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 This study aimed to investigate the potential relationship between urinary metals copper (Cu), arsenic (As), strontium (Sr), barium (Ba), iron (Fe), lead (Pb) and manganese (Mn) and grip strength. Methods We used linear regression models, quantile g-computation and Bayesian kernel machine regression (BKMR) to assess the relationship between metals and grip strength.Results In the multimetal linear regression, Cu (β=-2.119), As (β=-1.318), Sr (β=-2.480), Ba (β=0.781), Fe (β= 1.130) and Mn (β=-0.404) were significantly correlated with grip strength (P < 0.05). The results of the quantile g-computation showed that the risk of occurrence of grip strength reduction was -1.007 (95％ confidence interval:-1.362, -0.652; P < 0.001) when each quartile of the mixture of the seven metals was increased. Bayesian kernel function regression model analysis showed that mixtures of the seven metals had a negative overall effect on grip strength, with Cu, As and Sr being negatively associated with grip strength levels. In the total population, potential interactions were observed between As and Mn and between Cu and Mn (Pinteractions of 0.003 and 0.018, respectively).Conclusion In summary, this study suggests that combined exposure to metal mixtures is negatively associated with grip strength. Cu, Sr and As were negatively correlated with grip strength levels, and there were potential interactions between As and Mn and between Cu and Mn.

Objective To investigate the dosimetric effects of different calculation grid size(CGS)in helical tomotherapy(HT)planning system on stereotactic body radiation therapy(SBRT)for non-small cell lung cancer(NSCLC).Methods Nine NSCLC patients receiving radiation therapy for the first time at some hospital from March 2019 to December 2022 were selected as the subjects.SBRT planning was carried out through the HT system with three different CGS plans(Fine,Normal,and Coarse)and the same pitch,modulation factor(MF)and optimization conditions,and the target area indexes of the three CGS plans were compared including conformity index(CI),homogeneity index(HI),dosimetric parameters of the organ at risk(OAR),point dose verification pass rate,treatment time,number of monitor units and Sinograms.SPSS 22.0 was used for statistical analysis.Results For target area HI,there weres significant differences between CGS Fine plan and Coarse plan and between CGS Normal plan and Coarse plan(P＜0.05),while no statistical differences were found between CGS Fine plan and Normal plan(P＞0.05).For target area CI,there were significant differences between CGS Fine plan and Coarse plan(P＜0.05),while no statistical differences were found between CGS Fine plan and Normal plan and between CGS Normal plan and Coarse plan(P＞0.05).For OAR dosimetric parameters,CGS Fine plan and Coarse plan had significant differences in heart Dmax and Dmean,esophageal Dmax and Dmean,V5,V20,V30 and Dmean of the whole lung and affected lung,V5 and Dmax of the affected lung and heart V10 and V30(P＜0.05),CGS Normal plan and Coarse plan had obvious differences in esophageal Dmax(P＜0.05),and the remained dosimetric parameters were not statistically significant(P＞0.05).Fine,Normal and Coarse plans had the point dose verifica-tion pass rates being 0.96％,1.50％and 1.77％,respectively.In terms of treatment time and number of monitor units,there were significant differences between Fine plan and Coarse plan(P＜0.05)while no statistical differences were found between Fine and Normal plans and between Normal and Coarse plans(P＞0.05).Sinograms analyses showed Fine plan had evenly distributed segment color gradient,Coarse plan had areas of very dark and very light color gradients and Normal plan was somewhere in between.Conclusion Low CGS has to be used as much as possible to obtain accurate dose distribution during SBRT planning for NSCLC patients,which contributes to the execution of the radiation therapy plan and the prevention of ad-verse effects.[Chinese Medical Equipment Journal,2024,45(2):52-57]

Objective To investigate the radiotherapy dose impacts of different jaw widths on stereotactic body radiotherapy(SBRT)for hepatocellular carcinoma(HCC)with the hilical tomotherapy(HT)planning system.Methods Totally 16 HCC patients who received radiotherapy at some hospital from March 2021 to August 2023 were selected,and the planning was carried out with the same pitch,modulation factors and optimization conditions and the jaw widths being 1.0,2.5 and 5.0 cm.The dosimetric differences due to the jaw widths in planned targets and organs at risk(OAR)were compared,and the planned treatment time,monitor unit,gantry rotations and gantry period were evaluated.SPSS 22.0 was used for statistical analysis.Results Better dosimetric parameters and lower doses to OARs could be got with lower jaw widths.The widened jaw widths resulted in reduced planned treatment time,decreased monitor units and gantry rotations,shortened gantry period while enhanced treatment efficiency.Conclusion A 2.5 cm jaw width for HT planning contributes to improving treatment efficiency during HCC SBRT under the premise of ensured target dose distribution and satisfactory dose to OAR for clinical require-ments.[Chinese Medical Equipment Journal,2024,45(7):51-55]

