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

Lumbar disc (LD) herniation and aging are prevalent conditions that can result in substantial morbidity. This study aimed to clarify the mechanisms connecting the LD aging and herniation, particularly focusing on cellular senescence and molecular alterations in the nucleus pulposus (NP). We performed a detailed analysis of NP samples from a diverse cohort, including individuals of varying ages and those with diagnosed LD herniation. Our methodology combined histological assessments with single-nucleus RNA sequencing to identify phenotypic and molecular changes related to NP aging and herniation. We discovered that cellular senescence and a decrease in nucleus pulposus progenitor cells (NPPCs) are central to both processes. Additionally, we found an age-related increase in NFAT1 expression that promotes NPPC senescence and contributes to both aging and herniation of LD. This research offers fresh insights into LD aging and its associated pathologies, potentially guiding the development of new therapeutic strategies to target the root causes of LD herniation and aging.
Intervertebral Disc Displacement/metabolism* ; Humans ; Aging/pathology* ; Nucleus Pulposus/pathology* ; Male ; Female ; Transcriptome ; Middle Aged ; Lumbar Vertebrae/pathology* ; Adult ; Cellular Senescence ; Stem Cells/pathology* ; Aged ; Intervertebral Disc Degeneration/metabolism*

Under the background of forensic medicine becoming a first-level discipline,the opportuni-ties and challenges of discipline development coexist.Starting from the actual situation and characteris-tics of local medical colleges and universities,this paper discusses the problems and solutions for the development of forensic medicine discipline from the perspective of building a regional high-level medical university.Combined with the experiences of carrying out forensic medicine education in our college,this paper supplies our thoughts and practices on improving the discipline system,enhancing the ability to serve society,perfecting the talent cultivation model and promoting forensic culture,to provide reference and inspiration for the development of forensic medicine in other universities,jointly promote the advancement of forensic medicine in China to a new stage,and contribute the wisdom and strength of forensic medical experts to the construction of a law-based China,a safe China and a healthy China.

Recent studies have indicated that the expression of ubiquitin-specific protease 51 (USP51), a novel deubiquitinating enzyme (DUB) that mediates protein degradation as part of the ubiquitin‒proteasome system (UPS), is associated with tumor progression and therapeutic resistance in multiple malignancies. However, the underlying mechanisms and signaling networks involved in USP51-mediated regulation of malignant phenotypes remain largely unknown. The present study provides evidence of USP51's functions as the prominent DUB in chemoresistant triple-negative breast cancer (TNBC) cells. At the molecular level, ectopic expression of USP51 stabilized the 78 kDa Glucose-Regulated Protein (GRP78) protein through deubiquitination, thereby increasing its expression and localization on the cell surface. Furthermore, the upregulation of cell surface GRP78 increased the activity of ATP binding cassette subfamily B member 1 (ABCB1), the main efflux pump of doxorubicin (DOX), ultimately decreasing its accumulation in TNBC cells and promoting the development of drug resistance both in vitro and in vivo. Clinically, we found significant correlations among USP51, GRP78, and ABCB1 expression in TNBC patients with chemoresistance. Elevated USP51, GRP78, and ABCB1 levels were also strongly associated with a poor patient prognosis. Importantly, we revealed an alternative intervention for specific pharmacological targeting of USP51 for TNBC cell chemosensitization. In conclusion, these findings collectively indicate that the USP51/GRP78/ABCB1 network is a key contributor to the malignant progression and chemotherapeutic resistance of TNBC cells, underscoring the pivotal role of USP51 as a novel therapeutic target for cancer management.

Aim To explore the mechanism of the effect of siRNA-mediated MAGE-3 silencing on intesti-nal flora,gastric mucosal PTEN expression and liver metastasis in rats with gastric cancer based on MAPK/ERK signaling pathway.Methods Thirty rats were randomly divided into the normal(CO)group,model(MO)group,and MAGE-3 silenced(SM)group,with 10 rats in each group.The model of MO group and SM group was established by MNNG gavage meth-od.After successful modeling,the SM group was intri-toneally injected with 20 μg·kg-1 shRNA MAGE-3 lentiviral vector.The number of intestinal flora in rats was detected by selective medium of intestinal flora,the expression of PTEN in gastric mucosa was detected by immunohistochemistry,liver metastasis was detected by HE staining,and the protein expression of MAPK/ERK signaling pathway was detected by Western blot.The regulatory effect of siRNA-mediated MAGE-3 si-lencing on MAPK/ERK signaling pathway was verified in vitro.Results Compared with CO group,the con-tents of Enterococcus and Escherichia coli,the protein expressions of P-MEK1,P-ERK1 and P-ELK1 in MO group increased(P＜0.05),while the contents of Lactobacillus and Bifidobacterium and the expression of PTEN decreased(P＜0.05).In SM group,the con-tents ofEnterococcus,Escherichiacoli,P-MEK1,P-ERK1 and P-ELK1 protein expressions decreased(P＜0.05),while the contents of Lactobacillus,Bifidobac-terium and PTEN expression increased(P＜0.05).Compared with group CO,the protein expressions of P-MEK1,p-ERK1 and P-ELK1 in group MO were not significantly different(P＞0.05),while the protein expressions of P-MEK1,p-ERK1 and P-ELK1 in group SM were reduced compared with group MO(P＜0.05).Conclusions siRNA-mediated MAGE-3 si-lencing can significantly improve intestinal flora,pro-mote the expression of PTEN in gastric mucosa,and inhibit liver metastasis in rats with gastric cancer.The mechanism may be related to the inhibition of MAPK/ERK signaling pathway.

