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: Cancer is one of the leading causes of death globally, but its burden is not uniform. GLOBOCAN 2020 has newly updated the estimates of cancer burden. This study summarizes the most recent changing profiles of cancer burden worldwide and in China and compares the cancer data of China with those of other regions. METHODS: We conducted a descriptive secondary analysis of the GLOBOCAN 2020 data. To depict the changing global profile of the leading cancer types in 2020 compared with 2018, we extracted the numbers of cases and deaths in 2018 from GLOBOCAN 2018. We also obtained cancer incidence and mortality from the 2015 National Cancer Registry Report in China when sorting the leading cancer types by new cases and deaths. For the leading cancer types according to sex in China, we summarized the estimated numbers of incidence and mortality, and calculated China's percentage of the global new cases and deaths. RESULTS: Breast cancer displaced lung cancer to become the most leading diagnosed cancer worldwide in 2020. Lung, liver, stomach, breast, and colon cancers were the top five leading causes of cancer-related death, among which liver cancer changed from the third-highest cancer mortality in 2018 to the second-highest in 2020. China accounted for 24% of newly diagnosed cases and 30% of the cancer-related deaths worldwide in 2020. Among the 185 countries included in the database, China's age-standardized incidence rate (204.8 per 100,000) ranked 65th and the age-standardized mortality rate (129.4 per 100,000) ranked 13th. The two rates were above the global average. Lung cancer remained the most common cancer type and the leading cause of cancer death in China. However, breast cancer became the most frequent cancer type among women if the incidence was stratified by sex. Incidences of colorectal cancer and breast cancer increased rapidly. The leading causes of cancer death varied minimally in ranking from 2015 to 2020 in China. Gastrointestinal cancers, including stomach, colorectal, liver, and esophageal cancers, contributed to a massive burden of cancer for both sexes. CONCLUSIONS The burden of breast cancer is increasing globally. China is undergoing cancer transition with an increasing burden of lung cancer, gastrointestinal cancer, and breast cancers. The mortality rate of cancer in China is high. Comprehensive strategies are urgently needed to target China's changing profiles of the cancer burden.
China/epidemiology* ; Colorectal Neoplasms ; Female ; Humans ; Incidence ; Liver Neoplasms ; Male ; Neoplasms/epidemiology* ; Registries

Abstract: Our previous work revealed berberine can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, which suggested that berberine has synergistic antifungal activity with fluconazole. Preliminary SAR of berberine needs to be studied for the possibility of investigating its target and SAR, improving its drug-likeness, and exploring new scaffold. In this work, 13-substitutited benzyl berberine derivatives and N-benzyl isoquinoline analogues were synthesized and characterized by 1H NMR and MS. Their synergetic activity with fluconazole against fluconazole-resistant Candida albicans was evaluated in vitro. The 13-substitutited benzyl berberine derivatives 1a-1e exhibited comparable activity to berberine, which suggested that the introduction of functional groups to C-13 can maintain its activity. The N-benzyl isoquinolines, which were designed as analogues of berberine with its D ring opened, exhibited lower activity than berberine. However, compound 2b, 2c, and 4b showed moderate activity, which indicated that berberine may be deconstructed to new scaffold with synergistic antifungal activity with fluconazole. The results of our research may be helpful to the SAR studies on its other biological activities.
Antifungal Agents ; pharmacology ; Berberine ; pharmacology ; Candida albicans ; drug effects ; Drug Resistance, Fungal ; Drug Synergism ; Fluconazole ; pharmacology ; Isoquinolines ; pharmacology ; Microbial Sensitivity Tests

