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INTRODUCTION: Hair cortisol concentration (HCC) is a biomarker of long-term stress. Higher HCC is associated with higher adiposity in adults; however, associations are not well characterized in adolescents. OBJECTIVE: To examine cross-sectional associations of HCC with adiposity in late adolescence. METHODS: Amongst 336 non-Hispanic White participants (48.5% female, mean 17.7 years) in Project Viva, we used multivariable linear regression models, overall and sex-stratified, to estimate associations of HCC with body mass index (BMI), bioelectric impedance (BIA) percent body fat, waist circumference (WC) and dual X-ray absorptiometry-measured percent and total fat or trunk fat mass. We adjusted models for age and known predictors of adiposity. RESULTS: Median (interquartile range) HCC was 2.1 pm/mg (1.0-4.5) and mean (SD) BMI was 23.1 kg/m2 (3.9), BIA %body fat 20.2% (9.9) and WC 80.6 cm (10.9). In adjusted models, higher HCC (per doubling) was associated with higher BMI (ß = 0.19 kg/m2; 95%CI 0.00, 0.37) and BIA percent body fat (ß = 0.41%; 95%CI 0.04, 0.77). We observed no evidence of effect modification by sex. CONCLUSIONS: Higher HCC was associated with greater adiposity in late adolescence. Further research is needed to disentangle the relationship between HCC and adolescent adiposity, including the temporal direction of the relationship and sex-specific associations.
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Background: The rate at which the anticancer drug paclitaxel is cleared from the body markedly impacts its dosage and chemotherapy effectiveness. Importantly, paclitaxel clearance varies among individuals, primarily because of genetic polymorphisms. This metabolic variability arises from a nonlinear process that is influenced by multiple single nucleotide polymorphisms (SNPs). Conventional bioinformatics methods struggle to accurately analyze this complex process and, currently, there is no established efficient algorithm for investigating SNP interactions. Methods: We developed a novel machine-learning approach called GEP-CSIs data mining algorithm. This algorithm, an advanced version of GEP, uses linear algebra computations to handle discrete variables. The GEP-CSI algorithm calculates a fitness function score based on paclitaxel clearance data and genetic polymorphisms in patients with nonsmall cell lung cancer. The data were divided into a primary set and a validation set for the analysis. Results: We identified and validated 1184 three-SNP combinations that had the highest fitness function values. Notably, SERPINA1, ATF3 and EGF were found to indirectly influence paclitaxel clearance by coordinating the activity of genes previously reported to be significant in paclitaxel clearance. Particularly intriguing was the discovery of a combination of three SNPs in genes FLT1, EGF and MUC16. These SNPs-related proteins were confirmed to interact with each other in the protein-protein interaction network, which formed the basis for further exploration of their functional roles and mechanisms. Conclusion: We successfully developed an effective deep-learning algorithm tailored for the nuanced mining of SNP interactions, leveraging data on paclitaxel clearance and individual genetic polymorphisms.
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Oxygen-mediated triplet-triplet annihilation upconversion (TTA-UC) quenching limits the application of such organic upconversion materials. Here, we report that the photooxidation of organic amines is an effective and versatile strategy to suppress oxygen-mediated upconversion quenching in both organic solvents and aqueous solutions. The strategy is based on the dual role of organic amines in photooxidation, i.e., as singlet oxygen scavengers and electron donors. Under photoexcitation, the photosensitizer sensitizes oxygen to produce singlet oxygen for the oxidation of alkylamine, reducing the oxygen concentration. However, photoinduced electron transfer among photosensitizers, organic amines, and oxygen leads to the production of superoxide anions that suppress TTA-UC. To observe oxygen-tolerating TTA-UC, we find that alkyl secondary amines can balance the production of singlet oxygen and superoxide anions. We then utilize polyethyleneimine (PEI) to synthesize amphiphilic polymers to encapsulate TTA-UC pairs for the formation of water-dispersible, ultrasmall, and multicolor-emitting TTA-UC nanoparticles.