Background and Aims:Mucinous adenocarcinoma of the colorectum(MAC)is a distinct histologic subtype of colorectal cancer characterized by high malignancy and low diagnostic accuracy of preoperative biopsy,posing challenges for clinical decision-making.Given the critical role of the inflammatory microenvironment in tumor progression,this study aimed to develop and validate a nomogram model integrating preoperative systemic inflammatory indicators and clinical features to improve the preoperative diagnosis of MAC.Methods:Clinical data of 293 patients with colorectal cancer who underwent radical resection between June 2017 and June 2022 at the First Affiliated Hospital of the University of South China were retrospectively analyzed.Based on postoperative pathology,patients were classified into the mucinous adenocarcinoma(MAC)group and the non-specific adenocarcinoma(AC)group.Propensity score matching(PSM,1∶1)was used to balance age,T stage,and N stage.Differences in preoperative inflammatory indices were compared between groups.Univariate and multivariate logistic regression analyses were performed to identify independent predictors of MAC,which were incorporated into a diagnostic nomogram.The model's discrimination,calibration,and clinical utility were evaluated using the area under the receiver operating characteristic curve(AUC),calibration plots,and decision curve analysis(DCA).Results:Among the 293 patients,46 had MAC and 247 had AC,with a preoperative colonoscopic diagnostic rate of 54%for MAC.After PSM(43 pairs),platelet count,platelet lymphocyte ratio(PLR),systemic immune inflammation index(SII),inflammation related prognostic index(IPI),and systemic inflammation score(SIS)were significantly higher in the MAC group,while lymphocyte monocyte ratio(LMR)was lower(all P<0.05).Multivariate analysis identified tumor location,maximum tumor diameter,and preoperative IPI as independent predictors.The AUCs of the nomogram in the training(n=206)and validation(n=87)cohorts were 0.759(95%CI=0.662-0.856)and 0.776(95%CI=0.649-0.903),respectively.Calibration plots showed good agreement between predicted and observed probabilities,and DCA demonstrated satisfactory clinical applicability.Conclusion:A nomogram model integrating tumor location,tumor size,and preoperative IPI was successfully developed and validated for preoperative diagnosis of colorectal MAC.This model provides a practical,quantitative tool with good predictive performance to assist clinicians in individualized treatment planning,particularly for patients ineligible for surgical biopsy.

Aim To explore the mechanism of the effect of siRNA-mediated MAGE-3 silencing on intesti-nal flora,gastric mucosal PTEN expression and liver metastasis in rats with gastric cancer based on MAPK/ERK signaling pathway.Methods Thirty rats were randomly divided into the normal(CO)group,model(MO)group,and MAGE-3 silenced(SM)group,with 10 rats in each group.The model of MO group and SM group was established by MNNG gavage meth-od.After successful modeling,the SM group was intri-toneally injected with 20 μg·kg-1 shRNA MAGE-3 lentiviral vector.The number of intestinal flora in rats was detected by selective medium of intestinal flora,the expression of PTEN in gastric mucosa was detected by immunohistochemistry,liver metastasis was detected by HE staining,and the protein expression of MAPK/ERK signaling pathway was detected by Western blot.The regulatory effect of siRNA-mediated MAGE-3 si-lencing on MAPK/ERK signaling pathway was verified in vitro.Results Compared with CO group,the con-tents of Enterococcus and Escherichia coli,the protein expressions of P-MEK1,P-ERK1 and P-ELK1 in MO group increased(P＜0.05),while the contents of Lactobacillus and Bifidobacterium and the expression of PTEN decreased(P＜0.05).In SM group,the con-tents ofEnterococcus,Escherichiacoli,P-MEK1,P-ERK1 and P-ELK1 protein expressions decreased(P＜0.05),while the contents of Lactobacillus,Bifidobac-terium and PTEN expression increased(P＜0.05).Compared with group CO,the protein expressions of P-MEK1,p-ERK1 and P-ELK1 in group MO were not significantly different(P＞0.05),while the protein expressions of P-MEK1,p-ERK1 and P-ELK1 in group SM were reduced compared with group MO(P＜0.05).Conclusions siRNA-mediated MAGE-3 si-lencing can significantly improve intestinal flora,pro-mote the expression of PTEN in gastric mucosa,and inhibit liver metastasis in rats with gastric cancer.The mechanism may be related to the inhibition of MAPK/ERK signaling pathway.

