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 study the effect of angiopoietin-1(Ang-1)and tyrosine kinase receptor 2(Tie2)inhibitor on glucose transportation in the human umbilical vein endothelial cells(HUVECs)cultured under high glucose conditions,and to clarify its mechanism.Methods:The HUVECs were cultured in high glucose(30 mmol·L?1)in vitro and treated with 0,200,500,1 000,and 2 000 μg·L?1 Ang-1 and 0,2 500,5 000,and 7 500 nmol·L?1 Tie2 inhibitor;cell counting kit-8(CCK-8)method was used to detect the cell activity to screen the optimal concentrations of Ang-1 and Tie2 inhibitor.Glucose kit was used to detect the glucose level in the supernatant of the HUVECs after Ang-1 intervention.The HUVECs were randomly divided into blank control group(NG group),high glucose group(HG group),HG+Tie2 inhibitor group(HG+In-Tie2 group),HG+Ang-1 group,HG+Ang-1+Tie2 inhibitor group(HG+Ang-1+In-Tie2 group),and HG+Ang-1+phosphatidylinositol 3-kinase(PI3K)inhibitor group(HG+Ang-1+LY294002 group).5-Ethynyl-2'-deoxyuridine(EdU)method was used to detect the proliferation activities of the cells in various groups;YO-PRO-1/PI method was used to detect the apoptotic rates of the cells in various groups;real-time fluorescence quantitative PCR(RT-qPCR)method was used to detect the expression levels of Ang-1 mRNA and Tie2 mRNA in the cells in various groups;Western blotting method was used to detect the expression levels of Tie2,glucose transporter 1(GLUT1),and glucose transporter 4(GLUT4)proteins and the ratios of phosphorylated PI3K(p-PI3K)/PI3K and phosphorylated protein kinase B(p-AKT)/AKT in the cells in various groups.Results:The CCK-8 assay results showed that compared with 0 μg·L?1 Ang-1 group,the activity of the HUVECs was significantly increased after treated with 200 μg·L?1 Ang-1 for 48 h(P<0.01);compared with 0 nmol·L?1 Tie2 inhibitor group,the activity of the HUVECs was significantly decreased after treated with 2 500、5 000 and 7 500 nmol·L?1 Tie2 inhibitor(P<0.01);the optimal concentrations of Ang-1 and Tie2 inhibitor were 200 μg·L?1 and 2 500 nmol·L?1,respectively.Compared with NG group,the glucose level in the supernatant of the HUVECs in HG group was significantly increased(P<0.01);compared with HG group,the glucose level in the supernatant of the HUVECs in Ang-1 group was significantly decreased(P<0.01).The EdU assay results showed that compared with NG group,the proliferation activity of the HUVECs in HG group was significantly decreased(P<0.01);compared with HG group,the proliferation activity of the HUVECs in HG+In-Tie2 group was significantly decreased(P<0.01),and the proliferation activity of the HUVECs in HG+Ang-1 group was significantly increased(P<0.01);compared with HG+Ang-1 group,the proliferation activities of the HUVECs in HG+Ang-1+In-Tie2 group and HG+Ang-1+LY294002 group were significantly decreased(P<0.01).The YO-PRO-1/PI assay results showed that compared with NG group,the apoptotic rate of the HUVECs in HG group was significantly increased(P<0.01);compared with HG group,the apoptotic rate of the HUVECs in HG+In-Tie2 group was significantly increased(P<0.01),and the apoptotic rate of the HUVECs in HG+Ang-1 group was significantly decreased(P<0.01);compared with HG+Ang-1 group,the apoptotic rates of the HUVECs in HG+Ang-1+In-Tie2 group and HG+Ang-1+LY294002 group were significantly increased(P<0.01).The RT-qPCR results showed that compared with NG group,the expression levels of Ang-1 mRNA and Tie2 mRNA in the HUVECs in HG group and HG+In-Tie2 group were significantly decreased(P<0.01);compared with HG group,the expression levels of Ang-1 mRNA and Tie2 mRNA in HG+In-Tie2 group were significantly decreased(P<0.01),and the expression levels of Ang-1 mRNA and Tie2 mRNA in the HUVECs in HG+Ang-1 group were significantly increased(P<0.05);compared with HG+Ang-1 group,the expression levels of Ang-1 mRNA and Tie2 mRNA in the HUVECs in HG+Ang-1+In-Tie2 group and HG+Ang-1+LY294002 group were significantly decreased(P<0.05 or P<0.01).The Western blotting results showed that compared with NG group,the expression level of Tie2 protein in the HUVECs in HG group was significantly decreased(P<0.01),and the expression levels of GLUT1 and GLUT4 proteins were significantly increased(P<0.01);compared with HG group,the expression levels of Tie2,GLUT1,and GLUT4 proteins in the HUVECs in HG+In-Tie2 group were significantly decreased(P<0.01),the expression level of Tie2 protein in the HUVECs in HG+Ang-1 group was significantly increased(P<0.01),and the expression levels of GLUT1 and GLUT4 proteins were significantly decreased(P<0.01);compared with HG+Ang-1 group,the expression levels of Tie2,GLUT1,and GLUT4 proteins in the HUVECs in HG+Ang-1+In-Tie2 group and HG+Ang-1+LY294002 group were significantly decreased(P<0.01).Compared with NG group,the p-PI3K/PI3K and p-AKT/AKT ratios in the HUVECs in HG group were significantly increased(P<0.01);compared with HG group,the p-PI3K/PI3K and p-AKT/AKT ratios in the HUVECs in HG+In-Tie2 group were significantly decreased(P<0.01),and the p-PI3K/PI3K and p-AKT/AKT ratios in the HUVECs in HG+Ang-1 group were significantly decreased(P<0.01);compared with HG+Ang-1 group,the p-PI3K/PI3K and p-AKT/AKT ratios in the HUVECs in HG+Ang-1+In-Tie2 group and HG+Ang-1+LY294002 group were significantly decreased(P<0.01).Conclusion:Ang-1 down-regulates the expressions of GLUT1 and GLUT4 in the HUVECs cultured under high glucose conditions;the binding of Ang-1 to Tie2 may down-regulate GLUT1 and GLUT4 via the PI3K/AKT signaling pathway to participate in the glucose transportation in the HUVECs cultured under high glucose conditions.

