This study aims to elucidate the role and mechanism of clematichinenoside AR(CAR) in protecting bone marrow mesenchymal stem cells(BMSCs) from hypoxia-induced apoptosis. BMSCs were isolated by the bone fragment method and identified by flow cytometry. Cells were cultured under normal conditions(37℃, 5% CO_2) and hypoxic conditions(37℃, 90% N_2, 5% CO_2) and treated with CAR. The BMSCs were classified into eight groups: control(normal conditions), CAR(normal conditions + CAR), hypoxia 24 h, hypoxia 24 h + CAR, hypoxia 48 h, hypoxia 48 h + CAR, hypoxia 72 h, and hypoxia 72 h + CAR. The cell counting kit-8(CCK-8) assay and terminal-deoxynucleoitidyl transferase mediated nick end labeling(TUNEL) were employed to measure cell proliferation and apoptosis, respectively. The number of mitochondria and mitochondrial membrane potential were measured by MitoTracker®Red CM-H2XRo staining and JC-1 staining, respectively. The level of reactive oxygen species(ROS) was measured with the DCFH-DA fluorescence probe. The protein levels of B-cell lymphoma-2 associated X protein(BAX), caspase-3, and optic atrophy 1(OPA1) were determined by Western blot. The results demonstrated that CAR significantly increased cell proliferation. Compared with the control group, the hypoxia groups showed increased apoptosis rates, reduced mitochondria, elevated ROS levels, decreased mitochondrial membrane potential, upregulated expression of BAX and caspase-3, and downregulated expression of OPA1. In comparison to the corresponding hypoxia groups, CAR intervention significantly decreased the apoptosis rate, increased mitochondria, reduced ROS levels, elevated mitochondrial membrane potential, downregulated the expression of BAX and caspase-3, and upregulated the expression of OPA1. Therefore, it can be concluded that CAR may exert an anti-apoptotic effect on BMSCs under hypoxic conditions by regulating OPA1 to maintain mitochondrial homeostasis.
Mesenchymal Stem Cells/metabolism* ; Apoptosis/drug effects* ; Mitochondria/metabolism* ; Animals ; Rats ; Cell Hypoxia/drug effects* ; Homeostasis/drug effects* ; Reactive Oxygen Species/metabolism* ; Rats, Sprague-Dawley ; Membrane Potential, Mitochondrial/drug effects* ; Saponins/pharmacology* ; Caspase 3/genetics* ; Male ; bcl-2-Associated X Protein/genetics* ; Bone Marrow Cells/metabolism* ; Cell Proliferation/drug effects* ; Protective Agents/pharmacology* ; Cells, Cultured

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*

Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2(HER2)-low early breast cancer(BC)and HER2-IHC0 BC. Methods Patients diagnosed with HER2-negative BC(N=999)at our institution between January 2011 and December 2015 formed our study population.Clinicopathological characteristics,association between estrogen receptor(ER)expression and HER2-low,and evolution of HER2 immunohistochemical(IHC)score were assessed.Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes(5-year follow-up)between the HER2-IHC0 and HER2-low groups. Results HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor(PgR)positivity than HER2-IHC0 BC group(P<0.001).The rate of HER2-low status increased with increasing ER expression levels(Mantel-Haenszel χ2 test,P<0.001,Pearson's R=0.159,P<0.001).Survival analysis revealed a significantly longer overall survival(OS)in HER2-low BC group than in HER2-IHC0 group(P=0.007)in the whole cohort and the hormone receptor(HR)-negative group.There were no significant differences between the two groups in terms of disease-free survival(DFS).The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%. Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.

