ObjectiveTo characterize the changes in the overall chemical profile and key index components during nine-time repeating steaming and sun-drying processing of Rhei Radix et Rhizoma， and to reveal the change law of its material basis. MethodsHigh performance liquid chromatography（HPLC） was used to analyze the changes in the overall chemical profile of Rhei Radix et Rhizoma decoction pieces， and the contents of 15 main active components such as chrysophanol-8-O-β-D-glucoside， chrysophanol and gallic acid in the process of nine-time repeating steaming and sun-drying were determined. Combined with chemometrics， the contents and quantity ratio relationships of the glycosides， aglycones and tannins during the processing of Rhei Radix et Rhizoma were analyzed， and the partial least squares-discriminant analysis（PLS-DA） and cluster analysis of the main components in different steaming times were conducted， the statistically significant differential markers were selected with the variable importance in the projection（VIP） value>1. ResultsIn the nine-time repeating steaming and sun-drying process of Rhei Radix et Rhizoma， there were certain regularity in the number and peak area of characteristic peaks and the steaming and sun-drying times， the anthraquinone glycosides and aglycones could be roughly divided into three stages， including rapid change stage， fluctuation change stage and stable stage， and the total amount of tannins showed a decreasing trend. However， the ratios between the three components mentioned above tended to stabilize after five rounds of steaming and sun-drying. The results of PLS-DA and cluster heatmap showed that the content of each component in Rhei Radix et Rhizoma fluctuated greatly during the 1-4 steaming and sun-drying processes， while the content of each component was relatively close during the 5-9 steaming and sun-drying processes. After screening， it was found that chrysophanol， emodin， chrysophanol-8-O-β-D-glucoside， rhein， physcion and emodin-8-O-β-D-glucoside could be used as the index components for distinguishing the processed products of Rhei Radix et Rhizoma with different steaming and sun-drying times. ConclusionThe changes in the properties and efficacy of Rhei Radix et Rhizoma caused by the processing of nine-time repeating steaming and sun-drying are due to the changes in the composition and ratio of various glycosides and complex tannins in this herb， which is also the key to the formation of its characteristic of "purgation with supplement". This study can provide a basis for the research on the processing mechanism of Rhei Radix et Rhizoma and the establishment of processing specifications.

BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a promising target for sensitizing solid tumors to immune checkpoint blockades. However, the highly polar active sites of PTPN2 hinder drug discovery efforts. Leveraging small interfering RNA (siRNA) technology, we developed a novel glutathione-responsive nano-platform HPssPT (HA/PEIss@siPtpn2) to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma (HCC). HPssPT showed potent transfection and favorable safety profiles. PTPN2 deficiency induced by HPssPT amplified the interferon γ signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1, resulting in enhanced antigen presentation and T cell activation. The nano-platform was also able to promote the M1-like polarization of macrophages in vitro. The unique tropism of HPssPT towards tumor-associated macrophages, facilitated by hyaluronic acid coating and CD44 receptor targeting, allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages, thereby synergistically reshaping tumor microenvironment to an immunostimulatory state. In HCC, colorectal cancer, and melanoma animal models, HPssPT monotherapy provoked robust antitumor immunity, thereby sensitizing tumors to PD-1 blockade, which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.

