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1.
Mol Metab ; 89: 102030, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39293565

RESUMO

OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA. N-acetyltransferase 10 (NAT10) has not been fully explored in MASLD and MASH. METHODS: The clinical relevance of NAT10 was evaluated based on its expression in various mouse and human models of MASLD and MASH. Acetylated RNA immunoprecipitation sequencing and mRNA stability assays were used to explore the role of NAT10 in regulating ac4C modification and expression of target genes. Genetically engineered mice were employed to investigate the role of NAT10 in MASLD and MASH progression. RESULTS: Hepatic NAT10 expression was significantly increased in multiple mice and humans of MASLD and MASH. Genetic knockout of NAT10 protected mice from diet-induced hepatic steatosis and steatohepatitis, whereas overexpression of NAT10 exacerbated high-fat-diet-induced liver steatosis. Mechanistically, NAT10 binds to Srebp-1c mRNA, promoting its stability and expression, thereby upregulating lipogenic enzymes. Treatment with Remodelin, a NAT10-specific inhibitor, effectively ameliorates liver steatosis and dyslipidemia in a preclinical mouse model. CONCLUSIONS: Our findings indicate that NAT10 could regulate lipid metabolism in MASLD and MASH by stabilizing Srebp-1c mRNA and upregulating lipogenic enzymes. This study highlights the role of NAT10 and RNA acetylation in the pathogenesis of MASLD and MASH. Thus, our findings suggest a promising new therapeutic approach, such as the use of NAT10 inhibitor, for treating metabolic liver disease.

2.
Anal Chem ; 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39282756

RESUMO

Intracellular potassium ions play a crucial role in cellular homeostasis associated with physiological and pathological processes. It is still challenging but definitely crucial to precisely and dynamically image subcellular K+. Herein, the first mitochondria-targeted DNA tweezers (KLA-tweezers) were developed for the fluorescence imaging of mitochondrial K+ with high selectivity and accuracy. The proposed KLA-tweezers consisted of two DNA double-crossover (DX) motifs, a K+-aptamer, and a mitochondria-targeted peptide (KLA) which was conjugated at the rear of DX arms via complementary base pairing. Upon contact with K+, the K+-aptamer experienced a conformational change from an open-chain G-rich sequence to a G-quadruplex with a compact conformation, which was reflected by the Förster resonance energy transfer process between Cy3 and Cy5 labeled at the end of the DX arms. The open and closed states of the tweezers before and after KLA modification were confirmed by gel electrophoresis and fluorescence spectra together with atomic force microscopy (AFM) and transmission electron microscopy (TEM) images, suggesting the KLA assembly had no effect on the morphology change. The proposed tweezers and KLA-tweezers showed low cytotoxicity, excellent selectivity, and good reversibility upon alternating addition of 18-crown-6 and K+. Besides, the KLA-tweezers exhibited outstanding stability and accurate mitochondria location ability. Upon stimulation of ATP or nigericin, intracellular fluorescence imaging of mitochondrial K+ dynamics was successfully achieved. This strategy has broad prospects as a general optical sensing platform for other metal ions or organelles in living cells.

3.
J Health Psychol ; : 13591053241277978, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39248086

RESUMO

This study identified psychological profiles based on depressive symptoms, anxiety symptoms, positive affect, and posttraumatic growth in 298 patients receiving maintenance dialysis, and examined their relationships with self-management at baseline and 1-year follow-up. Five psychological response profiles were identified: well-being (42.95%), resilient (26.17%), moderate-distress-with-growth (17.79%), distressed (11.07%), and high-distress-with-growth (2.01%). Patients were more likely to be in the distressed profile if they were younger, had less social support, received peritoneal dialysis, and suffered from a greater symptom burden of kidney disease. The well-being profile showed better self-management behavior at baseline and 1-year follow-up. The distressed profile was associated with worse self-management at baseline and the resilient profile was associated with worse self-management at follow-up. The findings highlighted the beneficial role of positive psychological constructs in promoting self-management behavior, which implied that beyond eliminating psychological distress, it is important to facilitate positive psychological well-being.

