OBJECTIVE: This study aimed to investigate the therapeutic effects of Xiaoyao San (XYS), a herbal medicine formula, on exercise capacity and liver mitochondrial metabolomics in a rat model of depression induced by chronic unpredictable mild stress (CUMS). METHODS: A total of 24 male SD rats were randomly divided into four groups: control group (C), CUMS control group (M), Venlafaxine positive treatment group (V), and XYS treatment group (X). Depressive behaviour and exercise capacity of rats were assessed by body weight, sugar-water preference test, open field test, pole test, and rotarod test. The liver mitochondria metabolomics were analyzed by using liquid chromatography-mass spectrometry (LC-MS) method. TCMSP database and GeneCards database were used to screen XYS for potential targets for depression, and GO and KEGG enrichment analyses were performed. RESULTS: Compared with C group, rats in M group showed significantly lower body weight, sugar water preference rate, number of crossing and rearing in the open field test, climbing down time in the pole test, and retention time on the rotarod test (P < 0.01). The above behaviors and exercise capacity indices were significantly modulated in rats in V and X groups compared with M group (P < 0.05, 0.01). Compared with C group, a total of 18 different metabolites were changed in the liver mitochondria of rats in M group. Nine different metabolites and six metabolic pathways were regulated in the liver mitochondria of rats in X group compared with M group. The results of network pharmacology showed that 88 intersecting targets for depression and XYS were obtained, among which 15 key targets such as IL-1β, IL-6, and TNF were predicted to be the main differential targets for the treatment of depression. Additionally, a total of 1 553 GO signaling pathways and 181 KEGG signaling pathways were identified, and the main biological pathways were AGE-RAGE signaling pathway, HIF-1 signaling pathway, and calcium signaling pathway. CONCLUSION XYS treatment could improve depressive symptoms, enhance exercise capacity, positively regulate the changes of mitochondrial metabolites and improve energy metabolism in the liver of depressed rats. These findings suggest that XYS exerts antidepressant effects through multi-target and multi-pathway.

Objective:To investigate the influencing of portal vein embolization (PVE) and PVE combined with transcatheter arterial chemoembolization (TACE) on secondary hepatectomy and prognosis of patients with initially unresectable hepatocellular carcinoma (HCC).Methods:The retrospective cohort study was conducted. The clinicopathological data of 102 patients with initially unresectable HCC who were admitted to the Third Affiliated Hospital of Naval Medical University from October 26,2015 to December 31,2022 were collected. There were 82 males and 20 females, aged 52(range,25?73)years. Of 102 patients, 72 cases undergoing PVE combined with TACE were set as the PVE+TACE group, and 30 cases undergoing PVE were set as the PVE group. Observation indicators: (1) surgical resection rate of secondary hepatectomy and increase of future liver remnant (FLR); (2) situations of secondary hepatectomy; (3) follow-up. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M(range), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test or Fisher exact probability. Comparison of ordinal data was conducted using the Mann-Whitney U test. The Kaplan-Meier method was used to calculate survival rate and draw survival curve, and Log-Rank test was used for survival analysis. Results:(1) Surgical resection rate of secondary hepatectomy and increase of FLR. The surgical resection rate of secondary hepatectomy in the PVE+TACE group and the PVE group were 72.2%(52/72) and 53.3%(16/30), respectively, showing no significant difference between the two groups ( χ2=3.400, P>0.05). The surgical waiting time, increasing volume of FLR, growth rate of FLR in the 52 patients of PVE+TACE group receiving secon-dary hepatectomy were 20(range, 14?140)days, 140(range, 62?424)mL, 9.8(range, 1.5?26.5)mL/day, respectively. The above indicators in the 16 patients of PVE group receiving secondary hepatectomy were 16(range, 12?35)days, 160(range, 95?408)mL, 10.5(range, 1.2?28.0)mL/day, respectively. There was no significant difference in the above indicators between the 52 patients of PVE+TACE group and the 16 patients of PVE group ( Z=1.830, 1.498, 1.266, P>0.05). (2) Situations of secondary hepatectomy. The operation time, rate of tumor necrosis (>90%, 60%?90%,<60%), cases with complications ≥ grade Ⅲa in the 52 patients of PVE+TACE group receiving secondary hepatectomy were 200(range, 125?420)minutes, 8, 4, 40, 28, respectively. The above indicators in the 16 patients of PVE group receiving secondary hepatectomy were 170(range, 105?320)minutes, 0, 0, 16, 4, respectively. There were significant differences in the above indicators between the 52 patients of PVE+TACE group and the 16 patients of PVE group ( Z=2.132, ?2.093, χ2=4.087, P<0.05). (3) Follow-up. Sixty-eight patients who completed the surgery were followed up for 40(range, 10?84)months. The 1-, 3-, 5-year recurrence free survival rate in the 52 patients of PVE+TACE group receiving secondary hepatectomy were 73.0%, 53.3%, 35.4%, respectively. The above indicators in the 16 patients of PVE group were 62.5%, 37.5%, 18.8%, respectively. There was a significant difference in the recurrence free survival rate between the 52 patients of PVE+TACE group and the 16 patients of PVE group ( χ2=4.035, P<0.05). The 1-, 3-, 5-year overall survival rate in the 52 patients of PVE+TACE group receiving secondary hepatectomy were 82.5%, 61.2%, 36.6%, respectively. The above indica-tors in the 16 patients of PVE group receiving secondary hepatectomy were 68.8%, 41.7%,20.8%, respectively. There was a significant difference in the overall survival rate between the 52 patients of PVE+TACE group and the 16 patients of PVE group ( χ2=4.767, P<0.05). Conclusion:Compared with PVE, PVE+TACE as stage Ⅰ surgery can increase the surgical resection rate of secondary hepatec-tomy and the recurrence free survival rate of patients with initially unresectable HCC, prolong the long-term survival time, but not influence the growth rate of FLR.

