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Effects of NLRP3 Inflammasome Mediated Pyroptosis on Cardiovascular Diseases and Intervention Mechanism of Chinese medicine

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Chinese Journal of Integrative medicine 2024年第5期30卷 468-479页

作者： ZHONG Yi LI Xin-yue LIANG Tian-jun DING Bao-zhu MA Ke-xin REN Wen-xuan LIANG Wen-jie College of Integrated Traditional Chinese and Western medicine Hebei University of Chinese MedicineHebei Key Laboratory of Integrated Traditional Chinese and Western Medicine in Liver and Kidney DiseasesInstitute of Integrated Traditional Chinese and Western MedicineShijiazhuang 050200China Department of Cardiovascular Internal medicine the Second Affiliated Hospital of Jiujiang UniversityJiujiangJiangxi Province 332000China Graduate School Hebei Medical UniversityShijiazhuang 050017China Rural Physician College Hebei Medical UniversityShijazhuang 050017China medical Department the First Hospital of Hebei Medical UniversityShijiazhuang 050030China

Activation of the NOD-like receptor protein 3(NLRP3)inflammasome signaling pathway is an important mechanism underlying myocardial pyroptosis and plays an important role in inflammatory damage to myocardial tissue in patients with cardiovascular diseases(CVDs),such as diabetic cardiomyopathy,ischemia/reperfusion injury,myocardial infarction,heart failure and hypertension.Noncoding RNAs(nc RNAs)are important regulatory factors.Many Chinese medicine(CM)compounds,including their effective components,can regulate pyroptosis and exert myocardium-protecting effects.The mechanisms underlying this protection include inhibition of inflammasome protein expression,Toll-like receptor 4–NF-κB signal pathway activation,oxidative stress,endoplasmic reticulum stress(ERS),and mixed lineage kinase 3 expression and the regulation of silent information regulator 1.The NLRP3 protein is an important regulatory target for CVD prevention and treatment with CM.Exploring the effects of the interventions mediated by CM and the related mechanisms provides new ideas and perspectives for CVD prevention and treatment.

关键词： pyroptosis cardiovascular diseases Chinese medicine NOD-like receptor protein 3 mechanisms

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Tongxinluo Activates PI3K/AKT Signaling Pathway to Inhibit Endothelial Mesenchymal Transition and Attenuate Myocardial Fibrosis after Ischemia-Reperfusion in Mice

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Chinese Journal of Integrative medicine 2024年第7期30卷 608-615页

作者： WEI Ya-ru HOU Yun-long YIN Yu-jie LI Zhen LIU Yi HAN Ning-xin WANG Zi-xuan LIU Lu WANG Xiao-qi HAO Yuan-jie MA Kun GU Jiao-jiao JIA Zhen-hua Graduate School Hebei University of Chinese Medicine Shijiazhuang Yiling Pharmaceutical New Drug Evaluation Center hebei institute of Integrated Traditional and Western medicine National Key Laboratory for Innovation and Transformation of Luobing Theory Department of Cardiology Hebei Yiling Hospital Graduate School Hebei Medical University

Objective: To investigate the potential role of Tongxinluo(TXL) in attenuating myocardial fibrosis after myocardial ischemia-reperfusion injury(MIRI) in mice. Methods: A MIRI mouse model was established by left anterior descending coronary artery ligation for 45 min. According to a random number table, 66 mice were randomly divided into 6 groups(n=11 per group): the sham group, the model group, the LY-294002 group, the TXL group, the TXL+LY-294002 group and the benazepril(BNPL) group. The day after modeling, TXL and BNPL were administered by gavage. Intraperitoneal injection of LY-294002 was performed twice a week for 4 consecutive weeks. Echocardiography was used to measure cardiac function in mice. Masson staining was used to evaluate the degree of myocardial fibrosis in mice. Qualitative and quantitative analysis of endothelial mesenchymal transition(EndMT) after MIRI was performed by immunohistochemistry, immunofluorescence staining and flow cytometry, respectively. The protein expressions of platelet endothelial cell adhesion molecule-1(CD31), α-smoth muscle actin(α-SMA), phosphatidylinositol-3-kinase(PI3K) and phospho protein kinase B(p-AKT) were assessed using Western blot. Results: TXL improved cardiac function in MIRI mice, reduced the degree of myocardial fibrosis, increased the expression of CD31 and inhibited the expression of α-SMA, thus inhibited the occurrence of EndMT(P0.05). In addition, the use of the PI3K/AKT pathway-specific inhibitor LY-294002 to block this pathway and combination with TXL intervention, eliminated the protective effect of TXL, further supporting the protective effect of TXL. Conclusion: TXL activated the PI3K/AKT signaling pathway to inhibit EndMT and attenuated myocardial fibrosis after MIRI in mice.

