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 investigate the expressions of 12 cytokines(IL-1β,IL-2,IL-4,IL-5,IL-6,IL-8,IL-10,IL-12p70,IL-17,IFN-α,IFN-γ,TNF-α)and procalcitonin in patients with infective endocarditis(IE).Methods Ten IE patients admitted to our hospital from December 2021 to December 2022 were included into the IE group,10 patients with non-infectious and non-rheumatic valvular diseases who were admitted to our hospital at the same period were randomly selected as the control group,and blood sampling of all patients were conducted at admission.The expressions of 12 cytokines and blood routine indexes were detected by flow cytometry,and the level of procalcitonin was detected by ELISA.The correlations among the expression levels of cytokines in IE patients were analyzed by Pearson method and the correlations of IL-8 level and white blood cell count with procalcitonin in IE patients were analyzed by Spearman method.Results Compared with the control group,the levels of cytokines of IL-1β,IL-2,IL-6,IL-10,TNF-α,IFN-α,IFN-γ and IL-12p70 in the IE group were significantly increased(P<0.05),the white blood cell count,neutrophil percentage and procalcitonin were significantly increased(P<0.05).There was no significant difference in the percentage of monocytes between the two groups(P>0.05).IFN-α of IE patients was positively correlated with IL-2,TNF-α,IL-1β and IL-12p70,IL-2 was positively correlated with TNF-α and IL-1β,IL-12p70 was positively correlated with IFN-γ,and procalcitonin was significantly positively correlated with IL-8 and white blood cell count,with statistically significant differences(P<0.05).Conclusion The levels of IL-1β,IL-2,IL-6,IL-10,TNF-α,IFN-α,IFN-γ,IL-12p70 and procalcitonin in IE patients are significantly higher than those in the normal population,and the detections of these indicators are of guiding significance for the early diagnosis of IE and the evaluation of the severity of the disease.

Type 2 diabetes mellitus (T2DM) is a metabolic disease with an increasing incidence worldwide, which leads to damage to various tissues and organs including the liver. MiR-31 is conserved across species and closely associated with metabolic diseases, but its role in type 2 diabetic liver injury has not been elucidated. This study aimed to investigate the effect of miR-31 on liver injury in type 2 diabetes and its underlying mechanism. Four to six weeks old male FVB mice and miR-31-positive transgenic mice were randomly divided into FVB mice control group (C), FVB mice induced diabetes group (DM) and miR-31-overexpression transgenic mice induced diabetes group (31DM). After 1 week of adaptive feeding, the T2DM mouse model was induced by high-fat feeding combined with intraperitoneal injection of streptozotocin (STZ) for 6 weeks. The general condition of mice and related metabolic indicators showed that the increased food and water intake, weight loss and glucose and lipid metabolism disorders could be reversed by miR-31 in T2DM mice. HE staining and liver histological activity index (HAI) scoring results showed that miR-31 improved the inflammatory status in the liver tissue of T2DM mice and decreased the HAI score. RT-qPCR results showed that the high expression of miR-31 was accompanied by a decrease in the expression of activating transcription factor 6 (ATF6) mRNA in the liver of T2DM mice. Furthermore, Western blotting results showed that miR-31 inhibited the expression of endoplasmic reticulum stress-related proteins such as ATF6, glucoregulatory protein 78 (GRP78) and C/EBP homologous protein (CHOP) in the liver of T2DM mice. In conclusion, miR-31 may ameliorate liver injury in T2DM mice by regulating glucose and lipid metabolism disorders and insulin resistance, and inhibiting endoplasmic reticulum stress factors such as ATF6, GRP78, and CHOP.

