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CD137 signaling aggravates myocardial ischemia-reperfusion injury by inhibiting mitophagy mediated NLRP3 inflammasome activation

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Journal of Geriatric Cardiology 2023年第3期20卷 223-237页

作者： Guang-Yao ZANG Qing YIN Chen SHAO Zhen SUN Li-Li ZHANG Yao XU Li-Hua LI Zhong-Qun WANG department of Cardiology Affiliated Hospital of Jiangsu UniversityZhenjiangChina department of pathology Affiliated Hospital of Jiangsu UniversityZhenjiangChina

BACKGROUND The inflammatory response caused by the NLRP3 is closely related to the formation of myocardial ischemiareperfusion injury.Costimulatory receptor CD137 and its ligand play a crucial role in regulating the inflammatory immune response in atherosclerosis,which is the fundamental cause of cardiovascular diseases.However,the roles of CD137 signaling in the process of myocardial ischaemia-reperfusion(IR)injury remain unknown.METHODS Genetic ablation was used to determine the functional significance of CD137 in myocardial IR injury.Expression of CD137 was examined by Western-blot,quantitative real-time polymerase chain reaction,and immunohistochemistry in a murine IR model by coronary artery ligation.Even’s blue-TTC staining and echocardiography to evaluate the severity of myocardial IR injury.Furthermore,HL-1 cardiomyocytes treated with agonist-CD137 recombinant protein were used to explore the underlying mechanism in CD137 signaling-induced NLRP3 inflammasome activation in response to hypoxia/reoxygenation or LPS/ATP.RESULTS We demonstrated that CD137 knockout significantly improved cardiac function,accompanied by a markedly reduced NLRP3-mediated inflammatory response and IA/AAR which were reversed by mitophagy inhibitor Mdivi-1.Activating CD137 signaling significantly inhibited mitophagy and provoked NLRP3-mediated inflammatory response in H/R-injured or LPS-primed and ATP-stimulated HL-1 cardiomyocytes,the effects of which could be abolished by either anti-CD137 or mitophagy activator FCCP.Besides,mitochondrial ROS was augmented by activating CD137 signaling through the suppression of mitophagy.CONCLUSIONS Our results reveal that activating CD137 signaling aggravates myocardial IR injury by upregulating NLRP3 inflammasome activation via suppressing mitophagy and promoting mtROS generation.

关键词： CD137 NLRP3 inhibiting

Exosomes derived from human umbilical cord mesenchymal stem cells alleviate Parkinson’s disease and neuronal damage through inhibition of microglia

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Neural Regeneration Research 2023年第10期18卷 2291-2300页

作者： Zhong-Xia Zhang Yong-Jie Zhou Ping Gu Wei Zhao Hong-Xu Chen Ruo-Yu Wu Lu-Yang Zhou Qing-Zhuo Cui Shao-Kang Sun Lin-Qi Zhang Ke Zhang Hong-Jun Xu Xi-Qing Chai Sheng-Jun An department of Neurology the First Affiliated Hospital of Hebei Medical UniversityShijiazhuangHebei ProvinceChina Research Center Hebei University of Chinese MedicineShijiazhuangHebei ProvinceChina

Microglia-mediated inflammatory responses have been shown to play a crucial role in Parkinson’s disease. In addition, exosomes derived from mesenchymal stem cells have shown anti-inflammatory effects in the treatment of a variety of diseases. However, whether they can protect neurons in Parkinson’s disease by inhibiting microglia-mediated inflammatory responses is not yet known. In this study, exosomes were isolated from human umbilical cord mesenchymal stem cells and injected into a 6-hydroxydopamine-induced rat model of Parkinson’s disease. We found that the exosomes injected through the tail vein and lateral ventricle were absorbed by dopaminergic neurons and microglia on the affected side of the brain, where they repaired nigral-striatal dopamine system damage and inhibited microglial activation. Furthermore, in an in vitro cell model, pretreating lipopolysaccharide-stimulated BV2 cells with exosomes reduced interleukin-1β and interleukin-18 secretion, prevented the adoption of pyroptosis-associated morphology by BV2 cells, and increased the survival rate of SH-SY5Y cells. Potential targets for treatment with human umbilical cord mesenchymal stem cells and exosomes were further identified by high-throughput microRNA sequencing and protein spectrum sequencing. Our findings suggest that human umbilical cord mesenchymal stem cells and exosomes are a potential treatment for Parkinson’s disease, and that their neuroprotective effects may be mediated by inhibition of excessive microglial proliferation.