Objective:To investigate the possible mechanism of DiI labeled bone marrow mesenchymal stem cells (BMSCs) in contact co-cultured with neonatal rat cardiomyocytes (CMs) on polycaprolactone (PCL) film to make myocardial patch.Methods:BMSCs from Sprague Dawley rats (aged 5-6 weeks) were isolated, cultured, and characterized for surface marker expression using flow cytometry. CMs from 15 neonatal rats were isolated and cultured. After cultured for 3 generations, BMSCs were labeled with DiI dye. On PCL film, DiI labeled BMSCs were co-cultured with CMs as the experimental group, and CMs were replaced with the same amount of unlabeled BMSCs in the control group. After 24 h of co-culture, the cell growth was observed under fluorescence microscope and the co-culture was observed under scanning electron microscope. Immunofluorescence staining was performed after 7 days to detect myocardial markers, including cardiac troponin T (cTnT) and α-actinin. BMSC differentiation on the PCL film was observed under a fluorescence microscope. The differentiation efficiency of BMSCs into cardiomyoid cells was analyzed by flow cytometry on days 1 and 7 of co-culture. Intercellular dye transfer was observed by staining CMs with calcein and co-culturing them with DiI-labeled BMSCs on PCL film. The cells were stained with immunofluorescence to detect the expression of connexin 43 (Cx43) and observe the relationship between gap junction and contact co-culture.Results:Flow cytometry showed strong positivity for CD90 and CD44 and negativity for CD11b/c and CD45 on BMSCs. After 24 h of co-culture, DiI labeled BMSCs glowed red on the PCL film, while unlabeled CMs did not; the number of cells on PCL film was large and cell morphology appeared normal under scanning electron microscope. On the 7th day of co-culture, some DiI labeled BMSCs expressed cTnT and α-actinin. Flow cytometry showed a higher differentiation rate of stem cells in the experimental group on day 7 compared to the control group ((20.12±0.15)% vs. (3.49±0.20)%, P<0.05). From the second day of co-culture, some BMSCs exhibited green dot fluorescence in Cx43 immunofluorescence staining; and by the third day, dye transfer test showed green fluorescence emission from some BMSCs. Conclusion:Contact co-culture of DiI labeled BMSCs and CMs on PCL film can make myocardial patch. The mechanism of contact co-culture promoting the differentiation and formation of myocardial patch may be associated with gap junctions and intercellular signal pathways mediated by gap junctions.

