ObjectiveThis paper aims to explore the risk factors for chronic atrophic gastritis （CAG） with turbidity toxin accumulation syndrome and establish a prediction model. MethodsClinical data of 180 patients with CAG who participated in the "clinical study of Xianglian Huazhuo Particles blocking CAG cancer transformation" of Hebei Sheng Zhong Yi Yuan from July 2021 to March 2022 were collected. After confounding factors were controlled by propensity score matching， patients were divided into a training set （namely dev） and a validation set （namely vad） in a seven to three ratio. The risk factors for CAG with turbidity toxin accumulation syndrome in the training set were investigated by using univariate Logistic regression analysis and least absolute shrinkage and selection operator （namely Lasso） regression algorithms. Subsequently， a model， named model 1se， was developed by using the training set data to predict the risk factors for CAG with turbidity toxin accumulation syndrome. The accuracy of the prediction model was assessed by using various methods， including the receiver operating characteristic （ROC） curve， Hosmer-Lemeshow test （H-L）， calibration plot， and decision curve analysis （DCA）. ResultsAge， body mass index （BMI）， family history of cancer， job and life satisfaction， yellow and greasy fur with slippery pulse， and heavy body sensation were independent risk factors of the model. The prediction model showed excellent predictive value for both the training and validation sets. ConclusionThe established prediction model for CAG with turbidity toxin accumulation syndrome has high discrimination and excellent calibration， which could provide an excellent clinical basis for disease diagnosis and individualized treatment of patients.

ObjectiveThis paper aims to explore the risk factors for chronic atrophic gastritis （CAG） with turbidity toxin accumulation syndrome and establish a prediction model. MethodsClinical data of 180 patients with CAG who participated in the "clinical study of Xianglian Huazhuo Particles blocking CAG cancer transformation" of Hebei Sheng Zhong Yi Yuan from July 2021 to March 2022 were collected. After confounding factors were controlled by propensity score matching， patients were divided into a training set （namely dev） and a validation set （namely vad） in a seven to three ratio. The risk factors for CAG with turbidity toxin accumulation syndrome in the training set were investigated by using univariate Logistic regression analysis and least absolute shrinkage and selection operator （namely Lasso） regression algorithms. Subsequently， a model， named model 1se， was developed by using the training set data to predict the risk factors for CAG with turbidity toxin accumulation syndrome. The accuracy of the prediction model was assessed by using various methods， including the receiver operating characteristic （ROC） curve， Hosmer-Lemeshow test （H-L）， calibration plot， and decision curve analysis （DCA）. ResultsAge， body mass index （BMI）， family history of cancer， job and life satisfaction， yellow and greasy fur with slippery pulse， and heavy body sensation were independent risk factors of the model. The prediction model showed excellent predictive value for both the training and validation sets. ConclusionThe established prediction model for CAG with turbidity toxin accumulation syndrome has high discrimination and excellent calibration， which could provide an excellent clinical basis for disease diagnosis and individualized treatment of patients.

