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Stroke leads to persistently high risk for recurrent vascular events caused by systemic atheroprogression that is driven by endothelial cell (EC) activation. However, whether and how stroke induces sustained pro-inflammatory and proatherogenic endothelial alterations in systemic vessels remain poorly understood. We showed that brain ischemia induces persistent activation, the upregulation of adhesion molecule VCAM1, and increased senescence in peripheral ECs until 4 weeks after stroke onset. This aberrant EC activity resulted from sustained Notch1 signaling, which was triggered by increased circulating Notch1 ligands DLL1 and Jagged1 after stroke in mice and humans. Consequently, this led to increased myeloid cell adhesion and atheroprogression by generating a senescent, pro-inflammatory endothelium. Notch1- or VCAM1-blocking antibodies and the genetic ablation of endothelial Notch1 reduced atheroprogression after stroke. Our findings revealed a systemic machinery that induces the persistent activation of peripheral ECs after stroke, which paves the way for therapeutic interventions or the prevention of recurrent vascular events following stroke.
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Cells undergo metabolic adaptation during environmental changes by using evolutionarily conserved stress response programs. This metabolic homeostasis is exquisitely regulated, and its imbalance could underlie human pathological conditions. We report here that C9orf72, which is linked to the most common forms of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is a key regulator of lipid metabolism under stress. Loss of C9orf72 leads to an overactivation of starvation-induced lipid metabolism that is mediated by dysregulated autophagic digestion of lipids and increased de novo fatty acid synthesis. C9orf72 acts by promoting the lysosomal degradation of coactivator-associated arginine methyltransferase 1 (CARM1), which in turn regulates autophagy-lysosomal functions and lipid metabolism. In ALS/FTD patient-derived neurons or tissues, a reduction in C9orf72 function is associated with dysregulation in the levels of CARM1, fatty acids, and NADPH oxidase NOX2. These results reveal a C9orf72-CARM1 axis in the control of stress-induced lipid metabolism and implicates epigenetic dysregulation in relevant human diseases.
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Proteína C9orf72/fisiologia , Glucose/fisiologia , Metabolismo dos Lipídeos , Proteína-Arginina N-Metiltransferases/metabolismo , Estresse Fisiológico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Células Cultivadas , Ácidos Graxos/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Células HEK293 , Humanos , Lisossomos/metabolismo , Camundongos , Proteína-Arginina N-Metiltransferases/fisiologiaRESUMO
Lysosomes are key organelles maintaining cellular homeostasis in health and disease. Here, we report the identification of N-deacetylase and N-sulfotransferase 3 (NDST3) as a potent regulator of lysosomal functions through an unbiased genetic screen. NDST3 constitutes a new member of the histone deacetylase (HDAC) family and catalyzes the deacetylation of α-tubulin. Loss of NDST3 promotes assembly of the V-ATPase holoenzyme on the lysosomal membrane and thereby increases the acidification of the organelle. NDST3 is downregulated in tissues and cells from patients carrying the C9orf72 hexanucleotide repeat expansion linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Deficiency in C9orf72 decreases the level of NDST3, and downregulation of NDST3 exacerbates the proteotoxicity of poly-dipeptides generated from the C9orf72 hexanucleotide repeats. These results demonstrate a previously unknown regulatory mechanism through which microtubule acetylation regulates lysosomal activities and suggest that NDST3 could be targeted to modulate microtubule and lysosomal functions in relevant diseases.