关键词： 6-hydroxydopamine dopamine neurons exosomes inflammation mesenchymal stem cells microglia Parkinson’s disease pyroptosis

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

Role of ACLY in the development of gastric cancer under hyperglycemic conditions

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Quantitative Biology 2024年第1期12卷 100-116页

作者： Keran Sun Jingyuan Ning Keqi Jia Xiaoqing Fan Hongru Li Jize Ma Meiqi Meng Cuiqing Ma Lin Wei department of Immunology Immunology Department of Hebei Medical UniversityShijiazhuangChina department of pathology Pathology Department of the Fourth Hospital of Hebei Medical UniversityShijiazhuangChina

To investigate the impact of hyperglycemia on the prognosis of patients with gastric cancer and identify key molecules associated with high glucose levels in gastric cancer development,RNA sequencing data and clinical features of gastric cancer patients were obtained from The Cancer Genome Atlas(TCGA)database.High glucose-related genes strongly associated with gastric cancer were identified using weighted gene co-expression network and differential analyses.A gastric cancer prognosis signature was constructed based on these genes and patients were categorized into high-and low-risk groups.The immune statuses of the two patient groups were compared.ATP citrate lyase(ACLY),a gene significantly related to the prognosis,was found to be upregulated upon high-glucose stimulation.Immunohistochemistry and molecular analyses confirmed high ACLY expression in gastric cancer tissues and cells.Gene Set Enrichment Analysis(GSEA)revealed the involvement of ACLY in cell cycle and DNA replication processes.Inhibition of ACLY affected the proliferation and migration of gastric cancer cells induced by high glucose levels.These findings suggest that ACLY,as a high glucose-related gene,plays a critical role in gastric cancer progression.

关键词： ACLY gastric cancer high glucose immune microenvironment

Observation of the effect of targeted therapy of 64-slice spiral CT combined with cryoablation for liver cancer

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World Journal of Gastroenterology 2017年第22期23卷 4080-4089页

作者： Qiao-Huan Yan Dian-Guo Xu Yan-Feng Shen Ding-Ling Yuan Jun-Hui Bao Hai-Bin Li Ying-Gang Lv department of Geriatrics the first hospital of handan department of anatomy medical College of hebei University of Engineering department of Oncology Affiliated hospital of hebei University of Engineering department of imaging affiliated hospital of hebei medical University department of Radiology affiliated hospital of hebei University of Engineering

AIM To observe the effect of targeted therapy with 64-slice spiral computed tomography(CT) combined with cryoablation for liver cancer.METHODS A total of 124 patients(142 tumors) were enrolled into this study. According to the use of dual-slice spiral CT or 64-slice spiral CT as a guide technology, patients were divided into two groups: dual-slice group(n = 56, 65 tumors) and 64-slice group(n = 8, 77 tumors). All patients were accepted and received targetedtherapy by an argon-helium superconducting surgery system. The guided scan times of the two groups was recorded and compared. In the two groups, the lesion ice coverage in diameter of ≥ 3 cm and < 3 cm were recorded, and freezing effective rate was compared. Hepatic perfusion values [hepatic artery perfusion(HAp), portal vein perfusion(p Vp), and the hepatic arterial perfusion index(HAp I)] of tumor tissues, adjacent tissues and normal liver tissues at preoperative and postoperative four weeks in the two groups were compared. Local tumor changes were recorded and efficiency was compared at four weeks post-operation. Adverse events were recorded and compared between the two groups, including fever, pain, frostbite, nausea, vomiting, pleural effusion and abdominal bleeding.RESULTS Guided scan times in the dual-slice group was longer than that in the 64-slice group(t = 11.445, p = 0.000). The freezing effective rate for tumors < 3 cm in diameter in the dual-slice group(81.58%) was lower than that in the 64-slice group(92.86%)(χ2 = 5.707, p = 0.017). The HAp and HAp I of tumor tissues were lower at four weeks post-treatment than at pretreatment in both groups(all p < 0.05), and those in the 64-slice group were lower than that in the dualslice group(all p < 0.05). HAp and p Vp were lower and HAp I was higher in tumor adjacent tissues at post-treatment than at pre-treatment(all p < 0.05). Furthermore, the treatment effect and therapeutic efficacy in the dual-slice group were lower than the 64-slice group at four weeks post-treatment(all p < 0.05). Moreover, pleural e

