Poly(ADP-ribosyl)ation (PARylation) is a specific form of post-translational modification (PTM) predominantly triggered by the activation of poly-ADP-ribose polymerase 1 (PARP1). However, the role and mechanism of PARylation in the advancement of acute kidney injury (AKI) remain undetermined. Here, we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI, consistent with renal biopsy findings in patients with AKI. This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4 (H3K4me3). Furthermore, a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models. Mechanistically, liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1 (RACK1), thereby facilitating its subsequent phosphorylation. Moreover, the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α (HIF-1α) degradation, thereby exacerbating kidney injury. Additionally, we identified a PARP1 proteolysis-targeting chimera (PROTAC), A19, as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34, a previously identified PARP1 inhibitor. Collectively, both genetic and drug-based inhibition of PARylation mitigated kidney injury, indicating that the PARylated RACK1/HIF-1α axis could be a promising therapeutic target for AKI treatment.

Gene therapy, harnessing the power of CRISPR-Cas9 and/or DNAzyme systems, stands as a pivotal approach in cancer therapy, enabling the meticulous manipulation of genes pivotal to tumorigenesis and immunity. However, the pursuit of precise gene therapy encounters formidable hurdles. Herein, a near-infrared upconversion theranostic nanomachine is devised and tailors for CRISPR-Cas9/DNAzyme systems mediate precise gene therapy. An ingenious logic DNAzyme system consists of Chain 1 (C1)/Chain 2 (C2) and endogenous lncRNA is designed. We employ manganese modified upconversion nanoparticles for carrying ultraviolet-responsive C1-PC linker-C2 (C₂P) chain and Cas9 ribonucleoprotein (RNP), with outermost coats with hyaluronic acid. Upon reaching tumor microenvironment (TME), the released Mn²⁺ ions orchestrate a trifecta: facilitating endosomal escape, activating cGAS-STING signaling, and enabling T1-magnetic resonance imaging. Under near-infrared irradiation, Cas9 RNP/C₂P complex dissociates, releasing Cas9 RNP into the nucleus to perform gene editing of Ptpn2, while C1/C2 chains self-assemble with endogenous lncRNA to form a functional DNAzyme system, targeting PD-L1 mRNA for gene silencing. This strategy remodels the TME by activating cGAS-STING signaling and dual immune checkpoints blockade, thus realizing tumor elimination. Our theranostic nanomachine armed with the CRISPR-Cas9/DNAzyme logic systems, represents a resourceful and promising strategy for advancing cancer systemic immunotherapy and precise gene therapy.

ObjectiveTo retrospectively analyze the effect of modified Shugan Dingji Decoction （疏肝定悸汤） on the occurrence of endpoint events in patients with paroxysmal atrial fibrillation of liver constraint and qi stagnation. MethodsA retrospective cohort study was conducted using the electronic medical record database of Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine to screen and include patients with paroxysmal atrial fibrillation of liver constraint and qi stagnation from January 1st， 2018， to December 31th， 2021. The included patients were divided into an exposure group and a non-exposure group， each consisting of 100 cases， based on whether they received modified Shugan Dingji Decoction. General information of the patients including age， gender， body mass index， duration of illness and comorbidities， medication history， cardiac structure and function indicators such as left atrial diameter， left ventricular end-diastolic diameter， stroke volume and ejection fraction， and the occurrence of endpoint events assessed through 24-hour dynamic electrocardiography or electrocardiogram to determine the recurrence of paroxysmal atrial fibrillation were collected. Kaplan-Meier （K-M） curves and Log-Rank tests were used to conduct survival analysis on the occurrence of endpoint events in the two groups of patients. Univariate and multivariate Cox regression analyses were used to analyze the impact of various factors on entry into endpoint events. Additionally， a safety assessment was performed by comparing liver and kidney function indicators before and after treatment. ResultsIn the non-exposure group， a total of 49 cases （49.0%） experienced endpoint events， while in the exposure group， there were 26 cases （26.0%）. The Log-rank test indicated significant difference between the two groups （χ²=11.211， P=0.001）. Univariate Cox regression analysis showed that age， duration of illness， hypertension， diabetes， chronic heart failure， left atrial diameter， stroke volume， and the use of modified Shugan Dingji Decoction may be the influencing factors for the occurrence of endpoint events in patients with paroxysmal atrial fibrillation of liver constraint and qi stagnation （P＜0.05 or P＜0.01）. Multivariate Cox regression analysis showed that the risk of endpoint events in the exposure group was significantly lower than that in the non-exposure group （P＜0.01）. Patients with a duration of illness ＞12 months had a significantly higher risk of endpoint events compared to those with a duration of illness ≤12 months （P＜0.01）. Patients without concomitant hypertension had a lower risk of endpoint events compared to those with hypertension （P＜0.05）. Patients with left atrial diameter ＞40 mm had significantly higher risk of endpoint events than those with left atrial diameter ≤40 mm （P＜0.01）. There was no statistically significant difference in liver and kidney function indicators between the two groups before and after treatment （P＞0.05）. ConclusionThe use of modified Shugan Dingji Decoction is a protective factor for patients with paroxysmal atrial fibrillation of liver constraint and qi stagnation， which can help to reduce the recurrence and progression of atrial fibrillation. Long duration of illness， concomitant hypertension， and enlarged left atrial diameter are risk factors for patients to experience endpoint events.