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Lisossomos/metabolismo , Sulfotransferases/metabolismo , Tubulina (Proteína)/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Acetilação , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Sistemas CRISPR-Cas , Linhagem Celular , Imunofluorescência , Expressão Gênica , Técnicas de Silenciamento de Genes , Biblioteca Gênica , Genes Reporter , Humanos , Concentração de Íons de Hidrogênio , Macrolídeos/farmacologia , Macrolídeos/toxicidade , Camundongos , Microtúbulos/metabolismo , Modelos Biológicos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Testes Farmacogenômicos/métodos , Variantes Farmacogenômicos , Ligação Proteica , Sulfotransferases/genética , ATPases Vacuolares Próton-Translocadoras/genéticaRESUMO
Hepatitis B virus (HBV) damages liver cells through abnormal immune responses. Mitochondrial metabolism is necessary for effector functions of white blood cells (WBCs). The aim was to investigate the altered counts and mitochondrial mass (MM) of WBCs by two novel indicators of mitochondrial mass, MM and percentage of low mitochondrial membrane potential, MMPlow%, due to chronic HBV infection. The counts of lymphocytes, neutrophils and monocytes in the HBV infection group were in decline, especially for lymphocyte (p = 0.034) and monocyte counts (p = 0.003). The degraded MM (p = 0.003) and MMPlow% (p = 0.002) of lymphocytes and MM (p = 0.005) of monocytes suggested mitochondrial dysfunction of WBCs. HBV DNA within WBCs showed an extensive effect on mitochondria metabolic potential of lymphocytes, neutrophils and monocytes indicated by MM; hepatitis B e antigen was associated with instant mitochondrial energy supply indicated by MMPlow% of neutrophils; hepatitis B surface antigen, antiviral therapy by nucleos(t)ide analogues and prolonged infection were also vital factors contributing to WBC alterations. Moreover, degraded neutrophils and monocytes could be used to monitor immune responses reflecting chronic liver fibrosis and inflammatory damage. In conclusion, MM combined with cell counts of WBCs could profoundly reflect WBC alterations for monitoring chronic HBV infection. Moreover, HBV DNA within WBCs may be a vital factor in injuring mitochondria metabolic potential.
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Vírus da Hepatite B , Hepatite B Crônica , Mitocôndrias , Humanos , Hepatite B Crônica/virologia , Hepatite B Crônica/patologia , Masculino , Feminino , Vírus da Hepatite B/patogenicidade , Adulto , Mitocôndrias/metabolismo , Pessoa de Meia-Idade , Contagem de Leucócitos , Leucócitos/metabolismo , DNA Viral/sangue , Potencial da Membrana Mitocondrial , Monócitos/metabolismo , Monócitos/imunologia , Monócitos/virologia , Monócitos/patologia , Neutrófilos/metabolismo , Neutrófilos/imunologiaRESUMO
Addressing the existing gaps in our understanding of sex- and strain-dependent disparities in renal microhemodynamics, this study conducted an investigation into the variations in renal function and related biological oscillators. Using the genetically diverse mouse models BALB/c, C57BL/6, and Kunming, which serve as established proxies for the study of renal pathophysiology, we implemented laser Doppler flowmetry conjoined with wavelet transform analyses to interrogate dynamic renal microcirculation. Creatinine, urea, uric acid, glucose, and cystatin C levels were quantified to investigate potential divergences attributable to sex and genetic lineage. Our findings reveal marked sexual dimorphism in metabolite concentrations, as well as strain-specific variances, particularly in creatinine and cystatin C levels. Through the combination of Mantel tests and Pearson correlation coefficients, we delineated the associations between renal functional metrics and microhemodynamics, uncovering interactions in female BALB/c mice for creatinine and uric acid, and in male C57BL/6 mice for cystatin C. Histopathologic examination confirmed an augmented microvascular density in female mice and elucidating variations in the expression of estrogen receptor ß among the strains. These data collectively highlight the influence of both sex and genetic constitution on renal microcirculation, providing an understanding that may inform the etiologic exploration of renal ailments.
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Rim , Animais , Feminino , Masculino , Rim/metabolismo , Rim/irrigação sanguínea , Camundongos , Caracteres Sexuais , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microcirculação , Cistatina C/metabolismo , Cistatina C/sangue , Creatinina/sangue , Especificidade da Espécie , Fluxometria por Laser-Doppler , Ácido Úrico/sangue , Ácido Úrico/metabolismo , Fatores SexuaisRESUMO
Ginseng (Panax ginseng C. A. Mey.) is an important and valuable medicinal plant species used in traditional Chinese medicine, and its metabolite ginsenoside is the primary active ingredient. The FAR1/FHY3 gene family members play critical roles in plant growth and development as well as participate in a variety of physiological processes, including plant development and signaling of hormones. Studies have indicated that methyl jasmonate treatment of ginseng adventitious roots resulted in a significant increase in the content of protopanaxadiol ginsenosides. Therefore, it is highly significant to screen the FAR1/FHY3 gene family members in ginseng and preliminarily investigate their expression patterns in response to methyl jasmonic acid signaling. In this study, we screened and identified the FAR1/FHY3 family genes in the ginseng transcriptome databases. And then, we analyzed their gene structure and phylogeny, chromosomal localization and expression patterns, and promoter cis-acting elements, and made GO functional annotations on the members of this family. After that, we treated the ginseng adventitious roots with 200 mM methyl jasmonate and investigated the trend of the expression of four genes containing the largest number of methyl jasmonate cis-acting elements at different treatment times. All four genes were able to respond to methyl jasmonate, the most significant change was in the PgFAR40 gene. This study provides data support for subsequent studies of this family member in ginseng and provides experimental reference for subsequent validation of the function of this family member under methyl jasmonic acid signaling.