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OBJECTIVE: To investigate the effects of astragaloside IV (AS-IV) on podocyte injury of diabetic nephropathy (DN) and reveal its potential mechanism. METHODS: In in vitro experiment, podocytes were divided into 4 groups, normal, high glucose (HG), inositol-requiring enzyme 1 (IRE-1) α activator (HG+thapsigargin 1 µmol/L), and IRE-1α inhibitor (HG+STF-083010, 20 µmol/L) groups. Additionally, podocytes were divided into 4 groups, including normal, HG, AS-IV (HG+AS-IV 20 µmol/L), and IRE-1α inhibitor (HG+STF-083010, 20 µmol/L) groups, respectively. After 24 h treatment, the morphology of podocytes and endoplasmic reticulum (ER) was observed by electron microscopy. The expressions of glucose-regulated protein 78 (GRP78) and IRE-1α were detected by cellular immunofluorescence. In in vivo experiment, DN rat model was established via a consecutive 3-day intraperitoneal streptozotocin (STZ) injections. A total of 40 rats were assigned into the normal, DN, AS-IV [AS-IV 40 mg/(kg·d)], and IRE-1α inhibitor [STF-083010, 10 mg/(kg·d)] groups (n=10), respectively. The general condition, 24-h urine volume, random blood glucose, urinary protein excretion rate (UAER), urea nitrogen (BUN), and serum creatinine (SCr) levels of rats were measured after 8 weeks of intervention. Pathological changes in the renal tissue were observed by hematoxylin and eosin (HE) staining. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect the expressions of GRP78, IRE-1α, nuclear factor kappa Bp65 (NF-κBp65), interleukin (IL)-1ß, NLR family pyrin domain containing 3 (NLRP3), caspase-1, gasdermin D-N (GSDMD-N), and nephrin at the mRNA and protein levels in vivo and in vitro, respectively. RESULTS: Cytoplasmic vacuolation and ER swelling were observed in the HG and IRE-1α activator groups. Podocyte morphology and ER expansion were improved in AS-IV and IRE-1α inhibitor groups compared with HG group. Cellular immunofluorescence showed that compared with the normal group, the fluorescence intensity of GRP78 and IRE-1α in the HG and IRE-1α activator groups were significantly increased whereas decreased in AS-IV and IRE-1α inhibitor groups (P<0.05). Compared with the normal group, the mRNA and protein expressions of GRP78, IRE-1α, NF-κ Bp65, IL-1ß, NLRP3, caspase-1 and GSDMD-N in the HG group was increased (P<0.05). Compared with HG group, the expression of above indices was decreased in the AS-IV and IRE-1α inhibitor groups, and the expression in the IRE-1α activator group was increased (P<0.05). The expression of nephrin was decreased in the HG group, and increased in AS-IV and IRE-1α inhibitor groups (P<0.05). The in vivo experiment results revealed that compared to the normal group, the levels of blood glucose, triglyceride, total cholesterol, BUN, blood creatinine and urinary protein in the DN group were higher (P<0.05). Compared with DN group, the above indices in AS-IV and IRE-1α inhibitor groups were decreased (P<0.05). HE staining revealed glomerular hypertrophy, mesangial widening and mesangial cell proliferation in the renal tissue of the DN group. Compared with the DN group, the above pathological changes in renal tissue of AS-IV and IRE-1α inhibitor groups were alleviated. Quantitative RT-PCR and Western blot results of GRP78, IRE-1α, NF-κ Bp65, IL-1ß, NLRP3, caspase-1 and GSDMD-N were consistent with immunofluorescence analysis. CONCLUSION: AS-IV could reduce ERS and inflammation, improve podocyte pyroptosis, thus exerting a podocyte-protective effect in DN, through regulating IRE-1α/NF-κ B/NLRP3 signaling pathway.