Objective    To provide experimental data and theoretical support for further studying the maturity of cardiac patches in other in vitro experiments and the safety in other in vivo animal experiments, through standard chemically defined and small molecule-based induction protocol (CDM3) for promoting the differentiation of human induced pluripotent stem cells (hiPSCs) into myocardium, and preliminarily preparing cardiac patches. Methods    After resuscitation, culture and identification of hiPSCs, they were inoculated on the matrigel-coated polycaprolactone (PCL). After 24 hours, the cell growth was observed by DAPI fluorescence under a fluorescence microscope, and the stemness of hiPSCs was identified by OCT4 fluorescence. After fixation, electron microscope scanning was performed to observe the cell morphology on the surface of the patch. On the 1st, 3rd, 5th, and 7th days of culture, the cell viability was determined by CCK-8 method, and the growth curve was drawn to observe the cell growth and proliferation. After co-cultured with matrigel-coated PCL for 24 hours, hiPSCs were divided into a control group and a CDM3 group, and continued to culture for 6 days. On the 8th day, the cell growth was observed by DAPI fluorescence under a fluorescence microscope, and hiPSCs stemness was identified by OCT4 fluorescence, and cTnT and α-actin for cardiomyocyte marker identification. Results    Immunofluorescence of hiPSCs co-cultured with matrigel-coated PCL for 24 hours showed that OCT4 emitted green fluorescence, and hiPSCs remained stemness on matrigel-coated PCL scaffolds. DAPI emitted blue fluorescence: cells grew clonally with uniform cell morphology. Scanning electron microscope showed that hiPSCs adhered and grew on matrigel-coated PCL, the cell outline was clearly visible, and the morphology was normal. The cell viability assay by CCK-8 method showed that hiPSCs proliferated and grew on PCL scaffolds coated with matrigel. After 6 days of culture in the control group and the CDM3 group, immunofluorescence showed that the hiPSCs in the control group highly expressed the stem cell stemness marker OCT4, but did not express the cardiac markers cTnT and α-actin. The CDM3 group obviously expressed the cardiac markers cTnT and α-actin, but did not express the stem cell stemness marker OCT4. Conclusion    hiPSCs can proliferate and grow on matrigel-coated PCL. Under the influence of CDM3, hiPSCs can be differentiated into cardiomyocyte-like cells, and the preliminary preparation of cardiac patch can provide a better treatment method for further clinical treatment of cardiac infarction.

Objective:To study the clinical effects of portal vein embolization (PVE) with N-butyl cyanoacrylate copolymer (NBCA) and with gelatin sponge (GS) as embolization materials in patients with initially unresectable hepatocellular carcinoma (HCC).Methods:Clinical data of 90 patients with initial unresectable HCC who underwent PVE treatment at the Third Affiliated Hospital of Naval Medical University from November 2014 to April 2020 were included. There were 77 males and 13 females, aged 48 (25, 67) years old. Patients were divided into two groups according to the embolization materials selected in PVE: NBCA group ( n=60) and GS group ( n=30). Forty-eight and 18 patients finally underwent secondary hepatectomy in NBCA group (resectable NBCA group) and GS group (resectable GS group), respectively. Clinical data including future liver remnant (FLR) growth rate and secondary hepatectomy rate were analyzed. Survivals after hepatectomy was followed up by telephone, WeChat, and outpatient review. Results:The secondary hepatectomy rate in NBCA group was higher than that in GS group [80%(48/60) vs. 60%(18/30), P=0.043]. The waiting time from primary intervention to secondary hepatectomy in resectable NBCA group was 15 (7, 96) d, which was shorter than that in resectable GS group [40 (28, 118) d, P<0.001]. The FLR growth rate of resectable NBCA group was 9.03 (1.24, 29.64) ml/d, which was faster than that in resectable GS group [3.76 (0.08, 8.03) ml/d, P<0.001]. The recurrence-free survival (RFS) rates of patients in resectable NBCA group were 69.1%, 62.0% and 44.7% at 1, 2 and 3 years after surgery, and the overall survival (OS) rates were 76.4%, 69.5% and 59.6%, respectively. The RFS rates of patients in resectable GS group were 60.6%, 48.5% and 35.4% at 1, 2 and 3 years after surgery, and the OS rates were 66.7%, 60.6% and 42.4%, respectively. There were no significant differences in RFS and OS between two groups (all P>0.05). Conclusions:PVE with NBCA and GS as embolization material showed good efficacy in patients with initially unresectable HCC. The FLR growth rate and secondary hepatectomy rate of patients using NBCA were better than those of patients using GS.