Kidney transplantation is a mature and effective therapy for end-stage renal disease.Howev-er,immune rejection and infections are the important causes affecting the recipient's survival rate,pulmonary infections is the most common cause of infection caused death.The use of immunosuppressants,surgical modes,operation time,and other related complications as well as donor and recipient themselves factors con-tribute to pulmonary infections become as a major complication after kidney transplantation.Currently,pul-monary infections still remains one of the facing major challenges after kidney transplantation.Therefore,this article summarized and investigated the status quo and related factors of pulmonary infections after kidney transplantation,aiming at providing the ideas for the prevention and treatment of pulmonary infections after kidney transplantation.

Objective To study the relationship between the mandibular bone arch and the dental arch in patients with skeletal Class Ⅱ malocclusion and compare it with the Class Imalocclusion by establishing a 3D digital model.Methods A total of 25 cases with skeletal Class Ⅱ malocclusion and 25 cases with skeletal Class Ⅰ normal occlusion were selected.The mandibular model was scanned and a three-dimensional digital model was set up.After the determination of the WALA ridge and the FA point,the reference plane and coordinate system was established.Four degree polynomial curve fitting was performed with WALA ridge and FA point coordinates to re-present the corresponding basal and dental arch curves.The width difference between the basal arch curve and the dental arch curve was measured and calculated at 3 mm,10 mm,and 18 mm away from the horizontal axis of the coordinate.The differences of basal bone and dental arch width between skeletal Class Ⅱ and skeletal Class Ⅰ malocclusion was compared.Results The width differences be-tween the arch and the dental arch in the anterior,middle and posterior mandibular segments of skeletal Class Ⅱ patients were-1.58 mm,1.80 mm and 3.80 mm,respectively.The width differences between the arch and the dental arch in the anterior,middle and pos-terior mandibular segments of skeletal Class Ⅰ patients were 2.08 mm,2.92 mm and 4.24 mm,respectively.There was a significant difference between skeletal Class Ⅱ and skeletal Class Ⅰ in the anterior and middle segments(P＜0.05),but no significant difference in the posterior segment(P＞0.05).Conclusion In skeletal Class Ⅰ patients,the width of the basal bone is larger than that of the dental arch,and the dental arch was located medial to the basal bone.In skeletal Class Ⅱ patients,the width of the anterior arch is larger than the width of the basal bone,that is,the dental arch is located outside the basal bone.The width difference of the basal arch in skeletal Class Ⅱ is smaller than that in skeletal Class Ⅰ.

