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AIMS: This study aims to explore the concept of future orientation, which encompasses individuals' thoughts about the future, goal-setting, planning, response to challenges and behavioural adjustments in evolving situations. Often viewed as a psychological resource, future orientation is believed to be developed from psychological resilience. The study investigates the curvilinear relationship between childhood maltreatment and future orientation while examining the moderating effects of genotype. METHODS: A total of 14,675 Chinese adults self-reported their experiences of childhood maltreatment and their future orientation. The influence of genetic polymorphism was evaluated through genome-wide interaction studies (GWIS; genome-wide association study [GWAS] using gene × environment interaction) and a candidate genes approach. RESULTS: Both GWAS and candidate genes analyses consistently indicated that rs4498771 and its linked single-nucleotide polymorphisms, located in the intergenic area surrounding CSF3R, significantly interacted with early trauma to influence future orientation. Nonlinear regression analyses identified a quadratic or cubic association between future orientation and childhood maltreatment across some genotypes. Specifically, as levels of childhood maltreatment increased, future orientation declined for all genotypes. However, upon reaching a certain threshold, future orientation exhibited a rebound in individuals with specific genotypes. CONCLUSIONS: The findings suggest that individuals with certain genotypes exhibit greater resilience to childhood maltreatment. Based on these results, we propose a new threshold model of stress-related growth.
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Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Estresse Psicológico , Humanos , Adulto , Feminino , Masculino , Estresse Psicológico/psicologia , Estresse Psicológico/genética , Resiliência Psicológica , Genótipo , China , Pessoa de Meia-Idade , Maus-Tratos Infantis/psicologia , Povo Asiático/psicologia , Povo Asiático/genética , Desenvolvimento PsicológicoRESUMO
BACKGROUND: TRY-NAD metabolic network includes TRY (tryptophan), 5-HT (5-hydroxytryptamine), KYN (kynurenine), and NAD (nicotinamide adenine dinucleotide) pathway, which plays a significant role in neurological diseases and ageing. It is important to monitor these metabolites for studying the pathological anatomy of disease and treatment of responses evaluation. Although previous studies have reported quantitative methods for several metabolites in the network, the bottlenecks of simultaneously quantifying the whole metabolic network are their similar structures, diverse physico-chemical properties, and instability. Standardized protocols for the whole metabolic network are still missing, which hinders the in-depth study of TRY-NAD metabolic network in laboratory research and clinical screening. RESULTS: We developed a LC-MS/MS method for quantifying 28 metabolites in the TRY-NAD network simultaneously. Optimization was done for the mass spectral parameters, chromatographic conditions and sample pretreatment process. The developed method was fully validated in terms of standard curves, sensitivity, carryover, recovery, matrix effect, accuracy, precision, and stability. The pretreatment of 30 samples only takes 90 min, and the LC-MS/MS running time of one sample is only 13 min. With this method, we bring to light the chaos of global TRY-NAD metabolic network in sleep deprivation mice for the first time, including serum, clotted blood cells, hippocampus, cerebral cortex, and liver. NAD pathway levels in brain and blood decreased, whereas the opposite happened in the liver. The 5-HT pathway decreased and the concentration of KYN increased significantly in the brain. The concentration of many metabolites in KYN pathway (NAD+ de novo synthesis pathway) increased in the liver. SIGNIFICANCE: This method is the first time to determine the metabolites of KYN, 5-HT and NAD pathway at the same time, and it is found that TRY-NAD metabolic network will be disordered after sleep deprivation. This work clarifies the importance of the pH of the extraction solution, the time and temperature control in pretreatment in standardized protocols building, and overcoming the problems of inconsistent sample pretreatment, separation, matrix effect interference and potential metabolite degradation. This method exhibits great prospects in providing more information on metabolic disturbances caused by sleep deprivation as well as neurological diseases and ageing.