Objective To apply a COMSOL-based finite element analysis method to investigating the electric field effects produced by the human lower limb musculoskeletal system under the synergistic effects of stress field and electromagnetic field.Methods Firstly,a 3D human body model was constructed by Maxon Cinema 4D R21 software,and then imported into COMSOL 6.1 software in STL format.Secondly,an electromagnetic field intervention and stress loading model for the left lower limb of the human body was designed and constructed,in which 15 Hz quasi-pulse group current signals were used for electromagnetic field excitation and the stress field was realized by applying a vibration load with an average compressive force of about 90 N/cm2 to the left foot of the human body.Finally,the electromagnetic properties of human tissue were simulated by numerical simulation,and then the effects of stress field or elecromagnetic field or combined stress field and electromagnetic field on human bioelectric field were compared.Results Simulation results showed that the electric field intensity peaked at the leg joints under both electromagnetic and stress fields acting alone or synergistically,the bioelectric field intensity generated by the human body was related to the distance from the exogenous excitation loading location,and the electric field generated under synergistic action was equivalent to the linear superposition of the bioelectric field in the tissue induced by the electromagnetic field and the stress field acting alone.Conclusion Data supplement is provided for predicting bioelectric field changes within the musculoskeletal tissue,and theoretical foundation is laid for the development and application of multi-physics field synergistic intervention therapy for treating the disorders of the lower limb musculos-keletal system.[Chinese Medical Equipment Journal,2024,45(9):21-26]

AIM To study the chemical constituents from seeds of Canavalia gladiata(Jacq.)DC.,and their estrogen-like activities.METHODS The 75% ethanol extract from the seeds of C.gladiata was isolated and purified by various chromatography,then the structures of obtained compounds were identified by physicochemical properties and spectral data.The estrogen-like activities were evaluated by human breast cancer cells(MCF-7)stably transfected with estrogen receptor reporter gene(ER-Luc).RESULTS Twelve compounds were isolated and identified as biorobin(1),kaempferol 3-O-[O-β-D-apio-D-furanosyl(1→2)-O-[α-L-rhamno-pyranosyl(1 → 6)]-β-D-galactopyranoside(2),kaempferol 3-O-{β-D-glucopyranosyl(1 → 2)-[α-L-rhamonopyranosyl(1→6)]-β-D-galactopyranoside}(3),iso-quercitrin(4),quercetin 3-O-(6″-O-galloyl)-β-D-glucoside(5),isomyricitrin(6),myricetin-3-O-rutinoside(7)(3-ethenylphenyl)-1,2-ethanediol(8),1,3,6-tri-O-galloyl-β-D-glucopyranose(9),breynioside A(10),4-hydroxy-3-methoxyphenol-1-O-β-D-(6′-O-galloyl)glucoside(11),maesopsin-6-O-β-D-glucopyranoside(12).Compounds 1,3-5,8-9 in the concentration of 50 μmol/L,and compounds 2,12 in 100 μmol/L showed estrogen-like activities.CONCLUSION All compounds are isolated from the gene Canavalia for the first time.Compounds 1,3-5,8-9 showed stronger estrogen-like activities than compounds 2 and 12.

OBJECTIVES: To investigate the expression and significance of jumonji domain-containing protein 2B (JMJD2B) and hypoxia-inducible factor-1α (HIF-1α) in non-Hodgkin's lymphoma (NHL) tissues in children. METHODS: Immunohistochemistry was used to detect the expression of JMJD2B and HIF-1α in lymph node tissue specimens from 46 children with NHL (observation group) and 24 children with reactive hyperplasia (control group). The relationship between JMJD2B and HIF-1α expression with clinicopathological characteristics and prognosis in children with NHL, as well as the correlation between JMJD2B and HIF-1α expression in NHL tissues, were analyzed. RESULTS: The positive expression rates of JMJD2B (87% vs 21%) and HIF-1α (83% vs 42%) in the observation group were higher than those in the control group (P<0.05). The expression of JMJD2B and HIF-1α was correlated with serum lactate dehydrogenase levels and the risk of international prognostic index in children with NHL (P<0.05). The expression of JMJD2B was positively correlated with the HIF-1α expression in children with NHL (r_s=0.333, P=0.024). CONCLUSIONS JMJD2B and HIF-1α are upregulated in children with NHL, and they may play a synergistic role in the development of pediatric NHL. JMJD2B can serve as a novel indicator for auxiliary diagnosis, evaluation of the severity, treatment guidance, and prognosis assessment in pediatric NHL.
Humans ; Child ; Hypoxia-Inducible Factor 1, alpha Subunit ; Prognosis ; Hypoxia ; Lymphoma, Non-Hodgkin