Objective To evaluate the effects of fasting and high-fat diet on the pharmacokinetics of rabeprazole sodium enteric-coated tablets in healthy Chinese subjects.Methods A single-center,randomized,open,two-agent,two-sequence,four-cycle,fully repeated crossover,single-dose trial design was used in this study,healthy subjects were assigned to receive single dose of rabeprazole sodium enteric-coated tablets 0.1 g in either fasting or high-fat diet state,and blood samples were taken at different time points,respectively.The concentrations of rabeprazole sodium enteric-coated in plasma were determined by liquid chromatography-tandem mass spectrometry(LC-MS/MS),the model method of the non-compartmental was used to calculate the pharmacokinetic parameters by Phoenix WinNonlin 8.2.Results The main pharmacokinetic parameters of rabeprazole sodium enteric-coated tablets in fasting state and high-fat diet state were as follows:Cmax were(339.63±156.47)and(318.86±132.13)ng·mL-1;t1/2 were(2.34±0.68)and(3.60±2.40)h;AUC0_t were(556.62±251.65)and(528.50±201.78)ng·mL-1·h;AUC0-∞ were(563.39±255.69)and(535.15±203.24)ng·mL-1·h;tmax were 3.65 and 6.99 h.After high-fat diet,the Cmax and AUC of rapeprazole sodium after high-fat and high-calorie diet decreased,Cmax decreased by 6.12％,AUC0-t decreased by 5.05％,AUC0-∞ decreased by 5.01％,andtmaxwas delayed by about 3.34 h.Cmax,AUC0-t and AUC0-∞ 90％confidence interval were 73.13％-115.10％,83.22％-112.28％and 83.40％-112.13％,respectively.Neither was between 85.00％-125.00％.Conclusion High-fat diet affects the absorption rate and degree of rabeprazole sodium enteric-coated,so it is suitable to be administered on an empty stomach.

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

Peyronie's disease (PD) is a disorder characterized by fibrous plaque formation in the penile tissue that leads to curvature and complications in advanced stages. In this study, we aimed to compare four injectable induction agents for the establishment of a robust rat model of PD: transforming growth factor-β1 (TGF-β1), fibrin, sodium tetradecyl sulfate (STS) combined with TGF-β1, and polidocanol (POL) combined with TGF-β1. The results showed that injection of TGF-β1 or fibrin into the tunica albuginea induced pathological endpoints without causing penile curvature. The STS + TGF-β1 combination resulted in both histological and morphological alterations, but with a high incidence of localized necrosis that led to animal death. The POL + TGF-β1 combination produced pathological changes and curvature comparable to STS + TGF-β1 and led to fewer complications. In conclusion, fibrin, STS + TGF-β1, and POL + TGF-β1 all induced PD with a certain degree of penile curvature and histological fibrosis in rats. The POL + TGF-β1 combination offered comparatively greater safety and clinical relevance and may have the greatest potential for PD research using model rats.
Animals ; Male ; Penile Induration/drug therapy* ; Rats ; Transforming Growth Factor beta1/metabolism* ; Disease Models, Animal ; Fibrin ; Penis/drug effects* ; Polidocanol/administration & dosage* ; Rats, Sprague-Dawley ; Polyethylene Glycols/administration & dosage* ; Injections

