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Oxidative stress and neuroinflammation contribute to schizophrenia (SCZ) pathology and may influence treatment efficacy. Matrix metalloproteinase 9 (MMP9) is a critical molecular node mediating the interaction between oxidative stress and inflammation, and so may influence treatment efficacy. Here we examined the associations of plasma MMP9 concentration with antipsychotic drug responses, clinical symptoms, and brain structure. A total of 129 healthy controls and 124 patients with SCZ were included in this study. Patients were monitored clinically during 8 weeks of antipsychotic treatment and classified as poor responders (n = 49) or good responders (n = 75). We then compared plasma MMP9 concentrations in healthy controls at baseline and both SCZ responder groups at baseline and after the 8-week antipsychotic treatment regimen. Cognitive function was also examined using the MATRICS Consensus Cognitive Battery. In addition, we extracted regional white matter density from magnetic resonance images of patients. Compared to healthy controls, plasma MMP9 levels were significantly elevated in poor responders at baseline and negatively correlated with both white matter density in the right superior temporal gyrus and the change in cognitive symptoms after treatment. Conversely, there was no significant difference in plasma MMP9 between good responders and healthy controls, and no associations of plasma MMP9 with cognitive symptoms or regional white matter density among good responders. Elevated plasma MMP9 is associated with poor antipsychotic drug efficacy and white matter deficits in SCZ patients, and so may be a useful biomarker to guide personalized treatment.
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Post-stroke depression (PSD) is a complication of cerebrovascular disease, which can increase mortality after stroke. CRH is one of the main signaling peptides released after activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress. It affects synaptic plasticity by regulating inflammation, oxidative stress and autophagy in the central nervous system. And the loss of spines exacerbates depression-like behavior. Therefore, synaptic deficits induced by CRH may be related to post-stroke depression. However, the underlying mechanism remains unclear. The Keap1-Nrf2 complex is one of the core components of the antioxidant response. As an autophagy associated protein, p62 participates in the Keap1-NrF2 pathway through its Keap1 interaction domain. Oxidative stress is involved in the feedback regulation between Keap1-Nrf2 pathway and p62.However, whether the relationship between CRH and the Keap1-Nrf2-p62 pathway is involved in PSD remains unknown. This study found that serum levels of CRH in 22 patients with PSD were higher than those in healthy subjects. We used MCAO combined with CUMS single-cage SD rats to establish an animal model of PSD. Animal experiments showed that CRHR1 antagonist prevented synaptic loss in the hippocampus of PSD rats and alleviated depression-like behavior. CRH induced p62 accumulation in the prefrontal cortex of PSD rats through CRHR1. CRHR1 antagonist inhibited Keap1-Nrf2-p62 pathway by attenuating oxidative stress. In addition, we found that abnormal accumulation of p62 induces PSD. It alleviates depression-like behavior by inhibiting the expression of p62 and promoting the clearance of p62 in PSD rats. These findings can help explore the pathogenesis of PSD and design targeted treatments for PSD.
