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BACKGROUND: Stimulator of interferons genes (STING) is crucial for innate immune response. It has been demonstrated that cGAS-STING pathway was the driver of aging-related inflammation. However, whether STING is involved in cardiac dysfunction during the physiological aging process remains unclear. METHODS: Gene expression profiles were obtained from the Gene Expression Omnibus database, followed by weighted gene co-expression network analysis, gene ontology analysis and protein network interaction analysis to identify key pathway and genes associated with aging. The effects of STING on cardiac function, glucose homeostasis, inflammation, and autophagy in physiological aging were investigated with STING knockout mice. RESULTS: Bioinformatics analysis revealed STING emerged as a hub gene of interest. Subsequent experiments demonstrated the activation of STING pathway in the heart of aged mice. Knockout of STING alleviated the inflammation in aged mice. However, Knockout of STING impaired glucose tolerance, inhibited autophagy, enhanced oxidative stress and aggravated cardiac dysfunction in aged mice. CONCLUSION: Although reducing inflammation, long-term STING inhibition by genetic ablation exacerbated cardiac dysfunction in aged mice. Given the multifaceted nature of aging and the diverse cellular functions of STING beyond immune regulation, the negative effects of targeting STING as a strategy to mitigate aging phenotype should be fully considered.
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Skin damage caused by chemical corrosion is currently one of the common skin diseases and poisoning symptoms, with nitrogen mustard compounds causing the most persistent and severe damage. These chemicals penetrate the top layer of the skin, enter the dermis, and cause DNA damage, oxidative stress, and inflammation. However, to date, no effective drug treatment has been found. Even the potential antidotes could not effectively penetrate the top layer of the skin to exert their effects due to the skin barrier. To address this problem, an innovative transdermal drug delivery strategy based on aspirin microneedles was proposed. The classic medicine aspirin was first discovered not only to reduce inflammation and oxidative stress but also to promote DNA repair and reduce DNA damage. The aspirin microneedles directly delivered the drug to the damaged area, released aspirin through the skin barrier, and exhibited good biocompatibility. These findings indicate that aspirin microneedles have great potential for promoting wound healing and broad application prospects.
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Background: Critical illness, or acute organ failure requiring life support, threatens over five million American lives annually. Electronic health record (EHR) data are a source of granular information that could generate crucial insights into the nature and optimal treatment of critical illness. However, data management, security, and standardization are barriers to large-scale critical illness EHR studies. Methods: A consortium of critical care physicians and data scientists from eight US healthcare systems developed the Common Longitudinal Intensive Care Unit (ICU) data Format (CLIF), an open-source database format that harmonizes a minimum set of ICU Data Elements for use in critical illness research. We created a pipeline to process adult ICU EHR data at each site. After development and iteration, we conducted two proof-of-concept studies with a federated research architecture: 1) an external validation of an in-hospital mortality prediction model for critically ill patients and 2) an assessment of 72-hour temperature trajectories and their association with mechanical ventilation and in-hospital mortality using group-based trajectory models. Results: We converted longitudinal data from 94,356 critically ill patients treated in 2020-2021 (mean age 60.6 years [standard deviation 17.2], 30% Black, 7% Hispanic, 45% female) across 8 health systems and 33 hospitals into the CLIF format, The in-hospital mortality prediction model performed well in the health system where it was derived (0.81 AUC, 0.06 Brier score). Performance across CLIF consortium sites varied (AUCs: 0.74-0.83, Brier scores: 0.06-0.01), and demonstrated some degradation in predictive capability. Temperature trajectories were similar across health systems. Hypothermic and hyperthermic-slow-resolver patients consistently had the highest mortality. Conclusions: CLIF facilitates efficient, rigorous, and reproducible critical care research. Our federated case studies showcase CLIF's potential for disease sub-phenotyping and clinical decision-support evaluation. Future applications include pragmatic EHR-based trials, target trial emulations, foundational multi-modal AI models of critical illness, and real-time critical care quality dashboards.
