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PURPOSE: The abnormal central glucose metabolism in Alzheimer's disease (AD) is related to the brain-gut axis. This study aims to explore the target of Danggui-Shaoyao-San (DSS) in improving cognitive impairment. METHOD: This study analyzed the differences in mice intestinal flora by 16S rRNA sequencing. The cognitive protective effects of DSS were observed through the Morris water maze and the new object recognition. The mitigation effects of DSS on Aß and p-tau, regulatory effects on glucose metabolism targets, and intestinal structure effects were observed through brain and colon slices staining. The differences in neural ultrastructure were compared by transmission electron microscopy. FINDING: The results showed that DSS affected the composition of intestinal dominant bacteria and bacteria genera and regulated the abundance of intestinal bacteria in AD mice. DSS improved the behavior of AD mice, alleviated the deposition of AD pathological products in the brain and colon, regulated the expression of glycometabolism-related proteins, and improved the colon barrier structure and neural ultrastructure in the brain of mice with AD. CONCLUSION: Our findings suggest that DSS may affect AD central glucose metabolism and improve cognition by regulating the gut-brain axis.
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Doença de Alzheimer , Disfunção Cognitiva , Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Camundongos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Masculino , Modelos Animais de Doenças , Eixo Encéfalo-Intestino/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismoRESUMO
Rapid tissue reconstruction in acute and chronic injuries are challengeable, the inefficient repair mainly due to the difficulty in simultaneous promoting the regeneration of peripheral nerves and vascular, which are closely related. Main clinical medication strategy of tissue repair depends on different cytokines to achieve nerves, blood vessels or granulation tissue regeneration, respectively. However, their effect is still limited to single aspect with biorisk exists upon long-time use. Herein, for the first time, we have demonstrated that NA isolated from Malania oleifera has potential to simultaneously promote both neurogenesis and angiogenesis in vitro and in vivo. First, NA was identified by NMR and FTIR structural characterization analysis. In a model of oxidative stress in neural cells induced by hydrogen peroxide, the cells viability of RSC96 and PC12 were protected from oxidative stress injury by NA. Similarly, based on the rat wound healing model, effective blood vessel formation and wound healing can be observed in tissue staining under NA treatment. In addition, according to the identification of nerve and vascular related markers in the wound tissue, the mechanism of NA promoting nerve regeneration lies in the upregulation of the secretion NGF, NF-200 and S100 protein, and NA treatment was also able to up-regulate VEGF and CD31 to directly promote angiogenesis during wound healing. This study provides an important candidate drug molecules for acute or chronic wound healing and nerve vascular synchronous regeneration.
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Aim: CircRNAs have been identified as crucial regulators in tumorigenesis and progression. This study aimed to explore the biological role and underlying mechanism of circ_0084615 in hepatocellular carcinoma (HCC). Methods: The expression of RNAs was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The effects of circ_0084615 silencing on malignant behaviors of HCC cells were assessed by CCK-8, colony formation, wound healing, and Transwell assays in vitro and tumor transplantation experiment in vivo. The expression of proteins was detected by Western blotting. Dual-luciferase reporter assay and RNA-binding protein immunoprecipitation were performed to explore the mechanism of circ_0084615. Results: A significant upregulation of circ_0084615 was observed in HCC tissues, and positively correlated with the TNM staging. Silencing of circ_0084615 impeded HCC cell viability, colony formation, migration, invasion, epithelial-mesenchymal transition, and xenograft tumor growth. Mechanistically, circ_0084615 could bind to miR-1200 and eliminate its ability to destroy actin-like 6A (ACTL6A) mRNA, thereby increasing ACTL6A expression and facilitating the malignant behaviors of HCC cells. Conclusions: This study clarified the oncogenic activity and mechanism of circ_0084615, thereby providing potential diagnostic biomarker and therapeutic target for inhibiting HCC progression.