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Depressão , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina , Acidente Vascular Cerebral , Animais , Ratos , Masculino , Depressão/etiologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/psicologia , Acidente Vascular Cerebral/metabolismo , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Humanos , Regulação para Baixo/efeitos dos fármacos , Pessoa de Meia-Idade , Modelos Animais de Doenças , Feminino , Idoso , Proteína Sequestossoma-1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Hormônio Liberador da Corticotropina/metabolismoRESUMO
In recent years, Varicocele (VC) has been recognized as a common cause of male infertility that can be treated by surgery or drugs. How to reduce the damage of VC to testicular spermatogenic function has attracted extensive attention in recent years. Among them, overexpressed ROS and high levels of inflammation may play a key role in VC-induced testicular damage. As the key mediated innate immune pathways, cGAS-STING shaft under pathological conditions, such as in cell and tissue damage stress can be cytoplasmic DNA activation, induce the activation of NLRP3 inflammatory corpuscle, triggering downstream of the inflammatory cascade reaction. Chlorogenic acid (CGA), as a natural compound from a wide range of sources, has strong anti-inflammatory and antioxidant activities, and is a potential effective drug for the treatment of varicocele infertility. The aim of this study is to investigate the role of CGA in the spermatogenic dysfunction of the rat testis induced by VC and the potential mechanisms. The results of this study have shown that CGA gavage treatment ameliorated the pathological damage of seminiferous tubules, increased the number of sperm in the lumen, and increased the expression levels of Occludin and ZO-1, which indicated the therapeutic effect of CGA on spermatogenic dysfunction in the testis of VC rats. Meanwhile, the damage of mitochondrial structure was alleviated and the expression levels of ROS, NLRP3 and pro-inflammatory cytokines (IL-1ß, IL-6, IL-18) were significantly reduced in the testicular tissues of model rats after CGA treatment. In addition, we demonstrated for the first time the high expression status of cGAS and STING in testicular tissues of VC model rats, and this was ameliorated to varying degrees after CGA treatment. In conclusion, this study suggests that CGA can improve the spermatogenic function of the testis by reducing mitochondrial damage and inhibiting the activation of the cGAS-STING axis, inhibiting the activation of the NLRP3 inflammasome, and improving the inflammatory damage of the testis, highlighting the potential of CGA as a therapeutic agent for varicocele infertility.
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Ácido Clorogênico , DNA Mitocondrial , Inflamassomos , Proteínas de Membrana , Mitocôndrias , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nucleotidiltransferases , Varicocele , Animais , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Ratos , Varicocele/tratamento farmacológico , Varicocele/metabolismo , DNA Mitocondrial/metabolismo , Inflamassomos/metabolismo , Inflamassomos/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/antagonistas & inibidores , Nucleotidiltransferases/metabolismo , Ácido Clorogênico/farmacologia , Ácido Clorogênico/química , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ratos Sprague-Dawley , Espermatogênese/efeitos dos fármacos , Relação Dose-Resposta a Droga , Homeostase/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urinary system disease that is prone to recurrence. It typically leads to varying degrees of pelvic pain and discomfort, as well as symptoms related to the urinary system in affected patients. QianLieJinDan tablets (QLJD), a traditional Chinese medicine, have shown promising therapeutic effects on CP/CPPS in clinical practice, but the underlying mechanisms of QLJD in treating CP/CPPS have not been determined. Objective: To reveal the phytochemical characterization and multitarget mechanism of QLJD on CP/CPPS. Methods: The concentrations of the components of QLJD were determined using UHPLC-Q Exactive Orbitrap-MS. Utilizing network pharmacology approaches, the potential components, targets, and pathways involved in the treatment of CP/CPPS caused by QLJD were screened. Molecular docking calculations were employed to assess the affinity between the components of the QLJD and potential targets, revealing the optimal molecular conformation and binding site. Finally, the therapeutic efficacy and potential underlying mechanisms of QLJD were investigated through pharmacological experiments. Results: In this study, a total of 35 components targeting 29 CP-related genes were identified, among which quercetin, baicalin, icariin, luteolin, and gallic acid were the major constituents. Enrichment analysis revealed that the potential targets were involved mainly in the regulation of cytokines, cell proliferation and apoptosis, and the oxidative stress response and were primarily associated with the cytokineâcytokine receptor interaction pathway, the IL-17 signaling pathway, the Th17 cell differentiation pathway, and the JAK-STAT signaling pathway. In vivo experiments demonstrated that QLJD effectively attenuated the infiltration of CD3+ T cells and the expression of ROS in a CP/CPPS model rat prostate tissue. Furthermore, through the inhibition of IL-6 and STAT3 expression, QLJD reduced the differentiation of Th17 cells, thereby ameliorating pathological injury and prostatic index in prostate tissue. Conclusion: The potential of QLJD as an anti-CP/CPPS agent lies in its ability to interfere with the expression of IL-6 and STAT3, inhibit Th17 cell differentiation, reduce inflammatory cell infiltration in rat prostate tissue, and alleviate oxidative stress damage through its multi-component, multi-target, and multi-pathway effects.