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NAD , Privação do Sono , Espectrometria de Massas em Tandem , Triptofano , Animais , Espectrometria de Massas em Tandem/métodos , NAD/metabolismo , Camundongos , Triptofano/metabolismo , Triptofano/sangue , Triptofano/análise , Privação do Sono/metabolismo , Privação do Sono/sangue , Masculino , Redes e Vias Metabólicas , Cromatografia Líquida , Camundongos Endogâmicos C57BL , Espectrometria de Massa com Cromatografia LíquidaRESUMO
Introduction: Major depressive disorder is a condition involving microbiota-gut-brain axis dysfunction. Increasing research aims to improve depression through gut microbiota regulation, including interventions such as probiotics, prebiotics, and fecal microbiota transplants. However, most research focuses on exogenous depression induced by chronic stress or drugs, with less attention given to endogenous depression. Additionally, research on gut mycobiota in depression is significantly less than that on gut bacteria. Methods: In the present study, Wistar-Kyoto rats were used as an endogenous depression and treatment-resistant depression model, while Wistar rats served as controls. Differences between the two rat strains in behavior, gut bacteria, gut mycobiota, nervous system, endocrine system, immune system, and gut barrier were evaluated. Additionally, the effects of Lactobacillus helveticus NS8 supplementation were investigated. Results: Wistar-Kyoto rats demonstrated increased depressive-like behaviors in the forced swimming test, reduced sucrose preference in the sucrose preference test, and decreased locomotor activity in the open field test. They also exhibited abnormal gut bacteria and mycobiota, characterized by higher bacterial α-diversity but lower fungal α-diversity, along with increased butyrate, L-tyrosine, and L-phenylalanine biosynthesis from bacteria. Furthermore, these rats showed dysfunction in the microbiota-gut-brain axis, evidenced by a hypo-serotonergic system, hyper-noradrenergic system, defective hypothalamic-pituitary-adrenal axis, compromised gut barrier integrity, heightened serum inflammation, and diminished gut immunity. A 1-month L. helveticus NS8 intervention increased the fecal abundance of L. helveticus; reduced the abundance of Bilophila and Debaryomycetaceae; decreased immobility time but increased climbing time in the forced swimming test; reduced hippocampal corticotropin-releasing hormone levels; decreased hypothalamic norepinephrine levels; increased hippocampal glucocorticoid receptor, brain-derived neurotrophic factor dopamine, and 5-hydroxyindoleacetic acid content; and improved the gut microbiota, serotonergic, and noradrenergic system. Conclusion: The depressive phenotype of Wistar-Kyoto rats is not only attributed to their genetic context but also closely related to their gut microbiota. Abnormal gut microbiota and a dysfunctional microbiota-gut-brain axis play important roles in endogenous depression, just as they do in exogenous depression. Supplementing with probiotics such as L. helveticus NS8 is likely a promising approach to improve endogenous depression and treatment-resistant depression.
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Eixo Encéfalo-Intestino , Depressão , Modelos Animais de Doenças , Microbioma Gastrointestinal , Lactobacillus helveticus , Probióticos , Ratos Endogâmicos WKY , Animais , Ratos , Microbioma Gastrointestinal/efeitos dos fármacos , Probióticos/administração & dosagem , Probióticos/uso terapêutico , Depressão/imunologia , Depressão/metabolismo , Masculino , Comportamento Animal , Ratos WistarRESUMO
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel tick-borne bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS), with a high mortality rate of up to 30%. The envelope glycoproteins of SFTSV, glycoprotein N (Gn) and glycoprotein C (Gc), facilitate the recognition of host receptors and the process of membrane fusion, allowing the virus to enter host cells. We previously reported a monoclonal antibody, mAb 40C10, capable of neutralizing different genotypes of SFTSV and SFTSV-related viruses. However, the specific neutralization mechanism is poorly understood. In this study, we elucidated the high-resolution structure of the SFTSV Gn head domain in complex with mAb 40C10, confirming that the binding epitope in the domain I region of SFTSV Gn, and it represented that a novel binding epitope of SFTSV Gn was identified. Through in-depth structural and sequence analyses, we found that the binding sites of mAb 40C10 are relatively conserved among different genotypes of SFTSV and SFTSV-related Heartland virus and Guertu virus, elucidating the molecular mechanism underlying the broad-spectrum neutralizing activity of mAb 40C10. Furthermore, we humanized of mAb 40C10, which is originally of murine origin, to reduce its immunogenicity. The resulting nine humanized antibodies maintained potent affinity and neutralizing activity. One of the humanized antibodies exhibited neutralizing activity at picomolar IC50 values and demonstrated effective therapeutic and protective effects in a mouse infection model. These findings provide a novel target for the future development of SFTSV vaccines or drugs and establish a foundation for the research and development of antibody therapeutics for clinical applications.