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Adipocyte-secreted factors intricately regulate adipose tissue function, and the underlying molecular mechanisms are only partially understood. However, the function of PRELP, which is a key component of the extracellular matrix (ECM) in adipocytes, remains largely unknown. In this study, we demonstrate that PRELP was upregulated in both obese humans and mice, which exhibited a positive correlation with metabolic disorders. PRELP knockout could resist HFD-induced obesity and inhibit adipocyte differentiation. PRELP knockout improved glucose tolerance, insulin sensitivity and alleviated adipose tissue fibrosis. Mechanistically, PRELP was secreted into the ECM and bound to the extracellular domain of its receptor p75NTR in adipocytes, which further activated the FAK/MAPK (JNK, p38 MAPK, ERK1/2) signaling pathway, promoting adipocyte differentiation and exacerbating adipocyte fibrosis. Adipocyte PRELP plays a pivotal role in regulating obesity and adipose tissue fibrosis through an autocrine manner, and PRELP may be a therapeutic target for obesity and its related metabolic disorders.
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Missed appointments, or no-shows, disrupt healthcare delivery, exacerbating chronic disease management and leading to worse health outcomes. Telehealth has surged as a viable solution to reduce no-shows and improve healthcare accessibility, especially during the COVID-19 pandemic. However, telehealth disparities and its long-term efficacy across various medical specialties remain understudied. To address this, we performed a retrospective analysis of electronic health records from a heterogenous network of hospitals in Illinois, examining telehealth use and no-shows across among 444,752 adult patients with 1,973,098 outpatient encounters across nine specialties during the sustained pandemic phase (i.e., January 1, 2021 to July 1, 2022). Among them, 84,290 (4.27%) were no-shows, and telehealth constituted 202,933 (10.3%) of the total encounters. Telehealth use during the sustained phase varied significantly by specialty type. Overall, telehealth encounters were associated with reduced no-show odds compared to in-person encounters (OR, 0.28; 95% CI, 0.26-0.29). Black and Hispanic patients, as well as those with Medicaid, had higher no-show odds relative to their counterparts, even when using telehealth. Mental health specialty had the highest telehealth usage rate and the highest no-show odds (OR, 2.99; 95% CI, 2.84-3.14) relative to other specialties included in the study. Moreover, specialty type had differential effects on no-shows for telehealth. These results underscore the variability in telehealth use by specialty type and pervasive disparities telehealth use and no-shows. As we move beyond the pandemic, our findings can inform policymakers to tailor policies and incentives to reach different patient groups as well as specialties, with varying needs, to promote equitable telehealth utilization.
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Spatially resolved transcriptomics integrates high-throughput transcriptome measurements with preserved spatial cellular organization information. However, many technologies cannot reach single-cell resolution. We present STdGCN, a graph model leveraging single-cell RNA sequencing (scRNA-seq) as reference for cell-type deconvolution in spatial transcriptomic (ST) data. STdGCN incorporates expression profiles from scRNA-seq and spatial localization from ST data for deconvolution. Extensive benchmarking on multiple datasets demonstrates that STdGCN outperforms 17 state-of-the-art models. In a human breast cancer Visium dataset, STdGCN delineates stroma, lymphocytes, and cancer cells, aiding tumor microenvironment analysis. In human heart ST data, STdGCN identifies changes in endothelial-cardiomyocyte communications during tissue development.