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INTRODUCTION: The aim of this study is to investigate whether the testing time for unstimulated whole salivary flow (UWSF) can be shortened to 5 min in patients with suspected Sjögren's syndrome (SjS); and which SjS patients can use UWSF to evaluate salivary gland (SG) secretory function. METHOD: A diagnostic cohort comprising suspected SjS patients was conducted to investigate the correlation between UWSF measurements taken at 10 min (UWSF_10 min) and those taken at 5 min (UWSF_5 min). A group of SjS patients was enrolled for a comparison between UWSF and stimulated whole salivary flow (SWSF). RESULTS: In 734 suspected SjS patients, there was a remarkably high concordance between UWSF_10 min and UWSF_5 min (ICC 0.970, P < 0.001; r 0.973, P < 0.001). Reducing the testing time for UWSF to 5 min resulted in a high PPV of 83.8% and an exceptionally high NPV of 98.7%. In 408 SjS patients, the cut-off values of UWSF_10 min were investigated to classify SG secretory function. Using a threshold of > 0.2 mL/min (36.8%, 150/408) instead of SWSF > 0.7 mL/min (indicating mild secretory hypofunction), the specificity and PPV were found to be 94.2% and 94.0%, respectively; and using a threshold of < 0.05 mL/min (16.9%, 69/408) instead of SWSF ≤ 0.7 mL/min (indicating moderate to severe secretory hypofunction), the specificity was remarkably high at 97.6%, accompanied by a high PPV of 91.3%. CONCLUSIONS: This study supports the possibility of reducing UWSF testing time to 5 min; and the SWSF test may be skipped for SjS patients with USWF > 0.2 mL/min, indicating mild secretory hypofunction, or < 0.05 mL/min, indicating moderate to severe secretory hypofunction. Key Points â¢A diagnostic cohort of 734 patients with clinical suspicion of SjS provides compelling evidence for the potential to reduce the testing time for UWSF from 10 to 5 min. â¢Our finding challenges the 2019 treatment recommendation for SjS, which does not require SWSF measurement in SjS patients with UWSF ≥ 0.1 mL/min. â¢We propose that it may be feasible to consider utilizing UWSF instead of SWSF test for objective classification of SG secretory function in over half of SjS patients.
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Iron, one of the most abundant elements on earth and an essential element for living organisms, plays a crucial role in our daily metabolism. In the field of catalysis, the development of high-performance catalysts based on less toxic iron element is also of significant importance for green chemistry and a sustainable future. To construct Fe-based heterogeneous catalysts with excellent hydrogenation performance, precise modulation of the atomic coordination structure is a key strategy for enhancing catalytic activity. In this study, we present an in-situ coating method for applying a zeolitic imidazolate framework (ZIF) onto the surface of fungal hyphae. The asymmetric coordination structure of Fe1-N3P1 was precisely tailored by utilizing the phosphorus source from the fungus and the nitrogen source in the ZIFs. Detailed characterizations and density functional theory calculations revealed that the incorporation of ZIFs not only increased the specific surface area of catalysts, but also facilitated the dispersion of Fe2P nanoparticles into the Fe1-N3P1 center, making the lowest reaction energy barrier and resulting in the best performance for nitrobenzene hydrogenation when compared to the Fe2P nanoparticles and clusters. This research introduces a novel design concept for constructing asymmetric monoatomic configuration based on the inherent characteristics of natural microorganisms and the exogenous porous coordination polymers.
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Objective: Sleep disturbances among college students have become a significant issue affecting their daily lives. This study aims to explore the relationship between smartphone dependence and sleep quality and examine the mediating roles of negative emotions and health-promoting behaviors. Methods: A total of 23,652 college students were included in the study, and 21,314 valid questionnaires were collected. The survey assessed demographic factors, smartphone dependence, sleep quality, negative emotions, and health-promoting behaviors. A chain mediation analysis was conducted to examine the relationships among these factors. Results: Smartphone dependence was significantly positively correlated with sleep quality (r = 0.272, p < 0.001) and negative emotions (r = 0.414, p < 0.001), and significantly negatively correlated with health-promoting behaviors (r = -0.178, p < 0.001). Sleep quality was positively correlated with negative emotions (r = 0.472, p < 0.001) and negatively correlated with health-promoting behaviors (r = -0.218, p < 0.001).Smartphone dependence was a significant positive predictor of sleep quality. Moreover, negative emotions and health-promoting behaviors influenced the relationship between smartphone dependence and sleep quality. The total effect, direct effect, and indirect effect values were 0.304, 0.122, and 0.170, respectively. Conclusion: Different demographic factors (such as gender and place of residence) can lead to variations in different variables. Smartphone dependence and negative emotions have a positive impact on sleep quality among college students, while health-promoting behaviors have a negative impact. Smartphone dependence directly and positively affects sleep quality and can also influence it indirectly through the mediating effects of negative emotions and health-promoting behaviors, both individually and in a chain-like manner.