4.
Support Care Cancer ; 32(10): 658, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39271485

RESUMO

PURPOSE: To explore the trajectories of acceptance of disability in young and middle-aged breast cancer patients based on a latent class growth analysis, investigate factors associated with each trajectory, and identify whether return to normal living differs in different trajectories. METHODS: Young and middle-aged patients newly diagnosed with breast cancer who underwent surgery were followed up at baseline, and 1, 3, and 6 months in China. Participants completed sociodemographic information questionnaires, the Adaptation of Disability Scale Revised, and the Reintegration to Normal Living Index. A latent class growth analysis was used to explore the trajectories of acceptance of disability. RESULTS: Among 212 patients newly diagnosed with breast cancer, the mean age of patients was 45.44 years. The majority of participants were with invasive carcinoma (77.8%). Three classes were identified: high acceptance of disability increasing group (high-increasing, 13.7%), moderate acceptance of disability stable group (moderate-stable, 67.9%), and moderate acceptance of disability decreasing group (moderate-decreasing, 18.3%). Being unemployed or retired and receiving endocrine therapy are risk factors associated with acceptance of disability. Carcinoma in situ is a protective factor associated with acceptance of disability. Participants diagnosed with carcinoma in situ and who not receive endocrine therapy were more likely to be in high-increasing group. Unemployed participants before surgery were more likely to be in moderate-decreasing group. Moreover, the Reintegration to Normal Living Index scores had significant differences from baseline to 6 months of follow-up. The high-increasing group had the highest average Reintegration to Normal Living Index scores than the moderate-stable group and the moderate-decreasing group, showing similar patterns at four timepoints. CONCLUSION: We identified three trajectories of acceptance of disability. Dynamic and individualized intervention should be continuously provided to ensure patients acquire adequate medical resources to comprehensively increase acceptance of disability.


Assuntos
Neoplasias da Mama , Pessoas com Deficiência , Humanos , Neoplasias da Mama/psicologia , Neoplasias da Mama/cirurgia , Feminino , Pessoa de Meia-Idade , Estudos Longitudinais , China , Adulto , Pessoas com Deficiência/psicologia , Inquéritos e Questionários , Fatores de Risco
5.
Microb Pathog ; 195: 106880, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39181191

RESUMO

Toxoplasma gondii (T.gondii) can influence the host's neurotransmission, central immune responses, and brain structure, potentially impacting the onset and development of various psychiatric disorders such as schizophrenia. We employed Electrochemiluminescence Immunoassay (ECLIA) to measure anti-Toxoplasma antibodies in 451 schizophrenic patients and 478 individuals from the general population in Hunan, China. The incidence rate of T.gondii infection in schizophrenic patients (8.87 %) was higher than that in the general population (3.77 %). A significant difference was observed among females, but not in males. Age-stratified analysis revealed significant differences in the 21-40 and 41-60 age groups. The two populations had no significant difference in the antibody titer for T. gondii infection. Additionally, the profile of circulating metabolites in the serum of schizophrenic patients with or without T. gondii infection was examined using non-targeted metabolomics assay. A total of 68 metabolites were differentially expressed between Toxoplasma-positive and Toxoplasma-negative groups, potentially mediating the connection between T. gondii infection and schizophrenia. Our research suggests that schizophrenic patients are susceptible to T. gondii infection with distinct metabolic program.


