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 explore the value of catheter-based adrenal ablation in treating Cushing's syndrome (CS)-associated hypertension. Methods: A clinical study was conducted in patients with CS, who received catheter-based adrenal ablation between March 2018 and July 2023 in Daping Hospital. Parameters monitored were blood pressure (outpatient and 24-hour ambulatory), body weight, clinical characteristics, serum cortisol and adrenocorticotropic hormone (ACTH) at 8 am, 24-hour urinary free cortisol (24 h UFC), fasting blood glucose and postoperative complications. Procedure effectiveness was defined as blood pressure returning to normal levels (systolic blood pressure<140 mmHg (1 mmHg=0.133 kPa) and diastolic blood pressure<90 mmHg), cortisol and 24 h UFC returning to normal and improvement of clinical characteristics. The parameters were monitored during follow up in the outpatient department at 1, 3, 6, and 12 months after catheter-based adrenal ablation. Results: A total of 12 patients (aged (40.0±13.2) years) were reviewed. There were 5 males, with 5 cases of adenoma and 7 with hyperplasia from imaging studies. Catheter-based adrenal ablation was successful in all without interruption or surgical conversion. No postoperative complication including bleeding, puncture site infection, adrenal artery rupture or adrenal bleeding was observed. The mean follow up was 28 months. Compared to baseline values, body weight declined to (59.48±11.65) kg from (64.81±10.75) kg (P=0.008), fasting blood glucose declined to (4.54±0.83) mmol from (5.53±0.99) mmol (P=0.044), outpatient systolic blood pressure declined to (128±21) mmHg from (140±19) mmHg (P=0.005), diastolic blood pressure declined to (78±10) mmHg from (86±11) mmHg (P=0.041), and the mean ambulatory daytime diastolic blood pressure declined to (79±12) mmHg from (89±8) mmHg (P=0.034). Catheter-based adrenal ablation in 8 patients was defined as effective with their 24 h UFC significantly reduced after the procedure (1 338.41±448.06) mmol/L from (633.66±315.94) mmol/L, P=0.011). The change of 24 h UFC between the effective treatment group and ineffective group was statistically significant (P=0.020). The postoperative systolic blood pressure in the treated adenoma group was significantly lower than those of hyperplasia group (112±13) mmHg vs. (139±20) mmHg, P=0.026). Conclusions: For patients with CS-associated hypertension who are unwilling or unable to undergo surgical treatment, catheter-based adrenal ablation could improve the blood pressure and cortisol level. Catheter-based adrenal ablation could be a safe, effective, and minimally invasive therapy. However, our results still need to be validated in further large-scale studies.
Male ; Humans ; Cushing Syndrome/complications* ; Hydrocortisone ; Adrenal Gland Neoplasms/surgery* ; Feasibility Studies ; Blood Glucose ; Hyperplasia/complications* ; Hypertension/complications* ; Adenoma/complications* ; Body Weight ; Catheters/adverse effects*

