on the trajectory prediction accuracy. We evaluate these models across various custom datasets collected in Taiwan to provide a comprehensive assessment. Our analysis of the results derived from these integrated pipelines illuminates the significant influence of detection and tracking errors on downstream tasks, such as trajectory prediction and distance estimation.
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As a traditional Chinese medicine, Salvia miltiorrhiza Bunge was first recorded in the Shennong Materia Medica Classic and is widely used to treat "the accumulation of symptoms and masses". The main active ingredient of Salvia miltiorrhiza Bunge, Tanshinone IIA (TIIA), has shown anti-inflammatory, antitumor, antifibrosis, antibacterial, and antioxidative activities, etc. In this study, the results showed that TIIA could inhibit the proliferation and migration of HepG2 cells and downregulate glutathione (GSH) and Glutathione Peroxidase 4 (GPX4) levels; besides, TIIA induced the production of Reactive Oxygen Species (ROS), and upregulated the total iron content. Based on network pharmacology analysis, the antitumor effect of TIIA was found to be focused on the endoplasmic reticulum (ER)-mediated ferroptosis signaling pathway, with protein kinase R (PKR)-like ER kinase (PERK)-activating transcription factor 4 (ATF4)-heat shock 70 kDa protein 5 (HSPA5) as the main pathway. Herein, TIIA showed typical ferroptosis characteristics, and a ferroptosis inhibitor (ferrostatin-1) was used to verify the effect. The antitumor effects of TIIA, occurring through the inhibition of the PERK-ATF4-HSPA5 pathway, were further observed in vivo as significantly inhibited tumor growth and the improved pathological morphology of tumor tissue in H22-bearing mice. In summary, the antitumor mechanism of TIIA might be related to the downregulation of the activation of PERK-ATF4-HSPA5 pathway-mediated ferroptosis.
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Fator 4 Ativador da Transcrição , Ferroptose , Animais , Camundongos , Fator 4 Ativador da Transcrição/genética , Chaperona BiP do Retículo Endoplasmático , Abietanos/farmacologia , GlutationaRESUMO
BACKGROUND: Many studies have covered the prevalence of obesity in different populations. However, studies on the prevalence and predictors of obesity among medical staff are lacking. The aim of our study is to investigate the prevalence of obesity among medical staff and to identify the related predictors. METHODS: Using a snowballing recruitment strategy in the form of an electronic questionnaire, a cross-sectional survey was conducted among 1201 medical staff from cooperative hospitals between January and March 2022. We designed a questionnaire to investigate the participants' demographic, lifestyle, diet, physical activity, and work status. RESULTS: The overall prevalence of obesity was 8.5%, with males (13.7%) having a greater incidence than females (5.7%) (p < 0.001). Multiple logistic regression analyses showed that alcohol drinking (OR, 2.34; 95% CI 1.23-4.42, p = 0.01), sugar-sweetened beverages consumed > 3/week (OR, 2.50; 95% CI 1.02-6.15, p = 0.046), and working a night shift > 1/week (OR, 2.17; 95% CI 1.02-4.61, p = 0.043) were independent predictive factors for obesity in men. For women, having midnight snack having midnight snack (OR, 2.93;95% CI 1.24-6.96, p = 0.015), good sleep quality (OR, 4.47; 95% CI 1.10-21.70, p = 0.038), and working a night shift > 1/week (OR, 3.62; 95% CI 1.73-7.57, p = 0.001) were independently associated with obesity. CONCLUSIONS: Obesity presented a low prevalence among medical staff. Alcohol drinking, drinking sugar-sweetened beverages > 3/week, and night shift > 1/week predicted a higher risk of obesity in males. In females, having midnight snack, good sleep quality, and night shift > 1/week were independently associated with obesity. LEVEL OF EVIDENCE: V, descriptive study.