Malocclusion is one of the three most common oral diseases reported by World Health Organization(WHO). In China, its incidence rate is rising. Malocclusion seriously affects the dental and maxillofacial function, facial appearance and growth development of nearly 260 million children in China, and what is more, it affects their physical and mental health development. Malocclusion occurrence is related to genetic and environmental factors. Early treatment of malocclusion can create a good dental and maxillofacial development environment, correct abnormal growth and control the adverse effects of abnormal genetic factors. It can effectively reduce the prevalence of children's malocclusion and enhance their physical and mental health. This is an urgent need from the economic perspective of our society, so it has great practical and social significance. Experts from the project group "standard diagnose and treatment protocols for early orthodontic intervention of malocclusions of children" which initiated by China National Health Institute of Hospital Administration wrote the "China Experts' Consensus on Preventive and Interceptive Orthodontic Treatments of Malocclusions of Children", which aims to guide and popularize the clinical practice, improve the clinical theory and practice level, and accelerate the disciplinary development of early treatment of children's malocclusion in China. The consensus elaborates the harmfulness of malocclusion and the necessity of early treatment, and brings up the principles and fundamental contents. Based on the law of dental and maxillofacial development, this paper puts forward the guiding suggestions of preventive and interceptive treatments in different stages of dental development ranging from fetus to early permanent dentition. It is a systematic project to promote and standardize the early treatment of malocclusion. Through scientific and comprehensive stratified clinical practice and professional training, the clinical system of early treatment of malocclusion in China will eventually be perfected, so as to comprehensively care for children's dental and maxillofacial health, and improve their oral and physical health in China.
Child ; China/epidemiology* ; Consensus ; Dental Care ; Humans ; Malocclusion/prevention & control* ; Orthodontics, Interceptive

OBJECTIVE: Bufalin is an effective drug for the treatment of liver cancer. But its high toxicity, poor water-solubility, fast metabolism and short elimination half-life limit its use in tumor treatment. How to make the drug accumulate in the tumor and reduce side effects while maintaining its efficacy are urgent problems to be solved. The goal of this study is to solve these problems. METHODS: A copolymer with tunable poly-N-isopropylacrylamide and polylactic acid was designed and synthesized. The corresponding dual targeting immunomicelles (DTIs) loaded with bufalin (DTIs-BF) were synthesized by copolymer self-assembly in an aqueous solution. The size and structure of DTIs-BF were determined by ZetaSizer Nano-ZS and transmission electron microscopy. Then, its temperature sensitivity, serum stability, critical micelle concentration (CMC), entrapment efficiency (EE), drug release and non-cytotoxicity of blank block copolymer micelles (BCMs) were evaluated. Next, the effects of DTIs-BF on cellular uptake, cytotoxicity, and tumor cell inhibition were evaluated. Finally, the accumulation of DTIs-fluorescein isothiocyanate (FITC) and the in vivo anti-tumor effect were observed using an interactive video information system. RESULTS: DTIs-BF had a small size, spherical shape, good temperature sensitivity, high serum stability, low CMC, high EE, and slow drug release. The blank BCMs had very low cytotoxicity. Compared with free bufalin, the in vitro cellular internalization and cytotoxicity of DTIs-BF against SMMC-7721 cells were significantly enhanced, and the effects were obviously better at 40 °C than 37 °C. In addition, the therapeutic effect on SMMC-7721 cells was further enhanced by the programmed cell death specifically caused by bufalin. When DTIs-FITC were injected intravenously in BALB/c nude mice bearing liver cancer, the accumulation of FITC was significantly increased in tumors. CONCLUSION DTIs-BF is a potentially effective nano-formulation and has broad prospects in the clinical treatment of liver cancer.
Animals ; Antineoplastic Agents/pharmacology* ; Bufanolides ; Cell Line, Tumor ; Liver Neoplasms/drug therapy* ; Mice ; Mice, Inbred BALB C ; Mice, Nude

The tirucallane-type triterpenoids, composed of six isoprene units, belong to a group of tetracyclic triterpenoids. Although the naturally-derived tirucallane-type triterpenoids were found in a small amount, the kind of compounds showed various structures, which consist of apo-type, linear said-chain-type and cyclolike said-chain-type and broad bioactivities, such as cytotoxicity, anti-inflammation, antioxidation and anti-plasmin, etc. This paper summarized origins, structures and bioactivities of tirucallane-type triterpenoids in recent ten years. The future research and exploration of tirucallane-type triterpenoids were discussed and prospected.
Antineoplastic Agents, Phytogenic ; Molecular Structure ; Triterpenes