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BACKGROUND: Hypertensive disorders of pregnancy (HDP) such as preeclampsia and gestational hypertension are major contributors to maternal and child morbidity and mortality. Previous studies have reported associations with selected metals and vitamins but are limited in sample size and non-prospective study designs. We evaluated prospective associations of metal mixtures with HDP and tested interactions by vitamins. STUDY DESIGN: We measured first trimester (median = 10.1 weeks) concentrations of essential (copper, magnesium, manganese, selenium, zinc) and nonessential (arsenic, barium, cadmium, cesium, mercury, lead) metals in red blood cells (n = 1,386) and vitamins (B12 and folate) in plasma (n = 924) in Project Viva, a pre-birth US cohort. We collected diagnosis of HDP by reviewing medical records. We used multinomial logistic regression and Bayesian Kernel Machine Regression to estimate individual and joint associations of metals with HDP and interactions by vitamins, after adjusting for key covariates. RESULTS: The majority of participants were non-Hispanic white (72.5 %), never smokers (68.5 %) with a mean (SD) age of 32.3 (4.6) years. Fifty-two (3.8 %) developed preeclampsia and 94 (6.8 %) gestational hypertension. A doubling in first trimester erythrocyte copper was associated with 78 % lower odds of preeclampsia (OR=0.22, 95 % confidence interval: 0.08, 0.60). We also observed significant associations between higher erythrocyte total arsenic and lower odds of preeclampsia (OR=0.80, 95 % CI: 0.66, 0.97) and higher vitamin B12 and increased odds of gestational hypertension (OR=1.79, 95 % CI: 1.09, 2.96), but associations were attenuated after adjustment for dietary factors. Lower levels of the overall metal mixture and essential metal mixture were associated with higher odds of preeclampsia. We found no evidence of interactions by prenatal vitamins or between metals. CONCLUSION: Lower levels of a first-trimester essential metal mixture were associated with an increased risk of preeclampsia, primarily driven by copper. No associations were observed between other metals and HDP after adjustment for confounders and diet.
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The diagnosis of disease biomarkers is crucial for the identification, monitoring, and prognostic assessment of malignant disease. However, biological samples with autofluorescence, complex components, and heterogeneity pose major challenges to reliable biosensing. Here, we report the self-assembly of natural proteins and the triplet-triplet annihilation upconversion (TTA-UC) pair to form upconverted protein clusters (â¼8.2 ± 1.1 nm), which were further assembled into photon upconversion supramolecular assemblies (PUSA). This PUSA exhibited unique features, including a small size (â¼44.1 ± 4.1 nm), oxygen tolerance, superior biocompatibility, and easy storage via lyophilization, all of which are long sought after for photon upconversion materials. Further, we have revealed that the steric hindrance of the annihilator suppresses the stacking of the annihilator in PUSA, which is vital for maintaining the water dispersibility and enhancing the upconversion performance of PUSA. In conjunction with sarcosine oxidase, this near infrared (NIR)-excitable PUSA nanoprobe could perform background-free biosensing of urinary sarcosine, which is a common biomarker for prostatic carcinoma (PCa). More importantly, this nanoprobe not only allows for qualitative identification of urinary samples from PCa patients by the unaided eye under NIR-light-emitting diode (LED) illumination but also quantifies the concentration of urinary sarcosine. These remarkable findings have propelled photon upconversion materials to a new evolutionary stage and expedited the progress of upconversion biosensing in clinical diagnostics.