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Análisis de la Célula Individual , Transcriptoma , Humanos , Análisis de la Célula Individual/métodos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Microambiente Tumoral , Perfilación de la Expresión Génica/métodos , RNA-Seq/métodos , Análisis de Secuencia de ARN/métodosRESUMEN
Obesity is one of the threats to human health and survival. High fat diet (HFD)-induced obesity leads to adipose tissue fibrosis and a series of metabolic diseases. There are some people still thin under HFD, a phenomenon known as the "obesity resistance (OR) phenotype". It was found that Iroquois homeobox 3 (IRX3) is considered as a regulator in obesity, but the regulatory mechanism between OR and IRX3 is still unclear. In this study, we investigated OR on a HFD and the role of the IRX3 gene. Using mice, we observed that OR mice had lower body weights, reduced liver lipid synthesis, and increased white adipose tissue (WAT) lipolysis compared to obesity-prone (OP) mice. Additionally, OR mice exhibited spontaneous WAT browning and less fibrosis, correlating with higher Irx3 expression. Utilizing 3T3-L1 differentiated adipocytes, our study demonstrated that overexpression of Irx3 promoted thermogenesis-related gene expression and reduced adipocyte fibrosis. Therefore, Irx3 promotes WAT browning and inhibits fibrosis in OR mice. These results provide insight into the differences between obesity and OR, new perspectives on obesity treatment, and guidance for lessening adipose tissue fibrosis.
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Tejido Adiposo Pardo , Dieta Alta en Grasa , Fibrosis , Proteínas de Homeodominio , Obesidad , Factores de Transcripción , Animales , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Ratones , Obesidad/metabolismo , Obesidad/genética , Obesidad/patología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/patología , Dieta Alta en Grasa/efectos adversos , Masculino , Ratones Endogámicos C57BL , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Células 3T3-L1 , Termogénesis/genéticaRESUMEN
Amyloid-ß (Aß) and hyperphosphorylated tau protein are targets for Alzheimer's Disease (AD) immunotherapies, which are generally focused on single epitopes within Aß or tau. However, due to the complexity of both Aß and tau in AD pathogenesis, a multipronged approach simultaneously targeting multiple epitopes of both proteins could overcome limitations of monotherapies. Herein, we propose an active AD immunotherapy based on a nanoparticle vaccine comprising two Aß peptides (1-14 and pyroglutamate pE3-14) and three tau peptides (centered on phosphorylated pT181, pT217 and pS396/404). These correspond to both soluble and aggregated targets and are displayed on the surface of immunogenic liposomes in an orientation that maintains reactivity with epitope-specific monoclonal antibodies. Intramuscular immunization of mice with individual epitopes resulted in minimally cross-reactive antibody induction, while simultaneous co-display of 5 antigens ("5-plex") induced antibodies against all epitopes without immune interference. Post-immune sera recognized plaques and neurofibrillary tangles from human AD brain tissue. Vaccine administration to 3xTg-AD mice using a prophylactic dosing schedule inhibited tau and amyloid pathologies and resulted in improved cognitive function. Immunization was well tolerated and did not induce antigen-specific cellular responses or persistent inflammatory responses in the peripheral or central nervous system. Antibody levels could be reversed by halting monthly vaccinations. Altogether, these results indicate that active immune therapies based on nanoparticle formulations of multiple Aß and tau epitopes warrant further study for treating early-stage AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Modelos Animales de Enfermedad , Ratones Transgénicos , Proteínas tau , Animales , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/prevención & control , Proteínas tau/inmunología , Proteínas tau/metabolismo , Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/metabolismo , Ratones , Humanos , Vacunas contra el Alzheimer/inmunología , Vacunas contra el Alzheimer/administración & dosificación , Encéfalo/metabolismo , Femenino , Epítopos/inmunología , Nanopartículas , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/administración & dosificación , Anticuerpos , Vacunas de Subunidades ProteicasRESUMEN
Approaches to regenerating bone often rely on integrating biomaterials and biological signals in the form of cells or cytokines. However, from a translational point of view, these approaches are challenging due to the sourcing and quality of the biologic, unpredictable immune responses, complex regulatory paths, and high costs. We describe a simple manufacturing process and a material-centric 3D-printed composite scaffold system (CSS) that offers distinct advantages for clinical translation. The CSS comprises a 3D-printed porous polydiolcitrate-hydroxyapatite composite elastomer infused with a polydiolcitrate-graphene oxide hydrogel composite. Using a micro-continuous liquid interface production 3D printer, we fabricate a precise porous ceramic scaffold with 60 wt% hydroxyapatite resembling natural bone. The resulting scaffold integrates with a thermoresponsive hydrogel composite in situ to fit the defect, which is expected to enhance surface contact with surrounding tissue and facilitate biointegration. The antioxidative properties of citrate polymers prevent long-term inflammatory responses. The CSS stimulates osteogenesis in vitro and in vivo. Within 4 weeks in a calvarial critical-sized bone defect model, the CSS accelerated ECM deposition (8-fold) and mineralized osteoid (69-fold) compared to the untreated. Through spatial transcriptomics, we demonstrated the comprehensive biological processes of CSS for prompt osseointegration. Our material-centric approach delivers impressive osteogenic properties and streamlined manufacturing advantages, potentially expediting clinical application for bone reconstruction surgeries.