Chaigui granules(CG)are a compound composed of six herbal medicines with significant antidepressant effects.However,the antidepressant mechanism of CG remains unclear.In the present study,we attempted to elucidate the antidepressant mechanism of CG by regulating purine metabolism and purinergic signaling.First,the regulatory effect of CG on purine metabolites in the prefrontal cortex(PFC)of chronic unpredictable mild stress(CUMS)rats was analyzed by ultra high-performance liquid chro-matography tandem mass spectrometry(UHPLC-MS/MS)targeted quantitative analysis.Meanwhile,purinergic receptors(P2X7 receptor(P2X7R),A1 receptor(A1R)and A2A receptor(A2AR))and signaling pathways(nod-like receptor protein 3(NLRP3)inflammasome pathway and cyclic adenosine mono-phosphate(cAMP)-protein kinase A(PKA)pathway)associated with purine metabolism were analyzed by western blotting and enzyme-linked immunosorbent assay(ELISA).Besides,antidepressant mecha-nism of CG by modulating purine metabolites to activate purinergic receptors and related signaling pathways was dissected by exogenous supplementation of purine metabolites and antagonism of puri-nergic receptors in vitro.An in vivo study showed that the decrease in xanthine and the increase in four purine nucleosides were closely related to the antidepressant effects of CG.Additionally,purinergic re-ceptors(P2X7R,A1R and A2AR)and related signaling pathways(NLRP3 inflammasome pathway and cAMP-PKA pathway)were also significantly regulated by CG.The results of exogenous supplementation of purine metabolites and antagonism of purinergic receptors showed that excessive accumulation of xanthine led to activation of the P2X7R-NLRP3 inflammasome pathway,and the reduction of adenosine and inosine inhibited the A1R-cAMP-PKA pathway,which was significantly ameliorated by CG.Overall,CG could promote neuroprotection and ultimately play an antidepressant role by inhibiting the xanthine-P2X7R-NLRP3 inflammasome pathway and activating the adenosine/inosine-A1R-cAMP-PKA pathway.

In recent years, modeling and simulation technology based on pharmacometrics has received increasing attention in the development of innovation drugs. In August of 2021, FDA issued a guidance named Pharmacokinetic-Based Criteria for Supporting Alternative Dosing Regimens of Programmed Cell Death Receptor-1 (PD-1) or Programmed Cell Death-Ligand 1 (PD-L1) Blocking Antibodies for Treatment of Patients with Cancer Guidance for Industry, claiming the necessity of using population PK-based simulation method for the optimization of dosing regimens, and the corresponding implementation standards. This article first summarized the existing therapeutic regimens of PD-1/PD-L1 blocking antibodies in clinic as well as the main content of the guidance, and then cited some actual examples where population PK-based simulation method did contribute to the approval of the alternative dosing regimens. Besides, some critical considerations for the dosing regimen optimization of PD-1/PD-L1 blocking antibodies were also analyzed. In our view, this guidance would have positive impacts on the development of PD-1/PD-L1 blocking antibodies in the future. We hope that this article may provide some references for the colleagues in China.

Circular RNA (circRNA) is considered to be non-coding RNA due to the deletion of the 5' cap structure and lacks the function of encoding proteins or polypeptides. With the development of high-throughput transcriptome sequencing, ribosome sequencing and other technologies, researchers have discovered that there were short open reading frames (sORF) and internal ribosome entry sites (IRES) in the sequence of some circRNAs which can encode polypeptides or protein and play important roles in the proliferation of malignant tumors such as glioma, hepatoma, gastric cancer, breast cancer, and colon cancer. This paper reviews the coding function of circRNA and analyzes the role of its encoded production-polypeptides or protein in the proliferation mechanism of human malignant tumors.

Objective:To compare the effects of rosuvastatin and atorvastatin on coronary artery bypass grafting (CABG) on the incidence of acute kidney injury (AKI), and assess the independent risk factors of AKI.Methods:We retrospectively collected 550 patients aged 18 years or older who underwent CABG from May 2014 to May 2020. They were divided into the rosuvastatin group ( n=322), atorvastatin group ( n=125) and non statins group ( n=103) according to whether rosuvastatin or atorvastatin was routinely used before operation. Demographic data, clinical data before and after CABG and laboratory results were collected. Blood urea nitrogen (BUN), serum creatinine (Scr), creatinine clearance rate (Ccr) and incidence of postoperative AKI were compared among the three groups. Univariate analysis and binary logistic regression analysis were used to investigate the effect of statins on AKI in patients undergoing CABG. Results:Compared with preoperation, BUN showed no significant change ( P>0.05), while Scr was increased and Ccr was decreased significantly (both P<0.01); BUN in the rosuvastatin group was decreased significantly ( P<0.01), whereas Scr and Ccr had no significant change ( P>0.05); Scr in the atorvastatin group was increased significantly ( P<0.01), but there was no significant difference in BUN and Ccr ( P>0.05). BUN and Scr in the non statins group were increased significantly (both P<0.01), while Ccr was decreased significantly ( P<0.01). After operation, BUN and Scr in the rosuvastatin group and atorvastatin group were significantly lower than those in the non statins group (all P<0.01); Ccr was significantly higher than that in the non statins group ( P<0.01). BUN and Scr were not significantly different between the rosuvastatin and atorvastatin groups ( P>0.05), but Ccr was significantly higher than that in the atorvastatin group ( P< 0.05). There were significant differences in BUN, Scr and Ccr among the three groups ( χ2=48.925, 22.677 and 34.426, all P<0.01). The incidence of AKI among 550 patients was 15.1% (83/550), of which 9.6% (31/322) in the rosuvastatin group, 16.0% (20/125) in the atorvastatin group and 31.1% (32/103) in the non statins group. The incidence of AKI in the rosuvastatin and atorvastatin groups was significantly lower than that in the non statins group ( χ2=28.412, 7.282, P<0.01). Multivariate regression analysis showed that hypertension ( OR=3.555, 95% CI: 1.959-6.451, P<0.01), NHYAⅢ/Ⅳ ( OR=2.438, 95% CI: 1.187-5.008, P=0.015), and increased serum creatinine level ( OR=1.018, 95% CI: 1.003-1.032, P=0.016), and intraoperative cardiopulmonary bypass ( OR=2.936, 95% CI: 1.454-5.927, P=0.003) were independent risk factors for AKI after CABG, while preoperative conventional statin therapy ( OR=0.490, 95% CI: 0.247-0.974, P=0.042) and increased serum albumin level ( OR=0.920, 95% CI: 0.856-0.990, P=0.026) were protective factors for AKI after CABG. Conclusions:The incidence of AKI after CABG is common. Rosuvastatin or atorvastatin and increased preoperative serum albumin level can protect renal function and reduce the incidence of AKI, which are the protective factors of AKI after CABG. The hypertension, NHYAⅢ/Ⅳ, increased preoperative serum creatinine level and cardiopulmonary bypass are the independent risk factors of AKI after CABG.