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Anticorpos Neutralizantes , Anticorpos Antivirais , Phlebovirus , Humanos , Animais , Anticorpos Antivirais/imunologia , Phlebovirus/imunologia , Camundongos , Anticorpos Neutralizantes/imunologia , Febre Grave com Síndrome de Trombocitopenia/imunologia , Proteínas do Envelope Viral/imunologia , Anticorpos Monoclonais/imunologia , Epitopos/imunologia , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Amplamente Neutralizantes/imunologiaRESUMO
OBJECTIVE: Infliximab is a first-line biologic agent for the treatment of Crohn's disease (CD), in which loss of response (LOR) remains a challenge in the treatment of patients with CD. The study aimed to explore the association between body composition parameters and LOR to infliximab in CD patients. METHODS: 118 patients with CD admitted to the First Affiliated Hospital of Wenzhou Medical University and treated with infliximab from June 2015 to December 2021 were retrospectively enrolled. The body composition of patients was analyzed by computed tomography (CT). The primary outcome measure was the one-year LOR. Patients were divided into the Remission group and the LOR group to analyze the association between body composition parameters and the LOR to infliximab. RESULTS: The rate of sarcopenia in the LOR group was higher than in the Remission group (83.7% vs. 60.0%, P=0.008). Multivariate analysis showed that females had a lower risk of sarcopenia than males (OR=0.30, 95% CI 0.11-0.81, P =0.017); BMI was significantly associated with sarcopenia (OR=0.68, 95% CI 0.56-0.83, P <0.001); L1 CD and L2 CD had a lower risk of sarcopenia than L3 CD (OR=0.29, 95% CI 0.10-0.83, P =0.021; OR=0.25, 95% CI 0.07-0.87, P=0.028). CONCLUSIONS: Sarcopenia was identified as a risk factor for developing LOR in infliximab-treated patients.
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Hepatocellular carcinoma (HCC) has emerged as a major contributor to the worldwide cancer burden. Improved methods are needed for early cancer detection and image-guided surgery. Peptides have small dimensions that can overcome delivery challenges to achieve high tumor concentrations and deep penetration. We used phage display methods to biopan against the extra-cellular domain of the purified EpCAM protein, and used IRDye800 as a near-infrared (NIR) fluorophore. The 12-mer sequence HPDMFTRTHSHN was identified, and specific binding to EpCAM was validated with HCC cells in vitro. A binding affinity of kd = 67 nM and onset of k = 0.136 min-1 (7.35 min) were determined. Serum stability was measured with a half-life of T1/2 = 2.6 h. NIR fluorescence images showed peak uptake in vivo by human HCC patient-derived xenograft (PDX) tumors at 1.5 h post-injection. Also, the peptide was able to bind to foci of local and distant metastases in liver and lung. Peptide biodistribution showed high uptake in tumor versus other organs. No signs of acute toxicity were detected during animal necropsy. Immunofluorescence staining of human liver showed specific binding to HCC compared with cirrhosis, adenoma, and normal specimens.
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Nobiletin has been reported to protect against obesity-related metabolic disorders by enhancing the circadian rhythm; however its effects on lipid metabolism in adipose tissue are unclear. In this study, mice were fed with high-fat diet (HFD) for four weeks firstly and gavaged with 50 or 200 mg/kg bodyweight/day nobiletin at Zeitgeber time (ZT) 4 for another four weeks while still receiving HFD. At the end of the 8-week experimental period, the mice were sacrificed at ZT4 or ZT8 on the same day. Mature 3T3-L1 adipocytes were treated with nobiletin in the presence or absence of siBmal1, siRora, siRorc, SR8278 or SR9009. Nobiletin reduced the weight of white adipose tissue (WAT) and the size of adipocytes in WAT. At ZT4, nobiletin decreased the TG, TC and LDL-c levels and increased serum FFA level and glucose tolerance. Nobiletin triggered the lipolysis of mesenteric and epididymal WAT at both ZT4 and ZT16. Nobiletin increased the level of RORγ at ZT16, that of BMAL1 and PPARγ at ZT4, and that of ATGL at both ZT4 and ZT16. Nobiletin increased lipolysis and ATGL levels in 3T3-L1 adipocytes in Bmal1- or Rora/c- dependent manner. Dual luciferase assay indicated that nobiletin enhanced the transcriptional activation of RORα/γ on Atgl promoter and decreased the repression of RORα/γ on PPARγ-binding PPRE. Promoter deletion analysis indicated that nobiletin inhibited the suppression of PPARγ-mediated Atgl transcription by RORα/γ. Taken together, nobiletin elevated lipolysis in WAT by increasing ATGL levels through activating the transcriptional activity of RORα/γ and decreasing the repression of RORα/γ on PPARγ-binding PPRE.
