AIM: To study the effect of tick anticoagulant peptide-staphylococcal superantigen like protein 5 (TAP-SSL5), an anti-inflammatory and anticoagulant fusion protein , on the binding of activated platelets to human lym-phocytes.METHODS:Human periphery lymphocytes were isolated by magnetic activated cell sorting (MACS).The toxic-ity of TAP-SSL5 on the viability of Jurkat cell was assessed by CCK-8 assay.Flow cytometry was applied to detect the ex-pression of CD162 (PSGL-1) on the Jurkat cells (human peripheral blood leukemia T lymphocyte cell line ) and the inhibi-tory effect of TAP-SSL5 on the binding of mouse anti-human CD162 monoclonal antibody (KPL-1) to Jurkat cells.Platelets were activated by ADP at concentration of 20μmol/L, the binding rates of activated platelets to Jurkat cells or human lym-phocytes were assayed by flow cytometry .RESULTS:The concentration of TAP-SSL5 below 30 mg/L didn’ t affect the vi-ability of Jurkat cells .TAP-SSL5 at 10 mg/L competitively inhibited KPL-1 binding to Jurkat cells .The binding rates of activated platelets to Jurkat cells or lymphocytes were (11.86 ±4.49)% and (8.32 ±1.00)%, respectively, which de-creased to (6.73 ±2.71)%and (5.51 ±0.70)%after the Jurkat cells and lymphocytes were pre-incubated with 10 mg/L TAP-SSL5 (P <0.05).CONCLUSION:TAP-SSL5 binds to PSGL-1 expressed on lymphocyte surface and directly in-hibits the binding of activated platelets to human lymphocytes , which may be one of the anti-inflammatory mechanisms of TAP-SSL5.

AIM:Early calcification of atherosclerotic plaques are colocalized with macrophage and high mobility group box 1 (HMGB1), a cytokine associated with biomineralizing process under physiological and pathological conditions .Our study aims to evaluate whether HMGB1 induces ectopic mineralization via promoting the secretion of matrix vesicles ( MVs) from macrophages .METHODS:HMGB1 was added to the medium of macrophages , the secretion of MVs in the supernatant was tested by flow cytometry analysis .The mineral deposition in calcifying medium was detected by Alizarin Red staining and von Kossa staining .Transmission electron microscopy showed the formation of hydroxyapatite crystals in MVs .Then we subcutaneous injection into mice with MVs to induce regional minera-lization.RESULTS:HMGB1 significantly promoted secretion of MVs from macrophages as raveled by flow cytometry analysis .TNAP activity, considered as a marker of MVs maturation , was higher in HMGB1-induced MVs compared to the control-MVs.HMGB1-MVs also led to mineral deposition in an in vitro MVs-collagen mineralization model .Subcutaneous injection into mice with MVs derived from HMGB1-treated cells showed a greater potential to initiate regional mineralization .Mechanistic experiments revealed that HMGB 1 activated neutral sphingomyelinase 2 ( nSMase2 ) that involved the receptor for advanced glycation end products ( RAGE ) and p38 MAPK (upstream of nSMase2).Inhibition of nSMase2 with GW4869 or p38 MAPK with SB-239063 prevented MVs secretion and min-eral deposition .CONCLUSIONS: HMGB1 induces MVs secretion from macrophages at least in part , via the RAGE/p38 MAPK/nSMase2 signaling pathway .Our findings thus reveal a novel mechanism by which HMGB 1 may participated in the early calcification of atherosclerotic plaques .

Objective:To study the safety and efficacy of using the ultrasonic lithotripsy system (ULS) in assisting percutaneous nephroscopic retroperitoneal pancreatic necrosectomy in patients with acute necrotizing pancreatitis (ANP) extending to both sides of the retroperitoneal regions.Methods:The clinical data of 47 patients with extensive ANP who underwent video-assisted retroperitoneal debridement (VARD) from January 2017 to October 2022 at the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, were analyzed retrospectively. There were 32 males and 15 females, aged [ M( Q1, Q3)] 60(43, 75) years old. The patients were divided into two groups based on the debridement methods: patients treated by nephroscopic pancreatic necrosectomy (NPN) were included in the NPN group ( n=22), while patients treated by the ULS-assisted treatment were included in the ULS group ( n=25). The surgical debridement time, operation time and complications of the two groups were compared. Follow up on recurrence and death of patients was done by telephone, outpatient and/or re-hospitalization records. Results:All patients underwent the VARD operation successfully, without any need for conversion to laparotomy, transfer to intensive care unit and death related to the operations. The pancreatic exocrine function was not damaged in both groups. When compared with the ULS group, the NPN group required significantly more debridement time [3(2, 4) times/person vs. 2(1, 2) times/person], longer operation time [65(40, 85) min vs. 35(30, 50) min] and longer hospitalization time [91(76, 130) d vs. 72(62, 102) d, all P<0.05]. No complications occurred in the ULS group. In the NPN group, postoperative hemorrhage occurred in 3 patients, colon fistula in 1 patient, and delayed viral encephalitis in 1 patient. The incidence of postoperative complications in the NPN group was significantly higher than that in the ULS group [22.7%(5/22) vs. 0(0/25), P=0.032]. All the 47 patients with extensive ANP were followed up for a median of 28 months (range 3 to 60 months), and there were no patients who developed residual recurrence and death. Conclusion:For patients with extensive ANP, ULS-assisted nephroscopic pancreatic necrosectomy was safe and feasible. When compared with NPN, the ULS-assisted procedure showed more advantages in debridement efficiency, operation time and hospital stay.