Nanozyme is novel nanoparticle with enzyme-like activity, which can be classified into peroxidase-like nanozyme, catalase-like nanozyme, superoxide dismutase-like nanozyme, oxidase-like nanozyme and hydrolase-like nanozyme according to the type of reaction they catalyze. Since researchers first discovered Fe₃O₄ nanoparticles with peroxidase-like activity in 2007, a variety of nanoparticles have been successively found to have catalytic activity and applied in bioassays, inflammation control, antioxidant damage and tumor therapy, playing a key role in disease diagnosis and treatment. We summarize the use of nanozymes with different classes of enzymatic activity in the diagnosis and treatment of diseases and describe the main factors influencing nanozyme activity. A Mn-based peroxidase-like nanozyme that induces the reduction of glutathione in tumors to produce glutathione disulfide and Mn²⁺, which induces the production of reative oxygen species (ROS) in tumor cells by breaking down H₂O₂ in physiological media through Fenton-like action, thereby inhibiting tumor cell growth. To address the limitation of tumor tissue hypoxia during photodynamic tumor therapy, the effect of photodynamic therapy is significantly enhanced by using hydrogen peroxide nanozymes to catalyze the production of oxygen from H₂O₂. In pathological states, where excess superoxide radicals are produced in the body, superoxide dismutase-like nanozymes are able to selectively regulate intracellular ROS levels, thereby protecting normal cells and slowing down the degradation of cellular function. Based on this principle, an engineered nanosponge has been designed to rapidly scavenge free radicals and deliver oxygen in time to save nerve cells before thrombolysis. Starvation therapy, in which glucose oxidase catalyzes the hydrolysis of glucose to gluconic acid and hydrogen peroxide in cancer cells with the involvement of oxygen, attenuates glycolysis and the production of intermediate metabolites such as nucleotides, lipids and amino acids, was used to synthesize an oxidase-like nanozyme that achieved effective inhibition of tumor growth. Furthermore, by fine-tuning the Lewis acidity of the metal cluster to improve the intrinsic activity of the hydrolase nanozyme and providing a shortened ligand length to increase the density of its active site, a hydrolase-like nanozyme was successfully synthesized that is capable of cleaving phosphate bonds, amide bonds, glycosidic bonds and even biofilms with high efficiency in hydrolyzing the substrate. All these effects depend on the size, morphology, composition, surface modification and environmental media of the nanozyme, which are important aspects to consider in order to improve the catalytic efficiency of the nanozyme and have important implications for the development of nanozyme. Although some progress has been made in the research of nanozymes in disease treatment and diagnosis, there are still some problems, for example, the catalytic rate of nanozymes is still difficult to reach the level of natural enzymes in vivo, and the toxic effects of some heavy metal nanozymes material itself. Therefore, the construction of nanozyme systems with multiple functions, good biocompatibility and high targeting efficiency, and their large-scale application in diagnosis and treatment is still an urgent problem to be solved. (1) To improve the selectivity and specificity of nanozymes. By using antibody coupling, the nanoparticles are able to specifically bind to antigens that are overexpressed in certain cancer cells. It also significantly improves cellular internalization through antigen-mediated endocytosis and enhances the enrichment of nanozymes in target tissues, thereby improving targeting during tumor therapy. Some exogenous stimuli such as laser and ultrasound are used as triggers to control the activation of nanozymes and achieve specific activation of nanozyme. (2) To explore more practical and safer nanozymes and their catalytic mechanisms: biocompatible, clinically proven material molecules can be used for the synthesis of nanoparticles. (3) To solve the problem of its standardization and promote the large-scale clinical application of nanozymes in biomonitoring. Thus, it can go out of the laboratory and face the market to serve human health in more fields, which is one of the future trends of nanozyme development.

Aim To investigate the intracellular up-take and target protein binding characteristics of two Bruton's tyrosine kinase inhibitors(BTKi)with differ-ent selectivities to provide further insights into the mechanisms of drug off-target-related bleeding risk.Methods Ibrutinib(non-selective BTKi)and za-nubrutinib(selective BTKi)were used as study drugs.After incubation of MEC-1 cells and human platelets with drugs,the cellular thermal shift assay(CETSA)was combined with Western blot to obtain the melting curve and isothermal curve to analyze the binding char-acteristics of the two drugs with the target protein BTK.After incubation of MEC-1 cells and human platelets with drugs,the concentrations of the two drugs were detected by liquid chromatography-tandem mass spectrometry(LC-MS/MS)to analyze the intracellular uptake of the two drugs.Results CETSA analysis confirmed that zanubrutinib was more selective for the target protein BTK compared to ibrutinib.LC-MS/MS analysis showed that both drugs were uptaken intracel-lularly by MEC-1 cells and platelets in a concentration-dependent manner.Conclusions While BTKi targe-ting BTK to B lymphocytes exerts therapeutic effects,off-target effects on platelets due to differences in their intracellular uptake,and target-binding characteristics may be one of the reasons for the differences in bleed-ing risk across selective BTKi.