Assuntos
Anticorpos Antiprotozoários , Metabolômica , Esquizofrenia , Toxoplasma , Toxoplasmose , Humanos , Esquizofrenia/sangue , Esquizofrenia/epidemiologia , China/epidemiologia , Toxoplasmose/epidemiologia , Toxoplasmose/sangue , Feminino , Masculino , Adulto , Toxoplasma/imunologia , Pessoa de Meia-Idade , Anticorpos Antiprotozoários/sangue , Adulto Jovem , Estudos Soroepidemiológicos , Incidência
6.
J Mater Chem B ; 12(37): 9325-9334, 2024 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-39171436

RESUMO

Administration of antibiotics via inhalation is considered an effective strategy for pneumonia treatment; however, it encounters challenges related to the development of drug formulations with precise particle sizes and controlled release profiles. Herein, size-tailored and acid-degradable polyvinyl alcohol (PVA) microgels are utilized for nebulized inhalation delivery of piperacillin (PIP) antibiotics to effectively treat pneumonia. These microgels loaded with PIP (G@PIP) were prepared through the UV-crosslinking of thermo-triggered vinyl ether methacrylate-functionalized PVA (PVAVEMA) micro-aggregates in aqueous solution. The size of G@PIP microgels could be tailored by adjusting concentrations during the crosslinking process above phase-transition temperature at 15 °C. Additionally, under simulated inflammatory acidic conditions, the G@PIP microgels degraded and released PIP with relatively high inhibition efficiency against E. coli. Furthermore, in vivo therapeutic outcomes revealed that inhalational delivery of G@PIP microgel with a medium-size of 3.5 µm (G-3.5@PIP) exhibited superior lung deposition compared to other microgel sizes owing to its reduced exhalation and enhanced diffusion capacity within the pulmonary system. The high accumulation of G-3.5@PIP significantly reduced E. coli infection and associated inflammation while maintaining the biocompatibility of the microgels. Overall, these acid-degradable PVA microgels offer a versatile and efficacious inhalation therapy for pneumonia-associated infections.


Assuntos
Antibacterianos , Escherichia coli , Microgéis , Tamanho da Partícula , Pneumonia Bacteriana , Álcool de Polivinil , Álcool de Polivinil/química , Microgéis/química , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Administração por Inalação , Pneumonia Bacteriana/tratamento farmacológico , Animais , Escherichia coli/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Humanos
7.
Small Methods ; : e2400643, 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39161085

RESUMO

Additive engineering has emerged as a promising strategy to address the inherent instability challenges of perovskite solar cells (PSCs) in the pursuit of commercial viability. However, achieving multifunctionality using a singular additive remains a considerable challenge. In this study, a novel comb-like multifunctional perfluoroalkyl-g-polyethylenimmonium iodide (FPEI·HI) as additives to the PbI2 precursor solution to facilitate the formation of high-quality and water-resistant perovskite films is presented. FPEI·HI establishes robust interactions with both formamidinium iodide (FAI) and PbI2, mediated by hydrogen bonding and Lewis acid-base interactions. These interactions play a pivotal role in simultaneously passivating negative and positive charged defects within the perovskite structure. Furthermore, the inclusion of perfluoroalkyl chains serves as resilience against moisture intrusion. As a consequence of these effects, a notably high device efficiency of 24.29% is achieved, demonstrating comprehensive improvement in various photovoltaic parameters compared to the control device (22.51%). Notably, unencapsulated devices exhibit remarkable stability in high-humidity environments, retaining 90% of their initial efficiency even after 2500 h of storage. This work underscores the efficacy of FPEI·HI as a critical enabler for enhancing the stability and efficiency of perovskite solar cells, marking a significant stride toward their commercialization.

