This study aims to reveal the effect and mechanism of Gentianella turkestanorum total extract(GTI) in ameliorating non-alcoholic steatohepatitis(NASH). UPLC-Q-TOF-MS was employed to identify the chemical components in GTI. SwissTarget-Prediction, GeneCards, OMIM, and TTD were utilized to screen the targets of GTI components and NASH. The common targets shared by GTI components and NASH were filtered through the STRING database and Cytoscape 3.9.0 to identify core targets, followed by GO and KEGG enrichment analysis. AutoDock was used for molecular docking of key components with core targets. A mouse model of NASH was established with a methionine-choline-deficient high-fat diet. A 4-week drug intervention was conducted, during which mouse weight was monitored, and the liver-to-brain ratio was measured at the end. Hematoxylin-eosin staining, Sirius red staining, and oil red O staining were employed to observe the pathological changes in the liver tissue. The levels of various biomarkers, including aspartate aminotransferase(AST), alanine aminotransferase(ALT), hydroxyproline(HYP), total cholesterol(TC), triglycerides(TG), low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol(HDL-C), malondialdehyde(MDA), superoxide dismutase(SOD), and glutathione(GSH), in the serum and liver tissue were determined. RT-qPCR was conducted to measure the mRNA levels of interleukin 1β(IL-1β), interleukin 6(IL-6), tumor necrosis factor α(TNF-α), collagen type I α1 chain(COL1A1), and α-smooth muscle actin(α-SMA). Western blotting was conducted to determine the protein levels of IL-1β, IL-6, TNF-α, and potential drug targets identified through network pharmacology. UPLC-Q-TOF/MS identified 581 chemical components of GTI, and 534 targets of GTI and 1 157 targets of NASH were screened out. The topological analysis of the common targets shared by GTI and NASH identified core targets such as IL-1β, IL-6, protein kinase B(AKT), TNF, and peroxisome proliferator activated receptor gamma(PPARG). GO and KEGG analyses indicated that the ameliorating effect of GTI on NASH was related to inflammatory responses and the phosphoinositide 3-kinase(PI3K)/AKT pathway. The staining results demonstrated that GTI ameliorated hepatocyte vacuolation, swelling, ballooning, and lipid accumulation in NASH mice. Compared with the model group, high doses of GTI reduced the AST, ALT, HYP, TC, and TG levels(P<0.01) while increasing the HDL-C, SOD, and GSH levels(P<0.01). RT-qPCR results showed that GTI down-regulated the mRNA levels of IL-1β, IL-6, TNF-α, COL1A1, and α-SMA(P<0.01). Western blot results indicated that GTI down-regulated the protein levels of IL-1β, IL-6, TNF-α, phosphorylated PI3K(p-PI3K), phosphorylated AKT(p-AKT), phosphorylated inhibitor of nuclear factor kappa B alpha(p-IκBα), and nuclear factor kappa B(NF-κB)(P<0.01). In summary, GTI ameliorates inflammation, dyslipidemia, and oxidative stress associated with NASH by regulating the PI3K/AKT/NF-κB signaling pathway.
Animals ; Non-alcoholic Fatty Liver Disease/genetics* ; Mice ; Network Pharmacology ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Chromatography, High Pressure Liquid ; Liver/metabolism* ; Mice, Inbred C57BL ; Humans ; Mass Spectrometry ; Tumor Necrosis Factor-alpha/metabolism* ; Disease Models, Animal ; Molecular Docking Simulation

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 forecast mortality, age-standardized mortality, and probability of premature mortality from diabetes, and to simulate the impact of controlling risk factors by 2030 in China. Methods: We simulated the burden of disease from diabetes in six scenarios according to the development goals of risk factors control by the WHO and Chinese government. Based on the theory of comparative risk assessment and the estimates of the burden of disease for China from the Global Burden of Disease Study 2015, we used the proportional change model to project the number of deaths, age-standardized mortality, and probability of premature mortality from diabetes under different scenarios of risk factors control in 2030. Results: If the trends in exposures to risk factors from 1990 to 2015 continued. Mortality, age-standardized mortality, and probability of premature mortality from diabetes would increase to 32.57/100 000, 17.32/100 000, and 0.84% by 2030, respectively. During that time, mortality, age-standardized mortality and probability of premature mortality for males would all be higher than for females. If the goals of controlling risk factors were all achieved, the number of deaths from diabetes in 2030 would decrease by 62.10% compared to the predicted numbers based on the historical trends in exposure to risk factors, and the probability of premature mortality would drop to 0.29%. If only the exposure to a single risk factor were achieved by 2030, high fasting plasma glucose control would have the greatest impact on diabetes, resulting in a 56.00% reduction in deaths compared to the predicted numbers based on the historical trends, followed by high BMI (4.92%), smoking (0.65%), and low physical activity (0.53%). Conclusions: Risk factors control plays an important role in reducing the number of deaths, age-standardized mortality rate, and probability of premature mortality from diabetes. We suggest taking comprehensive measures to control relevant risk factors for certain populations and regions, to achieve the goal of reducing the burden of disease from diabetes as expected.
Male ; Female ; Humans ; Risk Factors ; Diabetes Mellitus/epidemiology* ; Mortality, Premature ; Smoking ; Cost of Illness ; China/epidemiology* ; Global Burden of Disease