Objective To study the effect of combined laparoscopic and percutaneous nephroscopic necrosectomy in the treatment of peripancreatic abscesses.Methods The clinical data of 8 patients with peripancreatic abscesses treated by combined laparoscopic and percutaneous nephroscopic necrosectomy in our hospital from June 2015 to June 2017 were retrospectively analyzed.Results 8 patients were treated with percutaneous puncture and drainage under Ultrasonic / Computed Tomography guidance.Combined laparoscopic and percutaneous nephroscopic necrosectomy was then carried out.Two patients underwent percutaneous nephroscopic surgery twice and laparoscopic surgery once,and 3 patients underwent percutaneous nephroscopic surgery thrice,and 3 patients underwent percutaneous nephroscopic surgery 4 times and laparoscopic surgery once.One patient after percutaneous nephroscopic necrosectomy was complicated with sinus tract hemorrhage,which was treated by haemostasis through a small incision.Two patients who developed postoperative colonic fistula were treated successfully by conservative treatment.The average length of hospital stay was 80 d (60 ～ 153 d),and there was no death.Conclusion Combined laparoscopic and percutaneous nephroscopic necrosectomy was a minimally invasive and efficacious method to treat peripancreatic abscesses.

Objective:To study the effect of peroxisome proliferator activated receptor- γ (PPAR-γ) agonists rosiglitazone on the hepatocytes of Sprague Dawley (SD) rats with severe acute pancreatitis (SAP) and the regulatory mechanism.Methods:Seventy two healthy male SD rats, weighing 255-315 g, aged 49-56 days, were randomly divided into SAP model group ( n=24, SAP model preparation), rosiglitazone group ( n=24, rosiglitazone intravenous injection after SAP model preparation) and sham operation group ( n=24, normal saline injection only). After 6 h, 12h and 24 hours of injection, 8 rats were treated at each time point. HE staining was used to study the liver tissue structure and detect the levels of serum tumor necrosis factor-α(TNF-α), interleukin (IL) -1β, IL-6, AST, ALT and lactate dehydrogenase (LDH) in the rats. Western blot was used to detect the expression of high mobility group box-1 protein (HMGB1), Janus activated kinase (JAK)2 and signal transducer and activator of transcription (STAT)3. Results:The levels of serum TNF-α , IL-1β, IL-6, AST, ALT, LDH in SAP model group and rosiglitazone group were significantly higher than those in the sham operation group (all P<0.05). IL-1β at 6, 12h and 24 h in rosiglitazone group was (226.5±52.1)ng/L, (458.2±82.3)ng/L, (556.4±83.4) ng/L, ALT was (158. 3±39.2) U/L, (235.0±44.6)U/L, (298.4±56.6) U/L, which was lower than that in SAP model group (443. 5±62.3) ng/L, (622.6±78.3) ng/L, (789.1±105.7) ng/L and (198.4±42.5)U/L, (253.8±47.0)U/L, (337.2±60.1) U/L, the differences were statistically significant (all P<0.05). AST and LDH in rosiglitazone group were also lower than those in SAP model group at each time point, and the differences were statistically significant (all P<0.05). HE staining showed that there were less inflammation, hemorrhage and necrosis in rosiglitazone group than those in SAP model group. Expression of STAT3 in liver of rosiglitazone group at 6 h, 12 h and 24 h was (0.22±0.03), (0.30±0.04), (0.31±0.06), lower than SAP model group (0. 28±0.04), (0.38±0.05), (0.40±0.06), the differences were statistically significant (all P<0.05). Expression of JAK2 and HMGB1 in rosiglitazone group at 12 h and 24 h was also lower than that in SAP model group (all P<0.05). Conclusion:PPAR-γ agonists rosiglitazone can protect the SAP rats suffering from hepatocyte injury and inflammation, through JAK2/STAT3 pathway.