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Emoções , Comportamentos Relacionados com a Saúde , Qualidade do Sono , Smartphone , Estudantes , Humanos , Feminino , Masculino , Estudantes/psicologia , Adulto Jovem , Inquéritos e Questionários , Universidades , Promoção da Saúde , Adolescente , AdultoRESUMO
Owing to their high sensitivity across a wide stress range, mechanical reliability, and rapid response time, flexible polymer foam piezoresistive sensors have been extensively used in various fields. The reliable application of these sensors under harsh environments, however, is severely limited by structural devastation and poor interfacial bonding between polymers and conductive nanoparticles. To address the above issues, robust MXene/CNT nanocoatings on the foam surface, where the chemical assembly of MXene nanosheets and the physical anchoring of CNTs lead to strong interfacial bonding, are designed and described, which endows foams with structural reliability and unexpected multi-functionalities without compromising their instinct properties. The optimized foam nanocomposites thus maintain outstanding wide-temperature flexibility (-60-210 °C) and elasticity (≈3% residual strain after 1000 cycles). Moreover, the nanocomposites display good sensitivity at a relatively wide stress range of 0-70% and remarkable stability under acidic and alkaline settings. Furthermore, the foams with exceptional fire resistance (UL-94 V-0 rating) can provide stable sensing behavior (over 300 cycles) even after being exposed to flames for 5 s, making them one of the most reliable sensing materials so far. Clearly, this work widens applications of flexible piezoresistive sensors based on silicone foam nanocomposites for various harsh environments.
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The incidence and mortality of breast cancer increase year by year, and it is urgent to find high-efficiency and low-toxicity anti-cancer drugs. Pterostilbene (PTE) is a natural product with antitumor activity, but the specific antitumor mechanism is not very clear. Aerobic glycolysis is the main energy supply for cancer cells. Pyroptosis is an inflammatory, programmed cell death. The aim of this study was to investigate the effect of PTE on glycolysis and pyroptosis in EMT6 and 4T1 cells and the specific mechanism, and to elucidate the role of pyruvate kinase 2 (PKM2), a key enzyme in glycolysis, in the antitumor role of PTE. Our study suggested that PTE induced pyroptosis by inhibiting tumor glycolysis. PKM2 played an important role in both the inhibition of glycolysis and the induction of pyroptosis by PTE.