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Técnicas Biossensoriais , Fótons , Humanos , Sarcosina/urina , Sarcosina/química , Sarcosina Oxidase/química , Proteínas/análise , Proteínas/químicaRESUMO
BACKGROUND: N6-methyladenosine (m6A) methylation modification exists in Epstein-Barr virus (EBV) primary infection, latency, and lytic reactivation. It also modifies EBV latent genes and lytic genes. EBV-associated gastric cancer (EBVaGC) is a distinctive molecular subtype of GC. We hypothesized EBV and m6A methylation regulators interact with each other in EBVaGC to differentiate it from other types of GC. AIM: To investigate the mechanisms of m6A methylation regulators in EBVaGC to determine the differentiating factors from other types of GC. METHODS: First, The Cancer Gene Atlas and Gene Expression Omnibus databases were used to analyze the expression pattern of m6A methylation regulators between EBVaGC and EBV-negative GC (EBVnGC). Second, we identified Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment of m6A-related differentially expressed genes. We quantified the relative abundance of immune cells and inflammatory factors in the tumor microenvironment (TME). Finally, cell counting kit-8 cell proliferation test, transwell test, and flow cytometry were used to verify the effect of insulin-like growth factor binding protein 1 (IGFBP1) in EBVaGC cell lines. RESULTS: m6A methylation regulators were involved in the occurrence and development of EBVaGC. Compared with EBVnGC, the expression levels of m6A methylation regulators Wilms tumor 1-associated protein, RNA binding motif protein 15B, CBL proto-oncogene like 1, leucine rich pentatricopeptide repeat containing, heterogeneous nuclear ribonucleoprotein A2B1, IGFBP1, and insulin-like growth factor 2 binding protein 1 were significantly downregulated in EBVaGC (P < 0.05). The overall survival rate of EBVaGC patients with a lower expression level of IGFBP1 was significantly higher (P = 0.046). GO and KEGG functional enrichment analyses showed that the immunity pathways were significantly activated and rich in immune cell infiltration in EBVaGC. Compared with EBVnGC, the infiltration of activated CD4+ T cells, activated CD8+ T cells, monocytes, activated dendritic cells, and plasmacytoid dendritic cells were significantly upregulated in EBVaGC (P < 0.001). In EBVaGC, the expression level of proinflammatory factors interleukin (IL)-17, IL-21, and interferon-γ and immunosuppressive factor IL-10 were significantly increased (P < 0.05). In vitro experiments demonstrated that the expression level of IGFBP1 was significantly lower in an EBVaGC cell line (SNU719) than in an EBVnGC cell line (AGS) (P < 0.05). IGFBP1 overexpression significantly attenuated proliferation and migration and promoted the apoptosis levels in SNU719. Interfering IGFBP1 significantly promoted proliferation and migration and attenuated the apoptosis levels in AGS. CONCLUSION: m6A regulators could remodel the TME of EBVaGC, which is classified as an immune-inflamed phenotype and referred to as a "hot" tumor. Among these regulators, we demonstrated that IGFBP1 affected proliferation, migration, and apoptosis.
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Lithium (Li) dendritic growth and huge volume expansion seriously hamper Li-metal anode development. Herein, we design a lightweight 3D Li-ion-affinity host enabled by silver (Ag) nanoparticles fully decorating a porous melamine sponge (Ag@PMS) for dendrite-free and high-areal-capacity Li anodes. The compact Ag nanoparticles provide abundant preferred nucleation sites and give the host strong conductivity. Moreover, the high specific surface area and polar groups of the elastic, porous melamine sponge enhance the Li-ion diffusion kinetics, prompting homogeneity of Li deposition and stripping. As expected, the integrated 3D Ag@PMS-Li anode delivered a remarkable electrochemical performance, with a Coulombic efficiency (CE) of 97.14% after 450 cycles at 1 mA cm-2. The symmetric cell showed an ultralong lifespan of 3400 h at 1 mA cm-2 for 1 mAh cm-2. This study provides a facile and cost-effective strategy to design an advanced 3D framework for the preparation of a stable dendrite-free Li metal anode.
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We report herein a visible-light induced, Fe-catalyzed selenocyclization of 2-ethynylanilines with diselenides under ambient conditions, employing ethyl acetate as a benign solvent with no stoichiometric additive required. The simple iron salt FeBr3 serves as both a photo-induced LMCT (Ligand-to-Metal Charge Transfer) catalyst and a Lewis acid catalyst to promote the desired transformation in a sustainable manner, enabling the facile synthesis of diverse 3-selenylindoles with extended substitution patterns. Moreover, gram-scale reactions and late-stage functionalization of bioactive molecules further highlight the synthetic practicality of this method.
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The parameter setting of functional electrical stimulation (FES) is important for active recovery training since it affects muscle health. Among the FES parameters, current amplitude is the most influential factor. To explore the FES effect on the maximum stimulation time, this study establishes a curve between FES current amplitude and the maximum stimulation time based on muscle fatigue. We collect 10 subjects' surface electromyography under dumbbell weightlifting training and analyze the muscle fatigue state by calculating the root mean square (RMS) of power. By analyzing signal RMS, the fatigue characteristic curves under different fatigue levels are obtained. According to the muscle response under FES, the relationship curve between the current amplitude and the maximum stimulation time is established and FES parameters' effect on the maximum stimulation time is obtained. The linear curve provides a reference for FES parameter setting, which can help to set stimulation time safely, thus preventing the muscles from entering an excessive fatigue state and becoming more active to muscle recovery training.