Methods The model of heart failure after myocardial infarction was established by left coronary artery liga-tion in rats. Two weeks after modeling, all rats were randomly divided into model group, LGZGD group, and captopril group. Meanwhile sham operation group was set up. The rats were given continuous intragastric administration with drug or distilled water for 28 days, once a day. The behavioral signs of rats in each group were observed. The cardiac function of rats in each group was examined by echocardiography. Serum BNP and NT-ProBNP content were detected by enzyme-linked immunoassay; The changes of myocardial his-topathological and collagen fibers in rats were detected using sirius staining. The contents of oxidative stress index including ROS, SOD in myocardial tissue of rats in each group were observed by DCFH-DA fluorescent probe and Enzyme-linked immunoassay. The ultra-structure of mitochondria was observed by transmission electron microscopy. Expressions of apoptotic proteins ( mitochondrial CytC, cytoplasmic CytC) were detec- ted by Western blot. Expression of proteins related to the Nrf2/BNIP3 pathway were examined by immunoflu-orescence and Western blot. Results LGZGD could significantly improve the cardiac function of rats, reduce the contents of BNP and NT-ProBNP, inhibit the excessive deposition of collagen in myocardial interstiti-um, reduce ROS, increase the content of SOD, improve mitochondrial structure damage, up-regulate the expression of Nrf2 and nuclear translocation, and reduce the expression of BNIP3. Conclusions LGZGD can inhibit the ventricular remodeling and prevent the occurrence of heart failure after myocardial infarction. Its pharmacological effects are mainly related to regulating the Nrf2/BNIP3 pathway, activating Nrf2, promoting its nuclear transfer, and further down-regulating BNIP3 , protecting mitochondrial function, and reducing cardiomyocyte apoptosis.

This paper introduces professor SUN Shen-tian's clinical thoughts and his characteristics of acupuncture techniques for the treatment of depression based on "psychosomatic medicine". Professor SUN, the master of traditional Chinese medicine, believes that depression refers to comorbidity of "heart mind" and "body", resulting from the "body-mind" disharmony, specially dominated by the emotional disorder. This disease is located in the brain, with the injury of mind and closely related to the heart and liver dysfunction. In pathogenesis, the dysfunction of brain mind and the unhealthy conditions of body and mind are involved. The treatment should focus on "regulating the mind, improving the intelligence, co-modulating the abdominal and brain functions and treating the physical and mental disorders". Baihui (GV 20), Ningshen (Extra) and emotional area on the head are selected as the main points to benefit the intelligence and calming down the mind; the abdominal region 1 and region 8 of "Sun's abdominal acupuncture" are used as the main points of the abdomen to regulate the brain functions. The point prescription is modified according to the symptoms and etiologies. The repeated transcranial acupuncture stimulation and electroacupuncture at low frequency (2 Hz) are crucial to the therapeutic effect. Reliving anxious emotions is specially considered before acupuncture, and the mind is protected and deqi is consolidated during acupuncture.
Humans ; Depression/therapy* ; Acupuncture Points ; Acupuncture Therapy/methods* ; Medicine, Chinese Traditional ; Acupuncture

OBJECTIVE: Arsenic (As) and fluoride (F) are two of the most common elements contaminating groundwater resources. A growing number of studies have found that As and F can cause neurotoxicity in infants and children, leading to cognitive, learning, and memory impairments. However, early biomarkers of learning and memory impairment induced by As and/or F remain unclear. In the present study, the mechanisms by which As and/or F cause learning memory impairment are explored at the multi-omics level (microbiome and metabolome). METHODS: We stablished an SD rats model exposed to arsenic and/or fluoride from intrauterine to adult period. RESULTS: Arsenic and/fluoride exposed groups showed reduced neurobehavioral performance and lesions in the hippocampal CA1 region. 16S rRNA gene sequencing revealed that As and/or F exposure significantly altered the composition and diversity of the gut microbiome，featuring the Lachnospiraceae_NK4A136_group, Ruminococcus_1, Prevotellaceae_NK3B31_group, [Eubacterium]_xylanophilum_group. Metabolome analysis showed that As and/or F-induced learning and memory impairment may be related to tryptophan, lipoic acid, glutamate, gamma-aminobutyric acidergic (GABAergic) synapse, and arachidonic acid (AA) metabolism. The gut microbiota, metabolites, and learning memory indicators were significantly correlated. CONCLUSION Learning memory impairment triggered by As and/or F exposure may be mediated by different gut microbes and their associated metabolites.
Rats ; Animals ; Arsenic/toxicity* ; Fluorides ; RNA, Ribosomal, 16S/genetics* ; Rats, Sprague-Dawley ; Metabolome ; Microbiota