关键词： 64 片螺线计算了断层摄影术 Cryoablation 肝癌症

Edible Bird's Nest Attenuates Menopause-Related Bone Degeneration in Rats via Increasing Bone Estrogen-Receptor Expression

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Chinese Journal of Integrative Medicine 2021年第4期27卷 280-285页

作者： HOU Zhi-ping TANG Shi-ying Jl Hai-ru HE Pei-yuan LI Yu-hong DONG Xian-ling DU Meng-nan Ismail Maznah HE Wen-jing department of pathology Chengde Medical UniversityChengdeHebei Province(067000)China department of Gastroenterology The Affiliated Hospital of Chengde Medical UniversityChengdeHebei Province(067000)China Department of Pathology The Affiliated Hospital of Hebei University BaodingHebei Province(0671000)China Laboratory of Molecular Biomedicine Institute of BioscienceUniversiti Putra MalaysiaSerdangSelangor(43400)Malaysia department of Gastroscopy Kuancheng Manchu Autonomous County HospitalChengdeHebei Province(067000)China

Objective:To investigate the mechanistic basis for the attenuation of bone degeneration by edible bird's nest(EBN)in ovariectomized rats.Methods:Forty-two female Sprage-Dawley rats were randomized into 7 groups(6 in each group).The ovariectomized(OVX)and OVX+6%,3%,and 1.5%EBN and OVX+estrogen groups were given standard rat chow alone,standard rat chow+6%,3%,and 1.5%EBN,or standard rat chow+estrogen therapy(0.2mg/kg per day),respectively.The sham-operation group was surgically opened without removing the ovaries.The control group did not have any surgical intervention.After 12 weeks of intervention,blood samples were taken for serum estrogen,osteocalcin,and osteoprotegerin,as well as the measurement of magnesium,calcium abd zinc concentrations.While femurs were removed from the surrounding muscles to measure bone mass density using the X-ray edge detection technique,then collected for histology and estrogen receptor(ER)immunohistochemistry.Results:Ovariectomy altered serum estrogen levels resulting in increased food intake and weight gain,while estrogen and EBN supplementation attenuated these changes.Ovariectomy also reduced bone ER expression and density,and the production of osteopcalcin and osteorotegerin,which are important pro-osteoplastic hormones that promote bone mineraliztion and density.Conversely,estrogen and EBN increased serum estrogen levels leading to increased bone ER expression,pro-osteoplastic hormone production and bone density(all P<0.05).Conclusion:EBN could be used as a safe alternative to hormone replacement therapys for managing menopausal complications like bone degeneration.

关键词： edible bird's nest menopause ovariectomy rats bone osteoporosis

Andrographolide Protects Retinal Ganglion Cells in Rats with Glaucoma by Regulating the Bcl-2/Bax/caspase-3 Signaling Pathway

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World Journal of Traditional Chinese Medicine 2022年第2期8卷 241-246页

作者： Jun Li Jing Lu Guang Chen Dan Li department of Ophthalmology Affiliated Hospital of Hebei UniversityBaodingChina

Objective:The aim is to investigate the protective effect of andrographolide(AP)on retinal ganglion cells(RGC)in rats with glaucoma and its mechanism.Methods:ninety-six adult male Wistar rats were randomly divided into normal control(NC)group,chronic ocular hypertension(CHOT)group,vehicle group,and AP group.The density of RGCs and the number of apoptotic cells in retinal slices were evaluated,and the function of RGC was evaluated by photopic negative wave response(PhNR).The expression of Bcl-2,Bax,and caspase-3 in the retina was detected.Results:(1)The density of RGC in the CHOT and vehicle groups were significantly lower than that in the NC and AP(P<0.01).After AP intervention,the RGC density of the rats significantly increased(P<0.01).The ganglion cell layer(GCL)of the CHOT and vehicle groups was obviously thinner,and the thickness of the GCL was partially restored in the AP group.(2)A large number of terminal deoxytransferase mediated dUTP nick end labeling(TUNEL)positive cells were found in the GCL of the CHOT and vehicle groups,but only a few TUNEL positive cells were found in the AP group.The percentage of TUNEL positive cells was 8.80±4.97%,37.00±5.27%,46.16±6.50%,and 22.29±3.52%for groups NC,CHOT,vehicle,and AP,respectively.(3)At 2 weeks,the amplitude of PhN R in the CHOT and vehicle groups decreased by 63.22±13.89%and 57.88±6.95%,respectively.The amplitude of PhNR in the AP group was only 22.56±6.44%lower than that in the NC group.The AP intervention significantly reduced the decrease of the PhNR amplitude in CHOT eyes.(4)Compared with the NC group,the expression of anti-apoptotic protein Bcl-2 was decreased in the CHOT and vehicle groups,and the expression of the pro-apoptotic protein Bax and caspase-3 significantly increased in the CHOT and vehicle groups,which could be reversed by AP treatment.The trend of the reverse transcription-polymerase chain reaction was consistent with that of the western blot analysis.Conclusion:The protective effect of caspase-3/Bcl-2 may be achieved through the regulation o