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Global climate change has led to shifts in the distribution ranges of many terrestrial species, promoting their migration from lower altitudes or latitudes to higher ones. Meanwhile, successful invaders have developed genetic adaptations enabling the colonization of new environments. Over the past 40â years, Rattus tanezumi (RT) has expanded into northern China (Northwest and North China) from its southern origins. We studied the cold adaptation of RT and its potential for northward expansion by comparing it with sympatric Rattus norvegicus (RN), which is well adapted to cold regions. Through population genomic analysis, we revealed that the invading RT rats have split into three distinct populations: the North, Northwest, and Tibetan populations. The first two populations exhibited high genetic diversity, while the latter population showed remarkably low genetic diversity. These rats have developed various genetic adaptations to cold, arid, hypoxic, and high-UV conditions. Cold acclimation tests revealed divergent thermoregulation between RT and RN. Specifically, RT exhibited higher brown adipose tissue activity and metabolic rates than did RN. Transcriptome analysis highlighted changes in genes regulating triglyceride catabolic processes in RT, including Apoa1 and Apoa4, which were upregulated, under selection and associated with local adaptation. In contrast, RN showed changes in carbohydrate metabolism genes. Despite the cold adaptation of RT, we observed genotypic and phenotypic constraints that may limit its ability to cope with severe low temperatures farther north. Consequently, it is less likely that RT rats will invade and overlap with RN rats in farther northern regions.
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Aclimatação , Temperatura Baixa , Animais , Ratos , Aclimatação/genética , China , Fenótipo , Variação Genética , Adaptação Fisiológica/genética , Regulação da Temperatura Corporal/genética , Mudança ClimáticaRESUMO
Breast cancer is one of the most common malignant tumors in women and is a serious threat to women's health. The pentose phosphate pathway (PPP) is a mode of oxidative breakdown of glucose that can be divided into oxidative (oxPPP) and non-oxidative (non-oxPPP) stages and is necessary for cell and body survival. However, abnormal activation of PPP often leads to proliferation, migration, invasion, and chemotherapy resistance in breast cancer. Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in PPP oxidation. Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) produced by G6PD is the raw material for cholesterol and lipid synthesis and can resist the production of oxygen species (ROS) and reduce oxidative stress damage to tumor cells. Transketolase (TKT) is a key enzyme in non-oxPPP. Ribose 5-phosphate (R5P), produced by TKT, is a raw material for DNA and RNA synthesis, and is essential for tumor cell proliferation and DNA damage repair. In this review, we describe the role and specific mechanism of the PPP and the two most important enzymes of the PPP, G6PD and TKT, in the malignant progression of breast cancer, providing strategies for future clinical treatment of breast cancer and a theoretical basis for breast cancer research.
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Neoplasias da Mama , Progressão da Doença , Glucosefosfato Desidrogenase , Via de Pentose Fosfato , Transcetolase , Transcetolase/metabolismo , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Glucosefosfato Desidrogenase/metabolismo , Via de Pentose Fosfato/efeitos dos fármacos , AnimaisRESUMO
With the development of renewable energy technologies, the demand for efficient energy storage systems is growing. Supercapacitors have attracted considerable attention as efficient electrical energy storage devices because of their excellent power density, fast charging and discharging capabilities, and long cycle life. Carbon nanofibers are widely used as electrode materials in supercapacitors because of their excellent mechanical properties, electrical conductivity, and light weight. Although environmental factors are increasingly driving the application of circular economy concepts in materials science, lignin is an underutilized but promising environmentally benign electrode material for supercapacitors. Lignin-based carbon nanofibers are ideal for preparing high-performance supercapacitor electrode materials owing to their unique chemical stability, abundance, and environmental friendliness. Electrospinning is a well-known technique for producing large quantities of uniform lignin-based nanofibers, and is the simplest method for the large-scale production of lignin-based carbon nanofibers with specific diameters. This paper reviews the latest research progress in the preparation of lignin-based carbon nanofibers using the electrospinning technology, discusses the prospects of their application in supercapacitors, and analyzes the current challenges and future development directions. This is expected to have an enlightening effect on subsequent research.