Objective To explore the demographic characteristics and clinical features of patients with idiopathic pulmonary arterial hypertension ( IPAH ) in China.Methods Between March 2007 and September 2010,IPAH diagnosis was confirmed by right heart catheterization in 150 adult patients from 31 clinical centers in China.Clinical and hemodynamic data were analyzed and patients were divided into WHO functional class Ⅰ / Ⅱ and WHO functional class Ⅲ/Ⅳ group.Results The mean age of 150 patients were 36 ± 13 years with female patient/male patient ratio of 2∶1,and mean BMI was ( 21.3 ± 3.5 ) kg/m2.Fatigue (n =123,82.0％ ) and dyspnea ( n =112,74.7％ ) are the most common symptoms.Accentuated pulmonic second sound ( P2 ) was detected in 92.0％ ( n =138 ) of patients during physical examination,which was also the most common sign.About 49.0％ ( n =73 ) patients were WHO functional class Ⅰ/ Ⅱ patients and 46.0％ ( n =68 ) patients were WHO functional class Ⅲ/Ⅳ patients. Six minutes walking distance (6MWD) and Borg dyspnea score was (337 ± 101 ) m and 2.0 (2.0,4.0),respectively.Right ventricular hypertrophy was suggested by ECG in 93.1％ ( n =140 ) patients.Right atrial pressure was (10 ±6) mm Hg,mean pulmonary artery pressure was (61 ±16) mm Hg,cardiac index was (2.3 ±0.8)L · min-1 · m-2 and pulmonary vascular resistance(1484 ±699) dyn · s-1 · cm-5 in this cohort.6 MWD (305 m ±89 m vs.377 m ±88 m) was significantly shorter while Borg dyspnea score [3.0 (3.0,5.0) vs.2.0 (2.0,3.0) ] was significantly higher in WHO functional class Ⅲ/Ⅳ patients than in WHO functional class Ⅰ/Ⅱ patients. Similarly hemodynamic parameters were also worse in WHO functional class Ⅲ/Ⅳ patients than in WHO functional class Ⅰ / Ⅱ patients ( all P ＜ 0.05).Conclusion Idiopathic pulmonary arterial hypertension patients in this cohort affect mostly young adults,dominated by female gender and lower body mass index. Fatigue and dyspnea are the most common symptoms and accentuated pulmonic second sound ( P2 ) is the most common sign.IPAH patients are often displaying severe functional and hemodynamic disturbance at first visit to hospitals.Dyspnea and hemodynamic impairment are related to 6MWD and WHO functional class.

BACKGROUNDThe down-regulation of constitutive nitric oxide synthase (cNOS) and up-regulation of inducible nitric oxide synthase (iNOS) are associated with the allergen-provocated airway hyperresponsiveness (AHR). This study aimed to determine whether their alteration also plays an important role in the AHR induced by lipopolysaccharide (LPS).

METHODSHartley male guinea pigs, weighing between 250 g and 350 g, were injected with LPS at a dose of 1 mg/kg every 24 hours for three days. A non-selective NOS inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), or a selective inducible NOS inhibitor, aminoguanidine (AG), were used thirty minutes before each injection of LPS. Airway reactions, nitric oxide (NO) production and inflammatory changes were detected 24 hours after the last dose of LPS.

RESULTSAG significantly decreased the NO production in the bronchoalveolar lavage fluid (BALF) and sharply reduced the intensity of bronchoconstriction to histamine challenge. L-NAME also significantly decreased the NO production in the BALF, but had no effect on airway reactions or, perhaps, a tendency to enhance the intensity of AHR.

CONCLUSIONSThe data suggest that inducible NOS contributes to the AHR induced by repetitive intraperitoneal LPS, and constitutive NOS was also involved.

Airway Resistance ; drug effects ; Animals ; Bronchial Hyperreactivity ; chemically induced ; Enzyme Inhibitors ; pharmacology ; Guanidines ; pharmacology ; Guinea Pigs ; Lipopolysaccharides ; toxicity ; Male ; NG-Nitroarginine Methyl Ester ; pharmacology ; Nitric Oxide ; biosynthesis ; Nitric Oxide Synthase ; antagonists & inhibitors ; physiology