Objective:To investigate the clinical characteristics and prognosis of patients with left ventricular assist device (LVAD) implantation during the perioperative period.Methods:This retrospective study included 14 patients with end-stage heart failure who underwent LVAD implantation in the department of intensive care medicine of Nanjing Hospital Affiliated to Nanjing Medical University from February 2022 to March 2023, including 12 males and 2 females patients, the mean age was (57.6±9.8)years old. All patients were implanted with Corheart 6 implantable left ventricular assist system, did not use other mechanical assisted circulatory devices. The clinical data of enrolled patients were collected, and the clinical characteristics and prognosis during ICU treatment were analyzed.Results:Dilated cardiomyopathy (DCM) was the most common primary cause of heart failure. The results of transthoracic echocardiography showed that the left ventricular ejection fraction (0.297±0.074 vs. 0.238±0.064, P=0.031) of patients was significantly increased, while the left ventricular end diastolic diameter[69.0(65.8, 74.3)mm vs. 76.5(72.8, 83.0)mm, P=0.003]and systolic end systolic diameter[61.5(53.7, 65.3)mm vs. 68.3(63.8, 71.9)mm, P=0.005]were significantly decreased post LVAD implantation as compared to before LVAD implantation. Within one week after implantation, there was no significant difference in LVAD rotational speed, flow rate, and pulsation index ( P>0.05). During ICU treatment, dobutamine (13 cases) was the most commonly used vasoactive agent. 9 patients used phosphodiesterase Ⅲ inhibitors for perioperative pulmonary hypertension. Targeted management of volume and pressure indicators was conducted for enrolled patients to prevent postoperative right heart failure and to reduce right heart burden. Within 72 hours after LVAD implantation, the average pulmonary artery pressure of patients was 24 (22, 26) mmHg to 26 (21, 28)mmHg (1 mmHg=0.133 kPa), while the fluid balance was(-581±778)ml to(-1 209±1 134)ml. All enrolled patients survived to 28 days after LVAD implantation. The length of stay in the ICU was (8.0±1.8) days and the total length of hospital stay was 33 (29, 41)days, while the time of mechanical ventilation was 8 (5, 28)h. Conclusion:LVAD implantation can help improve left ventricular systolic function, prolong survival time so as to serve as an important means of terminal treatment or bridging therapy for heart transplantation of patients with end-stage heart failure. To strengthen the perioperative hemodynamic regulation and maintain the cardiac function of patients with LVAD implantation is the important purposes of ICU postoperative management.