Objective:To investigate the association between hyperuricemia and the risk for stroke occurrence, as well as the mediating effect of hypertension on this association.Methods:In this study, the China Chronic Diseases and Nutrition Surveillance system in 2015 was used as baseline data. We identified hospital admissions for stroke using the electronic homepage of inpatient medical records from 2013-2020, and death data were obtained from the 2015-2020 National Mortality Surveillance System. A retrospective cohort was established after matching and linking the database. The Cox proportional hazard regression model was used to analyze the relationship between hyperuricemia and the risk of stroke and its subtypes. Restricted cubic spline analysis was conducted to examine the dose-response relationship between serum uric acid levels and the risk for stroke. Mediation analysis was performed to investigate the mediating effect of hypertension on the association between hyperuricemia and the risk for stroke and its subtypes. Subgroup analyses were conducted based on gender and age groups.Results:A total of 124 352 study subjects were included, with an accumulative follow-up time of 612 911.36 person-years. During the follow-up period, 4 638 cases of stroke were found, including 3 919 cases of ischemic stroke and 689 cases of hemorrhagic stroke. The incidence density of stroke was 756.72 per 100 000 person-years, 641.37 per 100 000 person-years for ischemic stroke, and 114.60 per 100 000 person-years for hemorrhagic stroke. Multivariable Cox proportional hazards regression models showed that after adjusting for covariates, compared to those without hyperuricemia, individuals with hyperuricemia had a 16% higher risk for stroke [hazard ratio ( HR)=1.16, 95% CI: 1.06-1.27], a 12% higher risk of ischemic stroke ( HR=1.12, 95% CI: 1.01-1.24), and a 39% higher risk of hemorrhagic stroke ( HR=1.39, 95% CI: 1.11-1.75). Mediation analysis showed that hypertension partially mediated the associations between hyperuricemia and the risk for stroke, ischemic stroke, and hemorrhagic stroke, with mediation proportions of 36.07%, 39.98%, and 25.34%, respectively. The mediating effect is pronounced in the male population and individuals below 65. Conclusion:Hyperuricemia is a risk factor for stroke, and hypertension partially mediates the effect of hyperuricemia on stroke.

Objective The potential mechanism of hepatotoxicity induced by rhubarb was preliminarily explored by network pharmacology and verified by cell experiments.Methods Based on network pharmacology,component collection and target prediction are carried out through multiple databases.PPI network construction,GO enrichment analysis and KEGG pathway analysis were combined with software to systematically predict the mechanism of hepatotoxicity induced by rhubarb.The pathway information predicted by network pharmacology was verified by primary hepatocyte experiments and Western blot experiments.Results The results of network pharmacology showed that RH was the main component of hepatotoxicity induced by rhubarb.Seventeen core targets of hepatotoxicity induced by rhubarb were obtained.KEGG results suggested that DNA damage and apoptosis were one of the key mechanisms of hepatotoxicity induced by rhubarb.The results of primary hepatocytes and Western blot showed that RH could inhibit the viability of primary hepatocytes in a time-dose dependent manner.ABT and SFP can significantly reduce the toxicity of RH on primary liver cells in mice,and RFP can increase the toxicity of RH to mouse primary liver cells.Upregulation of γ-H2AX and PARP-1 protein in primary liver cells of mice after treatment with different concentrations of RH.Conclusion RH in rhubarb can significantly inhibit the viability of mouse primary hepatocytes,and its toxicity to mouse primary hepatocytes is mainly caused by the metabolic activation of RH by CYP 2C9.RH can activate PARP-1 protein,phosphorylate H2AX,induce DNA damage and apoptosis in mouse primary hepatocytes.

【Objective】 To explore the safety of transrectal ultrasound-guided transperineal injection of sodium hyaluronate to expand the Dirichlet gap in laparoscopic radical prostatectomy. 【Methods】 A total of 14 healthy male purebred beagle dogs were selected and randomly divided into 2 groups, with 7 in either group.The control group was treated with conventional laparoscopic radical prostatectomy, while the experimental group was treated with laparoscopic radical prostatectomy after 2.5 mL sodium hyaluronate was injected into the Dirichlet gap under the guidance of transrectal ultrasound.The total operation time, prostate separation time, intraoperative blood loss and rectal status of the 2 groups were observed. 【Results】 After the injection of sodium hyaluronate into the Dirichlet gap between the prostate and the rectum, no rectal tissue was found in the prostate, and no obvious damage was found in the posterior rectum in either groups.The postoperative hemoglobin (HGB) was [(118.70±2.56) g/L vs.(122.10±2.19) g/L, P=0.02]; the total operation time was [(141.40±9.80) min vs.(119.10±9.16) min, P<0.05]; the prostate separation time was [(24.99±1.75) min vs.(16.64±2.34) min, P<0.05]; the amount of bleeding was [(47.43±4.32) mL vs.(34.86±5.18) mL, P<0.05] in the control group and experimental group. 【Conclusion】 Laparoscopic radical prostatectomy performed after 2.5 mL of sodium hyaluronate injection into the Dirichlet gap under the guidance of transrectal ultrasound can shorten the total operation time, the separation and resection time of the prostate, and reduce the amount of bleeding, which can improve and reduce the incidence of rectal injury, and prove the feasibility of this approach for prostatic cancer.