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Células 3T3-L1 , Tecido Adiposo Branco , Relógios Circadianos , Flavonas , Lipólise , Camundongos Endogâmicos C57BL , Animais , Flavonas/farmacologia , Lipólise/efeitos dos fármacos , Camundongos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Masculino , Relógios Circadianos/efeitos dos fármacos , Fatores de Transcrição ARNTL/metabolismo , Fatores de Transcrição ARNTL/genética , Dieta Hiperlipídica/efeitos adversos , PPAR gama/metabolismo , PPAR gama/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Lipase/metabolismo , Obesidade/metabolismo , Obesidade/tratamento farmacológico , Aciltransferases , Membro 3 do Grupo F da Subfamília 1 de Receptores NuclearesRESUMO
The present study utilizes the significant differences in θ, α, and ß band power spectra observed in electroencephalograms (EEGs) during distracted versus focused driving. Three subtasks, visual distraction, auditory distraction, and cognitive distraction, were designed to appear randomly during driving simulations. The θ, α, and ß band power spectra of the EEG signals of the four driving attention states were extracted, and SVM, EEGNet, and GRU-EEGNet models were employed for the detection of the driving attention states, respectively. Online experiments were conducted. The extraction of the θ, α, and ß band power spectrum features of the EEG signals was found to be a more effective method than the extraction of the power spectrum features of the whole EEG signals for the detection of driving attention states. The driving attention state detection accuracy of the proposed GRU-EEGNet model is improved by 6.3% and 12.8% over the EEGNet model and PSD_SVM method, respectively. The EEG decoding method combining EEG features and an improved deep learning algorithm, which effectively improves the driving attention state detection accuracy, was manually and preliminarily selected based on the results of existing studies.
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Atenção , Eletroencefalografia , Humanos , Eletroencefalografia/métodos , Atenção/fisiologia , Condução de Veículo , Algoritmos , Aprendizado Profundo , Redes Neurais de Computação , Processamento de Sinais Assistido por ComputadorRESUMO
BACKGROUND: Nuclear factor Y (NF-Y) plays a vital role in numerous biological processes as well as responses to biotic and abiotic stresses. However, its function in ginger (Zingiber officinale Roscoe), a significant medicinal and dietary vegetable, remains largely unexplored. Although the NF-Y family has been thoroughly identified in many plant species, and the function of individual NF-Y TFs has been characterized, there is a paucity of knowledge concerning this family in ginger. METHODS: We identified the largest number of NF-Y genes in the ginger genome using two BLASTP methods as part of our ginger genome research project. The conserved motifs of NF-Y proteins were analyzed through this process. To examine gene duplication events, we employed the Multiple Collinearity Scan toolkit (MCScanX). Syntenic relationships of NF-Y genes were mapped using the Dual Synteny Plotter software. Multiple sequence alignments were performed with MUSCLE under default parameters, and the resulting alignments were used to generate a maximum likelihood (ML) phylogenetic tree with the MEGA X program. RNA-seq analysis was conducted on collected samples, and statistical analyses were performed using Sigma Plot v14.0 (SYSTAT Software, USA). RESULTS: In this study, the ginger genome was utilized to identify 36 NF-Y genes (10 ZoNF-YAs, 16 ZoNF-YBs, and 10 ZoNF-YCs), which were renamed based on their chromosomal distribution. Ten distinct motifs were identified within the ZoNF-Y genes, with certain unique motifs being vital for gene function. By analyzing their chromosomal location, gene structure, conserved protein motifs, and gene duplication events, we gained a deeper understanding of the evolutionary characteristics of these ZoNF-Y genes. Detailed analysis of ZoNF-Y gene expression patterns across various tissues, performed through RNA-seq and qRT-PCR, revealed their significant role in regulating ginger rhizome and flower growth and development. Additionally, we identified the ZoNF-Y family genes that responded to abiotic stresses. CONCLUSION: This study represents the first identification of the ZoNF-Y family in ginger. Our findings contribute to research on evolutionary characteristics and provide a better understanding of the molecular basis for development and abiotic stress response. Furthermore, it lays the foundation for further functional characterization of ZoNF-Y genes with an aim of ginger crop improvement.
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Evolução Molecular , Família Multigênica , Filogenia , Estresse Fisiológico , Zingiber officinale , Zingiber officinale/genética , Estresse Fisiológico/genética , Fator de Ligação a CCAAT/genética , Fator de Ligação a CCAAT/metabolismo , Regulação da Expressão Gênica de Plantas , Perfilação da Expressão Gênica , Genoma de Planta , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Duplicação Gênica , SinteniaRESUMO
The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Fatores de Transcrição , Humanos , Animais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Linhagem Celular Tumoral , Fator 3 de Transcrição de Octâmero/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Transdução de Sinais , Regulação Neoplásica da Expressão Gênica , Fator 2 de Transcrição de OctâmeroRESUMO
Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, â¼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.