关键词： myocardial fibrosis endothelial mesenchymal transition myocardial ischemia-reperfusion injury phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway

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Comprehensive understanding of glioblastoma molecular phenotypes: classification, characteristics, and transition

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Cancer Biology & medicine 2024年第5期21卷 363-381页

作者： Can Xu Pengyu Hou Xiang Li Menglin Xiao Ziqi Zhang Ziru Li Jianglong Xu Guoming Liu Yanli Tan Chuan Fang School of Clinical medicine Hebei University Department of Neurosurgery Affiliated Hospital of Hebei University hebei Key Laboratory of Precise Diagnosis and Treatment of Glioma School of Basic medical Sciences Hebei University Department of Pathology Affiliated Hospital of Hebei University

Among central nervous system-associated malignancies, glioblastoma(GBM) is the most common and has the highest mortality rate. The high heterogeneity of GBM cell types and the complex tumor microenvironment frequently lead to tumor recurrence and sudden relapse in patients treated with temozolomide. In precision medicine, research on GBM treatment is increasingly focusing on molecular subtyping to precisely characterize the cellular and molecular heterogeneity, as well as the refractory nature of GBM toward therapy. Deep understanding of the different molecular expression patterns of GBM subtypes is critical. Researchers have recently proposed tetra fractional or tripartite methods for detecting GBM molecular subtypes. The various molecular subtypes of GBM show significant differences in gene expression patterns and biological behaviors. These subtypes also exhibit high plasticity in their regulatory pathways, oncogene expression, tumor microenvironment alterations, and differential responses to standard therapy. Herein, we summarize the current molecular typing scheme of GBM and the major molecular/genetic characteristics of each subtype. Furthermore, we review the mesenchymal transition mechanisms of GBM under various regulators.

关键词： Glioblastoma characteristic classification mesenchymal transition molecular phenotype

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Demonstration of safety characteristics and effects on gut microbiota of Lactobacillus gasseri HMV18

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Food Science and Human Wellness 2024年第2期13卷 611-620页

作者： Xianxian Jia Miaomiao Jia Xiang Gao Xiang Li Mengyuan Wang Shengqiang Du Rui Huang Xiaotong Li Jun Zhang Shujin Li Chunling Ma Yan Zhang Bin Cong Department of Pathogen Biology Institute of basic MedicineHebei Medical UniversityShijiazhuang 050017China Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology Chinese Academy of Medical SciencesShijiazhuang 050017China institute of Basic medicine Hebei Medical UniversityShijiazhuang 050017China College of Forensic medicine Hebei Key Laboratory of Forensic MedicineCollaborative Innovation Center of Forensic Medical Molecular IdentificationHebei Medical UniversityShijiazhuang 050017China hebei Food Safety Key Laboratory Hebei Food Inspection and Research InstituteShijiazhuang 050227China

Human normal flora is a source of probiotics.The safety characteristics of a specific isolate determine its application in foods or drugs.The food-borne-pathogen antagonist strain Lactobacillus gasseri HMV18 is one of the isolates from normal human flora.In this work,we assessed the in vitro pH tolerance,bile tolerance,biogenic amine production,mucin utilization,and safety of in vivo administration to mice to evaluate general health,organ-body weight index,organ histopathological change,whether L.gasseri HMV18 can colonize in the gut or modulate the gut microbiota after oral administration.The results suggest that L.gasseri HMV18 can tolerate pH 3 for 2 h,3%bile for 3 h,biogenic amine negative,mucin usage negative,does not encode verified toxins,and cause no visible change in mice's organs.L.gasseri HMV18 might not colonize in mice's gut,but can significantly affect the structure of gut microbiota.A bibliographical survey suggested that there were as few as 8 opportunistic infection cases from 1984 to 2022 and that the possibility for L.gasseri to cause infection is relatively low.Therefore,this work provides a basis for the foods or drugs application of L.gasseri HMV18 and gives a map of experiments for the safety assessment of probiotics.