OBJECTIVE To investigate the effects of Taohong siwu decoction modified granules on podocyte epithelial- mesenchymal-transition （EMT） and renal fibrosis in diabetic kidney disease （DKD） model rats. METHODS Eight rats were selected as normal group （ordinary feed）； the remaining rats were given a high-glucose and high-fat diet combined with intraperitoneal injection of streptozotocin （35 mg/kg） to induce the DKD model. Model rats were randomly divided into model group， irbesartan group [positive control， 13.5 mg/（kg·d）] and modified Taohong siwu decoction group [6.48 g/（kg·d）]， with 8 rats in each group. All groups were given relevant medicine intragastrically， once a day， for 16 consecutive weeks. Twenty-four- hour urinary total protein （24 h UTP） was detected at the end of the 4th， 8th， 12th and 16th week of administration. After the last medication， the body mass， water intake， food intake， urine output， the levels of fasting blood glucose， serum creatinine （Scr） and blood urea nitrogen （BUN） as well as mRNA and protein expressions of P-cadherin， nephrin， α -smooth muscle actin （α-SMA）， Wilms’ tumor gene 1 （WT1）， transforming growth factor-β1（ TGF-β1） and type Ⅳ collagen （Col-Ⅳ） in renal tissue were determined. The pathological and morphological changes in renal tissue were observed and the thickness of the glomerular basement membrane was determined. RESULTS Compared with the model group， 24 h UTP of rats was significantly decreased in modified Taohong siwu decoction group since the 8th weekend （P＜0.05）； the body weight of rats increased significantly， but the amount of water intake and urine decreased significantly； Scr and BUN level， mRNA expression of α-SMA， mRNA and protein expressions of TGF-β1 and Col-Ⅳ were significantly reduced， while the mRNA expressions of P-cadherin， nephrin and WT1 were increased significantly （P＜0.05）； the protein deposition of α-SMA was reduced， protein depositions of P-cadherin， nephrin and WT1 were increased； the pathological damage and fibrosis of renal tissue were relieved； the thickness of glomerular basement membrane was decreased significantly （P＜0.05）. CONCLUSIONS Taohong siwu decoction modified granules can inhibit the EMT of podocyte in DKD model rats， and alleviate renal pathological damage and podocyte damage， thus protecting renal function， and delaying the process of renal fibrosis.

Objective To analyze the characteristics of platelet changes and their influencing factors during postoperative hospitalization in patients who underwent transcatheter aortic valve implantation (TAVI). Methods The patients who underwent TAVI at Beijing Anzhen Hospital Valve Surgery Center between March 2017 and October 2021 were retrospectively selected. The patients were divided into a self-limiting group and a non-self-limiting group according to the characteristics of postoperative platelet decline. In addition, the general preoperative data, preoperative and postoperative ultrasound data, intraoperative data, and the use of anticoagulant drugs during the postoperative stay in the hospital were compared between the two groups. Results A total of 249 patients were enrolled in this study. There were 175 (70.3%) patients in the self-limiting group, including 100 males and 75 females, and there were 74 (29.7%) patients in the non-self-limiting group, including 43 males and 31 females, with no statistical difference between the two groups (P=0.863). The mean age of patients was 73.11±8.88 years in the self-limiting group and 71.54±10.39 years in the non-self-limiting group (P=0.231). The decline of platelets in the self-limiting group generally occurred on the postoperative day 2 and reached the lowest count on the postoperative day 4, and returned to the baseline level on the postoperative day 5-7, while the platelets in the non-self-limiting group changed by simple rise, fall or irregular fluctuation. Patients in the self-limiting group had severer preoperative aortic stenosis (P<0.001) and used more extracorporeal circulation assistance during surgery (P<0.001). Postoperatively, patients in the self-limiting group were more likely to have periaortic valve leakage than those in the non-self-limiting group (P=0.013). Conclusion Platelet changes in most patients after TAVI show a self-limiting decline, which may be related to the severity of patients’ preoperative aortic stenosis, intraoperative extracorporeal circulation device use, and postoperative perivalvular leakage.