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BACKGROUND: Autism and schizophrenia are environmental risk factors associated with prenatal viral infection during pregnancy. It is still unclear whether behavior phenotypes change at different developmental stages in offspring following the activation of the maternal immune system. METHODS: Sprague-Dawley rats received a single caudal vein injection of 10 mg/kg polyinosinic:polycytidylic acid (poly I:C) on gestational day 9 and the offspring were comprehensively tested for behaviors in adolescence and adulthood. RESULTS: Maternal serum levels of interleukin (IL)-6, IL-1ß and tumor necrosis factor-α were elevated in poly I:C-treated dams. The offspring of maternal poly I:C-induced rats showed increased anxiety, impaired social approach, and progressive impaired cognitive and sensorimotor gating function. CONCLUSION: Maternal immune activation led to developmental specificity behavioral impairment in offspring.
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Current treatments for schizophrenia (SCZ) remain largely ineffective in one-third of patients. Recent studies using stem cell therapy show a close relationship between stem cell immunomodulatory function and neuroinflammation in SCZ. To better investigate the efficacy of stem cell therapy for SCZ, human umbilical cord blood mesenchymal stem cells (hUC-MSC) with powerful immunomodulatory effects were administered to rats via the tail vein (once a week for 5 consecutive weeks starting from the weaning period) using a maternal immune activation (MIA) rodent model. Open field, PPI, Western blotting, Q-PCR, and immunofluorescence were used to assess the biological effects of repeated tail vein injections of hUC-MSC in offspring rats following the MIA model of SCZ. The results indicated that offspring of MIA rats exhibited schizophrenia-like (SCZ-like) anxiety behavior, with observed microglial activation triggering neuroinflammation. Furthermore, levels of IBA1, HMGB1, and PSD95 were significantly up-regulated, while SYP was significantly down-regulated. It is suggested that hUCB-MSCs may act through HMGB1, Iba1, PSD95, and related pathway molecules to alleviate neuroinflammation and repair synaptic damage by regulating the activity state of microglia. Consequently, this could improve the abnormal behavior observed in MIA offspring rats.
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Ansiedade , Modelos Animais de Doenças , Proteína HMGB1 , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Microglia , Ratos Sprague-Dawley , Esquizofrenia , Animais , Ratos , Esquizofrenia/terapia , Esquizofrenia/induzido quimicamente , Transplante de Células-Tronco Mesenquimais/métodos , Humanos , Feminino , Ansiedade/terapia , Proteína HMGB1/metabolismo , Gravidez , Proteína 4 Homóloga a Disks-Large/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas dos Microfilamentos/metabolismo , Masculino , Sangue Fetal/citologia , Doenças Neuroinflamatórias , Sinaptofisina/metabolismo , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Efeitos Tardios da Exposição Pré-NatalRESUMO
Understanding elevation changes on the Tibetan Plateau is crucial to comprehend the changes in topography, landscape, climate, environmental conditions, and water resources. However, some of the current products that track elevation changes only cover specific surface types or limited areas, and others have low spatial resolution. We propose an algorithm to extract ICESat-2 crossover points dataset for the Tibetan Plateau, and form a dataset. The crossover points dataset has a density of 2.015 groups/km², and each group of crossover points indicates the amount of change in elevation before and after a period of time over an area of approximately 17 meters in diameter. Comparing ICESat-2 crossover points data with existing studies on glaciers and lakes, we demonstrated the reliability of the derived elevation changes. The ICESat-2 crossover points provide a refined data source for understanding high-spatial-resolution elevation changes on the Tibetan Plateau. This dataset can provide validation data for various studies that require high-precision or high-resolution elevation change data on the Tibetan Plateau.