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Corpo Clínico , Obesidade , Masculino , Humanos , Feminino , Estudos Transversais , Projetos Piloto , Obesidade/epidemiologia , ChinaRESUMO
BACKGROUND: Post-radiation nasopharyngeal necrosis (PRNN) is a severe adverse event following re-radiotherapy for patients with locally recurrent nasopharyngeal carcinoma (LRNPC) and associated with decreased survival. Biological heterogeneity in recurrent tumors contributes to the different risks of PRNN. Radiomics can be used to mine high-throughput non-invasive image features to predict clinical outcomes and capture underlying biological functions. We aimed to develop a radiogenomic signature for the pre-treatment prediction of PRNN to guide re-radiotherapy in patients with LRNPC. METHODS: This multicenter study included 761 re-irradiated patients with LRNPC at four centers in NPC endemic area and divided them into training, internal validation, and external validation cohorts. We built a machine learning (random forest) radiomic signature based on the pre-treatment multiparametric magnetic resonance images for predicting PRNN following re-radiotherapy. We comprehensively assessed the performance of the radiomic signature. Transcriptomic sequencing and gene set enrichment analyses were conducted to identify the associated biological processes. RESULTS: The radiomic signature showed discrimination of 1-year PRNN in the training, internal validation, and external validation cohorts (area under the curve (AUC) 0.713-0.756). Stratified by a cutoff score of 0.735, patients with high-risk signature had higher incidences of PRNN than patients with low-risk signature (1-year PRNN rates 42.2-62.5% vs. 16.3-18.8%, P < 0.001). The signature significantly outperformed the clinical model (P < 0.05) and was generalizable across different centers, imaging parameters, and patient subgroups. The radiomic signature had prognostic value concerning its correlation with PRNN-related deaths (hazard ratio (HR) 3.07-6.75, P < 0.001) and all causes of deaths (HR 1.53-2.30, P < 0.01). Radiogenomics analyses revealed associations between the radiomic signature and signaling pathways involved in tissue fibrosis and vascularity. CONCLUSIONS: We present a radiomic signature for the individualized risk assessment of PRNN following re-radiotherapy, which may serve as a noninvasive radio-biomarker of radiation injury-associated processes and a useful clinical tool to personalize treatment recommendations for patients with LANPC.
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Neoplasias Nasofaríngeas , Recidiva Local de Neoplasia , Humanos , Carcinoma Nasofaríngeo/genética , Estudos Retrospectivos , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/genética , Prognóstico , Neoplasias Nasofaríngeas/diagnóstico por imagem , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Imageamento por Ressonância Magnética/métodosRESUMO
In an orbital angular momentum-shift keying free-space optical (OAM-SK FSO) communication system, precisely recognizing OAM superposed modes at the receiver site is crucial to improve the communication capacity. While deep learning (DL) provides an effective method for OAM demodulation, with the increase of OAM modes, the dimension explosion of OAM superstates results in unacceptable costs on training the DL model. Here, we demonstrate a few-shot-learning-based demodulator to achieve a 65,536-ary OAM-SK FSO communication system. By learning from only 256 classes of samples, the remaining 65,280 unseen classes can be predicted with an accuracy of more than 94%, which saves a large number of resources on data preparation and model training. Based on this demodulator, we first realize the single transmission of a color pixel and the single transmission of two gray scale pixels on the application of colorful-image-transmission in free space with an average error rate less than 0.023%. This work may provide a new, to the best of our knowledge, approach for big data capacity in optical communication systems.
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Ferroptosis, an iron-dependent cell death, is caused by lipid peroxidation. Noteworthily, accumulation of iron and lipid peroxidation are found in the proximity of the neuritic plaque, a hallmark of Alzheimer's disease (AD), but the relationship between ferroptosis and neuroinflammation in AD is unclear. Silibinin, extracted from the Silybum marianum, is possibly developed as an agent for AD treatment from its neuroprotective effect, but the effect of silibinin on sporadic AD that accounts for more than 95% of AD remains unclear. To determine whether silibinin alleviates the pathogenesis of sporadic AD and investigate the underlying mechanisms, STZ-treated HT22 murine hippocampal neurons and intracerebroventricular injection of streptozotocin (ICV-STZ) rats, a sporadic AD model, were used in this study. Results show that silibinin not only promotes survival of STZ-treated HT22 cells, but also ameliorates the cognitive impairment and anxiety/depression-like behavior of ICV-STZ rats. We here demonstrate that silibinin evidently inhibits the protein level of p53 as well as upregulates the protein level of cystine/glutamate antiporter SLC7A11 and ferroptosis inhibitor GPX4, but not p21, leading to the protection against STZ-induced ferroptotic damage. Immunofluorescent staining also shows that accumulation of lipid peroxidation induced by ferroptotic damage leads to increased fluorescence of 8-oxo-deoxyguanosine (8-OHDG), a maker of oxidized DNA. The oxidized DNA then leaks to the cytoplasm and upregulates the expression of the stimulator of interferon gene (STING), which triggers the production of IFN-ß and other inflammatory cascades including NF-κB/TNFα and NLRP3/caspase 1/IL-1ß. However, the treatment with silibinin blocks the above pathological changes. Moreover, in HT22 cells with/without STZ treatment, GPX4-knockdown increases the protein level of STING, indicating that the ferroptotic damage leads to the activation of STING signaling pathway. These results imply that silibinin exerts neuroprotective effect on an STZ-induced sporadic AD model by downregulating ferroptotic damage and thus the downstream STING-mediated neuroinflammation.