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Acetatos , Ciclopentanos , Regulação da Expressão Gênica de Plantas , Família Multigênica , Oxilipinas , Panax , Filogenia , Proteínas de Plantas , Oxilipinas/farmacologia , Ciclopentanos/farmacologia , Panax/genética , Panax/metabolismo , Panax/efeitos dos fármacos , Acetatos/farmacologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Reguladores de Crescimento de Plantas/farmacologia , Reguladores de Crescimento de Plantas/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Perfilação da Expressão Gênica , Genes de Plantas , GinsenosídeosRESUMO
Panax ginseng is an important medicinal plant, and ginsenosides are the main bioactive molecules of ginseng. The TCP (TBI, CYC, PCF) family is a group of transcription factors (TFs) that play an important role in plant growth and development, hormone signalling and synthesis of secondary metabolites. In our study, 78 PgTCP transcripts were identified from the established ginseng transcriptome database. A phylogenetic tree analysis showed that the 67 PgTCP transcripts with complete open reading frames were classified into three subfamilies, including CIN, PCF, and CYC/TB1. Protein structure analysis showed that PgTCP genes had bHLH structures. Chromosomal localization analysis showed that 63 PgTCP genes were localized on 17 of the 24 chromosomes of the Chinese ginseng genome. Expression pattern analysis showed that PgTCP genes differed among different lineages and were spatiotemporally specific. Coexpression network analysis indicated that PgTCP genes were coexpressed and involved in plant activities or metabolic regulation in ginseng. The expression levels of PgTCP genes from class I (PCF) were significantly downregulated, while the expression levels of PgTCP genes from class II (CIN and CYC/TB1) were upregulated, suggesting that TCP genes may be involved in the regulation of secondary metabolism in ginseng. As the PgTCP26-02 gene was found to be related to ginsenoside synthesis, its predicted protein structure and expression pattern were further analysed. Our results provide new insights into the origin, differentiation, evolution and function of the PgTCP gene family in ginseng, as well as the regulation of plant secondary metabolism.
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Ginsenosídeos , Panax , Ginsenosídeos/metabolismo , Panax/genética , Panax/metabolismo , Filogenia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma , Regulação da Expressão Gênica de Plantas , Raízes de Plantas/metabolismoRESUMO
Silica is a promising shell coating material for colloidal nanoparticles due to its excellent chemical inertness and optical transparency. To encapsulate high-quality colloidal nanocrystals with silica shells, the silane coupling hydrolysis is currently the most effective approach. However, this reaction requires water, which often adversely affects the intrinsic physicochemical properties of nanocrystals. Achieving a damage-free silica encapsulation process to nanocrystals by hydrolysis is a huge challenge. Here, a novel strategy is developed to coat colloidal nanocrystals with a denser silica shell via a proactively water-generating reaction at high temperature. In this work, water molecules are continuously and proactively released into the reaction system through the amidation reaction, followed by in situ hydrolysis of silane, completely avoiding the impacts of water on nanocrystals during the silica coating process. In this work, water sensitive perovskite nanocrystals (CsPbBr3) are selected as the typical colloidal nanocrystals for silica coating. Notably, this high-temperature in situ encapsulation technology greatly improves the optical properties of nanocrystals, and the silica shells exhibit a denser structure, providing nanocrystals with better protection. This method overcomes the challenge of the influence of water on nanocrystals during the hydrolysis process, and provides an important reference for the non-destructive encapsulation of colloidal nanocrystals.
