Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Objective To evaluate the regulatory effect of the adaptor related protein complex 2 subunit μ1(AP2M1)on proliferation and invasion of diffuse large B-cell lymphoma(DLBCL).Methods Human diffuse large B-cell lymphoma cell line OCI-LY8 was aliquoted into control group,NC-shRNA group,AP2M1-shRNA group,NC-LV group,and AP2M1-LV group.Lipofectamine 2000 was used for cell transfection.Cell proliferation was detected by tetramethylazolium salt(MTT)method,apoptosis was detected by flow cytometry and cell migration and invasion were detected by Transwell assay.The protein expression of AP2M1,epidermal growth factor receptor(EGFR),p-phosphatidylinositol 3 kinase(PI3K),PI3K,p-protein kinase B(Akt)and AKT was detec-ted by Western blot.Results Compared with control group,the relative expression of AP2M1 mRNA and protein in the AP2M1-shRNA group was decreased(P＜0.05).The relative cell viability was increased(P＜0.05).The cell apoptosis rate was decreased(P＜0.05).The counting number of migrating and invading cells was in-creased(P＜0.05).The relative expression level of EGFR protein and the phosphorylation level of PI3K and AKT were increased(P＜0.05).Compared with Control group,the expression of AP2M1 mRNA and protein relative ex-pression level in AP2M1-LV group was increased(P＜0.05).The relative cell viability was decreased(P＜0.05).The cell apoptosis rate was increased(P＜0.05).The number of migrating and invading cells was decreased(P＜0.05).The relative expression level of EGFR protein and the phosphorylation level of PI3K and AKT were all decreased(P＜0.05).Conclusions The over-expression of AP2M1 partially inhibits the proliferation and invasion of DLBCL cells by inhibiting the EGFR/PI3K/AKT signaling pathway.

ObjectiveThis study aimed to evaluate the clinical efficacy of Ruyi Zhenbaowan（RYZBW）in the treatment of initial and early knee osteoarthritis （KOA） through a prospective multicenter，randomized，double-blind，and placebo-parallel controlled trial. MethodFrom October 13^th， 2021 to December 25^th， 2021， 240 KOA subjects meeting the acceptance criteria were enrolled in 15 sub-centers including Wangjing Hospital， Chinese Academy of Chinese Medical Sciences， and they were randomly divided into observation group and control group， with 120 cases in each group. The intervention measures for the observation group were RYZBW + health education， and the intervention measures for the control group were RYZBW placebo + health education. The intervention period in both groups was four weeks， and they were followed up for four weeks after the intervention. The primary outcome measure was the total score of Western Ontario and McMaster University Osteoarthritis Index score （WOMAC score）， and the secondary outcome measures were the response rate of visual scale （VAS） pain score， WOMAC sub item scores （joint pain， joint stiffness， and joint function）， quality of life （SF-12） score， and traditional Chinese medicine （TCM） syndrome score. Result（1） Efficacy evaluation. The marginal model results showed that the observation group was better than the control group in improving the WOMAC total score and WOMAC pain score in the treatment of KOA with RYZBW， and the difference was statistically significant （P<0.05）. There was no significant difference between the two groups in improving VAS score response rate， WOMAC function score， WOMAC stiffness score， SF12-PCS （quality of life-physical health） score， SF12-MCS （quality of life-mental health） score， and TCM syndrome score. （2） Subgroup analysis. ① In terms of VAS score response rate， the response rate of the observation group was higher than that of the control group for subjects with baseline VAS score of （4， 5］， and the difference was statistically significant （P<0.05）. ② In terms of TCM syndrome score， for subjects aged ［56， 60］ and ［61， 65］， the decrease in total TCM syndrome score in the observation group was better than that in the control group， and the difference was statistically significant （P<0.05）. ConclusionTibetan medicine RYZBW has good clinical efficacy in improving WOMAC total score， VAS score response rate， WOMAC pain score， WOMAC function score， and TCM syndrome score for patients with initial and early KOA， which can fill the lack of Tibetan medicine RYZBW in the treatment of KOA and make a demonstration study for the inheritance and development of ethnic medicine.