Objective: Predictive models were used to evaluate the impact of common risk factors on the number of cardio-cerebrovascular deaths and the probability of premature death. Methods: Using the data for China estimated by the Global Burden of Disease study 2015 (GBD 2015), we calculated the population attribution fraction (PAF) of risk factors. The proportional change model was used to estimate the number of unattributable deaths by 2030, and to predict the number of deaths, mortality, standardized mortality and probability of premature death by 2030. Results: According to the natural change trend of risk factors from 1990 to 2015, the number of deaths and mortality would reach 6.12 million and 428.53/100 000 by 2030, with an increase of 59.92% and 52.87%. By 2030, the probability of premature death from cardio-cerebrovascular diseases among Chinese aged 30-70 years old would continue to decline, from 11.43% to 11.28% for men, and from 5.79% to 4.43% for women. If the goals of all included risk factors were reached by 2030, 2 289 200 cardio-cerebrovascular deaths would be avoided. If only the exposure to a single risk factor was achieved by 2030, blood pressure, total cholesterol, and fine particulate matter exposure were the three most important factors affecting cardio-cerebrovascular deaths, which would reduce 1 332 800, 609 100 and 306 800 deaths, respectively. Among the involved risk factors, the control of blood pressure would mostly decrease the number of deaths due to ischemic heart disease and hemorrhagic stroke, about 677 300 and 391 100 deaths, accordingly. Conclusion: The control of risk factors is of great significance in reducing deaths and probability of premature death due to cardio-cerebrovascular diseases. If the control targets of all risk factors could be achieved by 2030, the burden of cardio-cerebrovascular diseases would be reduced greatly.
Adult ; Aged ; Blood Pressure ; Cerebrovascular Disorders/epidemiology* ; China/epidemiology* ; Female ; Humans ; Male ; Middle Aged ; Mortality, Premature ; Risk Factors

Objective: To predict the number of deaths, standardized mortality and probability of premature mortality caused by malignant cancer in the context of risk factor control at different levels in China in 2030, and assess the possibility of achieving the target of reducing the probability of premature mortality of malignant cancer. Methods: According to the risk factor control standard for malignant cancer used both at home and abroad, the results of China from Global Burden of Disease Study 2015 were used to calculate the population attributable fraction of the risk factors. Based on the comparative risk assessment theory, the deaths of malignant cancer were classified as attributable deaths and un-attributable deaths. Proportional change model was used to predict risk factor exposure and un-attributable deaths of malignant cancer in the future, then the number of deaths, standardized mortality rate and probability of premature mortality of malignant cancer in 2030 was estimated. Data analyses were performed by using software R 3.6.1. Results: If the risk factor exposure level during 1990-2015 remains, the number of deaths, standardized mortality rate, and probability of premature mortality of malignant cancer would increase to 3.62 million, 153.96/100 000 and 8.92% by 2030, respectively. If the risk factor exposure control level meets the requirement, the probability of premature mortality from cancer in people aged 30-70 years would drop to 7.57% by 2030. Conclusions: The control of risk factor exposure will play an important role in reducing deaths, standardized mortality rate and probability of premature mortality of malignant cancer. But more efforts are needed to achieve the goals of Health China Action.
Adult ; Aged ; China/epidemiology* ; Cost of Illness ; Humans ; Middle Aged ; Mortality, Premature ; Neoplasms/epidemiology* ; Risk Factors