AIM To investigate the ameliorative effects of Schisandrol A(Sol A)in Suhuang antitussive capsule on post-infectious cough(PIC).METHODS The in vivo mouse PIC model was established by intratracheal instillation of lipopolysaccharide(LPS)combined with cigarette smoke exposure.The mice were randomly divided into the control group,the model group,the Suhuang antitussive capsule group(14 g/kg),the montelukast sodium positive control group(3 mg/kg),and low and high dose Sol A groups(10,30 mg/kg).The in vitro PIC model was established by stimulating human bronchial epithelial cells(BEAS-2B)with LPS.The cells were divided into the control group,the model group,the Suhuang antitussive capsule group(10 μg/mL)and low and high dose Sol A groups(3,10 μmol/L).HE and Masson staining were used to detect the pathological changes of the lung and bronchial tissues.ELISA was used to detect the levels of IL-1β,IL-6,TNF-α,ROS,MDA,SOD and GSH in the lung tissues.RT-qPCR was used to detect the IL-1β,IL-6 and TNF-α mRNA expressions in BEAS-2B cells.And Western blot was applied to detect the protein expressions of p-PI3K,p-Akt,NOX4,SIRT1,p-ERK,Fibronectin,E-cadherin,Vimentin and α-SMA in mouse lung tissue and BEAS-2B cells.RESULTS Compared with the model group,the groups intervened with Sol A or Suhuang antitussive capsule displayed prolonged cough latency(P＜0.01);reduced cough frequency(P＜0.01);relieved pulmonary inflammatory cell infiltration and collagen deposition in PIC mice;decreased pulmonary levels of IL-1β,IL-6,TNF-α,ROS,MDA and protein expressions of Fibronectin,Vimentin,α-SMA,p-ERK,p-PI3K,p-Akt,and NOX4(P＜0.05,P＜0.01);increased pulmonary levels of SOD and GSH and protein expressions of E-cadherin and SIRT1(P＜0.05,P＜0.01);decreased ROS level,IL-1β,IL-6,TNF-α mRNA expressions and p-ERK,p-PI3K,p-Akt,NOX4 protein expressions in vitro(P＜0.05,P＜0.01);and increased SIRT1 protein expression in vitro as well(P＜0.01).CONCLUSION Being the main antitussive component of Suhuang antitussive capsule upon the PIC model,Sol A inhibits the inflammation via SIRT1/ERK signaling pathway and relieve the oxidative stress via PI3K/Akt/NOX4 signaling pathway.

Familial exudative vitreoretinopathy(FEVR)is a hereditary disorder of retinal angiogenesis, of which the most typical clinical feature is the peripheral avascular area. The progression of the disease can lead to retinal detachment(RD), followed by secondary complications such as cataracts, glaucoma, corneal opacification, and even bulbi phthisis. As one of the main reasons for the RD in Asian children and juvenile, FEVR-associated retinal detachment(FEVR-RD)is mainly treated by surgery, including pars plana vitrectomy, scleral bucking, and combined with retinal photocoagulation or anti-vascular endothelial grouth factor(VEGF)sometimes. The surgery of FEVR-RD requires careful pre/intra-operative evaluation to determine the best surgical procedure and its outcome, including the nature of the affected eye, the stage, the fibrosis of fiber proliferation and the anterior complications, and the anatomy and prognosis of eyes in different stages vary greatly. Adult patients with rhegmatogenous RD have a higher rate of post-operative retina reattachment compared to young patients with tractional RD. In young or advanced patients, surgery is difficult and the prognosis is less optimistic, thus the surgery strategy is controversial. This article reviews the surgical outcomes and progress of FEVR-associated RD.