Background and Aims:Mucinous adenocarcinoma of the colorectum(MAC)is a distinct histologic subtype of colorectal cancer characterized by high malignancy and low diagnostic accuracy of preoperative biopsy,posing challenges for clinical decision-making.Given the critical role of the inflammatory microenvironment in tumor progression,this study aimed to develop and validate a nomogram model integrating preoperative systemic inflammatory indicators and clinical features to improve the preoperative diagnosis of MAC.Methods:Clinical data of 293 patients with colorectal cancer who underwent radical resection between June 2017 and June 2022 at the First Affiliated Hospital of the University of South China were retrospectively analyzed.Based on postoperative pathology,patients were classified into the mucinous adenocarcinoma(MAC)group and the non-specific adenocarcinoma(AC)group.Propensity score matching(PSM,1∶1)was used to balance age,T stage,and N stage.Differences in preoperative inflammatory indices were compared between groups.Univariate and multivariate logistic regression analyses were performed to identify independent predictors of MAC,which were incorporated into a diagnostic nomogram.The model's discrimination,calibration,and clinical utility were evaluated using the area under the receiver operating characteristic curve(AUC),calibration plots,and decision curve analysis(DCA).Results:Among the 293 patients,46 had MAC and 247 had AC,with a preoperative colonoscopic diagnostic rate of 54%for MAC.After PSM(43 pairs),platelet count,platelet lymphocyte ratio(PLR),systemic immune inflammation index(SII),inflammation related prognostic index(IPI),and systemic inflammation score(SIS)were significantly higher in the MAC group,while lymphocyte monocyte ratio(LMR)was lower(all P<0.05).Multivariate analysis identified tumor location,maximum tumor diameter,and preoperative IPI as independent predictors.The AUCs of the nomogram in the training(n=206)and validation(n=87)cohorts were 0.759(95%CI=0.662-0.856)and 0.776(95%CI=0.649-0.903),respectively.Calibration plots showed good agreement between predicted and observed probabilities,and DCA demonstrated satisfactory clinical applicability.Conclusion:A nomogram model integrating tumor location,tumor size,and preoperative IPI was successfully developed and validated for preoperative diagnosis of colorectal MAC.This model provides a practical,quantitative tool with good predictive performance to assist clinicians in individualized treatment planning,particularly for patients ineligible for surgical biopsy.

Objective With the widespread of transcatheter aortic valve replacement(TAVR)in patients with severe symptomatic aortic stenosis(AS),the life-cycle management has become a major determinant of prognosis.Methods A total of 408 AS patients who underwent successfully TAVR from June 2021 to August 2023 were consecutively enrolled in Hospital Valve Intervention Center.Patients were assigned to the Usual Care(UC)group between June 2021 and October 2022,while patients were assigned to the Heart Multi-parameter Monitoring(HMM)group between November 2022 and August 2023.The primary endpoint was defined as composite endpoint within 6 months post-TAVR,including all-cause death,cardiovascular death,stroke/transient ischemic attack,conduction block,myocardial infarction,heart failure rehospitalization,and major bleeding events.Secondary endpoints were the time interval(in hours)from event occurrence to medical consultation or advice and patient satisfaction.Statistical analysis was performed using Kaplan-Meier and multivariable Cox proportional hazards models.Results The incidence of primary endpoint in HMM group was significantly lower than that in UC group(8.9％vs.17.7％,P=0.016),the driving event was the rate of diagnosis and recognition of conduction block.The average time intervals from event occurrence to receiving medical advice were 3.02 h in HHM group vs.97.09 h in UC group(P＜0.001).Using cardiac monitoring devices and smart healthcare platforms provided significant improving in patients long-term management(HR 0.439,95％CI 0.244-0.790,P=0.006).Conclusions The utilization of cardiac monitoring devices and smart healthcare platforms effectively alerted clinical events and improved postoperative quality of life during long-term management post TAVR.