OBJECTIVES: To investigate the expression of soluble factor-related apoptosis ligand (sFasL) in peripheral blood and microRNA-147b (miR-147b) in monocytes in children with sepsis and their value in assessing prognosis. METHODS: A prospective study was conducted on 124 children with sepsis (sepsis group), 60 children with common infections (infection group), and 60 healthy children undergoing physical examinations (healthy control group). The independent risk factors for poor prognosis in children with sepsis were analyzed, and the value of serum sFasL and monocyte miR-147b in predicting poor prognosis in children with sepsis was assessed. RESULTS: The serum level of sFasL and the relative expression of miR-147b in monocytes were highest in the sepsis group, followed by the infection group and the healthy control group (P<0.05). The multivariate logistic regression analysis showed that the serum level of sFasL and the relative expression of miR-147b in monocytes were closely associated with the poor prognosis of children with sepsis (P<0.05). The receiver operating characteristic curve analysis showed that the combination of serum sFasL level and relative expression of miR-147b in monocytes had a larger area under the curve compared to each indicator alone in predicting the prognosis of children with sepsis (P<0.05). CONCLUSIONS There are significant increases in the level of sFasL in peripheral blood and the relative expression of miR-147b in monocytes in children with sepsis. The combined use of these two indicators has relatively high clinical value in assessing the prognosis of children with sepsis.
Humans ; Sepsis/diagnosis* ; MicroRNAs/blood* ; Male ; Female ; Monocytes/metabolism* ; Prognosis ; Child, Preschool ; Prospective Studies ; Child ; Infant ; TNF-Related Apoptosis-Inducing Ligand/blood* ; Logistic Models

Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca²⁺ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^-/- OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^-/- OPCs in vitro and myelination in Tmem63a^-/- mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca²⁺ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
Animals ; Cell Differentiation/physiology* ; Oligodendroglia/metabolism* ; Mice, Knockout ; Mice ; Male ; Myelin Sheath/metabolism* ; Humans ; Child ; Cells, Cultured ; Oligodendrocyte Precursor Cells/metabolism*

Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

Objective:To investigate the effect of genetic polymorphism of MTHFR C677T (rs1801133) on methotrexate (MTX) related toxicity in pediatric mature B-cell lymphoma patients. Methods:Fifty-eight intermediate and high risk patients under 18 years of age with mature B-cell lymphoma who received 5 g/m2 MTX (24 h intravenous infusion) in Sun Yat-sen University Cancer Center from August 2014 to December 2021 were included,and their toxicity of high-dose MTX (HD-MTX) were monitored and analyzed. Results:Among the 58 pediatric patients,the number of CC,CT,and TT genotypes for MTHFR C677T was 33,19 and 6,respectively. A total of 101 courses of HD-MTX therapy were counted,of which plasma MTX level>0.2 μmol/L at 48 h post-MTX infusion were observed in 35 courses,≤0.2 μmol/L in 66 courses. Inter-group comparison showed that plasma MTX level>0.2 μmol/L at 48 h post-MTX infusion increased the risk of developing oral mucositis (P<0.05). Compared with wild-type (CC genotype),patients in the mutant group (CT+TT genotype) were more likely to develop myelosuppression,manifested as anemia,leucopenia,neutropenia and thrombocytopenia. However,plasma MTX level at 48 h was not associated with MTHFR C677T gene polymorphism. Conclusion:The risk of developing oral mucositis in children with mature B-cell lymphoma is associated with plasma MTX concentration. Polymorphism of MTHFR C677T gene is not related to plasma MTX concentration in children with mature B-cell lymphoma,but is related to grade Ⅲ to Ⅳ hematological toxicity.

Objective:To explore the dynamic changes of thrombosbondin-1(TSP-1)and transforming growth factor beta(TGF-β)in patients who underwent hepatectomy and their clinical value in predicting post-hepatectomy liver failure(PHLF).Methods:Clinical data of 113 patients who received hepatectomy in the First Affiliated Hospital of Xinjiang Medical University from Janu-ary 2016 to March 2019 were retrospectively analyzed.The cohort comprised 59 males and 54 fe-males,with an average age of(41.00±13.98)years.According to the standard of the International Study Group of Liver Surgery(ISGLS),TSP-1 was divided into the PHLF group(n=40)and the non-PHLF group(n=73).The dynamic changes of plasma TSP-1 and TGF-β plasma levels during peri-operative period were observed.The definition and diagnostic criteria suggested by ISGLS was used to evaluate PHLF.The value of plasma TSP-1 and TGF-β level in predicting PHLF were ana-lyzed by calculating areas under the receiver operating characteristic curves(AUCs).Patients were divided into TSP-1 high group and TSP-1 low groups based upon the ROC cutoff values and their correlation with PHLF was analyzed.T test and Mann-Whitney rank sum test were performed to compare the TSP-1 and TGF-β levels between the two groups.The rate comparison was carried out by Chi-square test or Fisher's exact test.Results:In this study,40 patients experienced vary-ing degrees of PHLF.The plasma levels of TSP-1 on postoperative day I(POD1)and day 7(POD 7)in the PHLF group were significantly higher than those in the non-PHLF group(P＜0.05,P＜0.01,re-spectively).The area under the ROC curve of plasma TSP-1 level on postoperative 1 d in the diag-nosis of PHLF was 0.725,with sensitivity of 0.864 and specificity of 0.647.The area under the ROC curve of plasma TSP-1 level on postoperative 7 d in the diagnosis of PHLF was 0.81,with sensitiv-ity of 0.818 and specificity of 0.765.Conclusion:The incidence of PHLF is related to the extent of liver resection,Child-Pugh grade and TSP-1 levels on postoperative day 1.The concentration level of TSP-1 on POD land 7 might be utilized as an effective marker for predicting PHLF.