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Background: Oral mucositis (OM) poses a significant challenge in children undergoing hematopoietic stem cell transplantation (HSCT). There is a gap between clinical practice and the evidence, and nursing practices is not standardized. Objective: This study aims to evaluate the effectiveness of applying the evidence for preventing HSCT chemotherapy-induced OM in children and to elevate the nurses' compliance to the evidence. Methods: Following the clinical evidence practice application model of the Joanna Briggs Institute (JBI) evidence-Based Care Center. The process included reviewing literature, extracting evidence, identifying gaps, developing audit criteria, conducting a baseline audit, creating an action plan, implementing evidence-based interventions, and assessing outcomes. Results: After the evidence implementation, 6 out of 12 audit criteria with poor compliance are significantly improved, with statistically significant differences (P<0.05). The incidence of OM decreases, with a statistically significant difference (66.6% vs 36.7%, P=0.02). The incidence of grade I, II, III, and IV OM also decreases (30% vs 23.3%, 23.3% vs 13.4%, 10% vs 0%, and 3.3% vs 0%). Ultimately, the standardized oral care practice routine and workflows to prevent OM were established. Conclusion: Bridging the gap between evidence and clinical practice can standardize nurse behavior, decrease the incidence of OM, and lower the OM severity in children undergoing HSCT.
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The WNT5B ligand regulates the non-canonical wingless-related integration site (WNT)-planar cell polarity (PCP) pathway. However, the detailed mechanism underlying the activity of WNT5B in the WNT-PCP pathway in non-small cell lung cancer (NSCLC) is unclear. In this study, we assessed the clinicopathological significance of WNT5B expression in NSCLC specimens. WNT5B-overexpression and -knockdown NSCLC cell lines were generated in vivo and in vitro, respectively. WNT5B overexpression in NSCLC specimens correlates with advanced tumor node metastasis (TNM) stage, lymph node metastasis, and poor prognosis in patients with NSCLC. Additionally, WNT5B promotes the malignant phenotype of NSCLC cells in vivo and in vitro. Interactions were identified among WNT5B, frizzled3 (FZD3), and disheveled3 (DVL3) in NSCLC cells, leading to the activation of WNT-PCP signaling. The FZD3 receptor initiates DVL3 recruitment to the membrane for phosphorylation in a WNT5B ligand-dependent manner and activates c-Jun N-terminal kinase (JNK) signaling via the small GTPase RAC1. Furthermore, the deletion of the DEP domain of DVL3 abrogated these effects. Overall, we demonstrated a novel signal transduction pathway in which WNT5B recruits DVL3 to the membrane via its DEP domain through interaction with FZD3 to promote RAC1-PCP-JNK signaling, providing a potential target for clinical intervention in NSCLC treatment.