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Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Fatores de Transcrição , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Proliferação de Células , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Fator 3 de Transcrição de Octâmero/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genéticaRESUMO
Acupuncture can reduce blood pressure, heart rate (HR), and ameliorate cardiac damage by modulating the excitability of the sympathetic nervous system, but the exact mechanism of this effect remains unclear. This study investigated the potential mechanisms of acupuncture in the treatment of cardiac damage in hypertension. Spontaneously hypertensive rats (SHR) were used as the hypertension model with Wistar-Kyoto rats as the control. Manual acupuncture, electroacupuncture, and metoprolol were used as interventions. Systolic and diastolic blood pressure (SBP, DBP) plus HR were monitored with cardiac structure determined using Masson staining. Angiotensin II (Ang II) and norepinephrine in myocardium were detected with ELISA as was Ang(1-7) and gamma aminobutyric acid (GABA) in the rostral ventrolateral medulla (RVLM). Expression of mRNA for collagen type I (Col-I), Col-III, actin α1 (ACTA1), and thrombospondin 4 (THBS4) in myocardium was detected using real-time PCR. Expression of angiotensin converting enzyme (ACE), Ang II, angiotensin II type 1 receptor (AT1R), ACE2, and Mas receptor (MasR) proteins in RVLM was monitored using western blot. After manual acupuncture and electroacupuncture treatment, SHRs showed decreased SBP, DBP and HR, reduced myocardial damage. There was decreased expression of the ACE/Ang II/AT1R axis, and increased expression of the ACE2/Ang(1-7)/MasR axis within the RVLM. GABA levels were increased within the RVLM and norepinephrine levels were decreased in myocardial tissue. Metoprolol was more effective than either manual acupuncture or electroacupuncture. Acupuncture directed against hypertensive cardiac damage may be associated with regulation of ACE/Ang II/AT1R and the ACE2/Ang(1-7)/MasR pathway within the RLVM to reduce cardiac sympathetic excitability.
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Terapia por Acupuntura , Angiotensina II , Angiotensina I , Enzima de Conversão de Angiotensina 2 , Hipertensão , Bulbo , Fragmentos de Peptídeos , Peptidil Dipeptidase A , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptor Tipo 1 de Angiotensina , Animais , Angiotensina I/metabolismo , Hipertensão/metabolismo , Hipertensão/terapia , Fragmentos de Peptídeos/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Masculino , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Bulbo/metabolismo , Angiotensina II/metabolismo , Terapia por Acupuntura/métodos , Peptidil Dipeptidase A/metabolismo , Peptidil Dipeptidase A/genética , Proto-Oncogene Mas , Sistema Nervoso Simpático/metabolismo , Ratos , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Pressão Sanguínea/fisiologia , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Recent studies have shown that several long non-coding RNAs (lncRNAs) in the placenta are associated with preeclampsia (PE). However, the extent to which lncRNAs may contribute to the pathological progression of PE is unclear. RESULTS: Here, we report a hierarchical regulatory network involved in early-onset severe PE (EOSPE). We have carried out transcriptome sequencing on the placentae from patients and normal subjects to identify the differentially expressed genes (DEGs), including some lncRNAs (DElncRNAs). We then constructed a high-quality hierarchical regulatory network of lncRNAs, transcription factors (TFs), and target DEGs, containing 1851 lncRNA-TF interactions and 6901 TF-promoter interactions. The lncRNA-to-target regulatory interactions were further validated by the triplex structures between the DElncRNAs and the promoters of the target DEGs. The DElncRNAs in the regulatory network were clustered into 3 clusters, one containing DElncRNAs correlated with the blood pressure, including FLNB-AS1 with targeting 27.89% (869/3116) DEGs in EOSPE. We further demonstrated that FLNB-AS1 could bind the transcription factor JUNB to regulate a series members of the HIF-1 signaling pathway in trophoblast cells. CONCLUSIONS: Our results suggest that the differential expression of lncRNAs may perturb the lncRNA-TF-DEG hierarchical regulatory network, leading to the dysregulation of many genes involved in EOSPE. Our study provides a new strategy and a valuable resource for studying the mechanism underlying gene dysregulation in EOSPE patients.
