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Alterations of DNA damage response pathway:Biomarker and therapeutic strategy for cancer immunotherapy

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Acta Pharmaceutica Sinica B 2021年第10期11卷 2983-2994页

作者： Minlin Jiang Keyi Jia Lei Wang Wei Li Bin Chen Yu Liu Hao Wang Sha Zhao Yayi He Caicun Zhou Department of medical Oncology Shanghai Pulmonary HospitalTongji University Medical School Cancer InstituteTongji University School of MedicineShanghai 200433China Medical School Tongji UniversityShanghai 200433China

Genomic instability remains an enabling feature of cancer and promotes malignant transformation.Alterations of DNA damage response(DDR)pathways allow genomic instability,generate neoantigens,upregulate the expression of programmed death ligand 1(PD-L1)and interact with signaling such as cyclic GMPe AMP synthase-stimulator of interferon genes(cGASe STING)signaling.Here,we review the basic knowledge of DDR pathways,mechanisms of genomic instability induced by DDR alterations,impacts of DDR alterations on immune system,and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.

关键词： DNA damage response DNA repair Immunotherapy Genomic instability Tumor microenvironment PD-1 PD-L1 cGASe STING

GSDMD in peripheral myeloid cells regulates microglial immune training and neuroinflammation in Parkinson's disease

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药学学报:英文版 2023年第6期13卷 2663-2679页

作者： Bingwei Wang Yan Ma Sheng Li Hang Yao Mingna Gu Ying Liu You Xue Jianhua Ding Chunmei Ma Shuo Yang Gang Hu school of Medicine&Holistic Integrative Medicine Nanjing University of Chinese MedicineNanjing 210023China school of Basic medical Sciences Nanjing Medical UniversityNanjing 211166China

Peripheral bacterial infections without impaired blood brain barrier integrity have been attributed to the pathogenesis of Parkinson's disease(PD).Peripheral infection promotes innate immune training in microglia and exacerbates neuroinflammation.However,how changes in the peripheral environment mediate microglial training and exacerbation of infection-related PD is unknown.In this study,we demonstrate that GSDMD activation was enhanced in the spleen but not in the CNS of mice primed with low-dose LPS.GSDMD in peripheral myeloid cells promoted microglial immune training,thus exacerbating neuroinflammation and neurodegeneration during PD in an IL-1R-dependent manner.Furthermore,pharmacological inhibition of GSDMD alleviated the symptoms of PD in experimental PD models.Collectively,these findings demonstrate that GSDMD-induced pyroptosis in myeloid cells initiates neuroinflammation by regulating microglial training during infection-related PD.Based on these findings,GSDMD may serve as a therapeutic target for patients with PD.

关键词： Parkinson's disease Neuroinflammation Immune training GSDMD

Functional analysis of the emerging roles for the KISS1/KISS1R signaling pathway in cancer metastasis

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Journal of Genetics and Genomics 2022年第3期49卷 181-184页

作者： Zhenxi Li Jing Liu Hiroyuki Inuzuka Wenyi Wei Department of Pathology Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMA 02115USA

Cancer metastasis, a process that primary tumor cells disseminate to secondary organs, is the most lethal and least effectively treated characteristic of human cancers. Kisspeptins are proteins encoded by the KISS1 gene that was originally described as a melanoma metastasis suppressor gene. Then, Kisspeptins were discovered as the natural ligands of the G-protein-coupled receptor 54(GPR54) that is also called KISS1R. The KISS1/KISS1R signaling is essential to control Gn RH secretion during puberty and to establish mammalian reproductive function through the hypothalamic-pituitary-gonadal(HPG) axis. Although KISS1primarily plays a suppressive role in the metastasis progression in several cancer types, emerging evidence indicates that the physiological effect of KISS1/KISS1R in cancer metastasis is tissue context-dependent and still controversial. Here, we will discuss the epigenetic mechanism involved in the regulation of KISS1 gene expression, the context-dependent role of KISS1/KISS1R, prometastasis/anti-metastasis signaling pathways of KISS1/KISS1R, and the perspective anticancer therapeutics via targeting KISS1/KISS1R.