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ETHNOPHARMACOLOGICAL RELEVANCE: Perturbations in airway microbiota composition and disruption of microbe-metabolite interactions have been observed in respiratory infectious diseases (RIDs). The Yinhuang (YH) buccal tablet, as an ancient Chinese medicinal formula, has been traditionally employed for the management of upper RIDs. However, there is a lack of evidence for the effects of YH buccal tablets on upper respiratory tract microbiota and circulating metabolites. AIM OF THE STUDY: The aim of this study was to analyze the changes in respiratory microbiota composition and circulating metabolite profile after YH buccal tablets administration. MATERIALS AND METHODS: Throat swab samples and serum samples were collected from 60 healthy subjects for high-throughput 16S ribosomal RNA gene (16S rRNA) sequencing and non-targeted Ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. RESULTS: Airway microbial composition changed significantly after YH administration. The abundance of Actinomyces and Prevotella_7 increased, while the abundance of potentially pathogenic Pseudomonas and Corynebacterium decreased. A total of 168 significant HMDB taxonomic metabolites were identified in serum samples, of which lipid metabolites accounted for the largest proportion. Correlation analysis showed that circulatory metabolites were significantly correlated with changes in airway microbiota composition. CONCLUSIONS: YH buccal tablets can inhibit opportunistic pathogens, increase beneficial microorganisms in the upper respiratory tract, and regulate the body's metabolic pathways. These findings provide insights into the mechanism of action of YH buccal tablets in the treatment and prevention of respiratory diseases.
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Medicamentos de Ervas Chinesas , Microbiota , Humanos , Cromatografia Líquida , RNA Ribossômico 16S/genética , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/metabolismo , Espectrometria de Massas em Tandem/métodos , Sistema Respiratório , ComprimidosRESUMO
Background: Antiangiogenetic therapy is one of the effective strategies for non-small cell lung cancer (NSCLC) treatment. Four-and-a-half LIM-domain protein 2 (FHL2) serves as a key function in cell growth and metastasis of multiple cancers, but the role of FHL2 in NSCLC angiogenesis has not been intensely examined. Methods: FHL2 expression in NSCLC tissues and cell lines and its correlation with patients prognosis were investigated by using The Cancer Genome Atlas (TCGA) database and quantitative polymerase chain reaction (qPCR). Cell Counting Kit-8 (CCK-8) assay, EdU (5-ethynyl-2'-deoxyuridine) assay, and a xenograft model were used to investigate the effects of FHL2 on NSCLC progression in vitro and in vivo. CCK-8, wound-healing, Transwell invasion, tube formation, and permeability assays were performed to determine the roles of FHL2 in angiogenesis and vascular permeability. Vascular endothelial growth factor A (VEGFA) enzyme-linked immunosorbent assay (ELISA) assay, Western blot analysis, and MK-2206 were used to investigate the specific mechanism mediated by FHL2. Results: We demonstrated that FHL2 was significantly upregulated in NSCLC tissues and cell lines and was associated with poor prognosis. FHL2 overexpression enhanced the cell viability of NSCLC cells, as well as the proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs). In addition, we determined that FHL2 activated the AKT-mTOR signaling pathway in HUVECs by promoting VEGFA secretion from NSCLC cells, thereby inducing angiogenesis and vascular leakiness. We further confirmed that FHL2 also promoted NSCLC tumor growth in vivo. Conclusions: Our study revealed the role of FHL2 in NSCLC and the mechanism by which FHL2 promotes NSCLC tumorigenesis, providing novel insights into targeted therapy for NSCLC.
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Background: In recent years, single-hole thoracoscopic surgery technology is widely used in major medical centers and chest-specialized hospitals for the treatment of lung diseases. However, the single-hole minimally invasive surgery method focuses on one incision, and all surgical instruments need to pass through the same hole, resulting in repeated extrusion and tissue damage of the surgical incision. Therefore, we have improved the suture method of conventional surgical incision in order to reduce the probability of wound infection and dehiscence, promote early healing, and reduce the severity of postoperative wound scar, thereby enhancing the postoperative rapid recovery of patients. The purpose of this study is to explore the clinical efficacy of a modified surgical incision suture technique applied to uniportal thoracoscopic pulmonary resection. Methods: This study retrospectively analyzed 151 patients who were admitted to the Department of Thoracic Surgery and underwent pulmonary resection from January 2019 to October 2021 in the North District of Suzhou Municipal Hospital. The patients were divided into two groups according to the different surgical incision suture methods: a modified group and a conventional group. The postoperative general clinical indexes, incision infection rate, secondary suture rate, postoperative incision pain score, and the severity of postoperative incision scar were compared and analyzed between the two groups. Results: There were no statistically significant differences between the two groups in terms of chest tube duration or postoperative drainage and postoperative incision pain scores; the incision infection rate (1.3% vs. 6.7%, P<0.05), secondary suture rate (2.6% vs. 9.4%, P<0.05), and postoperative scar score (4.853 vs. 5.543, P=0.03) were better in the modified group than in the conventional group, and the differences between the two groups were statistically significant. Conclusions: Our modified suture method reduces the chance of infection and splitting and the severity of postoperative incision scar formation, promoting early healing. It can be safely and effectively applied to the incision suture of uniportal thoracoscopic pulmonary resection, enhancing the rapid postoperative recovery of patients.