8.
J Thorac Dis ; 16(7): 4195-4207, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39144345

RESUMO

Background: Despite widespread application of minimally invasive video-assisted thoracic surgery (VATS), postoperative pain following this procedure is still a constant clinical challenge. Serratus anterior plane (SAP) block is one of the regional analgesic techniques with promising outcomes. However, due to the limited duration of action, optimal analgesia is often not achieved with a single injection. We tested whether in patients who have been subjected to routine SAP block under preoperative anesthesia, the addition of a second SAP block 24 hours after surgery, improves quality of recovery, lowers postoperative opioid consumption, and reduces the prevalence of chronic pain. Methods: The present study is a single institutional, prospective, randomized, triple-blinded, placebo-controlled study. Ninety patients undergoing VATS from January 2022 to April 2022 were randomized at 1:1 ratio to receive ultrasound-guided second SAP block with 15 mL 0.375% ropivacaine (SAP block group) or 15 mL normal saline (control group) 24 hours after both groups received routine SAP block with 15 mL 0.375% ropivacaine. The primary outcome was quality of patient recovery, measured using 40-item quality of recovery questionnaire (QoR-40) at postoperative day 2 (POD 2). Secondary outcomes included: postoperative pain scores at rest, postoperative opioid consumptions, number of times that patient controlled analgesia (PCA) pump button was pressed, perioperative complications and adverse effects, prevalence of chronic pain at 2nd and 3rd month postoperatively, and length of hospital stay (LOS). Results: A total of 83 patients completed the study: 43 patients in SAP block group and 40 patients in the control group. The global QoR-40 scores on POD 2 and POD 3 were significantly higher among SAP block group patients (180.07±11.34, 182.09±8.20) compared with the control group (172.18±6.15, 177.50±6.94) (P=0.01, P=0.008) respectively. Postoperative pain scores, opioid consumptions and incidence of postoperative nausea and vomiting were significantly lower among patients in SAP block group versus control group. There were no statistically significant differences in perioperative complications and LOS between the two groups. The prevalence of chronic pain at the 2nd and 3rd month postoperatively for patients in SAP block group and control group was 16.3%, 14%, and 32.5%, 27.5% respectively. Conclusions: In patients undergoing VATS, application of ultrasound-guided second SAP block 24 hours after surgery improved postoperative quality of life, reduced opioid consumption and related side effects, and lowered the prevalence of chronic pain.

9.
Cell Metab ; 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39146936

RESUMO

Nonalcoholic fatty liver disease (NAFLD), including its more severe manifestation nonalcoholic steatohepatitis (NASH), is a global public health challenge. Here, we explore the role of deubiquitinating enzyme RPN11 in NAFLD and NASH. Hepatocyte-specific RPN11 knockout mice are protected from diet-induced liver steatosis, insulin resistance, and steatohepatitis. Mechanistically, RPN11 deubiquitinates and stabilizes METTL3 to enhance the m6A modification and expression of acyl-coenzyme A (CoA) synthetase short-chain family member 3 (ACSS3), which generates propionyl-CoA to upregulate lipid metabolism genes via histone propionylation. The RPN11-METTL3-ACSS3-histone propionylation pathway is activated in the livers of patients with NAFLD. Pharmacological inhibition of RPN11 by Capzimin ameliorated NAFLD, NASH, and related metabolic disorders in mice and reduced lipid contents in human hepatocytes cultured in 2D and 3D. These results demonstrate that RPN11 is a novel regulator of NAFLD/NASH and that suppressing RPN11 has therapeutic potential for the treatment.

10.
Artigo em Inglês | MEDLINE | ID: mdl-39105682

RESUMO

BACKGROUND: Global longitudinal strain (GLS) and atrial voltage are acknowledged markers for worse rhythm outcome after ablation of persistent atrial fibrillation (PeAF). The majority of research efforts have been directed towards the left atrium (LA), with relatively fewer studies focusing on the right atrium (RA). The aim of this study was to investigate the effect of the biatrial substrate on the outcome following radiofrequency catheter ablation (RFCA). METHODS: All patients underwent two-dimensional speckle tracking echocardiography (2D-STE) and high-density mapping (HDM) on LA and RA in preoperative and postoperative stages of RFCA. Atrial substrate was assessed by GLS, average voltage, and low voltage zone (LVZ). RESULTS: This retrospective study enrolled 48 patients. With a follow-up of 385.98 ± 161.78 days, 22.92% (11/48) of all patients had AF recurrence and 63.64% in low strain group. Left atrial-low voltage zone (LA-LVZ) prior to RFCA was 67.52 ± 15.27% and 54.21 ± 20.07%, respectively, in the recurrence group and non-recurrence group. Multivariate regression analysis showed that preoperative LA-GLS (OR 0.047, 95%CI 0.002-0.941, p = .046) was independent predictors of AF recurrence. Biatrial average voltage in preoperative and postoperative stages were positively correlated (preoperative: r = 0.563 p < .001; postoperative: r = 0.464 p = .002). There was no significant difference in the proportion of RA in the recurrence group except the septum in preoperative and postoperative stages. CONCLUSIONS: Low LA-GLS and high LA-LVZ may be predictors of RFCA recurrence in PeAF patients. Biatrial average voltage were positively correlated in preoperative and postoperative stages.