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Type 1 diabetes mellitus (T1DM) is predominantly managed using insulin replacement therapy, however, pancreatic microcirculatory disturbances play a critical role in T1DM pathogenesis, necessitating alternative therapies. This study aimed to investigate the protective effects of glycine supplementation on pancreatic microcirculation in T1DM. Streptozotocin-induced T1DM and glycine-supplemented mice (n = 6 per group) were used alongside control mice. Pancreatic microcirculatory profiles were determined using a laser Doppler blood perfusion monitoring system and wavelet transform spectral analysis. The T1DM group exhibited disorganized pancreatic microcirculatory oscillation. Glycine supplementation significantly restored regular biorhythmic contraction and relaxation, improving blood distribution patterns. Further-more, glycine reversed the lower amplitudes of endothelial oscillators in T1DM mice. Ultrastructural deterioration of islet microvascular endothelial cells (IMECs) and islet microvascular pericytes, including membrane and organelle damage, collagenous fiber proliferation, and reduced edema, was substantially reversed by glycine supplementation. Additionally, glycine supplementation inhibited the production of IL-6, TNF-α, IFN-γ, pro-MMP-9, and VEGF-A in T1DM, with no significant changes in energetic metabolism observed in glycine-supplemented IMECs. A statistically significant decrease in MDA levels accompanied by an increase in SOD levels was also observed with glycine supplementation. Notably, negative correlations emerged between inflammatory cytokines and microhemodynamic profiles. These findings suggest that glycine supplementation may offer a promising therapeutic approach for protecting against pancreatic microcirculatory dysfunction in T1DM.
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Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas , Camundongos , Animais , Microcirculação , Células Endoteliais , Ilhotas Pancreáticas/irrigação sanguínea , Ilhotas Pancreáticas/metabolismo , Suplementos NutricionaisRESUMO
The core plant circadian oscillator is composed of multiple interlocked transcriptional-translational feedback loops, which synchronize endogenous diel physiological rhythms to the cyclic changes of environmental cues. PSEUDO-RESPONSE REGULATORS (PRRs) have been identified as negative components in the circadian clock, though their underlying molecular mechanisms remain largely unknown. Here, we found that a subfamily of zinc finger transcription factors, B-box (BBX)-containing proteins, have a critical role in fine-tuning circadian rhythm. We demonstrated that overexpressing Arabidopsis thaliana BBX19 and BBX18 significantly lengthened the circadian period, while the null mutation of BBX19 accelerated the circadian speed. Moreover, BBX19 and BBX18, which are expressed during the day, physically interacted with PRR9, PRR7, and PRR5 in the nucleus in precise temporal ordering from dawn to dusk, consistent with the respective protein accumulation pattern of PRRs. Our transcriptomic and genetic analysis indicated that BBX19 and PRR9, PRR7, and PRR5 cooperatively inhibited the expression of morning-phased clock genes. PRR proteins affected BBX19 recruitment to the CCA1, LHY, and RVE8 promoters. Collectively, our findings show that BBX19 interacts with PRRs to orchestrate circadian rhythms, and suggest the indispensable role of transcriptional regulators in fine-tuning the circadian clock.
Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Ritmo Circadiano/genética , Fatores de Transcrição/genética , Arabidopsis/fisiologia , Proteínas de Arabidopsis/metabolismo , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica de Plantas , Mutação , Filogenia , Plantas Geneticamente Modificadas , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Fatores de Transcrição/metabolismoRESUMO
The limited elasticity and inadequate bonding of hydrogels made from guar gum (GG) significantly hinder their widespread implementation in personalized wearable flexible electronics. In this study, we devise GG-based self-adhesive hydrogels by creating an interpenetrating network of GG cross-linked with acrylic, 4-vinylphenylboronic acid, and Ca2+. With the leverage of the dynamic interactions (hydrogen bonds, borate ester bonds, and coordination bonds) between -OH in GG and monomers, the hydrogel exhibits a high stretchability of 700%, superior mechanical stress of 110 kPa, and robust adherence to several substrates. The adhesion strength of 54 kPa on porcine skin is obtained. Furthermore, the self-adhesive hydrogel possesses stable conductivity, an elevated gauge factor (GF), and commendable durability. It can be affixed to the human body as a strain sensor to obtain precise monitoring of human movement behavior. Our research offers possibilities for the development of GG-based hydrogels and applications in wearable electronics and medical monitoring.