Objective:To systematically evaluate the effect of cognitive behavioral therapy (CBT) in elderly patients with depression.Methods:The randomized controlled trials on the effect of CBT in elderly patients with depression, published until December 15, 2022, were searched in PubMed, CINHAL, Cochrane Library, China Biology Medicine, China National Knowledge Infrastructure, WanFang Data, and VIP. Two researchers independently screened the literature, extracted data, and used the revised Cochrane risk of bias tool for randomized trials (ROB 2.0) to evaluate the quality of the included studies. Statistical analysis was conducted using Stata 16.0, and the quality of evidence was rated using Appraisal of Guidelines for Research and Evaluation (GRADE) predictor software.Results:A total of 11 randomized controlled trials were included, with a total of 833 elderly patients with depression. Randomized effect models were used to analyze outcome indicators such as depression, anxiety, and quality of life by combining effect quantities. Meta-analysis and GRADE evidence quality showed that compared to the control group, medium quality evidence showed that CBT could relieve depression in elderly depression patients with a statistical difference [ SMD=-1.58, 95% CI (-2.16, -0.99), P<0.05]. Low quality evidence suggested that CBT could alleviate anxiety in elderly depression patients also with a statistical difference [ SMD=-2.25, 95% CI (-4.04, -0.47), P<0.05]. Very low quality evidence indicated that CBT did not significantly improve the quality of life in elderly depression patients compared to conventional or pharmacological treatment [ SMD=-0.09, 95% CI (-2.07, 1.88), P>0.05] . Conclusions:Existing evidence suggests that CBT can alleviate depression and anxiety in elderly depression patients, but its improvement in quality of life is not yet significant. Treatment feedback and forms of CBT may become a research focus in recent years on intervention for elderly depression patients.

A limited number of microRNAs (miRNAs, miRs) have been reported to control postnatal cardiomyocyte proliferation, but their strong regulatory effects suggest a possible therapeutic approach to stimulate regenerative capacity in the diseased myocardium. This study aimed to investigate the miRNAs responsible for postnatal cardiomyocyte proliferation and their downstream targets. Here, we compared miRNA profiles in cardiomyocytes between postnatal day 0 (P0) and day 10 (P10) using miRNA arrays, and found that 21 miRNAs were upregulated at P10, whereas 11 were downregulated. Among them, miR-31a-5p was identified as being able to promote cardiomyocyte proliferation as determined by proliferating cell nuclear antigen (PCNA) expression, double immunofluorescent labeling for α-actinin and 5-ethynyl-2-deoxyuridine (EdU) or Ki-67, and cell number counting, whereas miR-31a-5p inhibition could reduce their levels. RhoBTB1 was identified as a target gene of miR-31a-5p, mediating the regulatory effect of miR-31a-5p in cardiomyocyte proliferation. Importantly, neonatal rats injected with a miR-31a-5p antagomir at day 0 for three consecutive days exhibited reduced expression of markers of cardiomyocyte proliferation including PCNA expression and double immunofluorescent labeling for α-actinin and EdU, Ki-67 or phospho-histone-H3. In conclusion, miR-31a-5p controls postnatal cardiomyocyte proliferation by targeting RhoBTB1, and increasing miR-31a-5p level might be a novel therapeutic strategy for enhancing cardiac reparative processes.
Animals ; Cell Count ; MicroRNAs ; Myocardium ; Myocytes, Cardiac* ; Negotiating ; Proliferating Cell Nuclear Antigen ; Rats

With the increasing cost of drug development and clinical trials, it is of great value to make full use of all kinds of data to improve the efficiency of drug development and to provide valid information for medication guidelines. Model-based meta-analysis (MBMA) combines mathematical models with meta-analysis to integrate information from multiple sources (preclinical and clinical data, etc.) and multiple dimensions (targets/mechanisms, pharmacokinetics/pharmacodynamics, diseases/indications, populations, regimens, biomarkers/efficacy/safety, etc.), which not only provides decision-making for all key points of drug development, but also provides effective information for rational drug use and cost-effectiveness analysis. The classical meta-analysis requires high homogeneity of the data, while MBMA can combine and analyze the heterogeneous data of different doses, different time courses, and different populations through modeling, so as to quantify the dose-effect relationship, time-effect relationship, and the relevant impact factors, and thus the efficacy or safety features at the level of dose, time and covariable that have not been involved in previous studies. Although the modeling and simulation methods of MBMA are similar to population pharmacokinetics/pharmacodynamics (Pop PK/PD), compared with Pop PK/PD, the advantage of MBMA is that it can make full use of literature data, which not only improves the strength of evidence, but also can answer the questions that have not been proved or can not be answered by a single study. At present, MBMA has become one of the important methods in the strategy of model-informed drug development (MIDD). This paper will focus on the application value, data analysis plan, data acquisition and processing, data analysis and reporting of MBMA, in order to provide reference for the application of MBMA in drug development and clinical practice.