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Background: The incidence and mortality of non-small cell lung cancer (NSCLC) are extremely high. Previous research has confirmed that the signal transducer and activator of the transcription 3 (STAT3) protein critically participate in the tumorigenesis of NSCLC. Mebendazole (MBZ) has exerts a larger number of pharmacological activities and has anticancer effects in lung cancer, but its mechanism of action remains unclear. This study thus aimed to clarify the impacts of MBZ on NSCLC cell. Methods: Cell proliferation, migration, and apoptosis were investigated via cell counting kit 8 (CCK-8) assay, Transwell assay, colony formation assay, wound-healing assay, and flow cytometry. Reactive oxygen species (ROS) were detected with a multifunctional microplate reader. Markers of cell migration and apoptosis were detected with Western blotting. The transcriptional activity of STAT3 was detected via luciferase assay. ROS scavenger N-acetylcysteine (NAC) was used to determine the effect of MBZ on NSCLC via ROS-regulated STAT3 inactivation and apoptosis. A xenograft model was constructed in vivo to investigate the role of MBZ in NSCLC tumor growth. Results: The findings demonstrated that MBZ inhibited NSCLC cell proliferation and migration while promoting apoptosis through triggering ROS generation. In addition, the Janus kinase 2 (JAK2)-STAT3 signaling pathway was abrogated with the treatment of MBZ. NAC could distinctly weaken MBZ-induced apoptosis and STAT3 inactivation. Moreover, MBZ inhibited the tumor growth of NSCLC in vivo. Conclusions: In summary, MBZ inhibited NSCLC cell viability and migration by inducing cell apoptosis via the ROS-JAK2-STAT3 signaling pathway. These data provide a theoretical basis for the use of MBZ in treating NSCLC.
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RATIONALE: The precise diagnosis and treatment of cognitive impairment remains a major challenge in the field of schizophrenia (SCZ) research. Synaptic dysfunction and loss are thought to be closely related to the occurrence and development of SCZ and may be involved in cognitive dysfunction. OBJECTIVES: The purpose of this study was to investigate whether neuronal pentraxins (NPTXs) plays a role in the etiology of SCZ and provide evidence of its possible therapeutic value a new target for drug development. METHODS: We recruited 275 participants, of whom 148 were SCZ from psychiatric hospital and 127 healthy control (HC) subjects from communities. Plasma concentrations of NPTXs were measured in HC and SCZ at baseline and after 8 weeks of antipsychotic treatment. The MATRICS Cognitive Consensus Battery was used to evaluate cognitive function. Furthermore, the brain is parcellated into 246 subregions using the Brainnetome atlas, and we extracted regional white matter volumes from magnetic resonance images of the SCZ groups. RESULTS: Plasma NPTX2 levels were significantly lower in SCZ compared with HC subjects, but were significantly raised in SCZ after 8 weeks of antipsychotic treatment compared to baseline. In addition, baseline plasma NPTX2 levels were positively correlated with cognitive performance. CONCLUSIONS: These findings indicate that NPTX2 may reveal novel aspects of disease etiology and act as a promising target for new drug development.