Objective: To explore the value of catheter-based adrenal ablation in treating Cushing's syndrome (CS)-associated hypertension. Methods: A clinical study was conducted in patients with CS, who received catheter-based adrenal ablation between March 2018 and July 2023 in Daping Hospital. Parameters monitored were blood pressure (outpatient and 24-hour ambulatory), body weight, clinical characteristics, serum cortisol and adrenocorticotropic hormone (ACTH) at 8 am, 24-hour urinary free cortisol (24 h UFC), fasting blood glucose and postoperative complications. Procedure effectiveness was defined as blood pressure returning to normal levels (systolic blood pressure<140 mmHg (1 mmHg=0.133 kPa) and diastolic blood pressure<90 mmHg), cortisol and 24 h UFC returning to normal and improvement of clinical characteristics. The parameters were monitored during follow up in the outpatient department at 1, 3, 6, and 12 months after catheter-based adrenal ablation. Results: A total of 12 patients (aged (40.0±13.2) years) were reviewed. There were 5 males, with 5 cases of adenoma and 7 with hyperplasia from imaging studies. Catheter-based adrenal ablation was successful in all without interruption or surgical conversion. No postoperative complication including bleeding, puncture site infection, adrenal artery rupture or adrenal bleeding was observed. The mean follow up was 28 months. Compared to baseline values, body weight declined to (59.48±11.65) kg from (64.81±10.75) kg (P=0.008), fasting blood glucose declined to (4.54±0.83) mmol from (5.53±0.99) mmol (P=0.044), outpatient systolic blood pressure declined to (128±21) mmHg from (140±19) mmHg (P=0.005), diastolic blood pressure declined to (78±10) mmHg from (86±11) mmHg (P=0.041), and the mean ambulatory daytime diastolic blood pressure declined to (79±12) mmHg from (89±8) mmHg (P=0.034). Catheter-based adrenal ablation in 8 patients was defined as effective with their 24 h UFC significantly reduced after the procedure (1 338.41±448.06) mmol/L from (633.66±315.94) mmol/L, P=0.011). The change of 24 h UFC between the effective treatment group and ineffective group was statistically significant (P=0.020). The postoperative systolic blood pressure in the treated adenoma group was significantly lower than those of hyperplasia group (112±13) mmHg vs. (139±20) mmHg, P=0.026). Conclusions: For patients with CS-associated hypertension who are unwilling or unable to undergo surgical treatment, catheter-based adrenal ablation could improve the blood pressure and cortisol level. Catheter-based adrenal ablation could be a safe, effective, and minimally invasive therapy. However, our results still need to be validated in further large-scale studies.
Male ; Humans ; Cushing Syndrome/complications* ; Hydrocortisone ; Adrenal Gland Neoplasms/surgery* ; Feasibility Studies ; Blood Glucose ; Hyperplasia/complications* ; Hypertension/complications* ; Adenoma/complications* ; Body Weight ; Catheters/adverse effects*

Objective: To examine the clinical feasibility of mixed reality navigation (MRN) technology based on multimodal imaging for the resection of intracranial eloquent lesions. Methods: Fifteen patients with intracranial eloquent lesions admitted to the Department of Neurosurgery, the First Medical Center, People's Liberation Army General Hospital from September 2020 to September 2021 were retrospectively enrolled. There were 7 males and 8 females, aged (50±16) years (range: 16 to 70 years). Postoperative pathological diagnosis included meningioma (n=7), metastatic carcinoma (n=3), cavernous hemangioma, glioma, ependymoma, aneurysmal changes and lymphoma (n=1, respectively). The open-source software was used to perform the three-dimensional visualization of preoperative images, and the self-developed MRN system was used to perform the fusion and interaction of multimodal images, so as to formulate the surgical plan and avoid damaging the eloquent white matter fiber tracts. Traditional navigation, intraoperative ultrasound and fluorescein sodium angiography were used to determine the extent of lesion resection. The intraoperative conditions of MRN-assisted surgery were analyzed, and the setup time and localization error of MRN system were measured. The changes of postoperative neurological function were recorded. Results: MRN based on multimodal imaging was achieved in all patients. The MRN system setup time (M(IQR)) was 36 (12) minutes (range: 20 to 44 minutes), and the localization error was 3.2 (2.0) mm (range: 2.6 to 6.7 mm). The reliability of eloquent white matter fiber tracts localization based on MRN was rated as "excellent" in 11 cases, "medium" in 3 cases, and "poor" in 1 case. There were no perioperative death and no new impairment in motor, language, or visual functions after operation. Transient limb numbness occurred in 1 patient after operation, and recovered to the preoperative state in 2 weeks after operation. Conclusion: The MRN system based on multimodal imaging can improve the surgical accuracy and safety, and reduce the incidence of iatrogenic neurological dysfunction.
Humans ; Augmented Reality ; Reproducibility of Results ; Retrospective Studies ; Multimodal Imaging