Osteoarthritis (OA), a highly prevalent degenerative joint disease worldwide, is defined by articular cartilage degradation, abnormal bone remodeling, and persistent chronic inflammation. It severely compromises patients’ quality of life, and currently, there is no radical cure. Abnormal mechanical stress is widely regarded as a core driver of OA pathogenesis, and the exploration of mechanical signal perception and transduction mechanisms has become crucial for deciphering OA’s pathophysiological processes. Piezo1, a key mechanosensitive cation channel belonging to the Piezo protein family, has recently gained significant attention due to its pivotal role in mediating cellular responses to mechanical stimuli in joint tissues. This review systematically examines Piezo1’s expression patterns, regulatory mechanisms, and pathological functions in OA, with a particular focus on its dual roles in modulating chondrocyte homeostasis and bone metabolism disorders, while also delving into the underlying molecular signaling pathways and potential therapeutic implications. Piezo1, consisting of approximately 2 500 amino acids and forming a unique trimeric propeller-like structure, is widely expressed in chondrocytes, osteocytes, mesenchymal stem cells, and synovial cells. It exhibits permeability to cations such as Ca²⁺, K⁺, and Na⁺, and directly responds to membrane tension changes induced by mechanical stimuli like fluid shear stress and mechanical overload. In OA patients and animal models, Piezo1 expression is significantly upregulated, especially in cartilage regions subjected to abnormal mechanical stress (e.g., human temporomandibular joint cartilage). This overexpression is closely associated with aggravated cartilage degeneration, increased chondrocyte apoptosis, accelerated cellular senescence, and intensified inflammatory responses. Mechanical overload and pro-inflammatory cytokines (e.g., IL-1β) are key inducers of Piezo1 upregulation: IL-1β activates the PI3K/AKT/mTOR signaling pathway to enhance Piezo1 expression, forming a pathogenic positive feedback loop that inhibits chondrocyte autophagy, promotes apoptosis, and further accelerates joint degeneration. Mechanistically, Piezo1 mediates OA progression through multiple interconnected pathways. When activated by mechanical stress, Piezo1 triggers excessive Ca²⁺ influx, leading to endoplasmic reticulum stress (ERS) and mitochondrial dysfunction, which directly induce chondrocyte apoptosis. This process involves the activation of downstream signaling cascades such as cGAS-STING and YAP-MMP13/ADAMTS5. YAP, a transcriptional regulator, upregulates the expression of matrix metalloproteinase 13 (MMP13) and aggrecanase (ADAMTS5), thereby accelerating cartilage matrix degradation. Additionally, Piezo1-driven Ca²⁺ overload promotes the accumulation of reactive oxygen species (ROS) and upregulates senescence markers (p16 and p21), accelerating chondrocyte senescence via the p38MAPK and NF-κB pathways. Senescent chondrocytes secrete senescence-associated secretory phenotype (SASP) factors (e.g., IL-6, IL-1β), further amplifying joint inflammation. In terms of bone metabolism, Piezo1 maintains joint homeostasis by promoting the differentiation of fibrocartilage stem cells into chondrocytes and balancing bone formation and resorption through regulating the FoxC1/YAP axis and RANKL/OPG ratio. Therapeutically, targeting Piezo1 shows promising potential. Preclinical studies have demonstrated that Piezo1 inhibitors (e.g., GsMTx4) can reduce joint damage and alleviate pain in OA mice. Simultaneously, siRNA-mediated co-silencing of Piezo1 and TRPV4 (another mechanosensitive channel) decreases intracellular Ca²⁺ concentration, inhibits chondrocyte apoptosis, and promotes cartilage repair. Conditional knockout of Piezo1 using Gdf5-Cre transgenic mice alleviates cartilage degeneration in post-traumatic OA models by downregulating MMP13 and ADAMTS5 expression. Despite existing challenges, such as off-target effects of inhibitors, inefficient local drug delivery, and interindividual genetic variability, strategies like developing selective Piezo1 antagonists, optimizing targeted nanocarriers, and combining Piezo1-targeted therapy with physical therapy provide viable avenues for clinical translation. The authors propose that Piezo1 serves as a critical therapeutic target for OA, and future research should focus on deciphering its context-dependent regulatory networks, developing tissue-specific intervention strategies, and validating their efficacy and safety in clinical trials to address the unmet medical needs of OA patients.

Objective To investigate the spatio-temporal expression of nuclear receptor subfamily 0 group B member 1(NR0B1)in synovial tissues of rheumatoid arthritis(RA),and to uncover the potential upstream signalling pathway that may regulate NR0B1 expression in human fibroblast-like synovial cells,thereby clarifying the possible factors that induce the disorder of NR0B1 expression in RA.Methods Patients with 25 RA and 18 osteoarthritis(OA)who did not receive any immunotherapy were recruited to obtain the synovial tissues of knee joint,as well as their related clinical test information,and the expression characteristics of NR0B1 in synovial tissue were investigated using Real-time PCR,Western blotting,immunohistochemistry and double immunofluorescent staining.Meanwhile,Pearson Chi-square test was used to evaluate the correlation between NR0B1 mRNA expression level and clinical parameters in RA patients.Furthermore,the MH7ANR0B1-/-cells that were stably knocked down of endogenous NR0B1 were generated,and the effects of NR0B1 deficiency on the phenotype of rheumatoid synovial cells enhanced by vascular endothelial growth factor(VEGF)were then evaluated by means of cell viability and apoptosis assays,colony formation assay,wound healing assay,and cell invasion assay.Last,we studied the molecular mechanism underlying interleuikin 6(IL-6)-mediated regulation of NR0B1 expression at the transcriptional level by using the STAT3-specific inhibitor intervention,siRNA,and dual luciferase reporter gene detection.Results The expression level of NR0B1 mRNA in the RA synovial tissues was significantly higher than that in synovial tissues from OA patients(P＜0.05).This trend of the increased NR0B1 mRNA expression correlated to clinical parameters,including C-reactive protein(CRP),rheumatoid factor(RF)and erythrocyte sedimentation rate(ESR),in RA patients.NR0B1 protein was predominantly immunolocalized in fibroblast-like synoviocytes of RA synovial tissues.Functionally,knockdown of NR0B1 expression markedly neutralize the VEGF-mediated enhancement of cell viability,resistance to apoptosis,clonogenicity,as well as migration and invasion in the MH7A cells.Additionally,IL-6 could specifically regulate NR0B1 expression in the MH7A synovial cells.IL-6 upregulated the transcriptional expression of NR0B1 mainly through induction of the phosphorylation of its downstream STAT3 at the Tyr-705 site.Conclusion The upregulated NR0B1 expression in fibroblast-like synoviocytes is positively correlated with the progression of RA.The proinflammatory cytokine IL-6 potentiates the transactivation of NR0B1 by inducing the phosphorylation of Tyr-705 site of its downstream effector STAT3.NR0B1 may be a significant breakthrough point for understanding the interaction between IL-6 and VEGF signaling pathways and the progression of RA.