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Neoplasias da Mama , Caspase 8 , Piroptose , Transdução de Sinais , Estilbenos , Piroptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Estilbenos/farmacologia , Feminino , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Animais , Caspase 8/metabolismo , Humanos , Camundongos , Glicólise/efeitos dos fármacos , Piruvato Quinase/metabolismo , Proteínas de Ligação a Hormônio da Tireoide , Hormônios Tireóideos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Transporte/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Ligação a Fosfato/metabolismoRESUMO
BACKGROUND: Elevated circulatory phosphate levels are linked to age-related muscle dysfunction, yet the mechanisms remain unclear. This study investigated the hypothesis that inflammation plays a role in connecting elevated phosphate levels to muscular dysfunction in middle-aged and older individuals and explored potential sex-based differences in these associations. METHODS: The study, based on the I-Lan Longitudinal Aging Study Cohort, analyzed individuals' serum phosphate and hsCRP levels. Sex-specific analyses explored links between circulatory phosphate, inflammation, and muscle profiles (mass, handgrip strength, and walking speed). The study also examined potential mediation or synergistic effects of inflammation in the circulatory phosphate-muscle relationship. RESULTS: The study included 2006 participants (mean age: 65.5 ± 6.5 years; 49.8 % men). Women exhibited higher circulatory phosphate levels than men. Linear analyses revealed that higher phosphate levels were significantly associated with weaker handgrip strength but not with reduced muscle mass in both men and women. In women, circulatory phosphate was not associated with inflammation (hsCRP levels), while in men, higher phosphate levels were significantly associated with higher hsCRP levels. In men, a synergistic effect was observed, where the combination of high hsCRP and elevated phosphate levels had a more pronounced impact on reducing handgrip strength than either factor alone. CONCLUSIONS: This study highlights a sex-specific association of inflammation in the mechanisms of hyperphosphatemia-related muscle weakness. The findings emphasize the importance of managing both hyperphosphatemia and chronic inflammation to mitigate their collective impact on muscle function, particularly in older men. Addressing these factors is crucial for promoting muscle health in later life.
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Força da Mão , Inflamação , Músculo Esquelético , Fosfatos , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Fosfatos/sangue , Músculo Esquelético/fisiopatologia , Fatores Sexuais , Estudos Longitudinais , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Envelhecimento/fisiologia , Velocidade de Caminhada/fisiologia , Força Muscular/fisiologiaRESUMO
OBJECTIVE: Thermal ablation (TA) is a safe and effective treatment for benign thyroid nodules (BTNs). However, there has been no consensus on the optimal maximum diameter (MD) of BTNs for TA. This study aimed to identify the optimal MD of BTNs for TA based on complete disappearance rate after TA. MATERIALS AND METHODS: This retrospective study included 639 BTNs treated with TA from June 2014 to January 2022. The complete disappearance rate of BTNs after TA was summarized, related influencing factors were explored, and the optimal MD of BTNs for TA was identified. RESULTS: At the final follow-up (median: 40 months, range: 24-95 months), the overall volume reduction rate was 95.4 ± 9.0%, and 50.5% of the BTNs (323/639) completely disappeared. The MD was significantly negatively correlated with complete disappearance (odds ratio 0.89, 95% confidence interval 0.87-0.92; p < 0.001). Calcification, comet-tail artifacts, multilocular cysts, and composition of BTNs, as well as diabetes were negatively correlated with complete disappearance. Restricted cubic spline indicated that an MD of 25.0 mm was the optimal threshold of BTNs for TA, which was confirmed by subgroup logistic regression analysis. Compared with BTNs with MD ≤ 25.0 mm, those with MD > 25.0 mm had a greater complication rate (6.5% vs. 2.4%, p = 0.012). CONCLUSIONS: The MD of BTNs was negatively correlated with complete disappearance after TA; an MD > 25.0 mm indicated a reduced likelihood of complete disappearance compared with an MD ≤ 25.0 mm. An MD of 25.0 mm is an appropriate threshold of BTNs for TA on the basis of complete disappearance rate.
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Nódulo da Glândula Tireoide , Humanos , Nódulo da Glândula Tireoide/cirurgia , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Técnicas de Ablação/métodos , Idoso , Adulto Jovem , AdolescenteRESUMO
Background/purpose: Quantitative in vitro research was conducted on the learning process of a dynamic navigation system. This study provides guidance for the promotion and application of dynamic navigation technology in the endodontic apical surgery field. Materials and methods: Standardized models were designed and 3D printed to form the approach operation of endodontic apical surgery. 6 clinicians with no experience in dynamic navigation performed the operation. The distance deviation tolerance was set as 0.6 mm, and the angle deviation tolerance was set as 5°. Fifteen mm deep approach operation was completed using dynamic navigation. Each operator performed 10 consecutive exercises on the models. The positioning deviation and operation time of each operator for each practice were recorded. Based on this, the learning curve of the dynamic navigation of every operator was mapped. The learning difficulty of dynamic navigation was evaluated. Results: The learning curves of all operators reached a stable level after the 7th practice, which can ensure that the distance and angle deviations are maintained within the deviation tolerances (0.6 mm, 5°). Conclusion: Operators with no experience in dynamic navigation technology need practice to master dynamic navigation operations. For this navigation system, operators with no operational experience can master dynamic navigation operations after 7 exercises.