Objective:To evaluate the diagnostic accuracy of a noninvasive physiological parameter-based early sepsis screening model for elderly patients in comparison to the systemic inflammatory response syndrome(SIRS)and quick sequential organ failure assessment(qSOFA)scores.Methods:A retrospective study was conducted using data from the Medical Information Mart for Intensive Care Ⅳ(MIMIC-Ⅳ)database.The study focused on patients who were admitted to the intensive care unit(ICU)within 24 hours and were categorized into septic and non-septic groups based on the presence or absence of sepsis.Baseline data and patient outcomes were recorded.Additionally, the SIRS score and qSOFA scores within 24 hours of ICU admission were calculated.Physiological parameters that showed statistical significance in the univariate analysis included respiratory rate, heart rate, level of consciousness, body temperature, systolic blood pressure, and urine output.These parameters were then included in Logistic regression models.The specificity and sensitivity of the regression model for sepsis screening were calculated, and receiver operating characteristic(ROC)curves were plotted.The areas under the ROC curves(AUCs)of the screening model, SIRS, and qSOFA scoring systems were compared.Results:A total of 53 150 ICU hospitalization records were screened, and 23 681 patients with infection or suspected infection within 24 hours were included.Among them, 18 277 patients had sepsis.The 28-day mortality rate for septic patients was higher compared to non-septic patients(13.5% vs.5.1%, χ2=285.131, P<0.001).The baseline data within 24 hours showed significant differences between the two groups in terms of heart rate, respiratory rate, body temperature, state of consciousness, 24-hour urine output, and systolic blood pressure(all P<0.001).These variables were included in the regression equation: ∑β iX i=2.055+ 0.285(temperature: 0/1)+ 0.172(respiratory rate: 0/1)+ 0.073(heart rate: 0/1)+ 1.204(mental status: 0/1)-0.022(systolic blood pressure)+ 0.227(classification of urine output: 0/1/2), P=1/[1+ EXP(-∑β iX i)].The regression model diagnosed sepsis ROC area in young and middle-aged patients as 0.726(95% CI: 0.718 to 0.735), which was significantly higher than the SIRS score(0.585, 95% CI: 0.576 to 0.595)and the qSOFA score(0.676, 95% CI: 0.667 to 0.685)(both P<0.001).In elderly patients, the regression model diagnosed sepsis ROC area as 0.671(95% CI: 0.663 to 0.679), which was also significantly higher than the SIRS score(0.572, 95% CI: 0.563 to 0.580)and the qSOFA score(0.631, 95% CI: 0.623 to 0.639)(both P<0.001). Conclusions:The early sepsis diagnosis model, which utilizes noninvasive physiological parameters, has shown higher accuracy when compared to the SIRS and qSOFA scores.However, it is important to note that its accuracy is lower in elderly patients as compared to young and middle-aged patients.This indicates the necessity for further optimization of the model in order to improve its performance in diagnosing sepsis in the elderly.

Objective:To investigate whether malignant tumors are an independent risk factor for short-term mortality in elderly patients with sepsis in the intensive care unit(ICU), and to examine the dose-response relationship between the sequential organ failure assessment(SOFA)score and short-term mortality in this patient population.Methods:A retrospective analysis was conducted on elderly sepsis patients aged 80 and above from the Medical Information Mart for Intensive Care(MIMIC-Ⅳ)database spanning from 2008 to 2019.The patients were categorized into a tumor group and a non-tumor group based on the presence of malignant tumors, and a comparison was made between the baseline data and prognosis of these two groups.Furthermore, patients were classified into survival and mortality groups based on their ICU survival status within 28 days, and a comparison of baseline data was performed.Logistic regression analysis was employed to identify the risk factors associated with short-term mortality.Additionally, probability unit regression was utilized to model the dose-response relationship between the SOFA score and short-term mortality.Results:A total of 53 150 medical records were screened, identifying 5 126 elderly sepsis patients aged 80 and above.Among them, 754 had malignant tumors and 264 had metastatic tumors.The 28-day mortality rate in the tumor group was significantly higher than in the non-tumor group[26.79%(202/754) vs.18.85%(824/4 372), χ2=24.85, P<0.001].Logistic regression analysis revealed age( OR=1.073, 95% CI: 1.040-1.108, P<0.001), Charlson comorbidity index(CCI)excluding tumors( OR=1.134, 95% CI: 1.067-1.205, P<0.001), blood lactate concentration at ICU admission( OR=1.111, 95% CI: 1.048-1.179, P<0.001), mechanical ventilation( OR=1.603, 95% CI: 1.176-2.187, P=0.003), and SOFA score( OR=1.227, 95% CI: 1.182-1.273, P<0.001)as risk factors for short-term mortality.Conversely, CCI( OR=0.957, 95% CI: 0.867-1.057, P=0.380), use of vasoactive drugs( OR=1.370, 95% CI: 0.902-2.081, P=0.140), malignant tumors( OR=1.131, 95% CI: 0.449-2.848, P=0.794), and metastasis of malignant tumors( OR=1.799, 95% CI: 0.930-3.477, P=0.081)were not associated with short-term mortality.The dose-response curve illustrated that as the SOFA score increased, patients' 28-day mortality rate also rose, reaching 50% at a SOFA score of 11 and exceeding 80% at a score of 20. Conclusions:Malignant tumors and tumor metastasis do not appear to be independent risk factors for short-term mortality in elderly sepsis patients in the ICU.Instead, the short-term mortality rate of these patients seems to be correlated with the SOFA score in a dose-response manner.