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Condutividade Elétrica , Galactanos , Hidrogéis , Mananas , Gomas Vegetais , Hidrogéis/química , Mananas/química , Gomas Vegetais/química , Galactanos/química , Animais , Dispositivos Eletrônicos Vestíveis , Humanos , Suínos , Adesivos/químicaRESUMO
Chemodynamic therapy (CDT) has gained increasing attention by virtue of its high tumor specificity and low side effect. However, the low concentration of hydrogen peroxide (H2O2) in the tumor site suppresses the therapeutic efficacy of CDT. To improve the efficacy, introducing other kind of therapeutic modality is a feasible choice. Herein, we develop a self-amplified activatable nanomedicine (PCPTH NP) for chemodynamic/chemo combination therapy. PCPTH NP is composed of a H2O2-activatable amphiphilic prodrug PEG-PCPT and hemin. Upon addition of H2O2, the oxalate linkers within PCPTH NP are cleaved, which makes the simultaneous release of CPT and hemin. The released CPT can not only kill cancer cells but also upregulate the intracellular reactive oxygen species (ROS) level. The elevated ROS level may accelerate the release of drugs and enhance the CDT efficacy. PCPTH NP shows a H2O2concentration dependent release profile, and can effectively catalyze H2O2into hydroxyl radical (·OH) under acidic condition. Compared with PCPT NP without hemin, PCPTH NP has better anticancer efficacy bothin vitroandin vivowith high biosafety. Thus, our study provides an effective approach to improve the CDT efficacy with high tumor specificity.
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Nanopartículas , Neoplasias , Humanos , Hemina , Peróxido de Hidrogênio , Espécies Reativas de Oxigênio , Quimioterapia Combinada , Neoplasias/tratamento farmacológico , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
PURPOSE: To identify the symptom cluster among cancer survivors and examine their subgroup differences via network analysis based on nationally representative data. METHODS: This cross-sectional study included 2966 survivors participating in the 2020 National Health Interview Survey (NHIS). Participants self-reported the presence of 14 symptoms capturing four clusters (physical, somatic, sleep, and psychologic problems). Network analysis models were used to reveal the relationships between symptoms and those interactions. Network comparison tests were applied to compare subgroups. RESULTS: The core symptoms of the symptom cluster were fatigue (Bet = 33, Clo = 0.0067, Str = 0.9397), pain (Bet = 11, Clo = 0.0060, Str = 0.9226), wake up well rested (Bet = 25, Clo = 0.0057, Str = 0.8491), and anxiety (Bet = 5, Clo = 0.0043, Str = 0.9697) among cancer survivors. The core symptoms, network structure, and global strength were invariant between time since diagnoses (< 2 years vs. ≥ 2 years) or between numbers of cancers (1 vs. ≥ 2), yet varied between the comorbidity group and non-comorbidity group (≥ 1 vs. 0). CONCLUSIONS: Fatigue would be a potential target for alleviating other symptoms through a negative feedback loop of other related symptoms of cancer survivors. In particular, cancer survivors with other chronic diseases should be the focus of attention and strengthen targeted intervention.
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Sobreviventes de Câncer , Humanos , Sobreviventes de Câncer/estatística & dados numéricos , Estudos Transversais , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Fadiga/epidemiologia , Fadiga/etiologia , Neoplasias/complicações , Ansiedade/epidemiologia , Ansiedade/etiologia , Inquéritos Epidemiológicos , Inquéritos e Questionários , Estados Unidos/epidemiologiaRESUMO
Gastrin-releasing peptide (GRP) binds to its receptor (GRP receptor [GRPR]) to regulate multiple biological processes, but the function of GRP/GRPR axis in acute kidney injury (AKI) remains unknown. In the present study, GRPR is highly expressed by tubular epithelial cells (TECs) in patients or mice with AKI, while histone deacetylase 8 may lead to the transcriptional activation of GRPR. Functionally, we uncovered that GRPR was pathogenic in AKI, as genetic deletion of GRPR was able to protect mice from cisplatin- and ischemia-induced AKI. This was further confirmed by specifically deleting the GRPR gene from TECs in GRPRFlox/Flox//KspCre mice. Mechanistically, we uncovered that GRPR was able to interact with Toll-like receptor 4 to activate STAT1 that bound the promoter of MLKL and CCL2 to induce TEC necroptosis, necroinflammation, and macrophages recruitment. This was further confirmed by overexpressing STAT1 to restore renal injury in GRPRFlox/Flox/KspCre mice. Concurrently, STAT1 induced GRP synthesis to enforce the GRP/GRPR/STAT1 positive feedback loop. Importantly, targeting GRPR by lentivirus-packaged small hairpin RNA or by treatment with a novel GRPR antagonist RH-1402 was able to inhibit cisplatin-induced AKI. In conclusion, GRPR is pathogenic in AKI and mediates AKI via the STAT1-dependent mechanism. Thus, targeting GRPR may be a novel therapeutic strategy for AKI.