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Carcinoma de Pulmón de Células no Pequeñas , Proteínas Dishevelled , Receptores Frizzled , Neoplasias Pulmonares , Proteínas Wnt , Proteína de Unión al GTP rac1 , Humanos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores Frizzled/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Proteínas Dishevelled/metabolismo , Proteínas Wnt/metabolismo , Línea Celular Tumoral , Femenino , Masculino , Animales , Polaridad Celular , Persona de Mediana Edad , Fenotipo , Ratones Desnudos , Sistema de Señalización de MAP Quinasas , Ratones , Vía de Señalización WntRESUMEN
The aim of this study was to synthesize a quinoline-based MRI contrast agent, Gd-DOTA-FAPI04, and assess its capacity for targeting fibroblast activation protein (FAP)-positive tumors in vivo. Gd-DOTA-FAPI04 was synthesized by attaching a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complex of gadolinium(III) to FAP inhibitor FAPI04. The longitudinal relaxation time (T1) of the contrast agent was measured using a Siemens Prisma 3.0T MR system, and the CCK-8 assay was performed to evaluate its potential cytotoxicity. Male nude mice bearing tumors grown from FAP-expressing fibrosarcoma cells were divided into experimental (n = 4) and control (n = 4) groups, and T1-weighted image enhancement was measured at different times (0, 10, 30, 60, 90, and 120 min) postinjection of Gd-DOTA-FAPI04. The control group received an additional preinjection of excess FAPI04. FAP expression in tumor tissue was investigated by using immunohistochemistry with an anti-FAP antibody. The longitudinal relaxivities of gadodiamide and Gd-DOTA-FAPI04 were measured to be 3.734 mM-1 s-1 and 5.323 mM-1 s-1, respectively. The CCK-8 assay demonstrated that Gd-DOTA-FAPI04 has minimal toxicity to cultured human fibrosarcoma cells. In vivo MRI showed that peak accumulation of Gd-DOTA-FAPI04 in FAP-expressing tumors occurred 1 h postinjection and could be blocked by preinjection of excess FAPI04. Immunohistochemical analysis of harvested tumor tissue supported the above findings. Gd-DOTA-FAPI04 is a promising contrast agent for in vivo imaging of FAP.
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In recent years, two-dimensional (2D) van der Waals materials have emerged as a focal point in materials research, drawing increasing attention due to their potential for isolating and synergistically combining diverse atomic layers. Atomically thin transition metal dichalcogenides (TMDs) are one of the most alluring van der Waals materials owing to their exceptional electronic and optical properties. The tightly bound excitons with giant oscillator strength render TMDs an ideal platform to investigate strong light-matter coupling when they are integrated with optical cavities, providing a wide range of possibilities for exploring novel polaritonic physics and devices. In this review, we focused on recent advances in TMD-based strong light-matter coupling. In the foremost position, we discuss the various optical structures strongly coupled to TMD materials, such as Fabry-Perot cavities, photonic crystals, and plasmonic nanocavities. We then present several intriguing properties and relevant device applications of TMD polaritons. In the end, we delineate promising future directions for the study of strong light-matter coupling in van der Waals materials.