11.
Biology (Basel) ; 13(8)2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39194534

RESUMO

The nitrogen cycling process in alpine wetlands is profoundly affected by precipitation changes, yet the dynamic response mechanism of denitrifiers to long-term precipitation shifts in the alpine wetland of the Qinghai-Tibet Plateau remains enigmatic. Utilizing high-throughput sequencing analysis of nirS-type functional genes, this study delved into the dynamic response mechanism of nirS-type denitrifiers to precipitation changes in the alpine wetland of Qinghai Lake. The findings revealed that nirS-type denitrifiers in the alpine wetland of Qinghai Lake were primarily Proteobacteria, and Alpha diversity exhibited a negative correlation with the precipitation gradient, with deterministic processes predominating in the community assembly of denitrifying microbes. A 50% increase in rainfall shifted the community assembly process of denitrifiers from deterministic to stochastic. Dominant microflora at the genus level responded significantly to precipitation changes, with aerobic bacteria comprising the majority of differentially abundant taxa (55.56%). As precipitation increased, the complexity of the microbial interaction network decreased, and a 25% reduction in precipitation notably elevated the relative abundance of three key functional groups: chemoheterotrophic, aerobic chemoheterotrophic, and nitrogen fixation. Precipitation notably emerged as the primary regulator of nirS-type denitrifiers in the alpine wetland of Qinghai Lake, accounting for 51% of the variation in community composition. In summary, this study offers a fresh perspective for investigating the ecological processes of nitrogen cycling in alpine ecosystems by examining the diversity and community composition of nirS-type denitrifiers in response to precipitation changes.

12.
Front Neurol ; 15: 1459392, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39206293

RESUMO

Objective: Epilepsy-related stigma is a global problem, yet there has been an inadequate focus on children and adolescents. The purpose of this study was to determine the status quo of stigma and its determinants among children and adolescents with epilepsy in China. Methods: A multicenter cross-sectional study was conducted across nine hospitals in eight cities within six provinces in China from 10 October 2023 to 15 June 2024. Participants included patients aged 8 to 18 years with epilepsy and their caregivers. Felt stigma was assessed with the Kilifi Stigma Scale for Epilepsy (KSSE). Social support and self-efficacy were collected through the Social Support Rating Scale (SSRS) and the Generalized Self-Efficacy Scale (GSES). The data were analyzed using t-tests, analysis of variance (ANOVA), Spearman correlation analysis, and multiple linear regression analysis. Results: The study enrolled 281 children and adolescents, with a mean age of 12.25 years (SD = 2.56), including 46.6% females. A total of 35.6% participants had self-reported felt stigma. The mean KSSE score is 9.58 (SD = 7.11). Meanwhile, stigma scores correlated strongly with reduced social support (r = -0.55, p < 0.01) and self-efficacy (r = -0.43, p < 0.01). Place of residence (rural vs. non-rural), academic performance (average and above vs. fair or poor), region (western region vs. non-western region), duration of epilepsy (≤5 years vs. >5 years), drug-resistant epilepsy (yes vs. no), comorbidities (yes vs. no), social support and self-efficacy are major influencing factors among the complex factors influencing the felt stigma among children and adolescents. Conclusion: Medical staff should be more aware of stigma among children and adolescents with epilepsy, especially those who live in rural and western areas, have poor academic performance, have epilepsy duration of more than 5 years, have drug-resistant epilepsy, and have comorbidities, who are at higher risk of stigma. It is recommended that effective measures be taken to alleviate stigma by improving children and adolescents' self-efficacy and providing more social support for them and their families.

