Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.

Ferroptosis is an emerging form of regulated cell death characterized by iron-dependent lipid peroxidation and the failure of the antioxidant system，which results in iron-dependent oxidative damage to the cell membrane. Ferroptosis is implicated in various biological processes，including cell proliferation，aging，and differentiation. The regulation of oxidative stress by ferroptosis is closely associated with the inactivation of glutathione peroxidase 4（Gpx4），dysfunction of the cysteine/glutamate antiporter System Xc-，the production of reactive oxygen species derived from oxidized polyunsaturated fatty acids，and alterations in lipid metabolism. Oxidative stress is a critical mechanism underlying the onset and progression of benign prostatic hyperplasia（BPH）and plays a pivotal role in its pathogenesis. Ferroptosis may regulate the occurrence and development of BPH by mediating lipid oxidative stress response.

Objective:To explore the impact of changes of myocardial infarct size on left ventricular adverse remodeling in patients with acute ST-segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (PCI).Methods:This was a prospective cohort study. The STEMI patients who underwent primary PCI in the First Medical Center of the Chinese People′s Liberation Army General Hospital, Beijing Anzhen Hospital, Hainan Hospital of the Chinese People′s Liberation Army General Hospital and Guangxi Yulin First People Hospital from January 1, 2017 to January 1, 2022 were enrolled. Cardiac magnetic resonance (CMR) was performed to dynamically assess the myocardial infarct size and calculate the rate of infarct size change between the acute phase (5 to 7 days post-primary PCI) and 6-month follow-up. The endpoint was left ventricular adverse remodeling which was defined as an increase of more than 20% in left ventricular end-diastolic volume (LVEDV) assessed by CMR at 6 months after primary PCI compared with LVEDV at 1 week after primary PCI. Based on serial CMR assessments, the patients were divided into left ventricular adverse remodeling group and non-remodeling group. The receiver operating characteristic (ROC) curve was used to evaluate the predictive performance of infarct size change for left ventricular adverse remodeling, and according to the optimal cutoff value, improved infarct size was defined as a decrease of >20% in the infarct size measured by CMR at 6 months after primary PCI compared with infarct size at 1 week after primary PCI. Multivariate logistic regression analysis was performed to identify the protective factors and risk factors for left ventricular adverse remodeling.Results:A total of 267 patients were enrolled, aged (58±11) years, with 234 males (87.6%). And 73 cases in the left ventricular remodeling group and 194 cases in the non-remodeling group. Infarct size assessed by CMR at 6 months after primary PCI decreased significantly compared with infarct size at 1 week after primary PCI in the left ventricular remodeling group ((23±13)% vs. (27±12)%, P=0.004), the same as in the non-remodeling group ((18±10)% vs. (23±10)%, P<0.001). The area under the ROC curve for the rate of infarct size change in predicting left ventricular remodeling was 0.735 (95% CI 0.670-0.799, P<0.001), a 20% reduction was the optimal cut-off value. Compared to the patients with non-improved infarct size, the incidence of left ventricular adverse remodeling was significantly lower in the patients with improved infarct size (18% (24/133) vs. 37% (49/134), P=0.001). Multivariate logistic regression analysis showed that improvement in IS was a protective factor for left ventricular adverse remodeling ( OR=0.376, 95% CI 0.236-0.721, P=0.002). Conclusion:Patients with STEMI who experience obvious reduction in infarct size after primary PCI have a significantly reduced risk of left ventricular adverse remodeling.

Objective To analyze the clinical characteristics of renal cell carcinoma patients with extracapsular segmental vein tumor thrombus during partial nephrectomy and to explore the clinical significance,thereby contributing to an advanced comprehension of the pathogenesis of cancer thrombus in renal cell carcinoma.Methods A retrospective analysis was conducted on the clinical data of 209 renal cell carcinoma patients(162 with T1a stage,47 with T1b stage)who underwent partial nephrectomy in our hospital during Sep.2023 and Jul.2025.Among them,8 patients with extracapsular segmental vein tumor thrombus were identified,and the clinical and pathological characteristics were analyzed.Results Among the 8 cases of extracapsular segmental vein tumor thrombus,1 was in T1a stage and 7 were in T1b stage.Preoperativc CT revealed roundish,solid renal masses with heterogeneous density on non-contrast scans,significant enhancement on contrast-enhanced scans,and markedly weaker enhancement in the renal parenchymal phase compared to normal renal tissue.The average tumor diameter was(4.9±0.2)cm,with clear boundaries and no evidence of vascular invasion.Postoperative pathology confirmed clear cell carcinoma in all cases,with International Society of Urological Pathology(ISUP)grades ranging from Ⅰ to Ⅳ,and all surgical margins were negative.After surgery,5 patients received adjuvant immunotherapy.In a median follow-up of 10.3(3.8-22.8)months,no tumor recurrence or metastasis was observed.Conclusion Renal cell carcinoma has a high propensity of vascular invasion,and even clinically staged T1 tumors may develop extracapsular segmental vein tumor thrombus.This finding is significant for clinical prognosis.