BACKGROUND: Benvitimod cream, a novel synthetic small molecule, was effective in treating mild-to-moderate plaque psoriasis. We conducted a phase III clinical trial to assess the efficacy and safety of benvitimod cream in patients with mild-to-moderate plaque psoriasis. METHODS: We randomly assigned 686 patients (2:1:1) to receive 1% benvitimod cream, 0.005% calcipotriol ointment or placebo twice a day for 12 weeks. The primary efficacy end points were the percentage of patients with a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI 75) score and with a score of 0 or 1 in static physician's global assessment (sPGA) at week 12. RESULTS: The results showed that 50.4% of patients in the benvitimod group achieved PASI 75, which was significantly higher than that in the calcipotriol (38.5%, P < 0.05) and placebo (13.9%, P < 0.05) groups. The proportion of patients achieving an sPGA score 0 or 1 was 66.3% in the benvitimod group and 63.9% in the calcipotriol group, which were both significantly higher than that in the placebo group (34%, P < 0.05). In the long-term follow-up study, 50.8% of patients experienced recurrence. After retreatment with 1% benvitimod, 73.3% of patients achieved an sPGA score of 0 or 1 again at week 52. Adverse events included application site irritation, follicular papules, and contact dermatitis. No systemic adverse reactions were reported. CONCLUSION: During this 12-week study, benvitimod cream was demonstrated with high effectiveness and safety in patients with mild-to-moderate plaque psoriasis. TRIAL REGISTRATION Chinese Clinical Trial Registry (ChiCTR), ChiCTR-TRC-13003259; http://www.chictr.org.cn/showprojen.aspx?proj=6300.
Double-Blind Method ; Follow-Up Studies ; Humans ; Ointments ; Psoriasis/drug therapy* ; Resorcinols ; Severity of Illness Index ; Stilbenes ; Treatment Outcome

OBJECTIVE: To observe the clinical efficacy of 's external treatment combined with long-snake moxibustion at the governor vessel for neurogenic bladder after spinal cord injury. METHODS: A total of 64 patients with neurogenic bladder after spinal cord injury were randomly divided into an observation group and a control group, 32 cases in each group. The patients in the control group were treated with routine acupuncture and rehabilitation of bladder function; based on the treatment in the control group, the patients in the observation group were treated with 's external treatment combined with long-snake moxibustion at the governor vessel, twice a week for 8 weeks. Urodynamic test, including residual urine volume (RUV), maximum flow rate of urination (Qmax), bladder pressure at filling phase (Pves), maximum detrusor pressure (Pdet-max) and maximum urinary bladder volume (VMCC), was performed before and after 8-week treatment. RESULTS: The urodynamic indexes in the two groups were improved compared with before treatment (<0.01, <0.05); after treatment, VMCC in the observation group was significantly higher than the control group (<0.01), while RUV and Pves in the observation group were significantly lower than the control group (<0.05). After treatment, there was no significant difference in Qmax and Pdet-max between the two groups (>0.05). CONCLUSION Based on routine acupuncture and rehabilitation of bladder function, 's external treatment combined with long-snake moxibustion at the governor vessel could effectively improve urodynamic indexes, reduce residual urine, reduce bladder pressure and increase the maximum capacity of bladder, thereby improving bladder compliance and bladder function.
Acupuncture Therapy ; Animals ; Humans ; Moxibustion ; methods ; Spinal Cord Injuries ; complications ; Urinary Bladder, Neurogenic ; etiology ; therapy ; Urodynamics

Sesquiterpenes are a class of terpenoids composed of three isoprene units( 15 carbons). Sesquiterpenoids possess a variety of different structures,including acyclic sesquiterpenes,monocyclic sesquiterpenoids,bicyclic sesquiterpenoids,tricyclic sesquiterpenoids,tetracyclic sesquiterpenoids and macrocyclic sesquiterpenoids. Among them,a large number of monocyclic sesquiterpenoids were isolated and display extensive bioactivities,such as cytotoxic,antioxidant,anti-inflammatory,antibacterial and other activities. In this review,we summarized the progress about the phytochemistry and biological activities of monocyclic sesquiterpenoids( a total of161 compounds) reported from 2014 to 2018( 5 years),including megastigmanes,monocyclofarnesol-type,bisabolane-type,germacrane-type,and other types of monocyclic sesquiterpenoids. Furthermore,several future research perspectives and development of sesquiterpenoids as potential therapeutic agents were discussed as well.
Anti-Bacterial Agents ; pharmacology ; Anti-Inflammatory Agents ; pharmacology ; Antioxidants ; pharmacology ; Molecular Structure ; Sesquiterpenes ; pharmacology

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