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 analyze the related factors of treatment failure in children with acute lymphoblastic leukemia (ALL)in real-world.Methods:The clinical data of 1414 newly diagnosed children with ALL admitted to five hospital in Fujian province from April 2011 to December 2020 were retrospectively analyzed.Treatment failure was defined as relapse,non-relapse death,and secondary tumor.Results:Following-up for median time 49.7 (0.1-136. 9)months,there were 269 cases (19.0％)treatment failure,including 140 cases (52.0％)relapse,and 129 cases (48.0％)non-relapse death.Cox univariate and multivariate analysis showed that white WBC≥50 ×109/L at newly diagnosis,acute T-cell lymphoblastic leukemia (T-ALL),BCR-ABL1,KMT2A-rearrangement and poor early treatment response were independent risk factor for treatment failure (all HR>1.000,P<0.05).The 5-year OS of 140 relapsed ALL patients was only 23.8％,with a significantly worse prognosis for very early relapse (relapse time within 18 months of diagnosis).Among 129 patients died from non-relapse death,71 cases (26.4％)were died from treatment-related complications,56 cases (20.8％)died from treatment abandonment,and 2 cases (0.7％)died from disease progression.Among them,treatment-related death were significantly correlated with chemotherapy intensity,while treatment abandonment were mainly related to economic factors.Conclusion:The treatment failure of children with ALL in our province is still relatively high,with relapse being the main cause of treatment failure,while treatment related death and treatment abandonment caused by economic factors are the main causes of non-relapse related death.

We aimed to identify the infectious source of a case of melioidosis,to provide evidence for the prevention and control of melioidosis in Shanxi Province,China.The patient developed repeated fever,fatigue,diarrhea,and other symptoms after being caught in the rain while traveling in Hainan Province.The blood culture was positive,and the bacterial strain was i-dentified as Burkholderia thayensis and sent to the provincial Center for Disease Control and Prevention for further evaluation.MALDI-TOF MS and biochemical identification were used to identify the strain,whole genome sequencing was performed after nucleic acid extraction,MLST type and drug-resistance genes were analyzed,and a phylogenetic tree was constructed.The iso-lated strain was identified as Burkholderia pseudomallei by MALDI-TOF MS and biochemistry,and the MLST type was 366.The whole gene sequencing analysis indicated a close evolutionary relationship with the three isolates in Hainan Province,with high homology.This case of melioidosis was indeed imported from Hainan Province,according to molecular tracing analysis and epidemiological investigation,thus suggesting that medical institutions and disease control departments should strengthen understanding of melioidosis,and improve the diagnosis and treatment ability.

Aim To investigate the effect of safflower yellow (SY) on learning and memory ability of APP/ PS1 mice at different disease stages, and to explore the mechanism of SY anti- Alzheimer's disease by using 3-,6- and 9-month-old APP/PS 1 transgenic mice as experimental animal models. Methods Behavioral experiments were conducted to observe the effects of SY on learning and memory of APP/PS1 mice of different months. ELISA was used to detect the effect of SY on the expression of inflammatory factors in cortex of mice of different months. Western blot was used to detect the microglia activation marker protein, and its mechanism of action was further analyzed. Results SY could enhance the learning and memory ability of mice aged 3, 6 and 9 months, reduce the content of IL-6 and increase the content of TGF-β1 in brain tissue, up-regulate the expression levels of arginase-1 (arg-1) and triggering receptor expressed on myeloid cells 2 (tREM2) in brain tissue of mice of different months, and down-regulate the expression levels of inducible nitric oxide synthase (iNOS), Toll-like receptors 4 (tlr4) and nuclear factor-kappa B (nf-KB). Conclusions Compared with 3- and 9-month-old mice, SY is the most effective in improving learning memory in 6-month-old APP/PS1 mice. SY inhibits TLR4/NF-KB pathway activation by inducing TREM2 expression in brain tissue of APP/PS 1 transgenic mice, promotes microglia phenotype shift to anti-inflammatory phenotype, reduces chronic neuroinflammatory response, and improves learning memory in APP/PS1 mice at all months of age.