关键词： Probiotics Lactobacillus gasseri Safety assessment Gut microbiota

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A Dietary Supplement Jinghuosu Ameliorates Reproductive Damage Induced by Tripterygium Glycosides

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Chinese Journal of Integrative medicine 2024年第4期30卷 330-338页

作者： MA Jing SUN Bo TE Li-ger HUANG Xin ZUO Xin HAN Xiao-ke WANG Shu-song hebei Key Laboratory of Reproductive medicine Hebei Institute of Reproductive HealthHebei Reproductive Health HospitalShijiazhuang(050071)China Graduate School of hebei medical university Shijiazhuang(050017)China School of Chemistry and Materials Science Hebei Normal UniversityShijiazhuang(050024)China Xingtai Infertility Specialist Hospital XingtaiHebei Province(054000)China

Objective To determine the possible protective effects of Jinghuosu,a dietary supplement(DS),on tripterygium glycosides(TG)-induced reproductive system injury in rats and its underlying mechanisms.Methods A reproductive damage model was established in rats by feeding of TGs.Twenty-eight male Sprague Dawley rats were randomly divided into 4 groups using a random number table(n=7 in each):control(C)group,model(M)group,DS group and L-carnitine(LC)group.Rats in M,DS and LC groups received 40 mg/kg TGs orally.Starting from the 5th week,after administration of TGs for 4 h every day,rats in DS and LC groups were administered with 2.7 g/kg DS and 0.21 g/kg LC,respectively,for protective treatment over the next 4 weeks.Rats in Group C continued to receive the control treatment.Hematoxylin-eosin staining was used for histopathological analysis of rat testicular tissues.Enzyme-linked immunosorbent assay was performed to measure alkaline phosphatase(ALP),lactate dehydrogenase,alcohol dehydrogenase,total antioxidant capacity(T-AOC),superoxide dismutase,glutathione peroxidase(GSH-Px),and malondialdehyde(MDA)concentrations.Chemiluminescence assay was used to determine the serum testosterone content.Quantitative real-time PCR and Western blotting were conducted to analyze the expression of genes and proteins related to the testosterone synthesis pathway and the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 antioxidant pathway.Results Oral administration of TGs induced significant increases in the testicular levels of zinc transporter 1 and MDA(P<0.05).On the other hand,sperm concentration,sperm motility,and serum testosterone,serum zinc,testicular zinc,Zrt-,Irt-like protein 1,ALP,luteinizing hormone(LH)receptor,steroidogenic acute regulatory protein,Cytochrome P450 family 11 subfamily A member 1,3β-hydroxysteroid dehydrogenase 1 T-AOC,GSH-Px,nuclear factor erythroid 2-related factor 2,heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1 levels decreased following TGs exposure(P<0.05).All of these phenotypes were

关键词： dietary supplement Jinghuosu tripterygium glycosides reproductive damage infertility

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Asperuloside Promotes Apoptosis of Cervical Cancer Cells through Endoplasmic Reticulum Stress-Mitochondrial Pathway

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Chinese Journal of Integrative medicine 2024年第1期30卷 34-41页

作者： QI Zhi-min WANG Xia LIU Xia ZHAO Juan medical Examination Center Hebei Province Hospital of Chinese MedicineShijiazhuang(050011)China Department of Gynaecology and Obstetrics Hebei Province Hospital of Chinese MedicineShijiazhuang(050011)China Experimental Center for Teaching Hebei Medical UniversityShijiazhuang(050017)China

Objective: To investigate the effects of asperuloside on cervical cancer based on endoplasmic reticulum(ER) stress and mitochondrial pathway. Methods: Different doses(12.5–800 μg/mL) of asperuloside were used to treat cervical cancer cell lines Hela and CaSki to calculate the half maximal inhibitory concentration(IC_(50)) of asperuloside. The cell proliferation was analyzed by clone formation assay. Cell apoptosis, intracellular reactive oxygen species(ROS) and mitochondrial membrane potential were determined by flow cytometry. The protein expressions of cleaved-caspase-3, Bcl-2, Bax, Cyt-c, cleaved-caspase-4 and glucose-regulated protein 78(GRP78) were analyzed by Western blot. And the inhibitor of ER stress, 4-phenyl butyric acid(4-PBA) was used to treat cervical cancer cells to further verify the role of ER stress in the apoptosis of cervical cancer cells induced by asperuloside. Results: Asperuloside of 325, 650, and 1300 μg/mL significantly inhibited the proliferation and promoted apoptosis of Hela and CaSki cells(P<0.01). All doses of asperuloside significantly increased intracellular ROS levels, reduced mitochondrial membrane potential, significantly reduced Bcl-2 protein expression level, and increased Bax, Cyt-c, GRP78 and cleaved-caspase-4 expressions(P<0.01). In addition, 10 mmol/L 4-PBA treatment significantly promoted cell proliferation and reduced apoptosis(P<0.05), and 650 μg/mL asperuloside could reverse 4-PBA-induced increased cell proliferation, decreased apoptosis and cleaved-caspase-3,-4 and GRP78 protein expressions(P<0.05). Conclusion: Our study revealed the role of asperuloside in cervical cancer, suggesting that asperuloside promotes apoptosis of cervical cancer cells through ER stress-mitochondrial pathway.