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Background: More and more evidence supports the association between myocardial infarction (MI) and osteoarthritis (OA). The purpose of this study is to explore the shared biomarkers and pathogenesis of MI complicated with OA by systems biology. Methods: Gene expression profiles of MI and OA were downloaded from the Gene Expression Omnibus (GEO) database. The Weighted Gene Co-Expression Network Analysis (WGCNA) and differentially expressed genes (DEGs) analysis were used to identify the common DEGs. The shared genes related to diseases were screened by three public databases, and the protein-protein interaction (PPI) network was built. GO and KEGG enrichment analyses were performed on the two parts of the genes respectively. The hub genes were intersected and verified by Least absolute shrinkage and selection operator (LASSO) analysis, receiver operating characteristic (ROC) curves, and single-cell RNA sequencing analysis. Finally, the hub genes differentially expressed in primary cardiomyocytes and chondrocytes were verified by RT-qPCR. The immune cell infiltration analysis, subtypes analysis, and transcription factors (TFs) prediction were carried out. Results: In this study, 23 common DEGs were obtained by WGCNA and DEGs analysis. In addition, 199 common genes were acquired from three public databases by PPI. Inflammation and immunity may be the common pathogenic mechanisms, and the MAPK signaling pathway may play a key role in both disorders. DUSP1, FOS, and THBS1 were identified as shared biomarkers, which is entirely consistent with the results of single-cell RNA sequencing analysis, and furher confirmed by RT-qPCR. Immune infiltration analysis illustrated that many types of immune cells were closely associated with MI and OA. Two potential subtypes were identified in both datasets. Furthermore, FOXC1 may be the crucial TF, and the relationship of TFs-hub genes-immune cells was visualized by the Sankey diagram, which could help discover the pathogenesis between MI and OA. Conclusion: In summary, this study first revealed 3 (DUSP1, FOS, and THBS1) novel shared biomarkers and signaling pathways underlying both MI and OA. Additionally, immune cells and key TFs related to 3 hub genes were examined to further clarify the regulation mechanism. Our study provides new insights into shared molecular mechanisms between MI and OA.
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Biomarcadores , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Infarto del Miocardio , Osteoartritis , Mapas de Interacción de Proteínas , Biología de Sistemas , Infarto del Miocardio/genética , Infarto del Miocardio/inmunología , Osteoartritis/genética , Osteoartritis/metabolismo , Humanos , Bases de Datos Genéticas , Transcriptoma , Condrocitos/metabolismo , Condrocitos/inmunología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Animales , Biología Computacional/métodosRESUMEN
BACKGROUND: Stroke is a globally dangerous disease capable of causing irreversible neuronal damage with limited therapeutic options. Meldonium, an inhibitor of carnitine-dependent metabolism, is considered an anti-ischemic drug. However, the mechanisms through which meldonium improves ischemic injury and its potential to protect neurons remain largely unknown. METHODS: A rat model with middle cerebral artery occlusion (MCAO) was used to investigate meldonium's neuroprotective efficacy in vivo. Infarct volume, neurological deficit score, histopathology, neuronal apoptosis, motor function, morphological alteration and antioxidant capacity were explored via 2,3,5-Triphenyltetrazolium chloride staining, Longa scoring method, hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay, rotarod test, transmission electron microscopy and Oxidative stress index related kit. A primary rat hippocampal neuron model subjected to oxygen-glucose deprivation reperfusion was used to study meldonium's protective ability in vitro. Neuronal viability, mitochondrial membrane potential, mitochondrial morphology, respiratory function, ATP production, and its potential mechanism were assayed by MTT cell proliferation and cytotoxicity assay kit, cell-permeant MitoTracker® probes, mitochondrial stress, real-time ATP rate and western blotting. RESULTS: Meldonium markedly reduced the infarct size, improved neurological function and motor ability, and inhibited neuronal apoptosis in vivo. Meldonium enhanced the morphology, antioxidant capacity, and ATP production of mitochondria and inhibited the opening of the mitochondrial permeability transition pore in the cerebral cortex and hippocampus during cerebral ischemia-reperfusion injury (CIRI) in rats. Additionally, meldonium improved the damaged fusion process and respiratory function of neuronal mitochondria in vitro. Further investigation revealed that meldonium activated the Akt/GSK-3ß signaling pathway to inhibit mitochondria-dependent neuronal apoptosis. CONCLUSION: Our study demonstrated that meldonium shows a neuroprotective function during CIRI by preserving the mitochondrial function, thus prevented neurons from apoptosis.