关键词： KISS1/KISS1R Metastasis Anticancer therapeutics

Advancements in endometrial epithelial stem cell research

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Science China(Life Sciences) 2022年第1期65卷 215-218页

作者： Xiwen Zhang Guangfeng Zhao Yali Hu Nanjing University Medical School Nanjing 210008China Department of Obstetrics and Gynecology the Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008China

The human endometrium is a dynamic tissue that undergoes approximately 400 cycles of proliferation,decidualization,shedding,and regeneration.With the observation that superficial stratum functionalis loss and swift reepithelization occur every month,an original hypothesis is that stem cells,especially endometrial epithelial stem cells harbored in the deeper basalis,take on the responsibility of repairing and regenerating the endometrial functionalis.

关键词： endometrial superficial stratum

Spontaneous cerebral abscess due to Bacillus subtilis in an immunocompetent male patient: A case report and review of literature

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World Journal of Clinical Cases 2018年第16期6卷 1169-1174页

作者： Ioannis Tsonis Lydia Karamani Panagiota Xaplanteri Fevronia Kolonitsiou Petros Zampakis Georgios Gatzounis Markos Marangos Stelios F Assimakopoulos Department of Neurosurgery University of Patras Medical School Department of Microbiology University of Patras Medical School Department of Radiology University of Patras Medical School Department of Internal Medicine Division of Infectious Diseases University of Patras Medical School

BACKGROUND Bacillus subtilis(B. subtilis) is considered a nonpathogenic microorganism of the genus Bacillus and a common laboratory contaminant. Only scarce reports of B. subtilis central nervous system infection have been reported, mainly in the form of pyogenic meningitis,usually in cases of direct inoculation by trauma or iatrogenically.CASE SUMMARY A 51-year-old man, with a free previous medical history, presented to the Emergency Department of our hospital complaining of recurrent episodes of left upper limb weakness, during the last month, which had been worsened the last 48 h. During his presentation in Emergency Department he experienced a generalized tonic-clonic grand mal seizure. Brain magnetic resonance imaging(MRI) scan with intravenous Gadolinium revealed a 3.3 cm × 2.7 cm lesion at the right parietal lobe surrounded by mild vasogenic edema, which included the posterior central gyrus. The core of the lesion showed relatively homogenous restricted diffusion. Post Gadolinium T1 W1 image, revealed a ring-shaped enhancement. Due to the imaging findings, brain abscess was our primary consideration. Detailed examination for clinical signs of infectious foci revealed only poor oral hygiene with severe tooth decay and periodontal disease, but without detection of dental abscess. The patient underwent surgical treatment with right parietal craniotomy and total excision of the lesion. Pus and capsule tissue grew B. subtilis and according to antibiogram intravenous ceftriaxone 2 g bids was administered for 4 wk. The patient remained asymptomatic and follow-up MRI scan two months after operation showed complete removal of the abscess.CONCLUSION This case highlights the ultimate importance of appropriate oral hygiene and dental care to avoid potentially serious infectious complications and second, B. subtilis should not be considered merely as laboratory contaminant especially when cultivated by appropriate central nervous system specimen.

关键词： Bacillus subtilis Brain abscess Central nervous system infection Craniotomy Meningitis Case report

Metagenomic analysis reveals hidden links between gut microbes and habitat adaptation among cave and surface dwelling Sinocyclocheilus species

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Zoological Research 2023年第4期44卷 793-807页

作者： Hong-Yu Chen Chun-Qing Li Shan-Yuan Chen Hen Xiao school of Ecology and Environmental Sciences Yunnan UniversityKunmingYunnan 650500China Institute of medical Biology Chinese Academy of Medical Sciences and Peking Union Medical SchoolKunmingYunnan 650031China