13.
Sci Rep ; 14(1): 18202, 2024 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-39107445

RESUMO

Lung adenocarcinoma is the most common primary lung cancer seen in the world, and identifying genetic markers is essential for predicting the prognosis of lung adenocarcinoma and improving treatment outcomes. It is well known that alterations in circadian rhythms are associated with a higher risk of cancer. Moreover, circadian rhythms play a regulatory role in the human body. Therefore, studying the changes in circadian rhythms in cancer patients is crucial for optimizing treatment. The gene expression data and clinical data were sourced from TCGA database, and we identified the circadian clock-related genes. We used the obtained TCGA-LUAD data set to build the model, and the other 647 lung adenocarcinoma patients' data were collected from two GEO data sets for external verification. A risk score model for circadian clock-related genes was constructed, based on the identification of 8 genetically significant genes. Based on ROC analyses, the risk model demonstrated a high level of accuracy in predicting the overall survival times of lung adenocarcinoma patients in training folds, as well as external data sets. This study has successfully constructed a risk model for lung adenocarcinoma prognosis, utilizing circadian rhythm as its foundation. This model demonstrates a dependable capacity to forecast the outcome of the disease, which can further guide the relevant mechanism of lung adenocarcinoma and combine behavioral therapy with treatment to optimize treatment decision-making.


Assuntos
Adenocarcinoma de Pulmão , Relógios Circadianos , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/patologia , Prognóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Relógios Circadianos/genética , Feminino , Masculino , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Ritmo Circadiano/genética , Pessoa de Meia-Idade , Bases de Dados Genéticas
14.
Colloids Surf B Biointerfaces ; 242: 114091, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39018913

RESUMO

Radiotherapy, despite its precision and non-invasiveness, often fails due to the resistance of cancer stem cells (CSCs), which are characterized by high self-renewal capabilities and superior DNA repair mechanisms. These cells can evade RT and lead to tumor recurrence and metastasis. To address this challenge, a novel delivery system named PB has been introduced. This system combines liposomes with platelet membranes to encapsulate Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES), thus enhancing its delivery and release specifically at tumor sites. In addition, this system not only targets CSCs effectively but also increases the local concentration of BPTES upon X-ray irradiation, which reduces glutathione levels in tumor cells, thereby increasing oxidative stress and damaging mitochondria. PB-elicited mitochondrial damage as the STING signal initiator, which mediated significant upregulation in the expression of a cGAS-STING pathway-related protein thereby amplifying the STING signal. Systemic intravenous administration of PB remarkably promoted DC maturation and CD8+ T cell infiltration, thus eliciting strong antitumor effects. Overall, this PB system presents a potent method to overcome CSC-related resistance and offers a promising approach for future cancer treatment protocols.


Assuntos
Lipossomos , Mitocôndrias , Lipossomos/química , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Animais , Humanos , Camundongos , Imunoterapia/métodos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Neoplasias/patologia , Neoplasias/tratamento farmacológico , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL
15.
Cell Rep ; 43(8): 114529, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39046876