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OBJECTIVES: To develop an intrinsic capacity (IC) score and to investigate the association between IC transition with overall and cause-specific mortality, incident disability and healthcare utilization. DESIGN: Retrospective cohort study SETTING AND PARTICIPANTS: Data from 1852 respondents aged ≥ 65 years who completed the 1999 and 2003 surveys of the Taiwan Longitudinal Study on Aging were analyzed. MEASUREMENTS: Transitions of IC score were categorized into three groups: (1) Improved IC (IC2003-1999 >0), (2) Stable IC (IC2003-1999 = 0), (3) Worsened IC (IC2003-1999 <0). Cox regression and subdistribution hazard models were used to investigate IC transitions and 4-year overall and cause-specific mortality, respectively. Logistic regression were employed to develop weighted IC score (wIC, 0-16) and assess its association with incident disability and healthcare utilization. Similar analysis were repeated using non-weighted IC (nIC, 0-8) to ensure robustness. RESULTS: Comparing to decreased wIC group, stable or increased wIC participants had significantly lower 4-year all-cause mortality, and death from infection, cardiometabolic/cerebrovascular diseases, organ failure and other causes. (Hazard ratio (HR) ranged from 0.36 to 0.56, 95% CI ranged from 0.15 to 1.00, p ≤ 0.049 in the stable wIC group; HR ranged from 0.41 to 0.51, 95% CI ranged from 0.22 to 0.94, p ≤ 0.034 in the increased wIC group). Moreover, individuals with stable or increased wIC demonstrated lower risk of incident disability and hospitalization. (Odds ratio (OR) = ranged from 0.34 to 0.70, 95% CI ranged from 0.19 to 1.00, p ≤ 0.048). Participants with stable wIC also exhibited reduced risk of emergency department visits (OR = 0.58, 95% CI = 0.41 to 0.82, p = 0.002). These results were generally consistent in the nIC model. CONCLUSION: Participants with stable or increased IC experienced significantly lower all-cause and most cause-specific mortality, incident disability, and healthcare utilization, which was independent of baseline IC and comorbidities. The findings remained consistent across weighted and non-weighted IC model.
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Pessoas com Deficiência , Aceitação pelo Paciente de Cuidados de Saúde , Humanos , Masculino , Feminino , Idoso , Estudos Retrospectivos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Taiwan/epidemiologia , Pessoas com Deficiência/estatística & dados numéricos , Estudos Longitudinais , Idoso de 80 Anos ou mais , Causas de Morte , Avaliação Geriátrica/estatística & dados numéricos , Avaliação Geriátrica/métodos , Mortalidade , Modelos de Riscos Proporcionais , IncidênciaRESUMO
Observational studies indicate that variations in peripheral blood mononuclear cell (PBMC) subsets are associated with an increased risk of pulmonary tuberculosis (PTB) and coronavirus disease 2019 (COVID-19), but causal validation is lacking. Here, we combined single-cell expression quantitative trait locus (sc-eQTL) and two-sample mendelian randomization (MR) analyses to elucidate the causal relationship between PBMC subsets and the occurrence of PTB and COVID-19 and verified by RT-qPCR. We observed an increase in the CD4+ Effective Memory T Cell (CD4+ TEM) cluster in both PTB and COVID-19 patients according to the single-cell transcriptional landscape of PBMC. Through MR analysis using an inverse variance weighted (IVW) method, we found strong evidence of positive correlations between CD4+ TEM cell markers (GBP2, TRAV1-2, and ODF2L) and PTB, and between markers (LAG3 and SLFN5) and COVID-19, especially highlighted by lead eQTL-SNPs of GBP2 (rs2256752, p = 4.76321 × 10-15) and LAG3 (rs67706382, p = 6.16× 10-16). Similar results were observed in validation sets, and no pleiotropy was detected in sensitivity analyses including weighted median (WM), MR-Egger, MR-pleiotropy residual sum and outlier, and leave-one-out analyses (all p > 0.05). We visualized the colocalization of marker-eQTLs and markers of PTB and COVID-19 genome-wide association study (GWAS) associations. Based on CellChat analyses, monocytes communicated predominantly with CD4+ TEM cells positively expressing PTB markers (GBP2, TRAV1-2, and ODF2L) and COVID-19 markers (LAG3 and SLFN5) in both PTB and COVID-19. Our data suggest a causal effect between two key CD4+ TEM cell markers (GBP2 and LAG3) and the risk for PTB and COVID-19 infection. Our findings provide novel insights into the biological mechanism for PTB and COVID-19 infection, but future single-cell studies are necessary to further enhance understanding of this find.