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Antipsicóticos , Disfunção Cognitiva , Proteínas do Tecido Nervoso , Esquizofrenia , Humanos , Esquizofrenia/diagnóstico , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Proteína C-Reativa , Cognição/fisiologiaRESUMO
Anxiety disorders are the most prevalent mental disorders. However, the genetic etiology of anxiety disorders remains largely unknown. Here we conducted a genome-wide meta-analysis on anxiety disorders by including 74,973 (28,392 proxy) cases and 400,243 (146,771 proxy) controls. We identified 14 risk loci, including 10 new associations near CNTNAP5, MAP2, RAB9BP1, BTN1A1, PRR16, PCLO, PTPRD, FARP1, CDH2 and RAB27B. Functional genomics and fine-mapping pinpointed the potential causal variants, and expression quantitative trait loci analysis revealed the potential target genes regulated by the risk variants. Integrative analyses, including transcriptome-wide association study, proteome-wide association study and colocalization analyses, prioritized potential causal genes (including CTNND1 and RAB27B). Evidence from multiple analyses revealed possibly causal genes, including RAB27B, BTN3A2, PCLO and CTNND1. Finally, we showed that Ctnnd1 knockdown affected dendritic spine density and resulted in anxiety-like behaviours in mice, revealing the potential role of CTNND1 in anxiety disorders. Our study identified new risk loci, potential causal variants and genes for anxiety disorders, providing insights into the genetic architecture of anxiety disorders and potential therapeutic targets.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Animais , Predisposição Genética para Doença/genética , Genômica , Locos de Características Quantitativas/genética , Transtornos de Ansiedade/genéticaRESUMO
BACKGROUND: Abernethy malformation, also known as congenital extrahepatic portosystemic shunt, is an uncommon malformation resulting from aberrant development of the portal venous system. Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the CFTR gene. It mainly affects the exocrine glands of the respiratory, digestive and reproductive systems. It is considered extremely rare in the Asian population. We present a clinical case involving a pediatric patient of Asian descent who was diagnosed with Abernethy malformation and CF. CASE SUMMARY: A 12-year-old girl presented with a medical history of recurring respiratory infections and hemoptysis, and chest computed tomography (CT) showed bronchiectasis. Whole exome sequencing was performed for the patient, yielding findings that revealed a compound heterozygous variant of the CFTR gene: c.233_c.234insT/p.Trp79fsTer3 (maternal origin); c.2909G>A/p.Gly970Asp (paternal origin). CF was diagnosed. The physician's attention was drawn to the presence of splenomegaly during disease progression. Abdominal enhanced CT revealed splenomegaly, compression of the left kidney, and multiple tortuous dilated vascular shadows were seen at the splenic hilum, which flowed back into the left renal vein and portal vein, suggesting Abernethy malformation type II. Intraoperatively, the abnormal blood flow was seen to merge into the inferior vena cava through the left renal vein without hepatic processing, and the pathology of liver biopsy showed hypoplastic, dilated or absent portal vein branches, both of which supported the diagnosis of Abernethy malformation type II. This represents the initial documented instance of Abernethy malformation accompanied by a CFTR gene mutation in the existing body of literature. CONCLUSION: Coexisting Abernethy malformation and CF are rare. Detailed medical history information, abdominal enhanced CT, venography and genetic testing contribute to diagnosis as well as differential diagnosis.
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Purpose: This study aimed to investigate the main pharmacological action and underlying mechanisms of Jin Gu Lian Capsule (JGL) against rheumatoid arthritis (RA) based on network pharmacology and experimental verification. Methods: Network pharmacology approaches were performed to explore the core active compounds of JGL, key therapeutic targets, and signaling pathways. Molecular docking was used to predict the binding affinity of compounds with targets. In vivo experiments were undertaken to validate the findings from network analysis. Results: A total of 52 targets were identified as candidate JGL targets for RA. Sixteen ingredients were identified as the core active compounds, including, quercetin, myricetin, salidroside, etc. Interleukin-1 beta (IL1B), transcription factor AP-1 (JUN), growth-regulated alpha protein (CXCL1), C-X-C motif chemokine (CXCL)3, CXCL2, signal transducer and activator of transcription 1 (STAT1), prostaglandin G/H synthase 2 (PTGS2), matrix metalloproteinase (MMP)1, inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB) and transcription factor p65 (RELA) were obtained as the key therapeutic targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the efficacy of JGL was functionally involved in regulating immune-mediated inflammation, in which IL-17/NF-κB signaling was recommended as one of the main pathways. Molecular docking suggested that the core active compounds bound strongly to their respective targets. Experimentally, JGL treatment mitigated inflammation, showed analgesic activity, and ameliorated collagen-induced arthritis. Enzyme-linked immunosorbent assay showed that JGL effectively reduced the serum levels of cytokines, chemokines, and MMPs. Immunohistochemistry staining showed that JGL markedly reduced the expression of the targets in IL-17/NF-κB pathway including IL-17A, IL-17RA, NF-κB p65, C-X-C motif ligand 2, MMP1 and MMP13. Conclusion: This investigation provided evidence that JGL may alleviate RA symptoms by partially inhibiting the immune-mediated inflammation via IL-17/NF-κB pathway.