Objective:To explore the properties of gelatin-polyethylene glycol hydrogel loaded with silver nanoparticle (AgNP) Chlorella (hereinafter referred to as the composite hydrogel) and its effects on healing of infected full-thickness skin defect wounds in mice. Methods:The research was an experimental research. The simple gelatin-polyethylene glycol hydrogel (hereinafter referred to as the simple hydrogel) and the composite hydrogel were prepared, and the appearance and injectability of the two hydrogels were observed at 55 and 37 ℃, and under the irradiation of 808 nm near-infrared light, respectively. An electronic universal testing machine was employed to assess the tensile and compressive stress-strain properties of both types of hydrogels at room temperature. Additionally, the cyclic compressive stress-strain properties of the composite hydrogel were examined at 80% of the maximum compressive stress. Staphylococcus aureus or Escherichia coli solution was added to phosphate buffer solution (PBS), simple hydrogel, and composite hydrogel, respectively. The part of composite hydrogel containing Staphylococcus aureus or Escherichia coli solution was irradiated with near-infrared light for 5 minutes. After each sample was incubated for 6 h, the dilution plating method was used to detect and calculate the mortality rates of the two bacteria at 24 h of culture ( n=5). The discarded foreskin tissue was taken from a 6-year-old healthy boy admitted to the Department of Urology of the First Affiliated Hospital of Naval Medical University for circumcision. Primary human fibroblasts (HFbs) were isolated using the enzyme extraction method, routinely cultured to the 3 rd to 6 th passages for subsequent cellular experiments. Composite hydrogel extracts with final mass concentrations of 100.0, 50.0, 25.0, 12.5, and 0 mg/mL were respectively prepared and used to culture HFbs, and the cell proliferation after 24 h of culture was detected using a cell counting kit 8 ( n=3). A total of twenty 6-8 weeks old C57BL/6J female mice were utilized, and a full-thickness skin defect was surgically created on the back of each mouse. The wounds were infected with Staphylococcus aureus solution. The infected mice were divided into blank control group, simple hydrogel group, composite hydrogel group, and combined treatment group according to the random number table, and the wounds were treated with PBS, simple hydrogel, composite hydrogel, and composite hydrogel+light irradiation (under the irradiation of 808 nm near-infrared light for 5 min), respectively, with 5 mice in each group. On post injury day (PID) 0 (immediately after the first wound treatment), 3, 7, and 14, an overall assessment of wound exudation and healing were conducted, and the wound healing rates on PID 7 and 14 were calculated ( n=5). On PID 14, hematoxylin-eosin staining was performed to observe histopathological changes in the mouse wound. Results:Both simple hydrogel and composite hydrogel were in a solution state at 55 ℃ and transition to a gel state when cooling to 37 ℃. After the two hydrogels were irradiated by near-infrared light, only the composite hydrogel reheated up and returned to the solution state again with injectability. The maximum tensile stress of the composite hydrogel was up to 301.42 kPa, with a corresponding strain of 87.19%; the maximum compressive stress was up to 413.79 kPa, with a corresponding strain of 91.67%, which was similar to the tensile and compressive properties of the simple hydrogel. After 10 compression cycles, the maximum compressive stress of the composite hydrogel still reached 84.1% of the first compressive stress. After 24 h of culture, the mortality rate of Staphylococcus aureus treated with simple hydrogel was significantly higher than that treated with PBS ( P<0.05); the mortality rates of Escherichia coli and Staphylococcus aureus treated with composite hydrogel alone were significantly higher than those treated with simple hydrogel ( P<0.05); the mortality rates of Escherichia coli and Staphylococcus aureus treated with composite hydrogel+light irradiation were significantly higher than those treated with composite hydrogel alone ( P<0.05). After 24 h of culture, compared with that cultured in composite hydrogel immersion solution with final mass concentration of 0 mg/mL, the proliferation activity of HFbs cultured in composite hydrogel immersion solution with final mass concentrations of 25.0 and 50.0 mg/mL was significantly enhanced ( P<0.05), while the proliferation activity of HFbs cultured in composite hydrogel immersion solution with final mass concentration of 100 mg/mL was significantly decreased ( P<0.05). On PID 0 and 3, more purulent secretions were seen in the wounds of mice in blank control group and simple hydrogel group, while only a small amount of exudate was observed in the wounds of mice in composite hydrogel group, and no obvious infection was observed in the wounds of mice in combined treatment group. On PID 7 and 14, the wound healing rates of mice in simple hydrogel group were significantly higher than those in blank control group ( P<0.05); the wound healing rates of mice in composite hydrogel group were significantly higher than those in simple hydrogel group ( P<0.05); the wound healing rates in combined treatment group were significantly higher than those in composite hydrogel group ( P<0.05). On PID 14, the wounds of mice in blank control group exhibited a high infiltration of inflammatory cells with no new epithelial layer observed; the wounds of mice in simple hydrogel group displayed a short length of newly formed epithelium with a small amount of inflammatory cells; the wounds of mice in composite hydrogel group exhibited continuous formation of new epithelium and a large amount of immature granulation tissue; the wounds of mice in combined treatment group showed continuous epithelialization with less immature granulation tissue. Conclusions:The prepared composite hydrogel exhibits excellent thermosensitivity, photothermal properties, and injectability, as well as excellent mechanical properties, antibacterial properties, and biocompatibility, and can promote the healing of infected full-thickness skin defect wounds in mice.