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Antígenos CD , Linfócitos T CD4-Positivos , COVID-19 , Proteína do Gene 3 de Ativação de Linfócitos , Análise da Randomização Mendeliana , Locos de Características Quantitativas , SARS-CoV-2 , Humanos , COVID-19/genética , COVID-19/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Fatores de Risco , Antígenos CD/genética , Antígenos CD/metabolismo , Análise de Célula Única/métodos , Proteínas de Ligação ao GTP/genética , Células T de Memória/imunologia , Células T de Memória/metabolismo , Biomarcadores , Polimorfismo de Nucleotídeo Único , Masculino , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica AmplaRESUMO
INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease characterized by Amyloid plaques and neurofibrillary tangles. We explored the potential mechanism by which Danggui Shaoyao San (DSS) modulates central glucose metabolism via the insulin receptor substrate 1 (IRS1)/glycogen synthase kinase-3ß (GSK3ß)/Wnt3a-ß-catenin pathway, thereby exerting protective effects on cognitive functions. METHODS: In vitro, HT22 cells were induced with streptozotocin (STZ) to investigate the impact of GSK3ß on pathway transduction. The active components in the DSS stock solution were validated using mass spectrometry. Subsequently, an AD model in C57BL/6J mice was established through STZ injection into both ventricles. The success of the model was validated behaviorally and pathologically. The Morris Water Maze (MWM) test, immunohistochemistry, Western blotting, quantitative reverse transcription-PCR, and 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) were employed to evaluate the influence of DSS on memory and pathological changes in AD. RESULTS: The DSS stock solution, rich in active components, ameliorated the memory deficits in AD mice in the MWM. In vitro, GSK3ß exhibited regulatory control over Wnt and ß-catenin, with GSK3ß inhibition mitigating ß-amyloid and tau redundancies at protein and gene levels, facilitating signal transduction. In vivo, DSS impacted key targets in the IRS1/GSK3ß/Wnt3a-ß-catenin pathway, mitigated senile plaques resulting from amyloid ß (Aß) deposition and neurofiber tangles induced by tau hyperphosphorylation, and alleviated the decline in central glucose metabolism observed in FDG-PET. CONCLUSIONS: Our findings suggest that DSS potentially confers cognitive protection by alleviating central hypoglycemia through the IRS1/GSK3ß/Wnt3a-ß-catenin pathway. This may serve as a promising therapeutic avenue for AD.