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Carbono , Capacitância Elétrica , Lignina , Nanofibras , Lignina/química , Nanofibras/química , Carbono/química , Eletrodos , Técnicas Eletroquímicas/métodosRESUMO
BACKGROUND: The coronary artery disease-reporting and data system (CAD-RADS) 2.0 is used to standardize the reporting of coronary computed tomography angiography (CCTA) results. Artificial intelligence software can quantify the plaque composition, fat attenuation index, and fractional flow reserve. OBJECTIVE: To analyze plaque features of varying severity in patients with a combination of CAD-RADS stenosis and plaque burden categorization and establish a random forest classification model. METHODS: The data of 100 patients treated between April 2021 and February 2022 were retrospectively collected. The most severe plaque observed in each patient was the target lesion. Patients were categorized into three groups according to CAD-RADS: CAD-RADS 1-2 + P0-2, CAD-RADS 3-4B + P0-2, and CAD-RADS 3-4B + P3-4. Differences and correlations between variables were assessed between groups. AUC, accuracy, precision, recall, and F1 score were used to evaluate the diagnostic performance. RESULTS: A total of 100 patients and 178 arteries were included. The differences of computed tomography fractional flow reserve (CT-FFR) (H = 23.921, p < 0.001), the volume of lipid component (H = 12.996, p = 0.002), the volume of fibro-lipid component (H = 8.692, p = 0.013), the proportion of lipid component volume (H = 22.038, p < 0.001), the proportion of fibro-lipid component volume (H = 11.731, p = 0.003), the proportion of calcification component volume (H = 11.049, p = 0.004), and plaque type (χ2 = 18.110, p = 0.001) was statistically significant. CONCLUSION: CT-FFR, volume and proportion of lipid and fibro-lipid components of plaques, the proportion of calcified components, and plaque type were valuable for CAD-RADS stenosis + plaque burden classification, especially CT-FFR, volume, and proportion of lipid and fibro-lipid components. The model built using the random forest was better than the clinical model (AUC: 0.874 vs. 0.647).
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Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana , Estenose Coronária , Vasos Coronários , Reserva Fracionada de Fluxo Miocárdico , Placa Aterosclerótica , Índice de Gravidade de Doença , Humanos , Masculino , Feminino , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Estudos Retrospectivos , Angiografia por Tomografia Computadorizada/métodos , Pessoa de Meia-Idade , Angiografia Coronária/métodos , Estenose Coronária/fisiopatologia , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/diagnóstico , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/fisiopatologia , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/fisiopatologia , IdosoRESUMO
MicroRNA and mitofusin-2 (Mfn2) play an important role in the myocardial apoptosis induced by acute myocardial infarction (AMI). However, the target relationship and underlying mechanism associated with interorganelle interaction between endoplasmic reticulum (ER) and mitochondria under ischemic condition is not completely clear. MI-induced injury, Mfn2 expression, Mfn2-mediated mitochondrial function and ER stress, and target regulation by miRNA-15b (miR-15b) were evaluated by animal MI and cellular hypoxic models with advanced molecular techniques. The results confirmed that Mfn2 was down-regulated and miR-15b was up-regulated upon the target binding profile under ischemic/hypoxic condition. Our data showed that miR-15b caused cardiac apoptotic injury that was reversed by rAAV9-anti-miR-15b or AMO-15b. The damage effect of miR-15b on Mfn2 expression and mitochondrial function was observed and rescued by rAAV9-anti-miR-15b or AMO-15b. The targeted regulation of miR-15b on Mfn2 was verified by luciferase reporter and microRNA-masking. Importantly, miR-15b-mediated Mfn2 suppression activated PERK/CHOP pathway, by which leads to ER stress and mitochondrial dysfunction, and cardiac apoptosis eventually. In conclusion, our research, for the first time, revealed the missing molecular link in Mfn2 and apoptosis and elucidated that pro-apoptotic miR-15b plays crucial roles during the pathogenesis of AMI through down-regulation of Mfn2 and activation of PERK-mediated ER stress. These findings may provide an opportunity to develop new therapies for prophylaxis and treatment of ischemic heart disease.