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Doença de Alzheimer , Fármacos Neuroprotetores , Ratos , Camundongos , Animais , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Silibina/farmacologia , Silibina/uso terapêutico , Regulação para Baixo , Doenças Neuroinflamatórias , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estreptozocina/efeitos adversos , Modelos Animais de DoençasRESUMO
BACKGROUND: Utilizing the traditional Cox regression model to identify the factors affecting the risk of mortality due to microinvasive cutaneous squamous cell carcinoma (micSCC) may produce skewed results. Since cause-specific mortality can guide clinical decision-making, this study employed the Fine-Gray model based on the Surveillance, Epidemiology, and End Results (SEER) database to identify significant predictive variables for the risk of micSCC-related mortality. METHODS: This study used the information of patients with micSCC who were listed in the SEER database during 2000-2015. Cox regression and Fine-Gray models were utilized for the multivariable analysis, and Gray's test and the cumulative incidence function were used for the univariable analyses. RESULTS: There were 100 patients who died from other reasons and 38 who died from micSCC among the 1259 qualified patients with micSCC. Most were female, white, married, had localized metastasis, etc. According to the univariable Gray's test (P < 0.05), the cumulative incidence rate for events of interest was strongly associated with age, sex, marital status, American Joint Committee on Cancer staging, radiation status, summary stage, chemotherapy status, surgery status, and tumor size. Multivariable Cox regression analysis and multivariable competing-risks analysis indicated that age, tumor size, and income were independent risk variables for the prognosis of patients with micSCC. In both age and tumor size variables, the competing-risks model showed a slight decrease in the hazard ratio and a slight narrowing of the 95% confidence interval compared with the Cox regression model. However, this pattern is not evident in the income variable. CONCLUSIONS: This study established a Fine-Gray model for identifying the independent risk factors that influence the risk of mortality among patients with micSCC. This study uncovers that, in the context of competing risks, age, tumor size, and income serve as independent risk factors influencing the risk of mortality due to micSCC among patients. Our findings have the potential to provide more accurate risk assessments for patient outcomes and contribute to the development of individualized treatment plans.
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Carcinoma de Células Escamosas , Neoplasias Cutâneas , Humanos , Feminino , Masculino , Nomogramas , Carcinoma de Células Escamosas/terapia , Programa de SEER , Prognóstico , Medição de RiscoRESUMO
PURPOSE: The present study aims to determine the rectoanal colonization rate and risk factors for the colonization of present multidrug-resistant bacteria (MDRBs). In addition, the relationship between MDRB colonization and surgical site infection (SSI) following hemorrhoidectomy was explored. METHODS: A cross-sectional study was conducted in the Department of Colorectal Surgery of two hospitals. Patients with hemorrhoid disease, who underwent hemorrhoidectomy, were included. The pre-surgical screening of multidrug-resistant Gram-negative bacteria (MDR-GNB) colonization was performed using rectal swabs on the day of admission. Then, the MDRB colonization rate was determined through the rectal swab. Logistic regression models were established to determine the risk factors for MDRB colonization and SSI after hemorrhoidectomy. A p-value of < 0.05 was considered statistically significant. RESULTS: A total of 432 patients met the inclusion criteria, and the MDRB colonization prevalence was 21.06% (91/432). The independent risk factors for MDRB colonization were as follows: patients who received ≥ 2 categories of antibiotic treatment within 3 months (odds ratio (OR): 3.714, 95% confidence interval (CI): 1.436-9.605, p = 0.007), patients with inflammatory bowel disease (IBD; OR: 6.746, 95% CI: 2.361-19.608, p < 0.001), and patients with high serum uric acid (OR: 1.006, 95% CI: 1.001-1.010, p = 0.017). Furthermore, 41.57% (37/89) of MDRB carriers and 1.81% (6/332) of non-carriers developed SSIs, with a total incidence of 10.21% (43/421). Based on the multivariable model, the rectoanal colonization of MDRBs (OR: 32.087, 95% CI: 12.052-85.424, p < 0.001) and hemoglobin < 100 g/L (OR: 4.130, 95% CI: 1.556-10.960, p = 0.004) were independently associated with SSI after hemorrhoidectomy. CONCLUSION: The rectoanal colonization rate of MDRBs in hemorrhoid patients is high, and this was identified as an independent risk factor for SSI after hemorrhoidectomy.