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Apoptosis , Supervivencia Celular , Metilhidrazinas , Mitocondrias , Neuronas , Fármacos Neuroprotectores , Ratas Sprague-Dawley , Daño por Reperfusión , Animales , Fármacos Neuroprotectores/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Daño por Reperfusión/patología , Daño por Reperfusión/tratamiento farmacológico , Masculino , Supervivencia Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Metilhidrazinas/farmacología , Metilhidrazinas/uso terapéutico , Isquemia Encefálica/patología , Isquemia Encefálica/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , RatasRESUMEN
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory tissue disease. In view of the explosive growth in research on SLE, bibliometrics was performed to evaluate the 100 top-cited papers in this realm. We performed the search with terms "systemic lupus erythematosus" the Web of Science Core Collection database on May 3, 2023. Relevant literatures were screened. Data were extracted and analyzed by SPSS. The citations of 100 top-cited SLE studies spanned from 472 to 13,557. Most studies (60 out of 100) were conducted in the United States. Total citation times were positively associated with ACY, which was negatively correlated with the length of time since publication. Approximately half of the studies focused on the underlying mechanisms of SLE. New biologic therapies garnered attention and development. Our findings provide valuable insights into the developments in crucial areas of SLE and shed contributions to future studies.
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Bibliometría , Lupus Eritematoso Sistémico , HumanosRESUMEN
The municipal solid waste (MSW) management is significantly contributing to global greenhouse gas (GHG) emissions. Analyzing the emission pattern of GHGs from MSW is essential for formulating appropriate carbon mitigation policies. Based on IPCC Models, GHG emissions from MSW were calculated in Chinese provinces from 2004 to 2021 by landfilling and incineration operations, separately. Landfilling and incineration generated approximately 1271 MtCO2-eq and 198 MtCO2-eq from 2004 to 2021, respectively. GHG emissions from landfilling increased from 2004 to 2020 and declined in 2021, while GHG emissions from incineration demonstrated an increasing trend with three distinct growth stages. A panel regression model was then employed to identify the key factors influencing GHG emissions. GDP and population are positively related to GHG emissions from landfills, while PCCE is negatively related to GHG emissions from landfills. GDP and PCCE have a positive impact on GHG emissions from incineration, while population showed no significant impact. Multi-expression programming was used to develop an explicit model, forecasting GHG emissions from MSW by 2030. From 2022 to 2024, GHG emissions from landfills will quickly decrease, while GHG emissions from incineration will rapidly increase. Subsequently, the GHG emission rate of incineration will slow down, and GHGs from landfilling will slowly decrease due to no MSW for landfill disposal. The methods and results provide insightful information for policy-makers and waste management sector.
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Gases de Efecto Invernadero , Eliminación de Residuos , Residuos Sólidos , Gases de Efecto Invernadero/análisis , Residuos Sólidos/análisis , Eliminación de Residuos/métodos , China , Predicción , Contaminantes Atmosféricos/análisis , Incineración , Instalaciones de Eliminación de Residuos , Modelos Teóricos , Monitoreo del Ambiente/métodosRESUMEN
The mitochondrial citrate shuttle, which relies on the solute carrier family 25 member 1 (SLC25A1), plays a pivotal role in transporting citrate from the mitochondria to the cytoplasm. This shuttle supports glycolysis, lipid biosynthesis, and protein acetylation. Previous research has primarily focused on SLC25A1 in pathological models, particularly high-fat diet (HFD)-induced obesity. However, the impact of SLC25A1 inhibition on nutrient metabolism under HFD remains unclear. To address this gap, we used zebrafish (Danio rerio) and Nile tilapia (Oreochromis niloticus) to evaluate the effects of inhibiting Slc25a1. In zebrafish, we administered Slc25a1-specific inhibitors (CTPI-2) for 4 wk, whereas Nile tilapia received intraperitoneal injections of dsRNA to knock down slc25a1b for 7 days. Inhibition