OBJECTIVE: Gastric cancer (GC) is one of the most common malignancies seen in clinic and requires novel treatment options. Morin is a natural flavonoid extracted from the flower stalk of a highly valuable medicinal plant Prunella vulgaris L., which exhibits an anti-cancer effect in multiple types of tumors. However, the therapeutic effect and underlying mechanism of morin in treating GC remains elusive. The study aims to explore the therapeutic effect and underlying molecular mechanisms of morin in GC. METHODS: For in vitro experiments, the proliferation inhibition of morin was measured by cell counting kit-8 assay and colony formation assay in human GC cell line MKN45, human gastric adenocarcinoma cell line AGS, and human gastric epithelial cell line GES-1; for apoptosis analysis, microscopic photography, Western blotting, ubiquitination analysis, quantitative polymerase chain reaction analysis, flow cytometry, and RNA interference technology were employed. For in vivo studies, immunohistochemistry, biomedical analysis, and Western blotting were used to assess the efficacy and safety of morin in a xenograft mouse model of GC. RESULTS: Morin significantly inhibited the proliferation of GC cells MKN45 and AGS in a dose- and time-dependent manner, but did not inhibit human gastric epithelial cells GES-1. Only the caspase inhibitor Z-VAD-FMK was able to significantly reverse the inhibition of proliferation by morin in both GC cells, suggesting that apoptosis was the main type of cell death during the treatment. Morin induced intrinsic apoptosis in a dose-dependent manner in GC cells, which mainly relied on B cell leukemia/lymphoma 2 (BCL-2) associated agonist of cell death (BAD) but not phorbol-12-myristate-13-acetate-induced protein 1. The upregulation of BAD by morin was due to blocking the ubiquitination degradation of BAD, rather than the transcription regulation and the phosphorylation of BAD. Furthermore, the combination of morin and BCL-2 inhibitor navitoclax (also known as ABT-737) produced a synergistic inhibitory effect in GC cells through amplifying apoptotic signals. In addition, morin treatment significantly suppressed the growth of GC in vivo by upregulating BAD and the subsequent activation of its downstream apoptosis pathway. CONCLUSION Morin suppressed GC by inducing apoptosis, which was mainly due to blocking the ubiquitination-based degradation of the pro-apoptotic protein BAD. The combination of morin and the BCL-2 inhibitor ABT-737 synergistically amplified apoptotic signals in GC cells, which may overcome the drug resistance of the BCL-2 inhibitor. These findings indicated that morin was a potent and promising agent for GC treatment. Please cite this article as: Wang Y, Sun XY, Ma FQ, Ren MM, Zhao RH, Qin MM, Zhu XH, Xu Y, Cao ND, Chen YY, Dong TG, Pan YF, Zhao AG. Morin inhibits ubiquitination degradation of BCL-2 associated agonist of cell death and synergizes with BCL-2 inhibitor in gastric cancer cells. J Integr Med. 2025; 23(3): 320-332.
Humans ; Flavonoids/therapeutic use* ; Stomach Neoplasms/pathology* ; Animals ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Cell Line, Tumor ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Ubiquitination/drug effects* ; Mice ; Drug Synergism ; Mice, Inbred BALB C ; Mice, Nude ; Xenograft Model Antitumor Assays ; Flavones