Aim To study the active ingredients and mechanism of action of Xinkeshu tablets against myo-cardial ischemia by network pharmacology and ze-brafish model.Methods The anti-myocardial ische-mia activity of Xinkeshu tablets was evaluated by iso-prenaline hydrochloride(ISO)-induced zebrafish myo-cardial ischemia model and H2O2-induced H9c2 dam-age model.The active ingredients of Xinkeshu tablets were retrieved using databases such as TCMSP.The potential targets were predicted by PharmaMapper data-base.Myocardial ischemic disease targets were searched by OMIM database.The potential therapeutic targets of Xinkeshu tablets against myocardial ischemia were analyzed.GO and KEGG enrichment analysis were conducted on core targets.The active ingredients were verified by zebrafish and cell model.qRT-PCR was used to detect the expression of key targets.Re-sults Xinkeshu tablets could significantly alleviate ISO-induced pericardial edema and bradycardia.It al-so could increase sinus venous-bulb aortic(SV-BA)distance and improve the cell viability.The 30 poten-tial active ingredients of Xinkeshu tables mainly acted on 30 core targets,including ALB,AKT1 and MAPK1,to regulate 627 GO items,including protein phosphorylation,negative regulation of apoptosis and positive regulation of PI3K signal transduction.KEGG results showed that 117 signaling pathways,including PI3K/Akt,FOXO and Ras,exerted anti-myocardial ischemia effect.Salvianolic acid A,lithospermic acid,rosmarinic acid,salvianolic acid D,salvianolic acid B,ginsenoside Rg2,hyperoside,3'-methoxypuerarin,3'-hydroxypuerarin and ginsenoside Rg1 could alleviate ISO-induced zebrafish myocardial ischemia and im-prove the cell viability.Xinkeshu tablets could upregu-late the expression of genes such as ras and akt1,and downregulate the expression of genes such as mapk1 and mapk8.Conclusion The active ingredients,in-cluding salvianolic acid A in Xinkeshu tablets,exert anti-myocardial ischemia effects by targeting targets,such as AKT1,MAPK1,and regulating signaling path-ways,such as PI3K/Akt,MAPK and Ras.

Objective:To explore the expressions of zinc homeostasis-related proteins,G protein-coupled receptor 39(GPR39)and ANO1 mRNA in the sperm of patients with asthenozoospermia(AS),and analyze their correlation with sperm motility.Methods:We collected semen samples from 82 male subjects with PR+NP＜40％,PR＜32％and sperm concentration＞15 × 106/ml(the AS group,n=40)or PR+NP≥40％,PR≥32％and sperm concentration＞15 × 106/ml(the normal control group,n=42).We analyzed the routine semen parameters and measured the zinc content in the seminal plasma using the computer-assisted sperm analysis system,detected the expressions of zinc transporters(ZIP13,ZIP8 and ZNT10),metallothioneins(MT1G,MT1 and MTF),GPR39,and calcium-dependent chloride channel protein(ANO1)in the sperm by real-time quantitative PCR(RT qPCR),examined free zinc distribution in the sperm by laser confocal microscopy,and determined the expressions of GPR39 and MT1 proteins in the sperm by immunofluorescence staining,followed by Spearman rank correlation analysis of their correlation with semen parameters.Results:There was no statistically significant difference in the zinc concentration in the seminal plasma between the AS and normal control groups(P＞0.05).Compared with the controls,the AS patients showed a significantly reduced free zinc level(P＜0.05),relative expressions of MT1G,MTF,ZIP13,GPR39 and ANO1 mRNA(P＜0.05),and that of the GPR39 protein in the AS group(P＜0.05).No statistically significant differences were observed in the relative expression levels of ZIP8,ZNT10 and MT1 mRNA between the two groups(P＞0.05).The relative expression levels of GPR39,ANO1,MT1G and MTF mRNA were positively correlated with sperm motility and the percentage of progressively motile sperm(P＜0.05).Conclusion:The expressions of zinc homeostasis proteins(MT1G,MTF and ZIP13),GPR39 and ANO1 mRNA are downregulated in the sperm of asthenozoospermia pa-tients,and positively correlated with sperm motility.