Aim To explore the mechanism of the syn-ergistic effect of the ferroptosis inducer erastin com-bined with shikonin in promoting ferroptosis in human hypertrophic scar fibroblasts(HSFBs).Methods Hypertrophic scar tissues provided by the General Hos-pital of Ningxia Medical University were collected,and HSFBs were extracted.HSFBs were identified by HE staining and immunofluorescence.The inhibitory rates of Era and SHK on HSFBs at different concentrations were detected by CCK-8 assay,and the IC50 value was calculated.CompuSyn software was used to calculate the co-use index(CI).Control group,Erastin(Era)group,shikonin(SHK)group and Era+SHK group were set up,and the number and morphological chan-ges of cells were observed after 24 hours of interven-tion.The ability of cell migration and invasion was de-tected by scratch test and Transwell test.The changes of malondialdehyde(MDA),total iron ion and reactive oxygen species(ROS)were detected by corresponding biochemical kits.The expressions of collagen I,α-SMA and GOT1,SLC7A11,GPX4 and FTH1 were detected by Western blot.Results The IC50 value of Era and SHK of primary HSFBs was 2.22 μmol·L-1 and 3.94μmol·L-1 respectively,which was used as the single drug concentration for subsequent experiments.The CompuSyn software was employed to calculate the CI value when the two drugs were used in combination,and the concentrations corresponding to CI=0.39597(Era:1.2 μmol·L-1+SHK:1.5 μmol·L-1)were selected as subsequent combination concentrations(Because when CI was equal to 0.395 97,the concen-tration of each drug was lower than the concentration of single drug,and the inhibition rate of combined drug was greater than 50％).Compared with the monother-apy group,the number of HSFBs in the SHK+Era group was significantly reduced,cell membrane showed breakage and vesiculation,cell wrinkling became smal-ler,and cytoplasm was concentrated.The migration and invasion ability of HSFBs in the SHK+Era group were obviously weakened(P＜0.05),and the expres-sion of fibrosis-related proteins collagen Ⅰ and α-SMA was reduced(P＜0.05);the contents of MDA,total i-ron ions,and ROS in HSFBs of the SHK+Era group increased(P＜0.05),and the protein expression lev-els of SLC7A11,GOT1,GPX4,and FTH1 further de-creased(P＜0.05).Conclusions Erastin in combi-nation with shikonin can synergistically inhibit the pro-liferation,migration and fibrosis levels of HSFBs.The mechanism may be that erastin enhances the inhibition of shikotin on GOT1,increases the levels of cellular i-ron ions,ROS,and lipid peroxides,thereby promoting ferroptosis in HSFBs.