Objective:To assess the effectiveness of a 6-month Ba Duan Jin exercise program in improving the balance of community-dwelling older adults.Methods:A two arms, parallel-group, cluster randomized controlled trial was conducted in 1 028 community residents aged 60-80 years in 40 communities in 5 provinces of China. Participants in the intervention group (20 communities, 523 people) received Ba Duan Jin exercise 5 days/week, 1 hour/day for 6 months, and three times of falls prevention health education, and the control group (20 communities, 505 people) received falls prevention health education same as the intervention group. The Berg balance scale (BBS) score was the leading outcome indicator, and the secondary outcome indicators included the length of time of standing on one foot (with eyes open and closed), standing in a tandem stance (with eyes open and closed), the closed circle test, and the timed up to test.Results:A total of 1 028 participants were included in the final analysis, including 731 women (71.11%) and 297 men (28.89%), and the age was (69.87±5.67) years. After the 3-month intervention, compared with the baseline data, the BBS score of the intervention group was significantly higher than the control group by 3.05 (95% CI: 2.23-3.88) points ( P<0.001). After the 6-month intervention, compared with the baseline data, the BBS score of the intervention group was significantly higher than the control group by 4.70 (95% CI: 4.03-5.37) points ( P<0.001). Ba Duan Jin showed significant improvement ( P<0.05) in all secondary outcomes after 6 months of exercise in the intervention group compared with the control group. Conclusions:This study showed that Ba Duan Jin exercise can improve balance in community-dwelling older adults aged 60-80. The longer the exercise time, the better the improvement.

Objective To observe the therapeutic effect and mechanism of Baoyuan Decoction for chronic heart failure model rat.Methods SD rats were randomly divided into blank group,model group,Baoyuan Decoction group,Captopril group,Baoyuan Decoction+CCT020312[protein kinase R-like endoplasmic reticulum kinase(PERK)activator]group,15 rats in each group.Except for the blank group,the rats in the other groups were induced by Adriamycin to construct a chronic heart failure model.After corresponding drug intervention,cardiac function indexes[left ventricular end-diastolic diameter(LVEDD),left ventricular ejection fraction(LVEF),left ventricular fractional shortening(LVFS),brain natriuretic peptide(BNP),cardiac troponin I(cTnI)],inflammation-related factors[tumor necrosis factor α(TNF-α),interleukin 1β(IL-1β)],oxidative stress factors[malondialdehyde(MDA),superoxide dismutase(SOD)]were detected in each group.Changes in apoptosis-related indicators[B-cell lymphoma 2(Bcl-2),B-cell lymphoma 2-associated X protein(Bax),Caspase-3]and PERK/transcription activator 4(ATF4)signaling pathway-related proteins glucose-regulated protein 78(GRP78),PERK,ATF4,C/EBP homologous protein(CHOP)levels.Results Compared with the blank group,LVEDD,BNP,cTnI,TNF-α,IL-1β,MDA levels,protein expression levels of Bax,Caspase-3,GRP78,PERK,ATF4,CHOP in the model group were significantly increased,LVEF,LVFS,SOD levels and Bcl-2 protein expression level were significantly decreased(all P＜0.05).Compared with the model group and Baoyuan Decoction+CCT020312 group,LVEDD,BNP,cTnI,TNF-α,IL-1β,MDA levels,protein expression levels of Bax,Caspase-3,GRP78,PERK,ATF4,CHOP in Baoyuan Decoction group and Captopril group were significantly decreased,LVEF,LVFS,SOD levels and Bcl-2 protein expression level were significantly increased(all P＜0.05).Compared with the Captopril group,there was no significant change in the above indexes(except CHOP protein expression level)in the Baoyuan Decoction group(P＞0.05).Conclusion Baoyuan Decoction can delay the progression of chronic heart failure rats,and its mechanism may be related to inhibiting the PERK/ATF4 signaling pathway to alleviate cardiomyocyte apoptosis,further reducing the degree of inflammatory response and oxidative stress,thereby promoting the repair of cardiac function and myocardial injury.