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Redes Reguladoras de Genes , Pré-Eclâmpsia , RNA Longo não Codificante , Pré-Eclâmpsia/genética , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Feminino , Gravidez , Placenta/metabolismoRESUMO
BACKGROUND: Thrombocytopenia is the major clinical feature associated with the severity of SFTS, but the mechanism by which it occurs remains unclear. METHODS: RNA transcriptome analyses were performed on platelets purified from SFTS patients and SFTSV-infected mice. The functions of differentially expressed genes (DEGs) in the platelets were characterized. ELISA, flow cytometry, and qRT-PCR were used to measure the levels of platelet activation, SFTSV infection in platelets, formation of neutrophil extracellular traps (NETs), transcription of DEGs and percent of platelets undergoing cell death. RESULTS: Enhanced neutrophil activation and interferon (IFN) signaling involved in the viral life cycle were common platelet responses in SFTS, which may consume increasing numbers of platelets. Other functional changes may be associated with different outcomes of SFTS. SFTSV infection led to platelet destruction by pyroptosis, apoptosis, necroptosis, and autophagy. In contrast to SFTS patients, platelets in SFTSV-infected mice mainly play a role in adaptive immunity, and platelet death was not as severe as in humans. CONCLUSIONS: The altered functions of platelets, such as mediating leukocyte activation and undergoing cell death, contribute to thrombocytopenia in SFTS patients. The different mechanisms of thrombocytopenia in mice, suggest that platelet functions should be considered in experimental animal models.
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Emerging evidence indicates that gut microbial dysbiosis is associated with the development of antipsychotic-induced weight gain in schizophrenia (SZ). However, the exact taxonomic composition and functionality that constitute the "obesogenic" microbial profile remain elusive. Our retrospective survey identified two groups of the SZ population separated by BMI, with 1/3 of patients developing overweight/obesity after chronic antipsychotic treatment. Based on multi-omics analysis, we observed altered gut microbiota in SZ patients with overweight/obesity, characterized by a reduction in several beneficial bacteria genera, including Bacteroides, Parabacteroides, Akkermansia, and Clostridium. This microbial dysbiosis was accompanied by disrupted energy expenditure and nutritional metabolism, worsened metabolic indices, and reduced levels of beneficial metabolites, e.g. indole-3-carboxylic acid and propionic acid. Moreover, leveraging data from first-episode drug-naïve schizophrenia (FSZ) patients at one-month and one-year follow-up, both artificial neural network and random forest classifier-based prediction models demonstrated a strong ability of microbial profiles to predict antipsychotic-induced weight gain. Importantly, FSZ patients with higher relative abundance of Parabacteria distasonis were less susceptible to antipsychotic-induced weight gain. Thus, gut microbiota could serve as a noninvasive approach to predict antipsychotic-induced weight gain, guiding clinical antipsychotics administration and developing novel therapeutic strategies for weight management in SZ.
Assuntos
Antipsicóticos , Disbiose , Microbioma Gastrointestinal , Esquizofrenia , Aumento de Peso , Humanos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacologia , Adulto , Masculino , Feminino , Aumento de Peso/efeitos dos fármacos , Disbiose/induzido quimicamente , Disbiose/microbiologia , Estudos Retrospectivos , Obesidade/induzido quimicamente , Obesidade/microbiologia , Adulto Jovem , Pessoa de Meia-Idade , Sobrepeso/induzido quimicamente , Sobrepeso/microbiologia , MultiômicaRESUMO
BACKGROUND: Mucosal-associated invariant T (MAIT) cells assume pivotal roles in numerous autoimmune inflammatory maladies. However, scant knowledge exists regarding their involvement in the pathological progression of oral lichen planus (OLP). The focus of our study was to explore whether MAIT cells were altered across distinct clinical types of OLP. METHODS: The frequency, phenotype, and partial functions of MAIT cells were performed by flow cytometry, using peripheral blood from 18 adults with non-erosive OLP and 22 adults with erosive OLP compared with 15 healthy adults. We also studied the changes in MAIT cells in 15 OLP patients receiving and 10 not receiving corticosteroids. Surface proteins including CD4, CD8, CD69, CD103, CD38, HLA-DR, Tim-3, Programmed Death Molecule-1 (PD-1), and related factors released by MAIT cells such as Granzyme B (GzB), interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-17A, and IL-22 were detected. RESULTS: Within non-erosive OLP patients, MAIT cells manifested an activated phenotype, evident in an elevated frequency of CD69+ CD38+ MAIT cells (p < 0.01). Conversely, erosive OLP patients displayed an activation and depletion phenotype in MAIT cells, typified by elevated CD69 (p < 0.01), CD103 (p < 0.05), and PD-1 expression (p < 0.01). Additionally, MAIT cells exhibited heightened cytokine production, encompassing GzB, IFN-γ, and IL-17A in erosive OLP patients. Notably, the proportion of CD103+ MAIT cells (p < 0.05) and GzB secretion (p < 0.01) by MAIT cells diminished, while the proportion of CD8+ MAIT cells (p < 0.05) rose in OLP patients with corticosteroid therapy. CONCLUSIONS: MAIT cells exhibit increased pathogenicity and pro-inflammatory capabilities in OLP. Corticosteroid therapy influences the expression of certain phenotypes and functions of MAIT cells in the peripheral blood of OLP patients.
