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

Background and aim:Hepatic ischemia-reperfusion injury(IRI)is a significant challenge in liver trans-plantation,trauma,hypovolemic shock,and hepatectomy,with limited effective interventions available.This study aimed to investigate the role of leukocyte cell-derived chemotaxin 2(LECT2)in hepatic IRI and assess the therapeutic potential of Lect2-short hairpin RNA(shRNA)delivered through adeno-associated virus(AAV)vectors. Materials and methods:This study analyzed human liver and serum samples from five patients under-going the Pringle maneuver.Lect2-knockout and C57BL/6J mice were used.Hepatic IRI was induced by clamping the hepatic pedicle.Treatments included recombinant human LECT2(rLECT2)and AAV-Lect2-shRNA.LECT2 expression levels and serum biomarkers including alanine aminotransferase(ALT),aspartate aminotransferase(AST),creatinine,and blood urea nitrogen(BUN)were measured.Histological analysis of liver necrosis and quantitative reverse-transcription polymerase chain reaction were performed. Results:Serum and liver LECT2 levels were elevated during hepatic IRI.Serum LECT2 protein and mRNA levels increased post reperfusion.Lect2-knockout mice had reduced weight loss;hepatic necrosis;and serum ALT,AST,creatinine,and BUN levels.rLECT2 treatment exacerbated weight loss,hepatic necrosis,and serum biomarkers(ALT,AST,creatinine,and BUN).AAV-Lect2-shRNA treatment significantly reduced weight loss,hepatic necrosis,and serum biomarkers(ALT,AST,creatinine,and BUN),indicating thera-peutic potential. Conclusions:Elevated LECT2 levels during hepatic IRI increased liver damage.Genetic knockout or shRNA-mediated knockdown of Lect2 reduced liver damage,indicating its therapeutic potential.AAV-mediated Lect2-shRNA delivery mitigated hepatic IRI,offering a potential new treatment strategy to enhance clinical outcomes for patients undergoing liver-related surgeries or trauma.

Objective:To assess the efficiency and safety of combining lenvatinib with DEB-TACE for the treatment of unresectable large hepatocellular carcinoma,accompanied by PVTT,in order to provide insights into its potential as a therapeutic approach.Method:Patients with hepa-tocellular carcinoma and portal vein tumor thrombus,who were diagnosed and treated at Linyi Can-cer Hospital between June 2019 and June 2021,were chosen as the subjects of this study.Patient allocation into the experimental group(23 cases)and control group(27 cases)was based on indi-vidual preferences,ensuring a random distribution of participants.The DEB-TACE treatment was administered to the control group,while the experimental group received a combination of DEB-TACE and lenvatinib.The effectiveness of lenvatinib was assessed in the immediate post-surgery period,the patients'survival was monitored,and any associated side effects were documented.Result:3 months after treatment,the objective remission rates of the experimental group and the control group were 91.31％and 66.67％,and the disease control rates were 100％and 77.78％.The difference was statistically significant(P＜0.05).3 months after treatment,the regression rates of tumor thrombus in the experimental group and the control group were 60.87％and 29.63％,the difference was statistically significant(P＜0.05).The progression free survival time of the experi-mental group and the control group was 11 months and 8 months,the difference was statistically significant(P＜0.05);The median survival time of the experimental group and the control group was 20 months and 14 months,and the difference was statistically significant(P＜0.05).The main ad-verse reactions of the experimental group were hypertension,diarrhea,hand foot syndrome,rash,fatigue,loss of appetite,etc.,all of which were less than or equal to grade 3,and could be basically relieved after symptomatic treatment.Conclusion:The combination of DEB-TACE and lenvatinib is proven to be a safe and well-tolerated treatment for unresectable large hepatocellular carcinoma with portal vein tumor thrombus.This therapy not only effectively controls tumor progression but also prolongs survival time.