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GTP Fosfo-Hidrolases , MicroRNAs , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Masculino , eIF-2 Quinase/metabolismo , eIF-2 Quinase/genética , eIF-2 Quinase/antagonistas & inibidores , Transdução de Sinais/fisiologia , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/genética , Isquemia Miocárdica/patologia , Camundongos , Estresse do Retículo Endoplasmático/fisiologia , Estresse do Retículo Endoplasmático/genética , Apoptose , Camundongos Endogâmicos C57BLRESUMO
Glacial changes are crucial to regional water resources and ecosystems in the Sawir Mountains. However, glacial changes, including the mass balance and glacial meltwater of the Sawir Mountains, have sparsely been reported. Three model calibration strategies were constructed including a regression model based on albedo and in-situ mass balance of Muz Taw Glacier (A-Ms), regression model based on albedo and geodetic mass balance of valley, cirque, and hanging glaciers (A-Mr), and degree-day model (DDM) to obtain a reliable glacier mass balance in the Sawir Mountains and provide the latest understanding in the contribution of glacial meltwater runoff to regional water resources. The results indicated that the glacial albedo reduction was significant from 2000 to 2020 for the entire Sawir Mountains, with a rate of 0.015 (10a)-1, and the spatial pattern was higher in the east compared to the west. Second, the three strategies all indicated that the glacier mass balance has been continuously negative during the past 20 periods, and the average annual glacier mass balance was -1.01 m w.e. Third, the average annual glacial meltwater runoff in the Sawir Mountains from 2000 to 2020 was 22 × 106 m3, and its contribution to streamflow was 25.81 % from 2000 to 2018. The glacier contribution rates in the Ulkun- Ulastu, Lhaster, and Kendall River basins were 31.37 %, 22.51 %, and 19.27 %, respectively.
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PURPOSE: The purpose of the study was to evaluate the expression and function of basic leucine zipper ATF-like transcription factor (BATF) in colorectal cancer (CRC), and its correlation with 2-deoxy-2[18F]fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) parameters. METHODS: The TIMER database, GEPIA database, TCGA, and GEO database were used to analyze the expression profile of BATF in human cancers. The reverse transcriptionquantitative PCR and western blot analyses were used to evaluate the mRNA level and protein expression in different CRC cell lines. The expression of BATF in SW620 and HCT116 cells was silenced and cell counting kit-8 assays and clonogenic assay were utilized to evaluate the role of BATF in CRC proliferation. The expression of tumor BATF and glucose transporter 1 (GLUT-1) were examined using immunohistochemical tools in 37 CRC patients undergoing preoperative 18F-FDG PET/CT imaging. The correlation between the PET/CT parameters and immunohistochemical result was evaluated. RESULTS: In database, BATF was highly expressed in pan-cancer analyses, including CRC, and was associated with poor prognosis in CRC. In vitro, the results showed that knocking down of BATF expression could inhibit the proliferation of SW620 and HCT116 cells. In CRC patients, BATF expression was upregulated in tumor tissues compared with matched para-tumoral tissues, and was related with gender and Ki-67 levels. BATF expression was positively related to GLUT-1 expression and PET/CT parameters, including tumor size, maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis. The multiple logistic analyses showed that SUVmax was an independent predictor of BATF expression. With 15.96 g/cm3 as the cutoff, sensitivity was 85.71%, specificity 82.61%, and area-under-the-curve 0.854. CONCLUSION: BATF may be an oncogene associated with 18F-FDG PET/CT parameters in CRC. SUVmax may be an independent predictor of BATF expression.