Objective:To explore the predictive value of the prognostic nutritional index (PNI) in concurrently infected patients with acute-on-chronic liver failure (ACLF).Methods:220 cases with ACLF diagnosed and treated at the First Affiliated Hospital of Xi'an Jiaotong University from January 2011 to December 2016 were selected. Patients were divided into an infection and non-infection group according to whether they had co-infections during the course of the disease. Clinical data differences were compared between the two groups of patients. Binary logistic regression analysis was used to screen out influencing factors related to co-infection. The receiver operating characteristic curve was used to evaluate the predictive value of PNI for ACLF co-infection. The measurement data between groups were compared using the independent sample t-test and the Mann-Whitney U rank sum test. The enumeration data were analyzed using the Fisher exact probability test or the Pearson χ2 test. The Pearson method was performed for correlation analysis. The independent risk factors for liver failure associated with co-infection were analyzed by multivariate logistic analysis. Results:There were statistically significant differences in ascites, hepatorenal syndrome, PNI score, and albumin between the infection and the non-infection group ( P ?

Objective To investigate the effects and mechanisms of LINC00657 on oxidative glucose deprivation (OGD)-induced injury in mouse hippocampal neurons. Methods Mouse hippocampal neuron cell line HT22 was given OGD treatment to establish an injury model, with normally cultured HT22 cells as controls. The si-NC, si-LINC00657, microRNA(miR)-NC, and miR-224-3p mimics were transfected into HT22 cells, followed by OGD treatment. Co-transfection of si-LINC00657 and anti-miR-NC, or co-transfection of si-LINC00657 and anti-miR-224-3p, was performed in HT22 cells before OGD treatment. Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the relative expression levels of LINC00657 and miR-224-3p. CCK-8 assay and flow cytometry were used to detect cell viability and apoptosis rate, respectively. Kits were used to detect the activities of lactate dehydrogenase (LDH), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and the level of malondialdehyde (MDA). Dual-luciferase reporter gene assay was used to detect the effect of miR-224-3p overexpression on the luciferase activity of wild-type LINC00657 vector (WT-LINC00657) and mutant LINC00657 vector (MUT-LINC00657). Results Compared with controls, the expression of LINC00657 was upregulated and the expression of miR-224-3p was downregulated in OGD-induced HT22 cells (P < 0.05). Compared with transfection of si-NC or miR-NC, transfection of si-LINC00657 or miR-224-3p mimics resulted in increased cell viability, SOD activity, and GSH-Px activity, as well as decreased apoptosis rate, LDH activity, and MDA level(P < 0.05). Overexpression of miR-224-3p reduced the luciferase activity of WT-LINC00657 (P < 0.05). Compared with cells co-transfected with si-LINC00657 and anti-miR-NC, cells co-transfected with si-LINC00657 and anti-miR-224-3p showed decreased cell viability, increased apoptosis rate, increased LDH activity and MDA level, and decreased SOD and GSH-Px activities (P < 0.05). Conclusion Interference with LINC00657 can promote cell proliferation, inhibit apoptosis and oxidative stress response by upregulating miR-224-3p, thereby alleviating OGD-induced injury in mouse hippocampal neurons.