Intestinal microbes are closely related to vital host functions such as digestion and nutrient absorption,which play important roles in enhancing host adaptability.As a natural“laboratory”,caves provide an outstanding model for understanding the significance of gut microbes and feeding habits in the habitat adaptability of hosts.However,research on the relationship between gut microbes,feeding habits,and the adaptability of troglobites remains insufficient.In this study,we compared the characteristics of the intestinal microbes of Sinocyclocheilus cavefish and surface fish and further established the relationship between intestinal and habitat microbes.Furthermore,we conducted environmental DNA(eDNA)(metabarcoding)analysis of environmental samples to clarify the composition of potential food resources in the habitats of the Sinocyclocheilus cavefish and surface fish.Results showed that the structure of the Sinocyclocheilus gut microbes was more related to ecological type(habitat type)than phylogenetic relationships.While horizontal transfer of habitat microbes was a source of gut microbes,hosts also showed strong selection for inherent microbes as dominant microorganisms.Differences in the composition and structure of gut microbes,especially dominant microbes,may enhance the adaptability of the two Sinocyclocheilus fish types from the perspectives of food intake,nutrient utilization,and harmful substance metabolism,suggesting that food resources,predation patterns,intestinal flora,digestive and absorptive capacity,and feeding habits and preferences are linked to habitat adaptability.These results should facilitate our understanding of the significance of fish gut microbes to habitat adaptation and provide a new perspective for studying the adaptive mechanisms of cavefish.

关键词： Cavefish Intestinal microbes Sinocyclocheilus Adaptive mechanism

Oncogenic β-catenin-driven liver cancer is susceptible to methotrexate-mediated disruption of nucleotide synthesis

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Chinese medical Journal 2024年第2期137卷 181-189页

作者： Fangming Liu Yuting Wu Baohui Zhang Shuhui Yang Kezhuo Shang Jie Li Pengju Zhang Weiwei Deng Linlin Chen Liang Zheng Xiaochen Gai Hongbing Zhang Department of Physiology State Key Laboratory of Common Mechanism Research for Major DiseasesHaihe Laboratory of Cell EcosystemInstitute of Basic Medical Sciences and School of Basic MedicineChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100005China Department of Physiology Institute of Basic Medical Sciences and School of Basic MedicineGraduate School of Peking Union Medical CollegeChinese Academy of Medical SciencesBeijing100005China Department of Physiology School of Life ScienceChina Medical UniversityShenyangLiaoning 110122China school of Life Sciences Westlake UniversityHangzhouZhejiang 310024China Key Laboratory of Pediatric Hematology and Oncology Ministry of HealthInstitute of Pediatric Translational MedicineShanghai Children’s Medical CenterShanghai Jiao Tong School of MedicineShanghai 200127China

Background:Liver cancer is largely resistant to chemotherapy.This study aimed to identify the effective chemotherapeutics forβ-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1(CTNNB1),the most frequently altered proto-oncogene in hepatic neoplasms.Methods:Constitutiveβ-catenin-activated mouse embryonic fibroblasts(MEFs)were established by deleting exon 3(β-catenin^(Δ(ex3)/+)),the most common mutation site in CTNNB1 gene.A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibitedβ-catenin^(Δ(ex3)/+)but not for wild-type MEFs.Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis.The efficacy and selectivity of methotrexate(MTX)onβ-catenin-activated human liver cancer cells were determined in vitro.Immuno-deficient nude mice subcutaneously inoculated withβ-catenin wild-type or mutant liver cancer cells and hepatitis B virus(HBV);β-catenin^(lox(ex3)/+)mice were used,respectively,to evaluate the efficacy of MTX in the treatment ofβ-catenin mutant liver cancer.Results:MTX was identified and validated as a preferential agent against the proliferation and tumor formation ofβ-catenin-activated cells.Boosted nucleotide synthesis was the major metabolic aberration inβ-catenin-active cells,and this alteration was also the target of MTX.Moreover,MTX abrogated hepatocarcinogenesis of HBV;β-catenin^(lox(ex3)/+)mice,which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer.Conclusion:MTX is a promising chemotherapeutic agent forβ-catenin hyperactive liver cancer.Since repurposing MTX has the advantages of lower risk,shorter timelines,and less investment in drug discovery and development,a clinical trial is warranted to test its efficacy in the treatment ofβ-catenin mutant liver cancer.