G protein-coupled receptor (GPR) 40, as one of GPRs family, plays a potential role in regulating glucose and lipid metabolism. To study the effect of GPR40 novel agonist SZZ15-11 on hyperglycemia and hyperlipidemia and its potential mechanism, spontaneous type 2 diabetic KKA^y mice, human hepatocellular carcinoma HepG2 cells and murine mature adipocyte 3T3-L1 cells were used. KKA^y mice were divided into four groups, vehicle group, TAK group, SZZ (50 mg·kg^-1) group and SZZ (100 mg·kg^-1) group, with oral gavage of 0.5% sodium carboxymethylcellulose (CMC), 50 mg·kg^-1 TAK875, 50 and 100 mg·kg^-1 SZZ15-11 respectively for 45 days. Fasting blood glucose, blood triglyceride (TG) and total cholesterol (TC), non-fasting blood glucose were tested. Oral glucose tolerance test and insulin tolerance test were executed. Blood insulin and glucagon were measured via enzyme-linked immunosorbent assay (ELISA). After mice′s execution, liver tissue was harvested to test TG and TC content. Then pathological morphology of liver was observed through hematoxylin-eosin (HE) staining, and the lipid metabolism relative signal pathway was analyzed by Western blot and RT-PCR. The experiments were approved by the Institutional Animal Care and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. At the same time, Akt phosphorylation level in HepG2 cells and adiponectin in 3T3-L1 cells treated with TNFα were measured with Western blot. The results show that SZZ15-11 not only decreased blood glucose and lipid, improved insulin sensitivity, but also increased fasting blood glucagon and promoted insulin secretion after glucose loading in KKA^y mice. Additionally, SZZ15-11 alleviated hepatic steatosis and liver dysfunction in KKA^y mice. In liver tissue, SZZ15-11 increased AMPKα phosphorylation level and cholesterol metabolism relative gene Abcg8 transcription. In HepG2 cells, SZZ15-11 increased Akt phosphorylation level. In adipocyte 3T3-L1, SZZ15-11 recovered the decreased adiponectin expression by TNFα. This study proved that GPR40 agonist SZZ15-11 could be a candidate compound for regulating glucolipid metabolic disorder.

ObjectiveTo evaluate the efficacy and safety of first-line transcatheter arterial chemoembolization （TACE） combined with targeted therapy and immunotherapy in the treatment of patients with stage Ⅱb/Ⅲa hepatocellular carcinoma （HCC） based on China Liver Cancer Staging （CNLC）. MethodsA total of 198 patients who received first-line TACE combined with targeted therapy and immunotherapy or received TACE alone from January 2015 to December 2022 in the First Affiliated Hospital of Soochow University were enrolled in this study， and after propensity score matching， there were 50 patients in combination group and 50 patients in TACE group. The Kaplan-Meier method was used to calculate median overall survival （mOS） and median progression-free survival （mPFS）. Modified Response Evaluation Criteria in Solid Tumors was used to evaluate objective response rate （ORR） and disease control rate （DCR）， and Common Terminology Criteria for Adverse Events v5.0 was used to evaluate adverse events. The chi-square test was used for comparison of categorical data between two groups； the t-test was used for comparison of normally distributed continuous data between two groups， and the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data between two groups. The Kaplan-Meier method was used to estimate survival time and calculate 95% confidence interval （CI）， and the Log-rank test was used for comparison of mOS and mPFS between two groups. ResultsThe combination group had an mOS of 30.1 months （95%CI： 21.9‍ ‍—‍ ‍38.3）， and the TACE group had an mOS of 14.5 months （95%CI： 11.0 ‍—‍‍ ‍18.0）， with a significant difference between the two groups （χ²=17.8， P<0.001）； the combination group had an mPFS of 10.3 months （95%CI： 8.8‍ ‍—‍ ‍11.8）， and the TACE group had an mPFS of 7.1 months （95%CI： 5.8‍ — ‍8.4）， with a significant difference between the two groups （χ²=10.4， P<0.001）. There were significant differences between the combination group and the TACE group in ORR （84% vs 58%， P<0.05） and DCR （94% vs 80%， P<0.05）. There was no significant difference between the combination group and the TACE group in the incidence rate of adverse events （24% vs 16%， P=0.317）， and no adverse event-related deaths were observed in either group. ConclusionCompared with TACE alone， TACE combined with targeted therapy and immunotherapy has a better efficacy in the treatment of patients with CNLC stage Ⅱb/Ⅲa HCC， without increasing the incidence rate of severe adverse events.