Assuntos
Líquen Plano Bucal , Células T Invariantes Associadas à Mucosa , Humanos , Líquen Plano Bucal/imunologia , Líquen Plano Bucal/patologia , Células T Invariantes Associadas à Mucosa/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Antígenos CD , Idoso , Granzimas/metabolismo , Corticosteroides/uso terapêutico , Citocinas/metabolismo , Receptor de Morte Celular Programada 1 , Estudos de Casos e Controles , Antígenos de Diferenciação de Linfócitos T , Fenótipo , Citometria de Fluxo , Lectinas Tipo CRESUMO
OBJECTIVES: In this retrospective observational multicenter study, we aimed to assess efficacy and mortality between ceftazidime/avibactam (CAZ/AVI) or polymyxin B (PMB)-based regimens for the treatment of Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, as well as identify potential risk factors. METHODS: A total of 276 CRKP-infected patients were enrolled in our study. Binary logistic and Cox regression analysis with a propensity score-matched (PSM) model were performed to identify risk factors for efficacy and mortality. RESULTS: The patient cohort was divided into PMB-based regimen group (n = 98, 35.5%) and CAZ/AVI-based regimen group (n = 178, 64.5%). Compared to the PMB group, the CAZ/AVI group exhibited significantly higher rates of clinical efficacy (71.3% vs. 56.1%; p = 0.011), microbiological clearance (74.7% vs. 41.4%; p < 0.001), and a lower incidence of acute kidney injury (AKI) (13.5% vs. 33.7%; p < 0.001). Binary logistic regression revealed that the treatment duration independently influenced both clinical efficacy and microbiological clearance. Vasoactive drugs, sepsis/septic shock, APACHE II score, and treatment duration were identified as risk factors associated with 30-day all-cause mortality. The CAZ/AVI-based regimen was an independent factor for good clinical efficacy, microbiological clearance, and lower AKI incidence. CONCLUSIONS: For patients with CRKP infection, the CAZ/AVI-based regimen was superior to the PMB-based regimen.
RESUMO
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel tick-borne viral pathogen that causes severe fever with thrombocytopenia syndrome (SFTS). The disease was initially reported in central and eastern China, then later in Japan and South Korea, with a mortality rate of 13-30%. Currently, no vaccines or effective therapeutics are available for SFTS treatment. In this study, three monoclonal antibodies (mAbs) targeting the SFTSV envelope glycoprotein Gn were obtained using the hybridoma technique. Two mAbs recognized linear epitopes and did not neutralize SFTSV, while the mAb 40C10 can effectively neutralized SFTSV of different genotypes and also the SFTSV-related Guertu virus (GTV) and Heartland virus (HRTV) by targeting a spatial epitope of Gn. Additionally, the mAb 40C10 showed therapeutic effect in mice infected with different genotypes of SFTSV strains against death by preventing the development of lesions and by promoting virus clearance in tissues. The therapeutic effect could still be observed in mice infected with SFTSV which were administered with mAb 40C10 after infection even up to 4 days. These findings enhance our understanding of SFTSV immunogenicity and provide valuable information for designing detection methods and strategies targeting SFTSV antigens. The neutralizing mAb 40C10 possesses the potential to be further developed as a therapeutic monoclonal antibody against SFTSV and SFTSV-related viruses.