of the mitochondrial citrate shuttle effectively protected zebrafish from HFD-induced obesity, hepatic steatosis, and insulin resistance. Of note, glucose tolerance was unaffected. Inhibition of Slc25a1 altered hepatic protein acetylation patterns, with decreased cytoplasmic acetylation and increased mitochondrial acetylation. Under HFD conditions, Slc25a1 inhibition promoted fatty acid oxidation and reduced hepatic triglyceride (TAG) accumulation by deacetylating carnitine palmitoyltransferase 1a (Cpt1a). In addition, Slc25a1 inhibition triggered acetylation-induced inactivation of Pdhe1α, leading to a reduction in glucose oxidative catabolism. This was accompanied by enhanced glucose uptake and storage in zebrafish livers. Furthermore, Slc25a1 inhibition under HFD conditions activated the SIRT1/PGC1α pathway, promoting mitochondrial proliferation and enhancing oxidative phosphorylation for energy production. Our findings provide new insights into the role of nonhistone protein acetylation via the mitochondrial citrate shuttle in the development of hepatic lipid deposition and hyperglycemia caused by HFD.NEW & NOTEWORTHY The mitochondrial citrate shuttle is a crucial physiological process for maintaining metabolic homeostasis. In the present study, we found that inhibition of mitochondrial citrate shuttle (Slc25a1) could alleviate metabolic syndromes induced by high-fat diet (HFD) through remodeling hepatic protein acetylation modification. Briefly, Slc25a1 inhibition reduces hepatic triglyceride deposition by deacetylating Cpt1a and reduces glucose oxidative catabolism by acetylating Pdhe1α. Our study provides new insights into the treatment of diet-induced metabolic syndromes.
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Ácido Cítrico , Dieta Alta en Grasa , Pez Cebra , Animales , Dieta Alta en Grasa/efectos adversos , Ácido Cítrico/metabolismo , Síndrome Metabólico/metabolismo , Síndrome Metabólico/prevención & control , Síndrome Metabólico/genética , Síndrome Metabólico/etiología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Carnitina O-Palmitoiltransferasa/metabolismo , Carnitina O-Palmitoiltransferasa/genética , Obesidad/metabolismo , Obesidad/prevención & control , Obesidad/genética , Obesidad/etiología , Acetilación , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Resistencia a la Insulina , Hígado Graso/metabolismo , Hígado Graso/prevención & control , Hígado Graso/patología , Hígado Graso/etiología , Metabolismo de los Lípidos/efectos de los fármacosRESUMEN
BACKGROUND: Acute hypobaric hypoxia-induced brain injury has been a challenge in the health management of mountaineers; therefore, new neuroprotective agents are urgently required. Meldonium, a well-known cardioprotective drug, has been reported to have neuroprotective effects. However, the relevant mechanisms have not been elucidated. We hypothesized that meldonium may play a potentially novel role in hypobaric hypoxia cerebral injury. METHODS: We initially evaluated the neuroprotection efficacy of meldonium against acute hypoxia in mice and primary hippocampal neurons. The potential molecular targets of meldonium were screened using drug-target binding Huprot™ microarray chip and mass spectrometry analyses after which they were validated with surface plasmon resonance (SPR), molecular docking, and pull-down assay. The functional effects of such binding were explored through gene knockdown and overexpression. RESULTS: The study clearly shows that pretreatment with meldonium rapidly attenuates neuronal pathological damage, cerebral blood flow changes, and mitochondrial damage and its cascade response to oxidative stress injury, thereby improving survival rates in mice brain and primary hippocampal neurons, revealing the remarkable pharmacological efficacy of meldonium in acute high-altitude brain injury. On the one hand, we confirmed that meldonium directly interacts with phosphoglycerate kinase 1 (PGK1) to promote its activity, which improved glycolysis and pyruvate metabolism to promote ATP production. On the other hand, meldonium also ameliorates mitochondrial damage by PGK1 translocating to mitochondria under acute hypoxia to regulate the activity of TNF receptor-associated protein 1 (TRAP1) molecular chaperones. CONCLUSION: These results further explain the mechanism of meldonium as an energy optimizer and provide a strategy for preventing acute hypobaric hypoxia brain injury at high altitudes.