Objective: To forecast the burden of chronic obstructive pulmonary disease (COPD) in China by 2030 and evaluate the effectiveness of controlling risk factors based on the predictive model. Methods: Based on the relationship between the death of COPD and exposure to risk factors and the theory of comparative risk assessment, we used the estimates of the Global Burden of Disease Study 2015 (GBD2015) for China, targets for controlling risk factors, and proportion change model to project the number of deaths, standardized mortality rate, and probability of premature mortality from chronic respiratory diseases by 2030 in different scenarios and to evaluate the impact of controlling the included risk factors to the disease burden of COPD in 2030. Results: If the trends in exposure to risk factors from 1990 to 2015 continued, the number of deaths and the mortality for COPD would be 1.06 million and 73.85 per 100 000 population in China by 2030, respectively, with an increase of 15.81% and 10.69% compared to those in 2015. Compared to 2015, the age-standardized mortality rate would decrease by 38.88%, and the premature mortality would reduce by 52.73% by 2030. If the smoking rate and fine particulate matter (PM_2.5) concentration separately achieve their control targets by 2030, there would be 0.34 and 0.27 million deaths that could be avoided compared to the predicted numbers based on the natural trends in exposure to risk factors and the probability of premature death would reduce to 0.59% and 0.52%, respectively. If the control targets of all included risk factors were achieved by 2030, a total of 0.53 million deaths would be averted, and the probability of premature death would decrease to 0.44%. Conclusions: If the exposures to risk factors continued as showed from 1990 to 2015, the number of deaths and mortality for COPD would increase by 2030 compared to 2015, and the standardized mortality and the probability of premature death would decrease significantly, which would achieve the targets of preventing and controlling COPD. If the exposure to the included risk factors all achieved the targets by 2030, the burden of COPD would be reduced, suggesting that the control of tobacco use and air pollution should be enhanced to prevent and control COPD.
Air Pollutants/analysis* ; Air Pollution/prevention & control* ; China/epidemiology* ; Cost of Illness ; Environmental Exposure ; Humans ; Particulate Matter/analysis* ; Pulmonary Disease, Chronic Obstructive/prevention & control* ; Risk Factors

OBJECTIVE: To investigate the effects of Birinapant on hepatocellular carcinoma cells and its related molecular mechanisms. METHODS: Human hepatocellular carcinoma cells QGY-7701 were treated with 0, 1, 5, 25 and 125 nmol/L Birinapant for 24, 48 and 72 hours respectively, each experiment 3 wells.The proliferation activity of cells, the apoptosis levels, the cells nuclear type, the mitochondrial membrane potential, the transcription and expression levels of genes and the cytotoxicity of Birinapant were analyzed.At the same time, 4-week-old male BALB/C mice were randomly divided into 5 groups, with 20 mice in each group.The mice were inguinal injected with QGY-7701 cells, and then subcutaneous injected with Birinapant (concentrations ranging from 0, 1, 5, 25, 125 μg/kg) in each group after two days, once every other day.On 18 day since first Birinapant injection, 10 mice were killed in each group to weigh tumor tissue and survival time was recorded from the remaining 10 mice.The effects of Birinapant on the growth of the tumor and the survival time of tumor-bearing mice were observed. RESULTS: Compared with the negative control (NC) group, the proliferation activity of QGY-7701 was inhibited significantly after Birinapant treatment and the apoptosis levels were increased significantly (<0.01).The cell mitochondrial membrane potential was decreased and the karyotype was changed (<0.01).At the same time, the transcription and expression levels of genes cellular inhibitor of apoptosis protein 1(cIAP-1), cellular inhibitor of apoptosis protein 2(cIAP-2), ras, raf, mek and erk were significantly decreased (<0.01), while the expression levels of caspase-3 and caspase-9 genes were up-regulated (<0.01).Compared with the model group (MG), the growth of the tumor was inhibited significantly and the survival time of the tumor-bearing mice was prolonged after Birinapant treatment (<0.01). CONCLUSIONS Birinapant can inhibit the expression of cIAP-1, cIAP-2 and the proteins of Ras-Raf-MEK-ERK signal pathways, so as to activate the mitochondria mediated endogenous apoptosis pathway.Birinapant shows a certain inhibitory effect on liver cancer.
Animals ; Apoptosis ; Carcinoma, Hepatocellular ; Cell Line, Tumor ; Dipeptides ; Humans ; Indoles ; Liver Neoplasms ; Male ; Mice ; Mice, Inbred BALB C ; Mitochondrial Proteins

OBJECTIVETo evaluate the safety of human umbilical cord derived-mesenchymal stem cell (UC-MSC) transplantation therapy in patients with decompensated liver cirrhosis.

METHODSUC-MSCs were transplanted intravenously into patients with decompensated liver cirrhosis. Serum levels of glucose (GLU), total cholesterol (TC), blood urea nitrogen (BUN), alpha fetoprotein (AFP), white blood cells (WBC), and prothrombin activity (PA) were detected at different time points after UC-MSCs transplantation.

RESULTSMost UC-MSC transplanted patients experienced an improvement in quality of life, to varying degrees. With the exception of low-grade fever in a few patients, side effects and oncogenic events were rare (treatment group: 1/38 vs. control group: 1/16; P more than 0.05). The UC-MSCs transplantation showed no effect on GLU, TC, BUN, AFP, WBC, or PA.

CONCLUSIONUC-MSCs transplantation in patients with decompensated liver cirrhosis is safe and may improve the patient's quality of life.

Adult ; Aged ; Cord Blood Stem Cell Transplantation ; adverse effects ; Female ; Humans ; Liver Cirrhosis ; complications ; surgery ; Male ; Mesenchymal Stem Cell Transplantation ; adverse effects ; Middle Aged ; Prospective Studies