The paper explores the evolution of "bone-approaching" acupuncture, its effect target and mechanism. The concrete operation procedure of "bone-approaching" method is recorded originally in Huangdi Neijing (Inner Canon of Yellow Emperor) as short needling and Shu needling (referring to the category of the five needling technique). The periosteum is the most effective stimulation target of "bone-approaching" acupuncture for analgesia, regaining consciousness and regulating spirit. The "bone-approaching" acupuncture is not only prominently effective on bone bi syndrome, but also has the unique effect on painful, encephalogenic and emotional diseases. The paper summarizes and improves "bone-approaching" acupuncture, i.e. "touching bone surface" with needle tip by slow insertion, "touching bone surface" without pain by swift insertion and "touching bone" with needle body by oblique insertion. It contributes to the inheritance, development and supplementation to the bone needling techniques in Huangdi Neijing and is significant for broadening the clinical application range of acupuncture.
Humans ; Acupuncture Therapy ; Periosteum ; Analgesia ; Pain Management ; Consciousness ; Pain

Objective: To analyze the clinicopathologic characteristics and prognosis of testicular diffuse large B-cell lymphoma (DLBCL) . Methods: A retrospective analysis was performed on 68 patients with testicular DLBCL admitted to Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine from October 2001 to April 2020. The gene mutation profile was evaluated by targeted sequencing (55 lymphoma-related genes) , and prognostic factors were analyzed. Results: A total of 68 patients were included, of whom 45 (66.2% ) had primary testicular DLBCL and 23 (33.8% ) had secondary testicular DLBCL. The proportion of secondary testicular DLBCL patients with Ann Arbor stage Ⅲ-Ⅳ (P<0.001) , elevated LDH (P<0.001) , ECOG score ≥ 2 points (P=0.005) , and IPI score 3-5 points (P<0.001) is higher than that of primary testicular DLBCL patients. Sixty-two (91% ) patients received rituximab in combination with cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) -based first-line regimen, whereas 54 cases (79% ) underwent orchiectomy prior to chemotherapy. Patients with secondary testicular DLBCL had a lower estimated 5-year progression-free survival (PFS) rate (16.5% vs 68.1% , P<0.001) and 5-year overall survival (OS) rate (63.4% vs 74.9% , P=0.008) than those with primary testicular DLBCL, and their complete remission rate (57% vs 91% , P=0.003) was also lower than that of primary testicular DLBCL. The ECOG scores of ≥2 (PFS: P=0.018; OS: P<0.001) , Ann Arbor stages Ⅲ-Ⅳ (PFS: P<0.001; OS: P=0.018) , increased LDH levels (PFS: P=0.015; OS: P=0.006) , and multiple extra-nodal involvements (PFS: P<0.001; OS: P=0.013) were poor prognostic factors in testicular DLBCL. Targeted sequencing data in 20 patients with testicular DLBCL showed that the mutation frequencies of ≥20% were PIM1 (12 cases, 60% ) , MYD88 (11 cases, 55% ) , CD79B (9 cases, 45% ) , CREBBP (5 cases, 25% ) , KMT2D (5 cases, 25% ) , ATM (4 cases, 20% ) , and BTG2 (4 cases, 20% ) . The frequency of mutations in KMT2D in patients with secondary testicular DLBCL was higher than that in patients with primary testicular DLBCL (66.7% vs 7.1% , P=0.014) and was associated with a lower 5-year PFS rate in patients with testicular DLBCL (P=0.019) . Conclusion: Patients with secondary testicular DLBCL had worse PFS and OS than those with primary testicular DLBCL. The ECOG scores of ≥2, Ann Arbor stages Ⅲ-Ⅳ, increased LDH levels, and multiple extra-nodal involvements were poor prognostic factors in testicular DLBCL. PIM1, MYD88, CD79B, CREBBP, KMT2D, ATM, and BTG2 were commonly mutated genes in testicular DLBCL, and the prognosis of patients with KMT2D mutations was poor.
Male ; Adult ; Humans ; Prognosis ; Retrospective Studies ; Myeloid Differentiation Factor 88 ; China/epidemiology* ; Testicular Neoplasms/drug therapy* ; Cyclophosphamide ; Rituximab/therapeutic use* ; Lymphoma, Large B-Cell, Diffuse/drug therapy* ; Prednisone/therapeutic use* ; Doxorubicin/therapeutic use* ; Vincristine/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Immediate-Early Proteins/therapeutic use* ; Tumor Suppressor Proteins