OBJECTIVE: To investigate the effects of nuclear transcription factor-κB(NF-κB)/amide adenine dinucleotide phosphate oxidase 1(NOX1) signaling pathway in tumor necrosis factor-α(TNF-α) induced apoptosis of A549 cells. METHODS: i) A549 cells were stimulated with TNF-α at the concentrations of 0.00, 0.25, 0.50, and 1.00 nmol/L. CCK-8 assay was used to detect the cell viability to screen the optimal stimulating concentration of TNF-α. ii) A549 cells at logarithmic growth stage were randomly divided into four groups, the control group, the TNF-α group, the BAY11-7082(NF-κB inhibitor) group and the TNF-α+BAY11-7082 group. The cells in the control group were not treated. The TNF-α and BAY11-7082 groups were stimulated with 0.50 nmol/L TNF-α and 5 μmol/L BAY11-7082, respectively. The TNF-α+BAY11-7082 group was stimulated by both TNF-α and BAY11-7082. After 24 hours of culture, the cell survival rate was detected by CCK-8 assay. Flow cytometry was used to detect cell apoptotic rate, and Western blotting was used to detect the relative expression of NF-κB(p65) and NOX1 proteins. RESULTS: i) When A549 cells were stimulated with TNF-α at the concentration of 0.50 nmol/L, the cell proliferative activity was reduced and the cell apoptosis was promoted. This concentration was selected as the stimulation dose of TNF-α in subsequent experiments. ii) The survival rate of A549 cells in the TNF-α group decreased(P<0.05), the apoptotic rate and the protein expressions of NF-κB(p65) and NOX1 increased in TNF-α group(all P<0.05) compared with the control group. In BAY11-7082 group, the survival rate and the relative expression of NF-κB(p65) and NOX1 of A549 cells were decreased(all P<0.05), and the apoptotic rate of A549 cells was increased(P<0.05) compared with the control group. A549 cells in TNF-α+BAY11-7082 group changed from a long spindle shape to an irregular one. The cell survival rate increased(P<0.05), the apoptotic rate and the relative expression of NF-κB(p65) and NOX1 decreased(all P<0.05) compared with the TNF-α group. CONCLUSION: NF-κB/NOX1 signaling pathway is involved in A549 cells apoptosis induced by TNF-α.

OBJECTIVE: To investigate the expression of CD123 in patients with acute myeloid leukemia (AML) and its relationship between clinical features, concomitant fusion gene or gene mutation, efficacy and prognosis. METHODS: 365 patients with newly diagnosed AML (except M3) treated in the First Affiliated Hospital of Zhengzhou University were enrolled and retrospective analysis, and multi-parameter flow cytometry was performed to detect the expression of CD123 in myeloid leukemia cell population. CD123≥20% was defined as positive. Clinical features, concomitant fusion gene or gene mutation, efficacy and prognosis of CD123 RESULTS: The positive rate of CD123 in 365 newly diagnosed AML patients was 38.9%. Compared with the CD123 CONCLUSION CD123 positive indicates that AML patients have higher tumor burden and are more difficult to reach remission. It is an independent risk factor for OS and EFS in patients with normal karyotype and intermediate risk, which is important to evaluate the prognosis of patients with AML without specific prognostic marker.
Humans ; Interleukin-3 Receptor alpha Subunit ; Karyotype ; Leukemia, Myeloid, Acute/genetics* ; Mutation ; Patients ; Prognosis ; Retrospective Studies