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Infecções Bacterianas , Hemorroidectomia , Hemorroidas , Humanos , Infecções Bacterianas/microbiologia , Estudos Transversais , Hemorroidectomia/efeitos adversos , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/tratamento farmacológico , Hemorroidas/cirurgia , Hemorroidas/tratamento farmacológico , Ácido Úrico , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Fatores de Risco , Bactérias Gram-NegativasRESUMO
One-dimensional shaped ZnGa2O4, ZnO and ZnGa2O4/ZnO nanofibers were successfully prepared by electrostatic spinning technique and the photocatalytic degradation performance of tetracycline hydrochloride (TC-HCl) were studied. It was found that the S-scheme heterojunction formed in the ZnGa2O4/ZnO could greatly reduce the recombination of the photogenerated carriers and therefore improve the photocatalytic performance. By optimizing the ratio of the ZnGa2O4 and ZnO, the largest degradation rate could reach 0.0573 min-1, which was 20 times of the self-degradation rate of TC-HCl. It was verified that the h+ played the key role in the reactive groups for the high performance decomposition of TC-HCl by capture experiments. This work provides a new method for the highly efficient photocatalytic degradation of TC-HCl.
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Nanofibras , Óxido de Zinco , TetraciclinaRESUMO
Endogenous formaldehyde (FA) is produced in the human body via various mechanisms to preserve healthy energy metabolism and safeguard the organism. However, endogenous FA can have several negative effects on the body through epigenetic alterations, including cancer growth promotion; neuronal, hippocampal and endothelial damages; atherosclerosis acceleration; haemopoietic stem cell destruction and haemopoietic cell production reduction. Certain medications with antioxidant effects, such as glutathione, vitamin E, resveratrol, alpha lipoic acid and polyphenols, lessen the detrimental effects of endogenous FA by reducing oxidative stress, directly scavenging endogenous FA or promoting its degradation. This study offers fresh perspectives for managing illnesses associated with endogenous FA exposure.
RESUMO
In view of the significance of circular RNA (circRNA) in multiple carcinogeneses, our study focused on circ_0060937 and investigated its function and molecular mechanism in lung cancer. Quantitative real-time PCR (qPCR) and western blot assays were applied for expression analysis of circ_0060937, miR-1304-5p, LAD1, and several marker proteins. Functional experiments, including colony formation assay, EdU assay, transwell analysis, sphere formation assay, and flow cytometry experiment, were conducted for cell behavior analysis. The putative binding relationship between circ_0060937 and miR-1304-5p was validated by dual-luciferase reporter experiment and pull-down analysis. Animal models were established to ascertain the role of circ_0060937. Upregulation of circ_0060937 was shown in lung cancer tissues and cell lines. Circ_0060937 downregulation repressed A549 and H1299 cell proliferative, migratory, invasive, and sphere formation abilities, and circ_0060937 absence also decelerated tumorigenesis in animal models. Circ_0060937 bound to miR-1304-5p to positively regulate LAD1 expression. The inhibitory effects of circ_0060937 absence on A549 and H1299 cell malignant behaviors were largely reversed by miR-1304-5p inhibition or LAD1 overexpression, hinting that circ_0060937 affected lung cancer progression via modulating the miR-1304-5p/LAD1 axis. Circ_0060937 downregulation decreased the expression of LAD1 by releasing miR-1304-5p to effectively repress lung cancer cell growth and in vivo tumorigenesis.
Assuntos
Neoplasias Pulmonares , MicroRNAs , Animais , Neoplasias Pulmonares/genética , Carcinogênese , Linhagem Celular , Movimento Celular , Proliferação de Células , MicroRNAs/genéticaRESUMO
A novel particle combined electrode named TiO2/g-C3N4@AC (TGCN-AC) was prepared by loading TiO2 and g-C3N4 on activated carbon through gel method, which was used to degrade levofloxacin (LEF) in pharmaceutical wastewater by photoelectric process. The remarkable physicochemical features of particle electrodes were verified by using diverse characterization techniques including SEM-EDS, XRD, FT-IR, BET and pHZPC. EIS-CV and photocurrent showed excellent electrocatalysis and photoelectrocatalysis performance of particle electrodes. The photocatalytic characteristics and fluorescence properties of the particle electrode were proved by UV-vis DRS and PL spectra measurements. Combined with Tauc's plot and Mott-Schottky plots curves, the ECB and EVB of particle electrodes were determined. The experiments on different influence factors such as pH, ultrasonic, aeration, current density and the concentration of LEF were carried out in the photoelectric reactor. Under the conditions of pH values 3.0, 200 W ultrasonic, 8 L/min aeration, the mass ratio of g-C3N4 and TiO2 is 8%, after 4.0 h of photoelectric process, about 94.76% of LEF (20 mg/L) in water was degraded. TGCN-AC also has excellent reusability. The degradation rate of LEF can still reach 71.17% after repeated use for 6 times. Scavenger studies showed that h+ and O2- were the main active species. By observing the colony size of E. coli, it was proved that the LEF in the effluent had no antibacterial activity. The degradation pathways of LEF was analyzed and drawn by HPLC-MS spectra.