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Injúria Renal Aguda , Cisplatino , Animais , Camundongos , Cisplatino/efeitos adversos , Necroptose , Injúria Renal Aguda/metabolismo , Rim/metabolismo , Inflamação/metabolismo , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Depressive symptoms are one of the most common psychiatric disorders, with a high lifetime prevalence rate among middle-aged and elderly Chinese. Obesity may be one of the risk factors for depressive symptoms, but there is currently no consensus on this view. Therefore, we investigate the relationship and predictive ability of 13 obesity- and lipid-related indices with depressive symptoms among middle-aged and elderly Chinese. METHODS: The data were obtained from The China Health and Retirement Longitudinal Study (CHARLS). Our analysis includes individuals who did not have depressive symptoms at the baseline of the CHARLS Wave 2011 study and were successfully follow-up in 2013 and 2015. Finally, 3790 participants were included in the short-term (from 2011 to 2013), and 3660 participants were included in the long-term (from 2011 to 2015). The average age of participants in short-term and long-term was 58.47 years and 57.88 years. The anthropometric indicators used in this analysis included non-invasive [e.g. waist circumference (WC), body mass index (BMI), and a body mass index (ABSI)], and invasive anthropometric indicators [e.g. lipid accumulation product (LAP), triglyceride glucose index (TyG index), and its-related indices (e.g. TyG-BMI, and TyG-WC)]. Receiver operating characteristic (ROC) analysis was used to examine the predictive ability of various indicators for depressive symptoms. The association of depressive symptoms with various indicators was calculated using binary logistic regression. RESULTS: The overall incidence of depressive symptoms was 20.79% in the short-term and 27.43% in the long-term. In males, WC [AUC = 0.452], LAP [AUC = 0.450], and TyG-WC [AUC = 0.451] were weak predictors of depressive symptoms during the short-term (P < 0.05). In females, BMI [AUC = 0.468], LAP [AUC = 0.468], and TyG index [AUC = 0.466] were weak predictors of depressive symptoms during the long-term (P < 0.05). However, ABSI cannot predict depressive symptoms in males and females during both periods (P > 0.05). CONCLUSION: The research indicates that in the middle-aged and elderly Chinese, most obesity- and lipid-related indices have statistical significance in predicting depressive symptoms, but the accuracy of these indicators in prediction is relatively low and may not be practical predictors.
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Depressão , Obesidade , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , China/epidemiologia , Obesidade/epidemiologia , Depressão/epidemiologia , Depressão/sangue , Idoso , Estudos Longitudinais , Fatores de Risco , Índice de Massa Corporal , Lipídeos/sangue , Circunferência da Cintura , População do Leste AsiáticoRESUMO
BACKGROUND AND AIMS: Osteoarthritis (OA) is a prevalent degenerative joint disorder, marked by the progressive degeneration of joint cartilage, synovial inflammation, and subchondral bone hyperplasia. The synovial tissue plays a pivotal role in cartilage regulation. Exosomes (EXOs), small membrane-bound vesicles released by cells into the extracellular space, are crucial in mediating intercellular communication and facilitating the exchange of information between tissues. Our study aimed to devise a hydrogel microsphere infused with SOD3-enriched exosomes (S-EXOs) to protect cartilage and introduce a novel, effective approach for OA treatment. MATERIALS AND METHODS: We analyzed single-cell sequencing data from 4247 cells obtained from the GEO database. Techniques such as PCR, Western Blot, immunofluorescence (IF), and assays to measure oxidative stress levels were employed to validate the cartilage-protective properties of the identified key protein, SOD3. In vivo, OA mice received intra-articular injections of S-EXOs bearing hydrogel microspheres, and the effectiveness was assessed using safranine O (S.O) staining and IF. RESULTS: Single-cell sequencing data analysis suggested that the synovium influences cartilage via the exocrine release of SOD3. Our findings revealed that purified S-EXOs enhanced antioxidant capacity of chondrocytes, and maintained extracellular matrix metabolism stability. The S-EXO group showed a significant reduction in mitoROS and ROS levels by 164.2% (P < 0.0001) and 142.7% (P < 0.0001), respectively, compared to the IL-1ß group. Furthermore, the S-EXO group exhibited increased COL II and ACAN levels, with increments of 2.1-fold (P < 0.0001) and 3.1-fold (P < 0.0001), respectively, over the IL-1ß group. Additionally, the S-EXO group showed a decrease in MMP13 and ADAMTS5 protein expression by 42.3% (P < 0.0001) and 44.4% (P < 0.0001), respectively. It was found that S-EXO-containing hydrogel microspheres could effectively deliver SOD3 to cartilage and significantly mitigate OA progression. The OARSI score in the S-EXO microsphere group markedly decreased (P < 0.0001) compared to the OA group. CONCLUSION: The study demonstrated that the S-EXOs secreted by synovial fibroblasts exert a protective effect on chondrocytes, and microspheres laden with S-EXOs offer a promising therapeutic alternative for OA treatment.