Humans ; Lupus Erythematosus, Systemic/therapy* ; Thrombotic Microangiopathies/complications*

Objective To explore the short-term and medium-term efficacy of modified loop plate suspension fixation in the treatment of acromioclavicular joint dislocation.Methods A retrospective analysis was performed in 72 patients with acromioclavicular joint dislocation and treated in Yangzhou Hospital of Traditional Chinese Medicine from December 2020 to December 2022.The patients were divided into modified group(n=37)and traditional group(n=35)according to different surgical methods.The modified group was treated with modified loop plate suspension fixation,and the traditional group was treated with clavicular hook plate fixation.The perioperative indexes,Constant-Murley score,and shoulder joint mobility and pain visual analogue scale(VAS)score before operation,3 months and 6 months after operation,postoperative complications rates,excellent and good rate of shoulder joint function recovery at 6 months after operation were compared between the two groups.Results The incision length and recovery time in the modified group were significantly shorter than those in the traditional group(P＜0.001),and the intraoperative blood loss was significantly less than that in the traditional group(P＜0.001).The Constant-Murley score,shoulder flexion and abduction activity in both groups at 3 months and 6 months after operation were significantly higher than before operation(P＜0.05),and these improvements were greater in the modified group(P＜0.05).The VAS scores of the two groups at 3 months and 6 months after operation were significantly lower than before operation(P＜0.05),and these decreases were greater in the improved group(P＜0.05).There were no significant differences in the excellent and good rate of shoulder joint function recovery and the incidence of postoperative complications between the two groups.Conclusions The modified titanium loop plate suspension fixation in the treatment of acromioclavicular joint dislocation can reduce surgical trauma and postoperative pain,and promote the recovery of shoulder joint function.

OBJECTIVES: To study the clinical features and prognosis of high hyperdiploid (HHD) childhood acute lymphoblastic leukemia (ALL). METHODS: A retrospective analysis was performed on the medical data of 1 414 children who were newly diagnosed with ALL and were admitted to five hospitals in Fujian Province of China from April 2011 to December 2020. According to karyotype, they were divided into two groups: HHD (n=172) and non-HHD (n=1 242). The clinical features and treatment outcome were compared between the two groups, and the factors influencing the prognosis were further explored. RESULTS: Among the 1 414 children with ALL, 172 (12.16%) had HHD. Compared with the non-HHD group, the HHD group had significantly lower proportions of children with risk factors for poor prognosis at diagnosis (age of onset ≥10 years or <1 year, white blood cell count ≥50×10⁹/L, and T-cell phenotype) or positive fusion genes (TEL-AML1, BCR-ABL1, E2A-PBX1, and MLL gene rearrangement) (P<0.05). The HHD group had a significantly higher proportion of children with minimal residual disease (MRD) <0.01% at the end of induction chemotherapy (P<0.05). The 10-year event-free survival (EFS) rate and overall survival (OS) rate in the HHD group were significantly higher than those in the non-HHD group (P<0.05). The univariate analysis showed that the number of chromosomes of 58-66, trisomy of chromosome 10, trisomy of chromosome 17, bone marrow MRD <1% on day 15 or 19 of induction chemotherapy, and bone marrow MRD <0.01% on day 33 or 46 of induction chemotherapy were associated with a higher EFS rate (P<0.05), and trisomy of chromosome 10 was associated with a higher OS rate (P<0.05). The multivariate Cox analysis showed that trisomy of chromosome 17 was closely associated with a high EFS rate (P<0.05). CONCLUSIONS The ALL children with HHD have few risk factors for poor prognosis at diagnosis and often have good prognosis. The number of chromosomes and trisomy of specific chromosomes are associated with prognosis in these children.
Child ; Humans ; Retrospective Studies ; Trisomy ; Prognosis ; Treatment Outcome ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis* ; Neoplasm, Residual ; Disease-Free Survival

Child ; Humans ; Renal Insufficiency, Chronic ; Kidney Failure, Chronic