Objective:To analyze the risk factors of acute renal injury (AKI) after coronary artery bypass grafting (CABG) in the elderly patients.Methods:A total of 423 patients aged over 60 years who underwent CABG in Linyi People′s Hospital from May 2014 to May 2010 were retrospectively analyzed. Patients were divided into AKI group and control group according to whether AKI occurred. The risk factors of AKI were analyzed by multivariate logistic regression.Results:Among the 423 patients, 62 cases(14.7%)developed postoperative acute kidney injury. Compared with the patients without AKI ( n=361), the proportions of patients with hypertension, heart function (NYHA) ≥ Ⅲ, atrial fibrillation and cardiopulmonary bypass were higher in AKI group, the proportion of patients using statins before operation was lower [71.0%(44/62) vs. 50.7%(183/361),χ 2 =8.75, P<0.01;38.77%(24/62) vs. 7.5%(27/361),χ 2 =48.67, P<0.01;16.1%(10/62) vs. 4.4%(16/361),χ 2 =12.55, P<0.01;51.6%(32/62) vs. 21.3%(77/361),χ 2 =25.37, P<0.01;59.7%(37/62) vs. 85.6%(309/361),χ 2=23.87, P<0.01]. Patients in AKI group had higher level of blood uric acid, urea nitrogen and creatinine [353.8(275.5, 462.5)μmol/L vs. 314.5(262.9, 383.6)μmol/L, Z=2.75, P=0.01;5.5(4.3, 8.2)mmol/L vs. 5.1(4.3, 6.4)mmol/L, Z=2.44, P＝0.02; 74.9(58.5, 92.7)μmol/L vs. 67.0(57.1, 76.3)μmol/L, Z=2.90, P=0.01];and longer operation time, more blood loss and blood vessel bridge than those in control group [(403.2±124.1) vs. (350.6±110.2), t =3.41, P<0.01;(4.0±0.9) vs. (3.7±0.8), t=2.83, P=0.01;(3.8±0.7) vs. (3.5±0.8), t=3.58, P<0.01]. The multivariate logistic regression analysis showed that preoperative cardiac function (NYHA)≥Ⅲ( OR=8.528,95% CI:3.734-19.477, P<0.01),hypertension( OR=6.455,95% CI:2.605-15.997, P<0.01),extracorporeal circulation( OR＝3.046,95% CI:1.190-7.795, P=0.02),diabetes mellitus( OR=2.294,95% CI:1.047-5.026, P=0.04),elevated serum uric acid level( OR=1.004,95% CI:1.000-1.008, P=0.03)were the independent risk factors for AKI. Statins is a protective factor for postoperative AKI( OR=0.366,95% CI:0.154-0.873, P=0.02). Conclusions:AKI is a common complication after CABG in elderly patients. Cardiac function(NYHA) ≥ Ⅲ,hypertension,extracorporeal circulation,diabetes mellitus,elevated serum uric acid level are risk factors and administration of stating is protective factor for the incidence of acute kidney injury in elderly patients after coronary artery bypass grafting.