Objective To determine the clinical effect of warmed iodophor for preoperative disinfection in elderly patients undergoing laparoscopic hysterectomy.Methods A total of 84 elderly patients who underwent laparoscopic hysterectomy were selected and randomly divided into the room temperature group(disinfected with iodophor at a temperature of 24℃)and the warmed group(disinfected with iodophor at a temperature of 39℃),with 42 cases in each group.The disinfection qualification status,incision infection status,nasopharyngeal temperature,awakening time,adverse reactions,intraoperative blood loss,incision drainage volume,and hidden blood loss of patients in the two groups were compared.Results There was no statistically significant difference in the disinfection qualification rate or incision infection rate between the two groups(P>0.05).At 10 minutes,30 minutes,60 minutes after disinfection and the end of the operation,the nasopharyngeal temperatures of patients in the warmed group were significantly higher than those in the room temperature group(P<0.05).The awakening time of patients in the warmed group was significantly shorter than that in the room temperature group(P<0.05),and the incidences of intraoperative hypothermia and shivering reaction after awakening were significantly lower than those in the room temperature group(P<0.05).There was no statistically significant difference in the intraoperative blood loss or incision drainage volume of patients between the two groups(P>0.05),while the hidden blood loss of patients in the room temperature group was significantly higher than that in the warmed group(P<0.05).Conclusion The iodophor at a temperature of 39℃for preoperative disinfection in elderly patients undergoing laparoscopic hysterectomy can not only ensure the disinfection effect and surgical safety,but also effectively maintain intraoperative body temperature stability,promote postoperative awakening,and reduce hidden blood loss.

Objective:Exploring the efficacy and safety of the combination of programmed cell death protein 1 (PD-1) inhibitors with chemotherapy for the treatment of local recurrence at the primary tumor site of esophageal squamous cell carcinoma (ESCC) following definitive chemoradiotherapy.Methods:Seventy-six patients with local recurrence at the primary tumor site of ESCC following definitive chemoradiotherapy, who were treated at the Cancer Hospital Affiliated with Nanjing Medical University from January 2019 to January 2024. All patients received treatment with a PD-1 inhibitor combined with chemotherapy, and the short-term efficacy, long-term efficacy, and adverse reactions were observed. Univariate and multivariate Cox regression models were employed to identify the factors influencing overall survival (OS) and after-recurrence survival (ARS).Results:Among the 76 patients, 7 achieved partial response, 35 had stable disease, and 34 experienced progressive disease. The objective response rate was 9.2% (7/76), and the disease control rate was 55.3% (42/76). With a median follow-up time of 23.1 months, 33 out of 76 patients died. The median survival time was 38.5 months (95% CI: 29.6-47.3 months); the 1-year, 2-year, and 3-year OS were 94.5%, 66.6%, and 51.7%, respectively. The median ARS was 14.7 months (95% CI: 10.4-19.1 months); the 6-month, 12-month, and 24-month ARS were 85.8%, 59.6%, and 25.7%, respectively. Univariate analysis showed that the initial radiation dose, the Eastern Cooperative Oncology Group (ECOG) performance status of patients after recurrence, the recurrence-free interval (RFI), and the approach to chemotherapy treatment following local esophageal recurrence were factors affecting OS and ARS ( P＜0.05). Multivariate analysis showed that initial radiotherapy dose ( HR=0.268, 95% CI: 0.100-0.720), the ECOG performance status after recurrence ( HR=4.106, 95% CI: 1.228-13.728), and RFI ( HR=0.248, 95% CI: 0.106-0.582) were independent prognostic factors for OS. Additionally, the initial radiation dose ( HR=0.289, 95% CI: 0.098-0.853) and the ECOG performance status after recurrence ( HR=5.143,95% CI:1.404-18.838) were independent prognostic factors for ARS. The incidence of treatment-related adverse-reactions was 85.5% (65/76). Grade 3 or higher treatment-related adverse reactions primarily included anemia in 4 cases, leukopenia in 8 cases, neutropenia in 9 cases, thrombocytopenia in 2 cases, liver function abnormalities in 4 cases, and elevated troponin T in 2 cases. There were no cases of treatment-related mortality. Conclusions:The combination of PD-1 inhibitors with chemotherapy is safe and effective for local recurrence at the primary tumor site of ESCC following definitive chemoradiotherapy and can provide survival benefits for patients. This approach can be considered as a therapeutic option for local recurrence at the primary tumor site of ESCC following definitive chemoradiotherapy.