Cervical spondylotic radiculopathy(CSR)is a condition caused by the degeneration of cervical intervertebral discs and facet joints,primarily manifesting as the pain,sensory abnormalities,and motor dysfunction in the cervical nerve innervation area of neck,shoulder,and upper limb.For the treatment of CSR,tendon-bone syndrome differentiation in traditional Chinese medicine often faces the issues of conceptual confusion and non-standard syndrome differentiation.Based on the traditional tendon-bone syndrome differentiation and by integrating modern anatomical insights,Professor LIN Ding-Kun,an esteemed scholar of Traditional Chinese Medicine,proposed a classification system for the cervical spine that includes the categories of tendons,joints,bones and marrow.This paper explored the thoughts of Professor LIN for the tendon-bone syndrome differentiation of CSR,summarized the targets of manual therapy,and proposed the four kinds of pathological changes such as tendon overstrain,joint dislocation,bone lesion,and marrow injury,as well as the four techniques of traditional Chinese medicine manipulations,i.e.relaxation of tendons,reduction of joints,protection of marrow,and treatment of bones.The aim is to improve the syndrome-differentiation and treatment for CSR with orthopedic and traumatologic manipulations,and to provide reference for clinical practice.

Objective To analyze the influencing factors of pancreatic fat deposition in patients with type 2 diabetes mellitus(T2DM),and to explore the relationship between pancreatic fat deposition and islet function.Methods A survey on diabetes prevalence was conducted among 548 residents in the Nicheng community of Pudong New Area from October 2015 to December 2016,including 301 patients with T2DM and 247 subjects with normal glucose tolerance(NGT).General information of the subjects were recorded,blood biochemical and insulin indexes were measured,body composition was measured by dual-energy X-ray absorptiometry,and insulin resistance index(HOMA-IR)and islet cell sensitivity index(HOMA-β)were calculated.Fatty liver and pancreatic fat deposition were detected by ultrasound.Both the T2DM group and NGT group were further divided into two subgroups according to the pancreatic fat deposition.Differences in general demographic information,biochemical and body fat indices among the groups were compared.Multivariate logistic regression was used to analyze the influencing factors of pancreatic fat deposition.Results In the NGT group,the subgroup with pancreatic fat deposition showed higher levels of age,waist circumference,waist-to-hip ratio(WHR),body mass index(BMI),fasting insulin levels(FINS),2-hour postprandial insulin levels(2 h INS),triglycerides(TG),uric acid(UA),alanine aminotransferase(ALT),fatty liver prevalence,abdominal fat percentage,and abdomen-to-hip ratio(AHR),compared with the subgroup without pancreatic fat deposition.High-density lipoprotein cholesterol(HDL-C)and limb fat percentage were lower in the subgroup with pancreatic fat deposition.In the T2DM group,the subgroup with pancreatic fat deposition showed higher levels of waist circumference,BMI,FINS,2 h INS,TG,UA,ALT,aspartate aminotransferase(AST),fatty liver prevalence,and abdominal fat percentage,compared with the subgroup without pancreatic fat deposition,with statistically significant differences(P<0.05).The HOMA-IR and HOMA-β in both NGT and T2DM groups with pancreatic fat deposition were significantly higher than those in the groups without pancreatic fat deposition.The prevalence of insulin resistance also significantly increased,with statistically significant differences(P<0.05).The results of multivariate logistic regression analysis showed that HDL-C,HOMA-β,abdominal fat percentage,age and fatty liver were the influencing factors for pancreatic fat deposition in NGT.Conclusion Elderly individuals with abdominal obesity and fatty liver are more prone to developing pancreatic fat deposition,which can affect islet function and aggravate the insulin resistance.