OBJECTIVE: To explore clinical effect of arthroscopic modification of triangular fibrocartilage complex (TFCC) combined with oblique osteotomy shortening of distal ulna in treating ulna impact syndrome. METHODS: A retrospective analysis was performed on 49 patients with ulnar impingement syndrome admitted from 2017 to 2021, 3 patients were lost to follow-up, and 46 patients were finally included in study, including 23 males and 23 females, aged from 21 to 53 years old with an average of (36.5±3.3) years old. The patients were divided into TFCC group and control group according to different operation methods. Twenty-four patients in TFCC group, including 13 males and 11 females, aged from 21 to 53 years old with an average of (36.5±3.2) years old;10 patients on the left side and 14 patients on the right side;arthroscopic TFCC trimming combined with oblique osteotomy shortening of distal ulna was performed. Twenty-two patients in control group, including 10 males, 12 females, aged from 21 to 53 years old with an average of (36.5±3.3) years old;13 patients on the left side, 9 patients on the right side; oblique osteotomy of distal ulna was performed. Operative time, hospital stay, intraoperative bleeding and osteotomy healing time between two groups were observed and compared. Cooney wrist function score and visual analogue scale (VAS) were used to evaluate improvement of wrist function and pain before and 12 months after operation, respectively. The variation values of ulna and grip strength were compared. RESULTS: The follow-up time of TFCC group ranged from 12 to 21 months with an average of (15.10±2.67) months, and that of control group ranged from 12 to 20 months with an average of (15.06±2.81) months, there was no statistical significance between two groups (P>0.05). Operative time, osteotomy healing time, intraoperative bleeding and hospital stay in TFCC group were (68.51±13.50) min, (16.21±1.16) weeks, (25.13±4.22) ml and (7.35±1.20) d, respectively;while control group were (45.65±5.64) min, (17.46±2.06) weeks, (24.61±5.10) ml and (7.51±1.13) d, respectively; there were statistically significant differences in operative time and osteotomy healing time between two groups (P<0.05). There were no significant differences in intraoperative bleeding and hospital stay between two groups(P>0.05). There were no significant differences in total score and scores of Cooney wrist joint function between two groups before operation(P>0.05). Pain, functional status, range of motion, grip strength and Cooney wrist function score in TFCC group were higher than those in control group at 12 months after operation (P<0.05). According to Cooney wrist joint function score at 12 months after operation, 16 patients got excellent results, 6 good, and 2 fair in TFCC group; while 7 excellent, 11 good and 4 fair in control group;there was no significant difference between two groups (P>0.05). However, the proportion of wrist function recovery in TFCC group was higher than that in control group (P>0.05). At 12 months after operation, VAS of TFCC group (3.41±0.16) was lower than that of control group(3.52±0.13), P<0.005. There was no significant difference in ulnar variation between TFCC group and control group(P>0.05). The grip strength of TFCC group (93.6±10.1) % was better than that of control group (83.5±10.3) % (P<0.005). CONCLUSION Compared with oblique osteotomy shortening of distal ulna, TFCC trimming combined with oblique osteotomy shortening of distal ulna took longer to treat ulna collision syndrome, but the osteotomy healing time was shortened and wrist joint function was improved, especially pain, ulna variation, grip strength and motion were significantly improved.
Humans ; Male ; Female ; Adult ; Triangular Fibrocartilage/surgery* ; Osteotomy/methods* ; Ulna/surgery* ; Middle Aged ; Arthroscopy/methods* ; Retrospective Studies ; Young Adult

Humans ; Mitral Valve Stenosis/surgery* ; Transcatheter Aortic Valve Replacement ; Dilatation ; Catheterization ; Aortic Valve Stenosis/surgery* ; Aortic Valve/surgery* ; Treatment Outcome ; Heart Valve Prosthesis ; Heart Valve Prosthesis Implantation

Humans ; Mitral Valve Stenosis/surgery* ; Transcatheter Aortic Valve Replacement ; Dilatation ; Catheterization ; Aortic Valve Stenosis/surgery* ; Aortic Valve/surgery* ; Treatment Outcome ; Heart Valve Prosthesis ; Heart Valve Prosthesis Implantation

OBJECTIVE: To observe clinical efficacy of percutaneous endoscopic transforaminal discectomy (PETD) and target radioffrequency thermal coblation nucleoplasty(CN) on inclusive lumbar disc herniation(LDH) in different age groups, and provide a basis for clinical formulation of precise and individualized treatments. METHODS: A retrospective analysis of 219 patients with lumbar disc herniation treated with PETD and CN between January 2018 and June 2021 was performed, in which 107 patients were treated with PETD and 112 with CN. Patients were stratified by age into young group(≤45 years old), middle-aged group(>45 years old and <60 years old) and older group(≥60 years old). Before treatment, 3 days, 1 month and 6 months after treatment, visual analogue scale (VAS), Japanese Orthopaedic Association (JOA) score, infrared thermal imaging temperature difference (△T) and lumbar range of motion (ROM) were evaluated and clinical efficacy were compared in the different age groups between two treatment methods. RESULTS: ①VAS and JOA score outcomes, in the same age group and the same treatment method, the VAS and JOA scores at different time points postoperatively were obviously improved (P<0.05). For the same age group and the different treatment methods, the older group had lower VAS and higher JOA scores after PETD than after CN (P<0.05), and there was no significant difference between the young group and middle-aged group (P>0.05). There was no significant difference in VAS and JOA scores at the same time between age groups by PETD treatment (P>0.05). The VAS was higher and the JOA score was lower in older group than in young group and middle-aged group at 1, 6 months after CN treatment(P<0.05). ②△T and ROM outcomes, in the same age group and same treatment method, postoperative △T and ROM at different time points were obviously improved(P<0.05). There was no significant difference in △T between two methods of PETD and CN at the same age(P>0.05), there was no significant difference in ROM between young group and middle-aged group(P>0.05), ROM was higher after PETD treatment than after CN treatment(P<0.05). There was no significant difference in △T and ROM at the same time between age groups by PETD treatment(P>0.05). There was no significant difference in △T between age groups by CN treatment, but the ROM was smaller in older group than in young group and middle-aged group after CN treatment(P<0.05). CONCLUSION Both PETD and CN for inclusive LDH have good efficacy, the curative benefit for older patients receiving PETD within 6 months after surgery more than CN, and CN is more appropriate for young and middle-aged patients.
Middle Aged ; Humans ; Aged ; Intervertebral Disc Displacement/surgery* ; Retrospective Studies ; Lumbar Vertebrae/surgery* ; Diskectomy, Percutaneous/methods* ; Treatment Outcome ; Endoscopy/methods* ; Diskectomy/methods*