关键词： Andrographolide Bax Bcl-2 caspase-3 glaucoma

Arginine methylation of ALKBH5 by PRMT6 promotes breast tumorigenesis via LDHA-mediated glycolysis

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Frontiers of Medicine 2024年第2期18卷 344-356页

作者： Xue Han Chune Ren Aifang Jiang Yonghong Sun Jiayi Lu Xi Ling Chao Lu Zhenhai Yu department of Reproductive Medicine Affiliated Hospital of Weifang Medical UniversityWeifang261053China department of pathology Affiliated Hospital of Weifang Medical UniversityWeifang261053China

ALKBH5 is a master regulator of N6-methyladenosine(m6A)modification,which plays a crucial role in many biological processes.Here,we show that ALKBH5 is required for breast tumor growth.Interestingly,PRMT6 directly methylates ALKBH5 at R283,which subsequently promotes breast tumor growth.Furthermore,arginine methylation of ALKBH5 by PRMT6 increases LDHA RNA stability via m6A demethylation,leading to increased aerobic glycolysis.Moreover,PRMT6-mediated ALKBH5 arginine methylation is confirmed in PRMT6-knockout mice.Collectively,these findings identify a PRMT6-ALKBH5-LDHA signaling axis as a novel target for the treatment of breast cancer.

关键词： PRMT6 ALKBH5 N6-methyladenosine glycolysis tumor growth

LncRNA GAS5 enhances tumor stem cell-like medicated sensitivity of paclitaxel and inhibits epithelial-to-mesenchymal transition by targeting the miR-18a-5p/STK4 pathway in prostate cancer

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Asian Journal of Andrology 2022年第6期24卷 643-652页

作者： Ting-Ting Lu Xia Tao Hua-Lei Li Ling Gai Hua Huang Feng Li department of Laboratory Medicine Affiliated Hospital of Nantong UniversityNantong 226001China department of pathology Nantong University Medical SchoolNantong 226001China department of Pharmacy Affiliated Hospital of Nantong UniversityNantong 226001China department of Urology Affiliated Hospital of Nantong UniversityNantong 226001China department of Chemotherapy Affiliated Hospital of Nantong UniversityNantong 226001China department of pathology Affiliated Hospital of Nantong UniversityNantong 226001China

The onset of prostate cancer(PCa)is often hidden,and recurrence and metastasis are more likely to occur due to chemotherapy resistance.Herein,we identified downregulated long noncoding RNA(lncRNA)growth arrest-specific 5(GAS5)in PCa that was associated with metastasis and paclitaxel resistance.GAs5 acted as a tumor suppressor in suppressing the proliferation and metastasis of paclitaxel-resistant PCa cells.GAS5 overexpression in vivo inhibited the tumor growth of xenografts and elevated PCa sensitivity to paclitaxel.Combination of GAS5 and paclitaxel treatment showed great potential in PCa treatment.Moreover,mechanistic analysis revealed a novel regulatory network of GAS5/miR-18a-5p/serine/threonine kinase 4(STK4)that inhibits epithelial-to-mesenchymal transition(EMT)and enhances tumor stem cell-like-mediated sensitivity to paclitaxel in PCa.These findings provide a novel direction for the development of a potential adjunct to cancer chemotherapy that aims to improve the sensitivity of chemotherapy drugs in PCa.

关键词： epithelial-to-mesenchymal transition growth arrest-specific 5 long noncoding RNA paclitaxel prostate cancer