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Artrite Reumatoide , Medicamentos de Ervas Chinesas , Humanos , NF-kappa B , Fator de Transcrição RelA , Interleucina-17 , Simulação de Acoplamento Molecular , Farmacologia em Rede , Artrite Reumatoide/tratamento farmacológico , Inflamação/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologiaRESUMO
Intelligent manufacturing requires robots to adapt to increasingly complex tasks, and dual-arm cooperative operation can provide a more flexible and effective solution. Motion planning serves as a crucial foundation for dual-arm cooperative operation. The rapidly exploring random tree (RRT) algorithm based on random sampling has been widely used in high-dimensional manipulator path planning due to its probability completeness, handling of high-dimensional problems, scalability, and faster exploration speed compared with other planning methods. As a variant of RRT, the RRT*Smart algorithm introduces asymptotic optimality, improved sampling techniques, and better path optimization. However, existing research does not adequately address the cooperative motion planning requirements for dual manipulator arms in terms of sampling methods, path optimization, and dynamic adaptability. It also cannot handle dual-manipulator collaborative motion planning in dynamic scenarios. Therefore, in this paper, a novel motion planner named RRT*Smart-AD is proposed to ensure that the dual-arm robot satisfies obstacle avoidance constraints and dynamic characteristics in dynamic environments. This planner is capable of generating smooth motion trajectories that comply with differential constraints and physical collision constraints for a dual-arm robot. The proposed method includes several key components. First, a dynamic A* cost function sampling method, combined with an intelligent beacon sampling method, is introduced for sampling. A path-pruning strategy is employed to improve the computational efficiency. Strategies for dynamic region path repair and regrowth are also proposed to enhance adaptability in dynamic scenarios. Additionally, practical constraints such as maximum velocity, maximum acceleration, and collision constraints in robotic arm applications are analyzed. Particle swarm optimization (PSO) is utilized to optimize the motion trajectories by optimizing the parameters of quintic non-uniform rational B-splines (NURBSs). Static and dynamic simulation experiments verified that the RRT*Smart-AD algorithm for cooperative dynamic path planning of dual robotic arms outperformed biased RRT* and RRT*Smart. This method not only holds significant practical engineering significance for obstacle avoidance in dual-arm manipulators in intelligent factories but also provides a theoretical reference value for the path planning of other types of robots.
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An environmental risk factor for schizophrenia (SZ) is maternal infection, which exerts longstanding effects on the neurodevelopment of offspring. Accumulating evidence suggests that synaptic disturbances may contribute to the pathology of the disease, but the underlying molecular mechanisms remain poorly understood. Erythropoietin-producing hepatocellular B (EphB) receptor signaling plays an important role in synaptic plasticity by regulating the formation and maturation of dendritic spines and regulating excitatory neurotransmission. We examined whether EphB receptors and downstream associated proteins are susceptible to environmental risk factors implicated in the etiology of synaptic disturbances in SZ. Using an established rodent model, which closely imitates the characteristics of SZ, we observed the behavioral performance and synaptic structure of male offspring in adolescence and early adulthood. We then analyzed the expression of EphB receptors and associated proteins in the prefrontal cortex and hippocampus. Maternal immune activation offspring showed significantly progressive cognitive impairment and pre-pulse inhibition deficits together with an increase in the expression of EphB2 receptors and NMDA receptor subunits. We also found changes in EphB receptor downstream signaling, in particular, a decrease in phospho-cofilin levels which may explain the reduced dendritic spine density. Besides, we found that the AMPA glutamate, another glutamate ionic receptor associated with cofilin, decreased significantly in maternal immune activation offspring. Thus, alterations in EphB signaling induced by immune activation during pregnancy may underlie disruptions in synaptic plasticity and function in the prefrontal cortex and hippocampus associated with behavioral and cognitive impairment. These findings may provide insight into the mechanisms underlying SZ.