OBJECTIVE: To assess the efficacy of Qingda Granule (QDG) in ameliorating hypertension-induced cardiac damage and investigate the underlying mechanisms involved. METHODS: Twenty spontaneously hypertensive rats (SHRs) were used to develope a hypertension-induced cardiac damage model. Another 10 Wistar Kyoto (WKY) rats were used as normotension group. Rats were administrated intragastrically QDG [0.9 g/(kg•d)] or an equivalent volume of pure water for 8 weeks. Blood pressure, histopathological changes, cardiac function, levels of oxidative stress and inflammatory response markers were measured. Furthermore, to gain insights into the potential mechanisms underlying the protective effects of QDG against hypertension-induced cardiac injury, a network pharmacology study was conducted. Predicted results were validated by Western blot, radioimmunoassay immunohistochemistry and quantitative polymerase chain reaction, respectively. RESULTS: The administration of QDG resulted in a significant decrease in blood pressure levels in SHRs (P<0.01). Histological examinations, including hematoxylin-eosin staining and Masson trichrome staining revealed that QDG effectively attenuated hypertension-induced cardiac damage. Furthermore, echocardiography demonstrated that QDG improved hypertension-associated cardiac dysfunction. Enzyme-linked immunosorbent assay and colorimetric method indicated that QDG significantly reduced oxidative stress and inflammatory response levels in both myocardial tissue and serum (P<0.01). CONCLUSIONS Both network pharmacology and experimental investigations confirmed that QDG exerted its beneficial effects in decreasing hypertension-induced cardiac damage by regulating the angiotensin converting enzyme (ACE)/angiotensin II (Ang II)/Ang II receptor type 1 axis and ACE/Ang II/Ang II receptor type 2 axis.
Animals ; Drugs, Chinese Herbal/therapeutic use* ; Hypertension/pathology* ; Renin-Angiotensin System/drug effects* ; Rats, Inbred SHR ; Oxidative Stress/drug effects* ; Male ; Rats, Inbred WKY ; Blood Pressure/drug effects* ; Myocardium/pathology* ; Rats ; Inflammation/pathology*

OBJECTIVE: To explore the functional roles and underlying mechanisms of neferine in the context of angiotensin II (Ang II)-induced hypertension and vascular dysfunction. METHODS: Male mice were infused with Ang II to induce hypertension and randomly divided into treatment groups receiving neferine or a control vehicle based on baseline blood pressure using a random number table method. The hypertensive mouse model was constructed by infusing Ang II via a micro-osmotic pump (500 ng/kg per minute), and neferine (0.1, 1, or 10 mg/kg), valsartan (10 mg/kg), or double distilled water was administered intragastrically once daily for 6 weeks. A non-invasive blood pressure system, ultrasound, and hematoxylin and eosin staining were performed to assess blood pressure and vascular changes. RNA sequencing and network pharmacology were employed to identify differentially expressed transcripts (DETs) and pathways. Vascular ring tension assay was used to test vascular function. A7R5 cells were incubated with neferine for 24 h and then treated with Ang II to record the real-time Ca²⁺ concentration by confocal microscope. Immunohistochemistry (IHC) and Western blot were used to evaluate vasorelaxation, calcium, and the extracellular signal-regulated kinase (ERK)1/2 pathway. RESULTS: Neferine treatment effectively mitigated the elevation in blood pressure, pulse wave velocity, aortic thickening in the abdominal aorta of Ang II-infused mice (P<0.05). RNA sequencing and network pharmacology analysis identified 355 DETs that were significantly reversed by neferine treatment, along with 25 potential target genes, which were further enriched in multiple pathways and biological processes, such as ERK1 and ERK2 cascade regulation, calcium pathway, and vascular smooth muscle contraction. Further investigation revealed that neferine treatment enhanced vasorelaxation and reduced Ca²⁺-dependent contraction of abdominal aortic rings, independent of endothelium function (P<0.05). The underlying mechanisms were mediated, at least in part, via suppression of receptor-operated channels, store-operated channels, or voltage-operated calcium channels. Neferine pre-treatment demonstrated a reduction in intracellular Ca²⁺ release in Ang II stimulated A7R5 cells. IHC staining and Western blot confirmed that neferine treatment effectively attenuated the upregulation of p-ERK1/2 both in vivo and in vitro, which was similar with treatment of ERK1/2 inhibitor PD98059 (P<0.05). CONCLUSIONS Neferine remarkably alleviates Ang II-induced elevation of blood pressure, vascular dysfunction, and pathological changes in the abdominal aorta. This beneficial effect is mediated by the modulation of multiple pathways, including calcium and ERK1/2 pathways.
Animals ; Angiotensin II ; Male ; Benzylisoquinolines/therapeutic use* ; Network Pharmacology ; Blood Pressure/drug effects* ; Sequence Analysis, RNA ; Mice ; Hypertension/chemically induced* ; Mice, Inbred C57BL ; Calcium/metabolism*