RESUMO

Neuronal activation is required for the formation of drug-associated memory, which is critical for the development, persistence, and relapse of drug addiction. Nevertheless, the metabolic mechanisms underlying energy production for neuronal activation remain poorly understood. In the study, a large-scale proteomics analysis of lysine crotonylation (Kcr), a type of protein posttranslational modification (PTM), reveals that cocaine promoted protein Kcr in the hippocampal dorsal dentate gyrus (dDG). We find that Kcr is predominantly discovered in a few enzymes critical for mitochondrial energy metabolism; in particular, pyruvate dehydrogenase (PDH) complex E1 subunit α (PDHA1) is crotonylated at the lysine 39 (K39) residue through P300 catalysis. Crotonylated PDHA1 promotes pyruvate metabolism by activating PDH to increase ATP production, thus providing energy for hippocampal neuronal activation and promoting cocaine-associated memory recall. Our findings identify Kcr of PDHA1 as a PTM that promotes pyruvate metabolism to enhance neuronal activity for cocaine-associated memory.


Assuntos
Cocaína , Hipocampo , Memória , Neurônios , Piruvato Desidrogenase (Lipoamida) , Animais , Cocaína/farmacologia , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Piruvato Desidrogenase (Lipoamida)/metabolismo , Memória/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Processamento de Proteína Pós-Traducional , Lisina/metabolismo , Humanos
16.
Adv Sci (Weinh) ; 11(35): e2405575, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39033534

RESUMO

Photothermal therapy (PTT) holds considerable clinical promise. However, insufficient PTT-induced tumor recurrence and metastasis is an urgent practical problem that needs to be solved. Herein, a biomimetic mesoporous organosilicon nano-system called PSAB is designed to precisely deplete cancer stem cells (CSCs) and prevent tumor recurrence and metastasis after PTT. The PSAB system is made up of Aggregation-induced emission (AIE)-active photothermal agent, 2TT-oC26B, and SO2 prodrug, benzothiazole sulfinate (BTS), within mesoporous organosilicon nanoparticles (MON) enclosed by an exterior platelet membrane. PSAB effectively targets CSCs both in vitro and in vivo by P-selectin/CD44 interaction. The degradation of MON and subsequent release of BTS and AIE molecules are facilitated by intracellular glutathione (GSH). Subsequently, the acidic tumor environment triggers the SO2 gas therapy from BTS. This process leads to the depletion of GSH and CSCs elimination. After combining PSAB with photothermal therapy, there is no significant tumor recurrence or metastasis. These results indicate that SO2 gas therapy and AIE-mediated PTT act synergistically to offer a unique approach for preventing tumor recurrence and metastasis after PTT, thus holding significant promise for clinical applications in cancer PTT.


Assuntos
Neoplasias da Mama , Nanopartículas , Recidiva Local de Neoplasia , Terapia Fototérmica , Pró-Fármacos , Pró-Fármacos/farmacologia , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Camundongos , Terapia Fototérmica/métodos , Feminino , Nanopartículas/química , Modelos Animais de Doenças , Metástase Neoplásica , Humanos , Linhagem Celular Tumoral , Biomimética/métodos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo
17.
ACS Appl Mater Interfaces ; 16(30): 39917-39926, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39016554

RESUMO

We proposed and demonstrated highly sensitive hybrid surface-enhanced Raman scattering (SERS) substrates, which are grating-integrated gold nanograsses (GIGN) that are tip-selectively encapsulated by ZIF-8 nanospheres (GIGN/tip-ZIF). This unique structure is realized through the tip-selective modification of GIGN by polyvinylpyrrolidone (PVP), and then, the tips of the GIGN were encapsulated by ZIF-8 nanospheres. The ZIF-8 nanospheres can adsorb analyte molecules, resulting in the spatial overlap between the analyte molecules and the "hotspots" on the tips of GIGN. Such a unique GIGN/tip-ZIF hybrid SERS substrate exhibits high sensitivity and quantitative detection ability. The detection limits can reach as low as 10-11 M, and the relative standard deviation is 5.59% for 4-aminothiophenol (4-ATP). In a wide range of concentrations from 10-5 to 10-11 M, the SERS intensity and concentration relationship can be fitted as a sigmoidal curve with R2 = 0.988. These indicate that the GIGN/tip-ZIF hybrid SERS substrates have broad applications in detecting toxic and harmful substances in food safety, disease diagnosis, and environmental monitoring.