关键词： asperuloside Chinese medicine cervical cancer endoplasmic reticulum stress mitochondrial damage apoptosis

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TL1A Promotes Fibrogenesis in Colonic Fibroblasts via the TGF-β1/Smad3 Signaling Pathway

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Current medical Science 2024年第3期44卷 519-528页

作者： Jia SONG Dong-lei SUN Chen-yang LI Yu-xin LUO Qian LIU Yue YAO Hong ZHANG Ting-ting YANG Mei SONG Xin-li BAI Xiao-lan ZHANG Department of Gastroenterology The Second Hospital of Hebei Medical UniversityHebei Key Laboratory of GastroenterologyHebei Institute of GastroenterologyHebei Clinical Research Center for Digestive DiseasesShijiazhuang050000China Department of Pediatrics The Second Hospital of Hebei Medical UniversityShijiazhuang050000China

Objective Intestinal fibrosis is a refractory complication of inflammatory bowel disease(IBD).Tumor necrosis factor ligand-related molecule-1A(TL1A)is important for IBD-related intestinal fibrosis in a dextran sodium sulfate(DSS)-induced experimental colitis model.This study aimed to explore the effects of TL1A on human colonic fibroblasts.Methods A trinitrobenzene sulfonic acid(TNBS)-induced experimental colitis model of LCK-CD2-TL1A-GFP transgenic(Tg)or wild-type(WT)mice was established to determine the effect and mechanism of TL1A on intestinal fibrosis.The human colonic fibroblast CCD-18Co cell line was treated concurrently with TL1A and human peripheral blood mononuclear cell(PBMC)supernatant.The proliferation and activation of CCD-18Co cells were detected by BrdU assays,flow cytometry,immunocytochemistry and Western blotting.Collagen metabolism was tested by Western blotting and real-time quantitative polymerase chain reaction(RT-qPCR).Results The level of collagen metabolism in the TNBS+ethyl alcohol(EtOH)/Tg group was greater than that in the TNBS+EtOH/WT group.Transforming growth factor-β1(TGF-β1)and p-Smad3 in the TNBS+EtOH/Tg group were upregulated as compared with those in the TNBS+EtOH/WT group.The proliferation of CCD-18Co cells was promoted by the addition of human PBMC supernatant supplemented with 20 ng/mL TL1A,and the addition of human PBMC supernatant and TL1A increased CCD-18Co proliferation by 24.4%at 24 h.TL1A promoted cell activation and increased the levels of COL1A2,COL3A1,and TIMP-1 in CCD-18Co cells.Treatment of CCD-18Co cells with TL1A increased the expression of TGF-β1 and p-Smad3.Conclusion TL1A promotes TGF-β1-mediated intestinal fibroblast activation,proliferation,and collagen deposition and is likely related to an increase in the TGF-β1/Smad3 signaling pathway.

关键词： tumor necrosis factor ligand-related molecule-1A fibrosis inflammatory bowel disease myofibroblasts transforming growth factor-β1

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Intermittent fasting boosts antitumor immunity by restricting CD11b^(+)Ly6C^(low)Ly6G^(low) cell viability through glucose metabolism in murine breast tumor model

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Food Science and Human Wellness 2024年第4期13卷 2327-2345页

作者： Chenghao Fu Zhehao Liang Zemiao Niu Ning Chen Yuemin Li Zhenhua Liang Yanwei Huo Hao Xi Rong Wang Yonghuan Yan Xiaoruo Gan Mengtian Wang Yun Huang Yan Zhang Mingming Gao Pin Lü Postdoctoral Station for Basic medicine Cardiovascular Medical Science CenterDepartment of Cell BiologyKey Laboratory of Neural and Vascular Biology of Ministry of EducationHebei Medical UniversityShijiazhuang 050017China hebei Key Laboratory of Forensic medicine College of Forensic MedicineHebei Medical UniversityShijiazhuang 050017China hebei Food Safety Key Laboratory Hebei Food Inspection and Research InstituteShijiazhuang 050091China Laboratory of Lipid Metabolism Department of Biochemistry and Molecular BiologyKey Laboratory of Medical Biotechnology of Hebei ProvinceShijiazhuang 050017China

Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.