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Fatores de Transcrição de Zíper de Leucina Básica , Proliferação de Células , Neoplasias Colorretais , Progressão da Doença , Fluordesoxiglucose F18 , Regulação Neoplásica da Expressão Gênica , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Fluordesoxiglucose F18/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Feminino , Masculino , Linhagem Celular Tumoral , Pessoa de Meia-Idade , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 1/genética , IdosoRESUMO
Chlortoluron (CTU) is an herbicide extensively used in agricultural settings for crop cultivation. Its presence in water has been identified as a pollutant detrimental to aquatic species. The objective of the present study was to explore the metabolic activation and hepatotoxicity of CTU. Through human and rat liver microsomal incubations supplemented with CTU, nicotinamide adenine dinucleotide phosphate (NADPH), and either glutathione or N-acetyl cysteine, a benzylic alcohol metabolite (M1) was discerned, alongside a phenol metabolite (M2), a glutathione conjugate (M3), and an N-acetyl cysteine conjugate (M4). In rats exposed to CTU, biliary M3 and urinary M4 were detected in their bile and urine, respectively. The generation of M1 was detected in the presence of NADPH. The observation of M3 and M4 suggests the formation of an iminoquinone methide intermediate arising from the oxidation of M1. CYP3A4 was found to be the principal enzyme catalyzing the metabolic activation of CTU. Furthermore, CTU exhibited cytotoxic properties in cultured rat primary hepatocytes in a concentration-dependent pattern. Concomitant treatment of hepatocytes with ketoconazole mitigated their susceptibility to the cytotoxic effects of CTU.
Assuntos
Citocromo P-450 CYP3A , Hepatócitos , Microssomos Hepáticos , Animais , Ratos , Citocromo P-450 CYP3A/metabolismo , Humanos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Ratos Sprague-Dawley , Ativação Metabólica , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Estrutura Molecular , Herbicidas/toxicidade , Herbicidas/metabolismo , Relação Dose-Resposta a DrogaRESUMO
Rattus species are thought to live only at altitudes less than 2500 m, but the Asian house rat (R. tanezumi) (RT) has recently expanded to altitudes greater than 3500 m in China. Other Rattus species, especially brown rats (R. norvegicus) (RN), still reach only low altitudes on the Tibetan Plateau. Comparative genomics revealed the positive selection of hypoxia-inducible transcription factors 1 and 2 (HIFs) in RT, with the rapid evolution of HIF pathway genes in RT and Mus musculus (MM) but not RN or R. rattus. Population genomics revealed that genes associated with energy metabolism and oxygen transport were positively selected in RT compared with the other four Rattus species, and two specific substitutions (arginine 31 serine and leucine 33 methionine) were identified in the hemoglobin subunit beta (HBB) in RT. The above results suggested that RT possesses unique genetic adaptations to hypoxia, which was further confirmed by behavioral experiments on RT and RN. Normobaric hypoxia significantly reduced locomotion in RN but not in RT. Moreover, through intraspecific transcriptome analysis, the expression of Hbb and genes related to angiogenesis, oxygen transport, and glycolysis was upregulated, and the expression of genes associated with immunological functions in the liver, lungs, and/or sperm was downregulated in RT compared to those in RN. Interspecific transcriptome analysis further revealed that HIF-1α plays a role in modulating the hypoxic adaptation of RT rather than RN. Our work provides genomic, behavioral, and physiological insights into why RT, but not other Rattus species, could invade the Tibetan Plateau.
RESUMO
Amitriptyline (ATL), a tricyclic antidepressant, has been reported to cause various adverse effects, particularly hepatotoxicity. The mechanisms of ATL-induced hepatotoxicity remain unknown. The study was performed to identify the olefin epoxidation metabolite of ATL and determine the possible toxicity mechanism. Two glutathione (GSH) conjugates (M1 and M2) and two N-acetylcysteine (NAC) conjugates (M3 and M4) were detected in rat liver microsomal incubations supplemented with GSH and NAC, respectively. Moreover, M1/M2 and M3/M4 were respectively found in ATL-treated rat primary hepatocytes and in bile and urine of rats given ATL. Recombinant P450 enzyme incubations demonstrated that CYP3A4 was the primary enzyme involved in the olefin epoxidation of ATL. Treatment of hepatocytes with ATL resulted in significant cell death. Inhibition of CYP3A attenuated the susceptibility to the observed cytotoxicity of ATL. The metabolic activation of ATL most likely participates in the cytotoxicity of ATL.