Objective To investigate the correlation between the level of N-terminal pro-Brain natriuretic peptide(NT-proBNP)and cardiorespiratory fitness following acute exposure to high altitude.Methods Forty-six subjects were recruited from the Second Affiliated Hospital of Army Medical University in June 2022,including 19 males and 27 females.After completing cardiopulmonary exercise test(CPET),serological detection of myocardial cell-related markers,and multiple metabolites at a plain altitude(300 meters above sea level),all subjects flew to a high-altitude location(3900 meters above sea level).Biomarker testing and CPET were repeated on the second and third days after arrival at high altitude.Changes in serum biomarker and key CPET indicators before and after rapid ascent to high altitude were compared,and the correlation between serum levels of various myocardial cell-related markers and metabolites and high altitude cardiorespiratory fitness was analyzed.Results Compared with the plain altitude,there was a significant decrease in maximal oxygen uptake after rapid ascent to high altitude[(25.41±6.20)ml/(kg.min)vs.(30.17±5.01)ml/(kg.min),P<0.001].Serum levels of NT-proBNP,Epinephrine(E),plasma renin activity(PRA),angiotensin Ⅱ(Ang Ⅱ),angiotensin-converting enzyme 2(ACE2)and leptin(LEP)significantly increased,with all differences being statistically significant(P<0.05)after acute high altitude exposure.In contrast,no statistically significant differences were observed for creatine kinase MB(CK-MB),cardiac troponin I(cTnI),myoglobin(Myo)and norepinephrine(NE)(P>0.05).Correlation analysis showed a significant negative correlation between NT-proBNP at plain altitude(r=-0.768,P<0.001)and at high altitude(r=-0.791,P<0.001)with maximal oxygen uptake at high altitude.Multivariate linear regression analysis indicated that maximal oxygen uptake at plain altitude(t=2.069,P=0.045),NT-proBNP at plain altitude(t=-2.436,P=0.020)and at high altitude(t=-3.578,P=0.001)were independent influencing factors of cardiorespiratory fitness at high altitude.Conclusion Cardiorespiratory fitness significantly decreases after rapid ascent to high altitude,and the baseline NT-proBNP level at plain altitude is closely related to cardiorespiratory fitness at high altitude,making it a potential predictor indicator for high altitude cardiorespiratory fitness.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in tertiary hospitals in major regions of China in 2022.Methods Clinical isolates from 58 hospitals in China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2022 Clinical &Laboratory Standards Institute(CLSI)breakpoints.Results A total of 318 013 clinical isolates were collected from January 1,2022 to December 31,2022,of which 29.5％were gram-positive and 70.5％were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species(excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi)was 28.3％,76.7％and 77.9％,respectively.Overall,94.0％of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 90.8％of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis showed significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 94.2％in the isolates from children and 95.7％in the isolates from adults.The resistance rate to carbapenems was lower than 13.1％in most Enterobacterales species except for Klebsiella,21.7％-23.1％of which were resistant to carbapenems.Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.1％to 13.3％.The prevalence of meropenem-resistant strains decreased from 23.5％in 2019 to 18.0％in 2022 in Pseudomonas aeruginosa,and decreased from 79.0％in 2019 to 72.5％in 2022 in Acinetobacter baumannii.Conclusions The resistance of clinical isolates to the commonly used antimicrobial agents is still increasing in tertiary hospitals.However,the prevalence of important carbapenem-resistant organisms such as carbapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a downward trend in recent years.This finding suggests that the strategy of combining antimicrobial resistance surveillance with multidisciplinary concerted action works well in curbing the spread of resistant bacteria.