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female ; Humans ; Adolescent ; SARS-CoV-2 ; Smell ; COVID-19/complications* ; Cross-Sectional Studies ; COVID-19 Vaccines ; Incidence ; Olfaction Disorders/etiology* ; Taste Disorders/etiology* ; Prognosis

Objective:To investigate the long term outcome of artificial urinary sphincter implantation for patients with stress urinary incontinence.Methods:The data of 46 patients who underwent artificial urethral sphincter implantation in China Rehabilitation Research Center from April 2002 to April 2022 were retrospectively analyzed.The patients’ age ranged from 19-80 years old (median 45.6 years). There were 45 males and 1 female. The history of illness was 8 months to 33 years. The patients category were urethral injuries associated urinary incontinence ( n=24), neurogenic urinary incontinence ( n=9) and post-prostatectomy incontinence ( n=13). Preoperative daily pad usage was 3.5±1.0. The impact of incontinence on the quality of life (QOL)measured by the visual analogue scale (VAS)was 7.1±1.2. All 46 patients underwent artificial urethral sphincter implantation, of which 20 patients were treated with anticholinergic drugs (5 cases) or urinary tract related surgery (urethral stenosis incision in 2 cases, sphincterectomy in 3 cases, urethral dilation in 5 cases, urethral calculus lithotripsy in 1 case, and augmentation cystoplasty in 4 cases) before artificial urethral sphincter implantation. Of the 45 male patients, 25 patients had the transperineal approach and 20 had the trans-scrotal approach. The female case had a trans-retropubic approach. Different cuffs size was used based on individual circumference of bulbar urethra (45 male cases: 4.5cm in 16 cases, 4.0cm in 29 cases; one female case: 8.0cm). Long-term surgical efficacy was evaluated. Assessments included postoperative urinary continence (socially continent: one pad per day or less; complete dry: wearing no pads), artificial urinary sphincter status and complications. The influences of patients of different etiologies, surgical approaches and cuff size on surgical results were compared. Results:The mean follow-up time was 7.1 years ranged from 6 months to 19 years. At the latest visit, 32 patients (69.6%) maintained the primary functional artificial urinary sphincter. Three patients (6.5%) had artificial urinary sphincter revisions and maintained continence with the new device. 11 patients (23.9%) removed the artificial urinary sphincter because of post-complications. Thirty-five patients were socially continent, of which 16 patients were totally dry, leading to the overall social continent rate as 76.1%(35/46). There was a significant reduction in pad usage to 1.2±0.6 diapers per day ( P<0.001). The impact of incontinence on the QOL measured by the VAS dropped to 2.6±1.9 ( P<0.001). The complication rate was 32.6%(15/46), including infections ( n=4), erosions ( n=5), mechanical failure ( n=3), dysurie ( n=2) and urethral atrophy ( n=1). There were no significant differences in social continent rate between patients with different etiologies[75.0%(18/24)vs. 66.7%(6/9) vs. 84.6%(11/13)], perioperative complications [37.5%(9/24)vs. 33.3%(3/9) vs. 23.1%(3/13)] and device re-intervention rate[37.5%(9/24) vs. 33.3%(3/9)vs. 15.4%(2/13)]. There were no statistically significant differences in postoperative complete dry rate [32%(8/25)vs. 40%(8/20), P=0.76] and postoperative device failure free rate [60%(15/25)vs. 80%(16/20), P=0.20] between trans-perineal group and trans-scrotal group. There was no statistically significant difference in postoperative social continent rate between 4.5cm cuff and 4.0 cuff[75%(12/16) vs. 65.5%(19/29), P=0.74]. Conclusions:Artificial urethral sphincter implantation is an effective treatment for stress urinary incontinence due to intrinsic sphincter deficiency. There was no difference in the continent rate and complication rate between patients of different etiologies, different surgical approaches and cuff size selection.