Objective:To explore the dosimetric characteristics of proton and photon radiotherapy in the treatment of breast cancer.Methods:Four female breast cancer patients who needed radiotherapy at Shandong Cancer Hospital and Institute from January 2024 to May 2024 were selected as the research subjects. The target area ranges of 4 patients were left-sided breast cancer with lymph node involvement, left-sided breast cancer with lymph node involvement and internal mammary node, right-sided breast cancer with lymph node involvement and internal mammary node and synchronous bilateral breast cancer. Intensity modulated proton therapy (IMPT) and intensity modulated radiation therapy (IMRT) plans were designed respectively based on the prescribed dose in the target area and the limits of organs at risk (tomotherapy plan for bilateral breasts). The conformity index (CI), homogeneity index (HI), gradient index (GI) and organs at risk doses were evaluated. The dosimetric characteristics of IMPT and photon radiotherapy were compared.Results:Both IMPT and photon radiotherapy plans of the 4 breast cancer cases met the clinical dose requirements. The HI value of IMPT plans (0.10-0.14) was comparable to that of photon radiotherapy plans (0.10-0.12), and the average CI of the photon radiotherapy plans was 0.10 higher than that of the IMPT plans, and the average GI was 0.55 lower than that of the IMPT plans. The D mean of ipsilateral lung and heart of IMPT was lower, especially in the low-dose area (V 0-3), which was significantly lower than the photon radiotherapy plans, D mean of ipsilateral lung was reduced by 12.2%, 6.1%, 16.1% and 34.8%, respectively, D mean of heart was reduced by 47.2%, 57.0%, 72.4% and 83.0%, respectively. The ipsilateral lung V 20 of IMPT was not lower than photon radiotherapy plans (unilateral breast: IMPT was 30.0%-34.0%, IMRT was 29.0%-35.9%) . Conclusions:IMPT significantly reduces the D mean to the ipsilateral lung and heart while ensuring dose coverage of the target in breast cancer, preventing more volume of surrounding normal tissues from being irradiated. However, IMPT does not show much more advantage than photon radiotherapy plans in the ipsilateral lung V 20.

Objective To investigate the clinical efficacy and safety of facilitated percutaneous coronary intervention(PCI)with half-dose recombinant staphylokinase(r-SAK)in patients with ST-segment elevation myocardial infarction(STEMI)who are expected to undergo PCI within 120 minutes.Methods From October 2021 to August 2022,a total of 200 STEMI patients in eight centers were included and randomly assigned in a 1﹕1 ratio to either r-SAK group or control group.Patients received loading doses of aspirin and ticagrelor and intravenous heparin and were randomized to receive an intravenous bolus of either 5 mg r-SAK or normal saline prior to PCI.The outcomes were set as ST-segment resolution(STR)at 60-90 minutes after PCI,the proportion and transition of pathological Q waves on the 5th day after PCI,and the proportion of high-sensitivity cardiac troponin T(hs-cTnT)peaking within 12 hours of onset.The safety outcome was major bleeding events defined as Bleeding Academic Research Consortium(BARC)≥type 3 bleeding during hospitalization.Results Compared with the control group,the r-SAK group had a higher proportion of STR≥70%within 60-90 minutes after PCI(58.3%vs.40.3%,P=0.009);a lower proportion of pathological Q waves(59.1%vs.74.1%,P=0.040);a lower rate of Q wave progression(14.8%vs.43.2%,P＜0.001);a higher rate of Q wave disappearance(12.5%vs.3.7%,P=0.027);and a higher proportion of hs-cTnT peaking within 12 hours of symptom onset[31/40(77.5%)vs.17/33(51.5%),P=0.027].Regarding the safety outcome,no significant difference in BARC≥type 3 bleeding was found between the two groups during hospitalization(P＞0.05).Conclusions For STEMI patients who were expected to undergo primary PCI within 120 minutes of symptom onset,the facilitated PCI with half-dose r-SAK significantly increased the proportion of STR≥70%at 60-90 minutes after PCI,reduced the formation of pathological Q waves,and shortened the time to peak hs-cTnT,without increasing the risk of bleeding,which should be an alternative reperfusion strategy worthy of further study.