18.
Am J Transl Res ; 16(6): 2662-2669, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39006291

RESUMO

OBJECTIVE: This study assessed the impact of acupuncture combined with exercise rehabilitation on the quality of life in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS: In a retrospective study at the Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, 114 post-PCI ACS patients were analyzed from March 2021 to June 2023. Fifty-five underwent exercise rehabilitation (control group), while 59 received both acupuncture and exercise rehabilitation (joint group). Propensity score matching reduced each group to 38 patients. Traditional Chinese Medicine (TCM) scores, 6-minute walk distance, cardiac function, and biochemical indices were evaluated pre- and post-intervention. The Minnesota Living with Heart Failure Questionnaire (MLHFQ) measured quality of life changes, categorizing scores <24 as good and ≥24 as poor. Logistic regression identified factors affecting quality of life. RESULTS: The joint group showed significant improvements in TCM scores, 6-minute walk distance, left ventricular end-diastolic diameter, left ventricular ejection fraction, cardiac output, cardiac index, and levels of CK-MB, cTnT, and homocysteine compared to the control group (P<0.05). MLHFQ scores for physical limitations and disease symptoms decreased significantly in the joint group, with no marked changes in social relationship scores (P>0.05). CONCLUSIONS: Acupuncture alongside exercise rehabilitation significantly improves quality of life, cardiac function, and biochemical markers in ACS patients post-PCI, surpassing the effects of rehabilitation alone. This combination approach notably diminishes symptoms and improves daily functioning.

19.
Nat Commun ; 15(1): 5881, 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-38997250

RESUMO

Carbon chain elongation (CCE) is normally carried out using either chemical catalysts or bioenzymes. Herein we demonstrate a catalyst-free approach to promote demethylation C-C coupling reactions for advanced CCE constructed with functional groups under ambient conditions. Accelerated by the electric field, two organic cations containing a methyl group (e.g., ketones, acids, and aldehydes) approach each other with such proximity that the energy of the repulsive Coulomb interaction between these two cations exceeds the bond energy of the methyl group. This results in the elimination of a methyl cation and the coupling of the residual carbonyl carbon groups. As confirmed by high-resolution mass spectrometry and isotope-labeling experiments, the C-C coupling reactions (yields up to 76.5%) were commonly observed in the gas phase or liquid phase, for which the mechanism was further studied using molecular dynamics simulations and stationary-point calculations, revealing deep insights and perspectives of chemistry.

20.
J Int Med Res ; 52(7): 3000605241259669, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39053452

RESUMO

Parathyroid carcinoma (PC) is a rare and aggressive endocrine malignancy with limited treatment options. Current treatments such as chemotherapy and radiotherapy have demonstrated limited efficacy. Here, we report the case of a male patient who presented with symptoms including polydipsia, polyuria, and joint pain. Further examination revealed a neck lump, hypercalcemia, and hyperparathyroidism, leading to a diagnosis of PC after en bloc surgery. Seven months later, the patient developed local recurrence and lung metastases, which were resected via left lateral neck dissection and thoracoscopic wedge resection. A 422-gene panel test revealed the presence of epidermal growth factor receptor (EGFR) p.L858R (c. T2573G) mutation, which may sensitize the EGFR-tyrosine kinase inhibitor response, and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) p.E545KV (c. G1633A) mutation. After multidisciplinary treatment discussions, the patient was treated with the multi-target tyrosine kinase inhibitor, anlotinib, resulting in survival benefits for 19 months. This case highlights the potential of targeted therapy in terms of long-term survival in patients with distant metastatic PC, as well as the importance of precision therapy guided by genome sequencing to identify potential therapeutic targets.


Assuntos
Receptores ErbB , Mutação , Neoplasias das Paratireoides , Humanos , Masculino , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/patologia , Pessoa de Meia-Idade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia
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