Nonobstructive azoospermia (NOA), one of the most severe types of male infertility, etiology often remains unclear in most cases. Therefore, this study aimed to detect four biallelic detrimental variants (0.5%) in the minichromosome maintenance domain containing 2 ( MCMDC2 ) genes in 768 NOA patients by whole-exome sequencing (WES). Hematoxylin and eosin (H&E) demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients (c.1360G>T, c.1956G>T, and c.685C>T) and hypospermatogenesis in one patient (c.94G>T), as further confirmed through immunofluorescence (IF) staining. The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis. The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses. The results revealed four MCMDC2 variants related to NOA, which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
Humans ; Male ; Azoospermia/genetics* ; Meiosis/genetics* ; Spermatogenesis/genetics* ; Adult ; Exome Sequencing ; Microtubule-Associated Proteins/genetics* ; Alleles ; Infertility, Male/genetics*

AIM To investigate the effect of Tongmai Kaiqiao Pills on angiogenesis and JAK2/STAT3/VEGF signaling pathway in rats with vascular cognitive impairment(VCI).METHODS Ten of seventy-two male SD rats were randomly selected as sham operation group,and the remaining rats were made VCI rat model by ligation of common carotid artery in stages.Rats after successful modeling were randomly divided into model group,low and high dose groups of Tongmai Kaiqiao Pills(13.8 g/kg,27.6 g/kg),nimodipine group(10 mg/kg)and high dose of Tongmai Kaiqiao Pills+AG490(JAK2 inhibitor)group(Tongmai Kaiqiao Pills 27.6 g/kg+AG490 3 mg/kg).The samples were taken after 4 weeks of corresponding dose of drugs.Pathological changes in hippocampus were observed by HE staining.Nissl staining was used to observe the loss of neurons in hippocampus.Western blot was used to detect the protein expressions of p-JAK2,p-STAT3 and VEGF in hippocampus.The ultrastructure of neurons in hippocampus was observed by transmission electron microscope.The expression of CD34 was detected by immunofluorescence staining and the microvessel density(MVD)of ischemic penumbra was calculated.RESULTS Compared with the sham operation group,the escape latency of the model group was prolonged(P＜0.01),and the times of crossing the platform were reduced(P＜0.01);neurons in hippocampus were loose in structure and disordered in arrangement;the number of Nissl bodies decreased and the loss was serious;mitochondrial crista dissolved and disappeared,and mitochondrial damage was aggravated;the protein expressions of p-JAK2,p-STAT3 and VEGF in hippocampus increased(P＜0.05);the number of MVD in hippocampus increased(P＜0.01).Compared with the model group,the escape latency of rats in each dose group of Tongmai Kaiqiao Pills and nimodipine group were shortened(P＜0.01),and the times of crossing the platform were increased(P＜0.01);the number of hippocampal neurons increased,the morphology was normal,and the disorder degree improved;Nissl's corpuscles were abundant and the loss is reduced;mitochondrial damage was reduced and gradually returned to normal shape;the protein expressions of p-JAK2,p-STAT3 and VEGF in hippocampus increased(P＜0.05,P＜0.01);the number of MVD in hippocampus increased(P＜0.05,P＜0.01).AG490 reversed the high-dose effect of Tongmai Kaiqiao Pills(P＜0.05,P＜0.01).CONCLUSION Tongmai Kaiqiao Pills may promote angiogenesis,reduce neuronal damage and promote the recovery of brain function by activating JAK2/STAT3/VEGF signaling pathway,thus playing an improving role in VCI rats.

With the rapid development of competitive sports, the incidence of anterior cruciate ligament (ACL) injury is on the rise. Such injuries may shorten athletes′ career and lead to other long-term adverse consequences. Although athletes generally recover well after ACL reconstruction, many still struggle to return to their pre-injury performance levels. Advances in the understanding of ACL anatomy and injury mechanisms, along with the evolution of surgical techniques and rehabilitation methods, have provided more individualized and tailored options for athletes following ACL injuries. However, there is currently no consensus in China regarding surgical and rehabilitation strategies for competitive athletes aiming to return to sports after ACL injuries. To this end, the Sports Medicine Committee of the Chinese Research Hospital Association and the Editorial Board of the Chinese Journal of Trauma jointly formulated the Expert consensus on surgical treatment and rehabilitation for competitive sports athletes returning to sports after anterior cruciate ligament injury ( version 2025), and presented 14 recommendations covering surgical indications, preoperative rehabilitation, surgical timing, surgical strategies and postoperative rehabilitation strategies, aiming to improve the surgical treatment and rehabilitation system for ACL injuries in competitive athletes and facilitate their return to high-level sports performance after injury.