OBJECTIVE: To evaluate the safety and efficacy of allogeneic natural killer (NK) cells in the treatment of primary hepatocellular carcinoma (HCC), and to elucidate the mechanism of NK cells therapy. METHODS: Twenty-one patients with primary HCC treated with allogeneic NK cells at the Fifth Medical Center of the PLA General Hospital were followed up for 1 year. Peripheral blood mononuclear cells (PBMCs) were isolated from patient-related donors and cultured in vitro for 15 days and infused to the patients in two consecutive days. Clinical data and laboratory data were collected and analyzed, including survival, clinical features, imaging changes, hematology, immunology, and biochemical indicators to evaluate the safety and efficacy of allogeneic NK cell therapy. The changes of peripheral blood lymphocyte subsets after treatment were also analyzed to explore the possible anti-tumor mechanisms. RESULTS: (1) Of the 21 patients with primary HCC, 11 patients were treated once, 5 patients were treated twice, and 5 patients were treated 3 times. After allogeneic NK cells infusion, 10 patients had fever, 1 patient had slight hepatalgia and 1 patient had slight headache, no other adverse events occurred including acute and chronic graft-versus-host disease (GVHD). They resolved spontaneously within 8 hours without other treatment. (2) The total disease control rate was 76.2% during one-year follow-up. Among them, the patients with Barcelona clinic liver cancer (BCLC) stage A had a disease control rate of 100%, stable disease (SD) in 10 cases; BCLC stage B patients had a disease control rate of 60%, partial response (PR) in 1 case, and SD 2 in cases; BCLC stage C patients had a disease control rate of 50%, complete response (CR) in 1 case, and 2 cases of PR. (3) The frequencies of NK cells and CD8+ T cells in peripheral blood were significantly lower than that before at 24 hours after treatment, and the frequencies of CD4+ T cells and CD4/CD8 were significantly higher than the baseline. CONCLUSION Allogeneic NK cells have good safety and efficacy in the treatment of primary HCC. The anti-tumor effect of the allogeneic NK cells may play an important role in the activation of the patient's natural immune system and delay disease progression, suggesting that allogeneic NK cells combined with sorafenib may be a very effective treatment for advanced HCC, and further large-sample multicenter randomized controlled clinical trials are needed to validate this result.
Carcinoma, Hepatocellular ; Graft vs Host Disease ; Humans ; Killer Cells, Natural ; Leukocytes, Mononuclear ; Liver Neoplasms

Objective Studies are rarely reported on how to avoid complement system attack during the transplantation of bone marrow mesenchymal stem cells (BMSCs).We explored the effect of the overexpression of CD59 on complement membrane attack-induced damage to rat BMSCs (rBMSCs) during autologous transplantation.Methods BMSCs from SD rats were cultured and treated with CD59 overexpression plasmid or rBMSC empty vector or left untreated,followed by detection of the expression of CD59 in the rBMSCs by flow cytometry.Then the rBMSCs were incubated with autologous rat serum (ARS),inactivated ARS (iARS),CD59+ARS,or CD59+iARS or not incubated.The cytotoxicity of the serum complement on the rBMSCs was observed by PI staining and the apoptosis of the rBMSCs determined by flow cytometry.Results The expression of CD59 was significantly higher in the rBMSCs treated with CD59 than in those untreated (7,4.9％ vs 50.5％,P＜0.05).The apop tosis rate was remarkably lower in the rBMSCs not incubated ([8.4± 1.1] ％) and those incubated with CD59+ARS ([19.1 ±3.1] ％) than in those incubated with ARS ([40.3±4.3] ％) (P＜0.05).The deposition of the complement membrane attack complex was significantly decreased in the rBMSCs not incubated (50.1％) and those incubated with CD59+ARS (71.0％) as compared with those incubated with ARS (99.7％) (P＜0.05).The apoptosis rate of the rBMSCs treated with CD59 was markedly lower than that of those left untreated (P＜0.05).Conclusion The overexpression of CD59 inhibits the damage induced by complement to rBMSCs by reducing the formation of the complement membrane attack complex during autologous transplantation.

OBJECTIVETo evaluate the objectivity and comprehensiveness of Response Evaluation Criteria of Traditional Chinese Medicine for Solid Tumor (Draft, REC-TCM-ST) in application of Chinese medicine therapeutic effect in patients with advanced non-small cell lung cancer (NSCLC).

METHODSA retrospective clinical research was used in 104 NSCLC patients in stages of III-IV, 53 cases were in Chinese medicine (CM) group and 51 cases were in Western medicine (WM) group. The therapeutic effect of the two groups was evaluated with both REC-TCM-ST and Response Evaluation Criteria in Solid Tumor (RECIST). Kaplan-Meier method was used to analyze the survival time. Kappa test method was used to test the consistency of the two kinds of evaluation results.