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Condrócitos , Exossomos , Osteoartrite , Estresse Oxidativo , Superóxido Dismutase , Membrana Sinovial , Animais , Osteoartrite/terapia , Osteoartrite/metabolismo , Exossomos/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Condrócitos/metabolismo , Humanos , Superóxido Dismutase/metabolismo , Membrana Sinovial/metabolismo , Masculino , Progressão da Doença , Nanopartículas/química , Camundongos Endogâmicos C57BL , Hidrogéis/química , Microesferas , Cartilagem Articular/metabolismo , Matriz Extracelular/metabolismoRESUMO
OBJECTIVE: Hypertension refers to the persistent elevation of blood pressure above the established normal range, resulting in increased pressure exerted by blood on the walls of blood vessels during its circulation. Recent studies have identified significant associations between obesity and lipid-related indices, as well as hypertension. Nevertheless, these studies have yet to comprehensively examine the correlation between the two variables. Our objective is to identify the fat and lipid-related indices that have the strongest correlation with hypertension. METHOD: There was a total of 9488 elderly and middle-aged Chinese citizens who participated in this investigation. The participants in this research were separated into distinct gender cohorts. The participants were classified into normal and hypertensive categories according to their gender, with hypertension defined as a blood pressure level of 140/90 mmHg or higher, or a history of hypertension. Through the utilization of binary logistic regression analyses and the receiver operator curve (ROC), the optimal among fourteen indicators associated with obesity and lipids were identified. RESULTS: After adjusting for variables, statistical analysis showed that all 14 measures of obesity and lipid were risk factors for hypertension. The receiver operating characteristic (ROC) curve analysis reveals that the Chinese visceral adiposity index (CVAI) has the highest degree of relationship to hypertension. Simultaneously, a statistically significant association between hypertension and these 14 variables was observed in both males and females. CONCLUSION: There was a significant independent association between various parameters related to obesity and lipid-related index and the presence of hypertension, indicating that these factors can be considered risk factors for hypertension. CVAI and WHtR (waist height ratio) can be used to screen the high-risk groups of hypertensions in middle-aged and elderly people in China, and then take individualized health care measures to reduce the harm of hypertension.