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Doença de Alzheimer , Disfunção Cognitiva , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Glicogênio Sintase Quinase 3 beta , Proteínas Substratos do Receptor de Insulina , Camundongos Endogâmicos C57BL , Proteína Wnt3A , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , Medicamentos de Ervas Chinesas/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteína Wnt3A/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/etiologia , Masculino , beta Catenina/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Reactive astrocyte activation in the context of cerebral ischemia/reperfusion (I/R) injury gives rise to two distinct subtypes: the neurotoxic A1 type and the neuroprotective A2 type. DJ-1 (Parkinson disease protein 7, PARK7), originally identified as a Parkinson's disease-associated protein, is a multifunctional anti-oxidative stress protein with molecular chaperone and signaling functions. SHP-1 (Src homology 2 domain-containing phosphatase-1) is a protein tyrosine phosphatase closely associated with cellular signal transduction. miR-155 is a microRNA that participates in cellular functions by regulating gene expression. Recent studies have uncovered the relationship between DJ-1 and astrocyte-mediated neuroprotection, which may be related to its antioxidant properties and regulation of signaling molecules such as SHP-1. Furthermore, miR-155 may exert its effects by influencing SHP-1, providing a potential perspective for understanding the molecular mechanisms of stroke. A middle cerebral artery occlusion/reperfusion (MCAO/R) model and an oxygen-glucose deprivation/reperfusion (OGD/R) model were established to simulate focal cerebral I/R injury in vivo and in vitro, respectively. The in vivo interaction between DJ-1 and SHP-1 has been experimentally validated through immunoprecipitation. Overexpression of DJ-1 attenuates I/R injury and suppresses miR-155 expression. In addition, inhibition of miR-155 upregulates SHP-1 expression and modulates astrocyte activation phenotype. These findings suggest that DJ-1 mediates astrocyte activation via the miR-155/SHP-1 pathway, playing a pivotal role in the pathogenesis of cerebral ischemia-reperfusion injury. Our results provide a potential way for exploring the pathogenesis of ischemic stroke and present promising targets for pharmacological intervention.
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Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by continuous inflammation and ulcer formation in the intestinal mucosa.Its pathogenesis involves immune dysfunction,dysbiosis of gut microbiota,and mucosal damage caused by inflammation.Ferroptosis is an iron-dependent form of cell death regulated by disturbances in iron metabolism,lipid peroxidation,and depletion of glutathione (GSH).Studies have indicated that ferroptosis plays a crucial role in the pathogenesis of UC,particularly in regulating inflammatory responses and damaging intestinal epithelial cells.This article reviews the regulatory mechanisms and roles of ferroptosis in UC and discusses the potential therapeutic strategies to alleviate UC symptoms by modulating iron metabolism,reducing lipid peroxidation,and maintaining GSH levels,providing new targets and directions for the diagnosis and treatment of UC.
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Colite Ulcerativa , Ferroptose , Humanos , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Ferro/metabolismo , Peroxidação de Lipídeos , Glutationa/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Microbioma Gastrointestinal , Inflamação , AnimaisRESUMO
Several observational studies have reported a correlation between the gut microbiota (GM) and the risk of acute pancreatitis (AP). However, the causal relationship between them remains uncertain. We conducted a 2-sample Mendelian randomization (MR) study using pooled data from genome-wide association studies of 211 taxa (131 genera, 35 families, 20 orders, 16 classes, and 9 phyla) and AP patients. We evaluated the causal relationship between the GM and AP using methods such as inverse-variance weighting, MR-Egger, weighted medians, simple mode, and weighted mode. Cochran Q test, MR-Egger regression intercept analysis, and MR-PRESSO were used to examine the heterogeneity, multipotency, and outlier values of the variables, respectively. The reverse causal relationship between AP and the GM was assessed with reverse MR. In total, 5 gut microbial taxa were significantly associated with AP. The inverse-variance weighting results indicated that Acidaminococcaceae (odds ratio [OR]: 0.81, 95% confidence interval [CI]: 0.66-1.00, Pâ =â .045) and Ruminococcaceae UCG004 (OR: 0.85, 95% CI: 0.72-0.99, Pâ =â .040) were protective factors against the occurrence of AP. Coprococcus 3 (OR: 1.32, 95% CI: 1.03-1.70, Pâ =â .030), Eisenbergiella (OR: 1.13, 95% CI: 1.00-1.28, Pâ =â .043), and the Eubacterium fissicatena group (OR: 1.18, 95% CI: 1.05-1.33, Pâ =â .006) were risk factors for the development of AP. A comprehensive sensitivity analysis proved our results to be reliable. Reverse MR analysis did not indicate any causal relationship between AP and the GM. This study revealed a complex causal relationship between 5 GM taxa and AP, providing new insights into the diagnostic and therapeutic potential of the GM in AP patients.