Aim To explore the improvement effect of Bazi Bushen capsule on thymic degeneration in SAMP6 mice and the possible mechanism.Methods Twenty 12 week old male SAMP6 mice were randomly divided into the model group(SAMP6)and the Bazi Busheng capsule treatment group(SAMP6+BZBS).Ten SAMR1 mice were assigned to a homologous control group(SAMR1).The SAMP6+BZBS group was oral-ly administered Bazi Bushen capsule suspension(2.8 g·kg-1)daily,while the other two groups were orally administered an equal amount of distilled water.After nine weeks of administration,the morphology of the thymus in each group was observed and the thymus in-dex was calculated;HE staining was used to observe the structural changes of thymus tissue;SA-β-gal stai-ning was used to detect thymic aging;flow cytometry was used to detect the proportion of thymic CD3+T cells in each group;Western blot was used to detect the levels of p16,Bax,Bcl-2,and cleaved caspase-3 proteins in thymus;immunofluorescence was applied to detect the proportion of cortical thymic epithelial cells in each group;ELISA was employed to detect IL-7 lev-els in thymus.Results Compared with the SAMP6 group,the thymic index of the SAMP6+BZBS group significantly increased(P＜0.05);the disordered thy-mic structure was significantly improved;the positive proportion of SA-β-gal staining significantly decreased(P＜0.01);the proportion of CD3+T cells apparently increased(P＜0.05);the level of p16 protein signifi-cantly decreased(P＜0.05);the level of Bcl-2 pro-tein significantly increased(P＜0.05),while the lev-el of cleaved caspase-3 protein markedly decreased(P＜0.05);the proportion of cortical thymic epithelial cells evidently increased;the level of IL-7 significantly increased(P＜0.01).Conclusions Bazi Bushen capsule can delay thymic degeneration,inhibit cell ap-optosis in thymus and promote thymic cell development in SAMP6 mice,which may be related to increasing the proportion of cortical thymic epithelial cells and promoting IL-7 secretion.

OBJECTIVE To investigate the transcriptomal charactersistics of the striatum in the chronic social defeat stress(CSDS)model mice by using spatial transcriptome analysis and to address the underlying mechanism of the striatum in regulating depressive states.METHODS The CSDS para-digm was employed to establish a depression-like mouse model.The depressive indicators of behavioral despair,anhedonia,and social disorders were assessed through a battery of tests,including the tail suspension test,forced swim test,sucrose preference test,and social interaction experiments.The control mice and the mice exhibiting CSDS-sensitive depression-like behaviors were selected for spatial tran-scriptome sequencing of the striatal region.This sequencing aimed to identify highly expressed genes,followed by KEGG and GO enrichment analyses using the DAVID database.RESULTS The CSDS mouse model effectively induced behavioral despair,anhedonia and social avoidance(P<0.05,P<0.01).Spatial transcriptome analysis revealed 193 differentially expressed genes in the striatum of normal mice.KEGG and GO analyses indicated that these genes were primarily associated with striatal devel-opment,locomotor behaviors,and drug addiction.They were strongly implicated in signaling pathways such as cyclic adenosine monophosphate,cyclic guanosine monophosphate-protein kinase G,calcium signaling,Ras-related protein 1,and mitogen-activated protein kinase,and synaptic linked to GABAergic and dopaminergic neurons.In contrast,CSDS modeling mice led to the identification of 298 differentially expressed genes in the striatum compared with the normal control mice.These genes were significantly enriched in pathways related to neurodegenerative diseases,including Huntington disease,Alzheimer disease,and Parkinson disease.CONCLUSION Depressive states induced by CSDS are associated with the pathological processes underlying neurodegenerative diseases in the striatum.

AIM To investigate the clinical effects of Xuanfei Jiejing Decoction combined with conventional treatment on patients with asthma of Wind-Phlegm Obstructing Lung Pattern.METHODS One hundred and fifty patients were randomly assigned into control group(75 cases)for 4-week intervention of conventional treatment,and observation group(75 cases)for 4-week intervention of both Xuanfei Jieshi Decoction and conventional treatment.The changes in clinical effects,TCM syndrome scores,airway inflammatory indices(ECP,IL-4,IgE),lung function indices(FVC,FEV1/FVC,PEF)and putum and mucus indices(4 h sputum volume,sputum viscosity,mucin 5AC)were detected.RESULTS The observation group demonstrated higher total effective rate than the control group(P＜0.05).After the treatment,the two groups displayed decreased TCM syndrome scores,airway inflammatory indices,putum and mucus indices(P＜0.05),and increased lung function indices(P＜0.05),especially for the observation group(P＜0.05).CONCLUSION For the patients with asthma of Wind-Phlegm Obstructing Lung Pattern,Xuanfei Jiejing Decoction combined with conventional treatment can reduce airway inflammatory levels,inhibit airway mucus secretion,improve lung functions,and alleviate clinical symptoms.