Assuntos
Hipertensão , Obesidade , Idoso , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Transversais , Índice de Massa Corporal , Obesidade/diagnóstico , Obesidade/epidemiologia , Fatores de Risco , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Obesidade Abdominal , Lipídeos , China/epidemiologiaRESUMO
BACKGROUND: To investigate the cross-sectional and longitudinal associations between depressive symptoms and the prevalence of frailty and its components in a nationally representative sample of middle-aged and older Chinese adults. METHOD: The China Health and Retirement Longitudinal Study (CHARLS) provided data on 2581 (after inclusion and exclusion criteria) adults aged ≥ 45 years. Every two years, face-to-face, computer-aided personal interviews (CAPI), and structured questionnaires were used to follow up with the respondents. The Chinese version of the Center for Epidemiologic Studies-Depression Scale (CES-D) was used to evaluate depressive symptoms, and the Fried criteria were used to measure frailty. The odds ratio (OR) and 95% confidence interval (CI) for the association of exposure (depressive symptoms at baseline) with the onset of the outcome (frailty and its components) in the individuals at baseline were analyzed by binary logistic regression. RESULTS: At baseline, 11.62% of participants had frailty, and 57.92% had depressive symptoms. In the cross-sectional analysis, depressive symptoms (OR = 5.222, 95%CI 3.665-7.442) were associated with frailty. In the longitudinal analysis, after adjusting for the full set of covariates among participants free of baseline frailty, depressive symptoms were significantly associated with incident frailty during the short term (OR = 2.193, 95%CI 1.324-3.631) and the long term (OR = 1.926, 95%CI 1.021-3.632). Meanwhile, depressive symptoms were associated with an increased risk of weakness (OR = 1.990, 95%CI 1.250-3.166), slowness (OR = 1.395, 95%CI 1.044-1.865), and exhaustion (OR = 2.827, 95%CI 2.150-3.719) onset during the short-term. Depressive symptoms were associated with an increased risk of exhaustion (OR = 2.869, 95%CI 2.004-4.109) onset during the long-term. CONCLUSION: Among middle-aged and older adults, depressive symptoms could predict frailty during 2 years of follow-up and 4 years of follow-up. When considering potential confounding factors, depressive symptoms were considered a predictor of weakness, slowness, and exhaustion. Interventions aimed at preventing depressive symptoms may be beneficial in reducing frailty and its components.
Assuntos
Depressão , Fragilidade , Humanos , Estudos Longitudinais , Masculino , Feminino , Depressão/epidemiologia , Pessoa de Meia-Idade , Idoso , China/epidemiologia , Fragilidade/epidemiologia , Fragilidade/psicologia , Estudos Transversais , Prevalência , Idoso Fragilizado/estatística & dados numéricos , Idoso Fragilizado/psicologia , Idoso de 80 Anos ou mais , Inquéritos e QuestionáriosRESUMO
The ancestors of marine mammals once roamed the land and independently committed to an aquatic lifestyle. These macroevolutionary transitions have intrigued scientists for centuries. Here, we generated high-quality genome assemblies of 17 marine mammals (11 cetaceans and six pinnipeds), including eight assemblies at the chromosome level. Incorporating previously published data, we reconstructed the marine mammal phylogeny and population histories and identified numerous idiosyncratic and convergent genomic variations that possibly contributed to the transition from land to water in marine mammal lineages. Genes associated with the formation of blubber (NFIA), vascular development (SEMA3E), and heat production by brown adipose tissue (UCP1) had unique changes that may contribute to marine mammal thermoregulation. We also observed many lineage-specific changes in the marine mammals, including genes associated with deep diving and navigation. Our study advances understanding of the timing, pattern, and molecular changes associated with the evolution of mammalian lineages adapting to aquatic life.
Assuntos
Adaptação Fisiológica , Evolução Molecular , Genoma , Genômica , Mamíferos/fisiologia , Filogenia , Termogênese/genética , Animais , Fatores de Transcrição NFI/genética , Fatores de Transcrição NFI/metabolismo , Seleção Genética , Semaforinas/genética , Semaforinas/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
We aimed to synthesize hydroxyethyl starch (HES) 200/0.5-loaded bovine serum albumin nanoparticles (HBNs) and investigate the compatibility and binding mechanism in simulated physiological environments. Here, to elucidate the morphology, biocompatibility, and formation mechanism of HBNs, techniques such as scanning electron microscopy, haemolysis test, fluorescence, and circular dichroism spectroscopy were applied. The thermodynamic parameters at body temperature (ΔS° = -26.7 J·mol-1 ·K-1 , ΔH° = -3.20 × 104 J·mol-1 , and ΔG = -2.35 × 104 J·mol-1 ) showed a 1:1 binding stoichiometry, which was formed by hydrogen bonds and van der Waals interactions. In addition, the conformational analysis showed that the microenvironment of fluorophores was altered with the adaptational protein secondary structural changes. Energy transfer occurred from the fluorophores to HES with a high possibility. All these results provided accurate and complete primary data for demonstrating the interaction mechanisms of HES with BSA, which helps to understand its pharmaceutical effects in blood.