RESULTSAccording to REC-TCM-ST, the effective rate on relieving tumor mass in the CM group was significantly lower than that in the WM group (P<0.05), but there was no significant difference in tumor-mass stable rate (P>0.05); the symptom of weakness in the CM group was improved significantly, indicating better therapeutic effect than that in the WM group (P<0.01). Karnofsky score in the CM group was significantly better than that in the WM group (P<0.01). In terms of survival conditions, the median survival time and the survival rate of 6 months, 1 year and 2 years of the CM group were higher than the WM group. The total effective rate was 9.62%, and the total stable rate was 72.12% for 104 cases according to RECIST; while the total effective rate was 34.62%, and the total stable rate was 84.62% according to REC-TCM-ST, thus there were significant differences between the results of the two criteria (P<0.01), and there was also some consistency between them, but not satisfactory.

CONCLUSIONSREC-TCM-ST was used to evaluate the therapeutic effect of CM in the treatment of advanced NSCLC, which shows that its evaluation results can better reflect the advantages and disadvantages of CM, and the effectiveness of CM is more objective and comprehensive than RECIST, so REC-TCM-ST is worthy of further improvement and clinical expansion.

Adult ; Aged ; Aged, 80 and over ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; pathology ; Female ; Humans ; Karnofsky Performance Status ; Lung Neoplasms ; drug therapy ; pathology ; Male ; Medicine, Chinese Traditional ; Middle Aged ; Neoplasm Staging ; Response Evaluation Criteria in Solid Tumors ; Survival Analysis

BACKGROUNDThrombolysis with recombinant tissue plasminogen activator (rt-PA) has gained international recognition, clinical outcomes following this thrombolytic therapy varied from patient to patient. Factors affecting clinical outcomes have not been well understood yet, so this retrospective case-control study aimed to investigate factors that may influence clinical outcomes of acute ischemic stroke treated with intravenous rt-PA.

METHODSOne hundred and one patients with acute ischemic stroke who received intravenous rt-PA thrombolysis within 4.5 hours from disease onset were included. Patients were divided into good or poor outcome group according to modified Rankin Scale (mRS) score, good outcome group: mRS score of 0-1; poor outcome group: mRS of 2-6. Stroke characteristics were compared between the two groups. Factors for stroke outcomes were analyzed via univariate analysis and Logistic regression.

RESULTSOf the 101 patients studied, patients in good outcome group (n = 55) were significantly younger than patients in poor outcome group (n = 46, (62.82 ± 14.25) vs. (68.81 ± 9.85) years, P = 0.029). Good outcome group had fewer patients with diabetic history (9.09% vs. 28.26%, P = 0.012), fewer patients with leukoaraiosis (7.27% vs. 28.26%, P = 0.005) and presented with lower blood glucose level ((5.72 ± 1.76) vs. (6.72 ± 1.32) mmol/L, P = 0.012), lower systolic blood pressure level ((135.45 ± 19.36) vs. (148.78 ± 19.39) mmHg, P = 0.003), lower baseline NIHSS score (12.02 ± 5.26 vs. 15.78 ± 4.98, P = 0.002) and shorter onset-to-treatment time (OTT) ((2.38 ± 1.21) vs. (2.57 ± 1.03) hours, P = 0.044) than poor outcome group. Logistic regression analysis showed that absence of diabetic history (odds ratio (OR) 0.968 (95% CI 0.941-0.996)), absence of leukoaraiosis (OR 0.835 (95% CI 0.712-0.980)), lower baseline NIHSS score (OR 0.885 (95% CI 0.793-0.989)), lower pre-thrombolysis systolic blood pressure (OR 0.962 (95% CI 0.929-0.997)), and lower blood glucose level (OR 0.699 (95% CI 0.491-0.994)) before thrombolysis were significantly associated with better outcome.

CONCLUSIONPatients with no history of diabetes, no leukoaraiosis, low blood glucose level, low systolic blood pressure level and low baseline NIHSS score before thrombolysis have a better outcome.

Aged ; Blood Pressure ; Case-Control Studies ; Female ; Fibrinolytic Agents ; therapeutic use ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Stroke ; drug therapy ; Thrombolytic Therapy ; Tissue Plasminogen Activator ; therapeutic use ; Treatment Outcome