关键词： Liver cancer β-catenin Methotrexate Nucleotide synthesis Chemotherapy

Network pharmacological prediction and molecular docking analysis of the combination of Atractylodes macrocephala Koidz.and Paeonia lactiflora Pall.in the treatment of functional constipation and its verification

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Animal Models and Experimental Medicine 2022年第2期5卷 120-132页

作者： Yuxiao Meng Xiaojun Li Xiaoting Wang Lu Zhang Jiaqi Guan school of Pharmacy Zhejiang Chinese Medical UniversityZhejiangChina

Background:We aimed to reveal the mechanism of functional constipation in the treatment of Atractylodes macrocephala Koidz.(AMK)and Paeonia lactiflora Pall.(PLP).Methods:The main active ingredients of AMK and PLP were screened by the Traditional Chinese Medicine Systems Pharmacology(TCMSP)platform.A database of functional constipation targets was established by GeneCard and OMIM.An“ingredient-target”network map was constructed with Cytoscape software(version 3.7.1),and molecular docking analysis was performed on the components and genes with the highest scores.The rats in the normal group were given saline,and those in the other groups were given 10 mg/kg diphenoxylate once a day for 14 days.The serum and intestinal tissue levels of adenosine monophosphate(cAMP),protein kinase A(PKA),and adenylyl cyclase(AC)of the rats and aquaporin(AQP)1,AQP3,and AQP8 were measured.Results:AMK and PLP had a significant role in the regulation of targets in the treatment of functional constipation.After treatment with AMK,PLP,or mosapride,the serum and intestinal tissue levels of AC,cAMP,and PKA were significantly downregulated.Groups receiving AMK and PLP or mosapride exhibited a reduction in the level of AQP1,AQP3,and AQP8 to varying degrees.Conclusion:Molecular docking analysis revealed that AMK and PLP had a significant role in the regulation of targets in the treatment of functional constipation.Studies have confirmed that AMK and PLP can also affect AC,cAMP,and PKA.AC,cAMP,and PKA in model rats were significantly downregulated.AQP expression is closely related to AC,cAMP,and PKA.AMK and PLP can reduce the expression of AQP1,AQP3,and AQP9 in the colon of constipated rats.

关键词： coupling of AMK and PLP functional constipation mechanism network pharmacology

Inhibition of TYRO3/Akt signaling participates in hypoxic injury in hippocampal neurons

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Neural Regeneration Research 2016年第5期11卷 752-757页

作者： Yan-zhen Zhu Wei Wang Na Xian Bing Wu school of Basic medical Sciences Fujian Medical University

In this study, we investigated the role of the TYRO3/Akt signaling pathway in hypoxic injury to hippocampal neurons. 3-（4,5-Dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay showed that hypoxia inhibited the proliferation and viability of hippocampal neurons. Terminal deoxynucleotidyl transferase-mediated d UTP nick end labeling assay demonstrated that hypoxia induced neuronal apoptosis in a time-dependent manner, with a greater number of apoptotic cells with longer hypoxic exposure. Immunofluorescence labeling revealed that hypoxia suppressed TYRO3 expression. Western blot assay showed that hypoxia decreased Akt phosphorylation levels in a time-dependent manner. Taken together, these findings suggest that hypoxia inhibits the proliferation of hippocampal neurons and promotes apoptosis, and that the inhibition of the TYRO3/Akt signaling pathway plays an important role in hypoxia-induced neuronal injury.

关键词： nerve regeneration TYRO3 Akt apoptosis hippocampal neurons primary culture hypoxia proliferation neural regeneration