Objective:To investigate the occurrence of malignancy in psoriatic arthritis (PsA) patients, and further explore the factors related to malignancy.Methods:Based on the PsA prospective follow-up cohort (PKUPsA-PC) in our center, we collected the demographics and clinical characteristics of patients who visited from January 2016 to January 2024, especially those regarding the malignant tumor. The clinical characteristics of patients with and without malignant tumor were compared through the method of non-parametric tests and chi-square tests. Multivariate logistic regression was applied to analyze the factors related to malignant tumors.Results:Three hundred and eighty two patients with PsA were enrolled. The median follow-up duration was 6.0 (2.8,12.8) years. Twenty two (5.8%) patients were complicated with malignant tumors. The median age of confirmed tumors was 56.4 (45.8, 67.3) years. Among them, 14 (63.6%) patients were female, and 16 (72.7%) patients had malignant tumors after the diagnosis of PsA. As for the tumor types, solid tumors were great majority (21 cases, 95.5%), including breast cancer (7 cases), urinary system tumors (5 cases), skin cancer (3 cases), colorectal/rectal cancer (2 cases), and thyroid cancer, liver cancer, endometrial carcinoma in situ, retroperitoneal malignant tumor (1 case respectively). There was only 1 (4.5%) patient with hematological tumor (chronic lymphocytic leukemia). Compared with patients without malignant tumors, PsA patients with malignancy had a higher proportion of women (63.6% vs. 40.8%, χ2=4.42, P=0.035), older age [56.4 (45.8, 67.3)years vs. 47.0 (36.0, 56.6) years, Z=-2.94, P=0.003], had a longer duration of psoriasis [20.0 (11.2, 33.5)years vs. 14.0 (6.0, 23.0) years, Z=-2.02, P=0.043], a longer duration of arthritis [8.0 (4.0, 17.0)years vs. 3.0 (1.0, 7.0) years, Z=-2.65, P=0.008], and a higher proportion of HLA-B27 positivity (25.0% vs. 4.4%, χ2=3.98, P=0.046). Age[ OR(95% CI)=1.056(1.008, 1.107), P=0.023], duration of PsA [ OR(95% CI)=1.051( 1.068, 1.106), P=0.010], and HLA-B27 positivity [ OR(95% CI)=5.086(1.278, 20.238), P=0.021] were the factors related to the occurrence of malignancy in PsA patients. Conclusion:Malignancy is not rare in PsA patients. Breast cancer, urinary system tumors and skin cancer are relatively common. PsA patients with older age, longer duration of PsA and positive HLA-B27 are more likely to have malignancy, which arouses more alert.

Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.

Objective To analyze the clinical characteristics of renal cell carcinoma patients with extracapsular segmental vein tumor thrombus during partial nephrectomy and to explore the clinical significance,thereby contributing to an advanced comprehension of the pathogenesis of cancer thrombus in renal cell carcinoma.Methods A retrospective analysis was conducted on the clinical data of 209 renal cell carcinoma patients(162 with T1a stage,47 with T1b stage)who underwent partial nephrectomy in our hospital during Sep.2023 and Jul.2025.Among them,8 patients with extracapsular segmental vein tumor thrombus were identified,and the clinical and pathological characteristics were analyzed.Results Among the 8 cases of extracapsular segmental vein tumor thrombus,1 was in T1a stage and 7 were in T1b stage.Preoperativc CT revealed roundish,solid renal masses with heterogeneous density on non-contrast scans,significant enhancement on contrast-enhanced scans,and markedly weaker enhancement in the renal parenchymal phase compared to normal renal tissue.The average tumor diameter was(4.9±0.2)cm,with clear boundaries and no evidence of vascular invasion.Postoperative pathology confirmed clear cell carcinoma in all cases,with International Society of Urological Pathology(ISUP)grades ranging from Ⅰ to Ⅳ,and all surgical margins were negative.After surgery,5 patients received adjuvant immunotherapy.In a median follow-up of 10.3(3.8-22.8)months,no tumor recurrence or metastasis was observed.Conclusion Renal cell carcinoma has a high propensity of vascular invasion,and even clinically staged T1 tumors may develop extracapsular segmental vein tumor thrombus.This finding is significant for clinical prognosis.