Objective:To investigate the genetic subtypes and drug resistance monitoring of newly reported human immunodeficiency virus (HIV) infection/AIDS virus in Anhui Province from 2020 to 2023.Methods:An observational design study was used to collect blood samples from patients diagnosed with HIV/AIDS in the AIDS Prevention and Control Department of Anhui Provincial Center for Disease Control and Prevention from January 2020 to December 2023.The HIV-1 pol gene was amplified by reverse transcription-nested PCR, and the genetic subtypes were identified by phylogenetic tree analysis using MEGA 7.0 software. The mutation sites of drug resistance were analyzed by the online software tool of Stanford University′s HIV Drug resistance database. The influencing factors of drug resistance before treatment were analyzed by multivariate logistic analysis.Results:A total of 335 plasma samples were collected, and 332 HIV-1 pol gene sequences were obtained successfully. The main gene subtypes were CRF01-AE, accounting for 35.55% (118/332), followed by CRF07-BC, B and B+C types [29.22% (97/332), 11.74% (39/332), 9.93% (33/332)]. The total drug resistance rate before treatment was 30.12%(32/100), and the drug resistance rate of protease inhibitor (PIs) in HIV-1 was 6.33% (21/332). The drug resistance rate of nucleoside reverse transcriptase inhibitors (NRTI) before treatment was 6.33% (21/332). The drug resistance rate of non-nucleoside reverse transcriptase inhibitors (NNRTI) before treatment was 17.47% (58/332).The comparison of drug resistance rate of different drug types showed statistical significance ( χ2=30.435, P<0.05).Among the 100 cases of drug resistance, the main mutation point of HIV-1 protease inhibitor was Q58E (21.00%), and the main mutation point of nucleoside reverse transcriptase inhibitor was M184V/I (6.00%). Non-nucleoside reverse transcriptase inhibitor resistance mutation points mainly K103N (22.00%).There were statistically significant differences in the starting time of antiviral therapy, the number of CD4 +T cells at baseline and the drug resistance rate of gene subtypes (the chi-square values are respectively 24.152, 32.516, 11.652, P<0.05).Multivariate logistic analysis showed that the baseline CD4 +T cell count was <200/μl, subtype B, subtype B+C, CRF01-AE subtype, CRF55-01B subtype and 01-BC subtype was the influential factor of drug resistance before treatment (the chi-square values are respectively 4.577, 8.202, 4.416, 5.206, 7.603 and 4.804, P<0.05). Conclusion:The newly reported HIV/AIDS population in Anhui Province from 2020 to 2023 has a variety of viral gene subtypes, and NNRTIs are the main types of drug resistance gene mutations before treatment. Attention should be paid to the number of baseline CD4 +T cells, the duration of antiviral treatment, and the distribution of gene subtypes to reduce the drug resistance of HIV/AIDS patients before treatment.

Objective To predict the risk of in-hospital death in patients with chronic heart failure(CHF)complicated by lung infections using interpretable machine learning.Methods The clinical data of 1415 patients diagnosed with CHF complicated by lung infections were obtained from the MIMIC-IV database.According to the pathogen type,the patients were categorized into bacterial pneumonia and non-bacterial pneumonia groups,and their risks of in-hospital death were compared using Kaplan-Meier survival curves.Univariate analysis and LASSO regression were used to select the features for constructing LR,AdaBoost,XGBoost,and LightGBM models,and their performance was compared in terms of accuracy,precision,F1 value,and AUC.External validation of the models was performed using the data from eICU-CRD database.SHAP algorithm was applied for interpretive analysis of XGBoost model.Results Among the 4 constructed models,the XGBoost model showed the highest accuracy and F1 value for predicting the risk of in-hospital death in CHF patients with lung infections in the training set.In the external test set,the XGBoost model had an AUC of 0.691(95%CI:0.654-0.720)in bacterial pneumonia group and an AUC of 0.725(95%CI:0.577-0.782)in non-bacterial pneumonia group,and showed better predictive ability and stability than the other models.Conclusion The overall performance of the XGBoost model is superior to the other 3 models for predicting the risk of in-hospital death in CHF patients with lung infections.The SHAP algorithm provides a clear interpretation of the model to facilitate decision-making in clinical settings.