Assuntos
Anticorpos Monoclonais , Anticorpos Antivirais , Camundongos Endogâmicos BALB C , Phlebovirus , Phlebovirus/imunologia , Phlebovirus/genética , Animais , Anticorpos Monoclonais/imunologia , Camundongos , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/imunologia , Feminino , Febre Grave com Síndrome de Trombocitopenia/imunologia , Febre Grave com Síndrome de Trombocitopenia/virologia , Epitopos/imunologia , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/genética , Glicoproteínas/imunologia , Glicoproteínas/genética , Infecções por Bunyaviridae/imunologia , Infecções por Bunyaviridae/virologia , Infecções por Bunyaviridae/prevenção & controle , HumanosRESUMO
The enumeration of circulating tumor cells (CTCs) in peripheral blood plays a crucial role in the early diagnosis, recurrence monitoring, and prognosis assessment of cancer patients. There is a compelling need to develop an efficient technique for the capture and identification of these rare CTCs. However, the exclusive reliance on a single criterion, such as the epithelial cell adhesion molecule (EpCAM) antibody or aptamer, for the specific recognition of epithelial CTCs is not universally suitable for clinical applications, as it usually falls short in identifying EpCAM-negative CTCs. To address this limitation, we propose a straightforward and cost-effective method involving triplex fluorescently labelled aptamers (FAM-EpCAM, Cy5-PTK7, and Texas Red-CSV) to modify Fe3O4-loaded dendritic SiO2 nanocomposite (dmSiO2@Fe3O4/Apt). This multi-recognition-based strategy not only enhanced the efficiency in capturing heterogeneous CTCs, but also facilitated the rapid and accurate identification of CTCs. The capture efficiency of heterogenous CTCs reached up to 93.33%, with a detection limit as low as 5 cells/mL. Notably, the developed dmSiO2@Fe3O4/Apt nanoprobe enabled the swift identification of captured cells in just 30 min, relying solely on the fluorescently modified aptamers, which reduced the identification time by approximately 90% compared with the conventional immunocytochemistry (ICC) technique. Finally, these nanoprobe characteristics were validated using blood samples from patients with various types of cancers.
Assuntos
Aptâmeros de Nucleotídeos , Corantes Fluorescentes , Nanocompostos , Células Neoplásicas Circulantes , Dióxido de Silício , Humanos , Células Neoplásicas Circulantes/patologia , Dióxido de Silício/química , Aptâmeros de Nucleotídeos/química , Nanocompostos/química , Corantes Fluorescentes/química , Separação Imunomagnética/métodos , Molécula de Adesão da Célula Epitelial/imunologia , Limite de Detecção , Linhagem Celular Tumoral , Óxido Ferroso-Férrico/químicaRESUMO
SCOPE: Alcoholic liver disease (ALD) is a global public health concern. Nobiletin, a polymethoxyflavone abundant in citrus fruits, enhances circadian rhythms and ameliorates diet-induced hepatic steatosis, but its influences on ALD are unknown. This study investigates the role of brain and muscle Arnt-like protein-1 (Bmal1), a key regulator of the circadian clock, in nobiletin-alleviated ALD. METHODS AND RESULTS: This study uses chronic ethanol feeding plus an ethanol binge to establish ALD models in Bmal1flox/flox and Bmal1 liver-specific knockout (Bmal1LKO) mice. Nobiletin mitigates ethanol-induced liver injury (alanine aminotransferase [ALT]), glucose intolerance, hepatic apoptosis, and lipid deposition (triglyceride [TG], total cholesterol [TC]) in Bmal1flox/flox mice. Nobiletin fails to modulated liver injury (ALT, aspartate aminotransferase [AST]), apoptosis, and TG accumulation in Bmal1LKO mice. The expression of lipogenic genes (acetyl-CoA carboxylase alpha [Acaca], fatty acid synthase [Fasn]) and fatty acid oxidative genes (carnitine pamitoyltransferase [Cpt1a], cytochrome P450, family 4, subfamily a, polypeptide 10 [Cyp4a10], and cytochrome P450, family4, subfamily a, polypeptide 14 [Cyp4a14]) is inhibited, and the expression of proapoptotic genes (Bcl2 inteacting mediator of cell death [Bim]) is enhanced by ethanol in Bmal1flox/flox mice. Nobiletin antagonizes the expression of these genes in Bmal1flox/flox mice and not in Bmal1LKO mice. Nobiletin activates protein kinase B (PKB, also known as AKT) phosphorylation, increases the levels of the carbohydrate response element binding protein (ChREBP), ACC1, and FASN, and reduces the level of sterol-regulatory element binding protein 1 (SREBP1) and phosphorylation of ACC1 in a Bmal1-dependent manner. CONCLUSION: Nobiletin alleviates ALD by increasing the expression of genes involved in fatty acid oxidation by increasing AKT phosphorylation and lipogenesis in a Bmal1-dependent manner.