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Carcinoma Hepatocelular , Eritropoetina , Neoplasias Hepáticas , Feminino , Gravidez , Ratos , Animais , Masculino , Neurônios/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Córtex Pré-Frontal/metabolismo , Hipocampo/metabolismo , Ácido Glutâmico/metabolismo , Eritropoetina/metabolismo , Eritropoetina/farmacologia , Receptores da Família Eph/metabolismo , Fatores de Despolimerização de Actina/metabolismo , Fatores de Despolimerização de Actina/farmacologia , Plasticidade NeuronalRESUMO
Following the publication of the above article, an interested reader drew to the authors' attention that the 'Control' and 'miR218 / BMI1' data panels for the Transwell invasion assay experiments shown in Figs. 4D and 5D on p. 100 and 101 respectively contained apparently overlapping data, albeit presented in different orientations, such that these data would have been derived from the same original source, even though they were intended to have shown the results from different experiments. On reexamining their original data, the authors realized that they had inadvertently assembled the data from the Transwell assay experiments incorrectly in Figs. 2, 4 and 5. The authors elected to repeat these Transwell assay experiments in view of the errors made in assembling these figures, and the revised versions of Figs. 2, 4 and 5 (specificially, containing the replacement Transwell assay data in Figs. 2F, 4D and 5D) are shown on the next three pages. Note that the errors made in assembling these figures did not affect the overall conclusions reported in the paper. All the authors agree with the publication of this corrigendum, and are grateful to the Editor of International Journal of Molecular Medicine for granting them the opportunity to publish this. Furthermore, they apologize to the readership for any inconvenience caused. [International Journal of Molecular Medicine 36: 93102, 2015; DOI: 10.3892/ijmm.2015.2216].
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In the continuous liquid distribution process, the emulsion drag-reducing agent has poor viscosity-increasing ability and a low solid content, resulting in a high concentration and high cost. To solve this problem, a nanosuspension agent with a "shelf structure," a dispersion accelerator, and a density regulator were used as auxiliary agents to realize the stable suspension of a polymer dry powder in an oil phase. The results show that the molecular weight of the synthesized polymer powder could reach nearly 28 million when the mass ratio of acrylamide (AM) to acrylic acid (AA) was 80:20 and a chain extender was added. The synthesized polymer powder was dissolved in tap water and 2% brine separately, and the viscosity of the solutions was measured. The dissolution rate of up to 90% was reached at 30 °C, and the viscosity was 33 and 23 mPa s in tap water and in 2% brine, respectively. A stable suspension can be obtained without obvious stratification in one week and with good dispersion after 6 months by using the following composition: 37% oil phase + 1% nanosuspension agent + 10% dispersion accelerator + 50% polymer dry powder + 2% density regulator. The drag-reduction performance is good, remaining close to 73% with increasing time. The viscosity of the suspension solution is 21 mPa s in 50% standard brine, and the salt resistance is good. The rate at which the suspension fracturing fluid damages the formation is 7.56%, and the reservoir damage is unsubstantial. Its performance in field applications illustrated that its sand-carrying capacity, referring to the capacity of the fracturing fluid to carry proppants into the fracture and place them in a predetermined position, reaches 10%. The results show that the fracturing fluid can be used as a pre-fluid to break the formation, form fractures, and expand fracture networks under low-viscosity conditions and can be used as a sand-carrying fluid to carry proppants into the formation under high-viscosity conditions. Additionally, the fracturing fluid can directly realize the fast conversion between high and low viscosities and allow for multiple uses of one agent.