关键词： Intermittent fasting Ly6G^(low)myeloid-derived suppressor cell apoptosis Extramedullary hematopoiesis Colony stimulating factor Glucose metabolism restriction

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Huoxue Jiedu Huayu recipe(活血解毒化瘀方) inhibits macrophage-secreted vascular endothelial growth factor-a on angiogenesis and alleviates renal fibrosis in the contralateral kidneys of unilateral ureteral obstruction rats

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Journal of Traditional Chinese medicine 2024年第3期44卷 458-467页

作者： GAO Xiaomeng QIANG Panpan CHANG Jingyue FAN Lili YANG Fan XU Qingyou Graduate School Hebei University of Chinese Medicine hebei Key Laboratory of Integrative medicine on Liver-Kidney Patterns Hebei University of Chinese Medicine institute of Integrative medicine Hebei University of Chinese Medicine

OBJECTIVE: To elucidate the mechanism by which Huoxue Jiedu Huayu recipe( 活血解毒化瘀方, HJHR) regulates angiogenesis in the contralateral kidney of unilateral ureteral obstruction(UUO) rats and the mechanism by which it reduces of renal fibrosis. METHODS: Male Wistar rats were randomly divided into 4 groups: the sham group, UUO group(180 d of left ureter ligation), UUO plus eplerenone(EPL) group, and UUO plus HJHR group. After 180 d of oral drug administration, blood and contralateral kidneys were collected for analysis. Angiogenesis-and fibrosis-related indexes were detected. RESULTS: HJHR and EPL improved structural damage and renal interstitial fibrosis in the contralateral kidney and reduced the protein expression levels of α-smooth muscle actin(α-SMA), vimentin and collagen I. Moreover, these treatments could reduce the expression of vascular endothelial growth factor-A(VEGFA) by inhibiting the infiltration of macrophages. Furthermore, HJHR and EPL significantly reduced the expression of CD34 and CD105 by downregulating VEGFA production, which inhibited angiogenesis. Finally, the coexpressions of CD34, CD105 and α-SMA were decreased in the HJHR and EPL groups, indicating that endothelial-to-mesenchymal transition was inhibited. CONCLUSIONS: These findings confirm that HJHR alleviates contralateral renal fibrosis by inhibiting VEGFAinduced angiogenesis, encourage the use of HJHR against renal interstitial fibrosis and provide a theoretical basis for the clinical management of patients with CKD.

关键词： aldosterone epithelial-mesenchymal transition eplerenone Huoxue Jiedu Huayu recipe mineralocorticoid receptors unilateral ureteral obstruction

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Waist subcutaneous soft tissue metastasis of rectal mucinous adenocarcinoma: A case report

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World Journal of Clinical Cases 2024年第14期12卷 2412-2419页

作者： Zi-Xing Gong Guo-Lei Li Wen-Min Dong Zhao Xu Rui Li Wen-Xia Lv Jing Yang Zhong-Xin Li Wei Xing Department of General Surgery Hebei Provincial Hospital of Chinese MedicineShijiazhuang 050011Hebei ProvinceChina Department of medical Imaging Hebei Provincial Hospital of Chinese MedicineShijiazhuang 050011Hebei ProvinceChina Department of Pathology Hebei Provincial Hospital of Chinese MedicineShijiazhuang 050011Hebei ProvinceChina Department of Gastroendoscopy Hebei Provincial Hospital of Chinese MedicineShijiazhuang 050011Hebei ProvinceChina Gastrointestinal Disease Diagnosis and Treatment Center The First Hospital of Hebei Medical UniversityShijiazhuang 050000Hebei ProvinceChina

BACKGROUND Rectal mucinous adenocarcinoma(MAC)is a rare pathological type of rectal can-cer with unique pathological features and a poor prognosis.It is difficult to diag-nose and treat early because of the lack of specific manifestations in some aspects of the disease.The common metastatic organs of rectal cancer are the liver and lung;however,rectal carcinoma with metastasis to subcutaneous soft tissue is a rare finding.CASE SUMMARY In this report,the clinical data,diagnosis and treatment process,and postope-rative pathological features of a patient with left waist subcutaneous soft tissue masses were retrospectively analyzed.The patient underwent surgical treatment after admission and recovered well after surgery.The final pathological diagnosis was rectal MAC with left waist subcutaneous soft tissue metastasis.CONCLUSION Subcutaneous soft tissue metastasis of rectal MAC is rare,and it can suggest that the tumor is disseminated,and it can appear even earlier than the primary ma-lignant tumor,which is occult and leads to a missed diagnosis and misdiagnosis clinically.When a subcutaneous soft tissue mass of unknown origin appears in a patient with rectal cancer,a ma-lignant tumor should be considered.

关键词： Colorectal cancer Rectal mucinous adenocarcinoma Cancer metastasis Subcutaneous soft tissue Hematogenous Case report

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