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Immune microenvironment of pheochromocytomas and paragangliomas

Basic & Clinical Medicine.2024;44(6):742-747. doi:10.16352/j.issn.1001-6325.2024.06.0742

Pheochromocytomas/Paragangliomas(PPGLs)are rare neuroendocrine tumors with a high hereditary predisposition.The pseudo-hypoxic PPGLs dominated by SDHx mutations show a higher potential of metastasis.Ap-proximately 10%-17%of PPGLs develop metastasis and patients with metastatic diseases have restricted treatment options and a poor prognosis.Tumor immune microenvironment(TIME)plays a crucial role in the development and progression of tumors as well as predicting patients'prognosis and their response to immune checkpoint inhibitors.Several studies have initially characterized the immune landscape of PPGLs.This review focuses on the infiltration of immune cells,the expression of immune checkpoints in the TIME of PPGLs and their relationships with genetics and metastasis of tumors in order to better understand the mechanisms of tumor immune evasion in PPGLs and pro-vide insights to support novel treatment strategy for metastatic PPGLs.

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Genetic and molecular mechanism changes of adrenocortical carcinoma

Jinghua LIU ; Lin LU

Basic & Clinical Medicine.2024;44(6):748-752. doi:10.16352/j.issn.1001-6325.2024.06.0748

Adreno-cortical carcinoma(ACC)is an uncommon tumor,some of them may produce excessive steroid hormone.The prognosis of ACC is quite poor and current treatment options are relatively limited,especially for pa-tients whose tumor is metastatic and difficult to remove by surgical operation.This makes the management of ACC challenging.Existing studies have shown that the mechanisms of ACC are complex.The molecular changes happen in adrenocortical development and homeostasis may explain the occurrence of ACC.This review focuses on recent studies and summarizes the genetic and molecular mechanism changes that potentially associated with ACC in the development process of the adrenal cortex and multi-omics studies,including genomic changes,epigenetic changes,differences in non-coding RNA,immune microenvironment and features found through multi-omics analy-sis.This information may support screening of therapeutic targets of ACC in future.

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Electrical excitability and aldosterone secretion in the zona glomerulosa cells:the role of ion channels

Xuefeng ZHANG ; Changlong HU

Basic & Clinical Medicine.2024;44(6):753-757. doi:10.16352/j.issn.1001-6325.2024.06.0753

Aldosterone is a kind of steroid hormone produced by the zona glomerulosa(ZG)cells of the adre-nal cortex which plays a crucial regulatory role in fluid-electrolyte balance and blood pressure stability.Aldo-sterone biosynthesis is a calcium-dependent process,and ion channels play a key role in this process.Primary aldosteronism is closely related to mutations in ion channels.Recent studies have highlighted an intriguing rela-tionship between the unique rosette structure of ZG cells and their electrical excitability.Elucidating the con-nection between rosettes and ZG cell electrical excitability as well as aldosterone secretion leads to a deeper un-derstanding of the mechanisms regulating aldosterone secretion and may provide new insights into the pathogen-esis of primary aldosteronism.

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Mechanisms of cell death and proliferation of aldosterone-producing adenoma

Yinjie GAO ; Anli TONG

Basic & Clinical Medicine.2024;44(6):758-762. doi:10.16352/j.issn.1001-6325.2024.06.0758

Aldosterone-producing adenoma(APA)is one of the main causes of primary aldosteronism(PA).Cur-rent researches on its autonomous secretion of aldosterone mainly focus on the detection of somatic driver genetic mutations.However,the specific mechanisms underlying the death and proliferation of adrenal cortical cells and the occurrence and development of adenomas are still unclear.This study aims to review the research progress on the mechanisms of cell death and proliferation of APA by combining previously published studies on genomics,tran-scriptomics,metabolomics,and epigenetics related to adrenal tissues.

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Therapeutic effect of CAR-γδT cells targeting at BCMA in multiple myeloma

Yinghui LI ; Yi XU ; Jianmin ZHANG ; Hui CHEN ; Wei HE

Basic & Clinical Medicine.2024;44(6):763-771. doi:10.16352/j.issn.1001-6325.2024.06.0763

Objective To construct chimeric antigen receptors modified γδT cells targeting at BCMA(BCMA CAR-γδT)and to evaluate its efficacy of anti-multiple myeloma in vitro.Methods Lentiviral vectors containing BCMA single-chain variable fragment were constructed and transiently transfected into 293T cells.The expression of foreign genes was verified by fluorescence microscopy and Western blot;the lentivirus was packaged and the virus titer was determined by flow cytometry.Human peripheral blood αβT cells were infected and γδT cells were examined for its infection efficiency;LDH release method was used to detect the cytotoxic activity of BCMA CAR-γδT cells against human multiple myeloma cell lines in vitro,and the difference of cytotoxic activity between CAR-γδT cells and CAR-αβT cells was compared by Incucyte S3 Live-Cell Analysis Instrument.Results Twenty-four hours after BCMA-CAR lentiviral vector was transferred into 293T cells,the expression of exogenous ZsGreen was microscopied by fluorescence microscope;CD3ζ was detected by Western blot,which showed that BCMA-CAR could be success-fully expressed.The lentivirus was packaged,collected and concentrated(virus titer of 2.23×108 Tu/mL).Infected αβT cells and γδT cells from human peripheral blood in MOI=5,and the results of flow cytometry showed that infection efficiency of αβT cells was 59.18%±2.56%,γδT cells was 48.15±9.86%.The cytotoxic activity of CAR-γδT cells against human myeloma cell lines MM1.S,H929 with high expression of BCMA and K562 cells with over-expression of BCMA was higher than that of empty vector control γδ T cells,which were signifi-cantly enhanced(P＜0.001),but there was no difference in cell lines negative for BCMA expression;Live-Cell Analysis Instrument results showed that the cytotoxic activity of BCMA CAR-γδT cells and BCMA CAR-αβT cells against H929 in vitro was significantly better than their vector control cells.There was no difference in the cytotoxic activities of BCMA CAR-γδT cells as compared with against BCMA negative cell lines,and so do BCMA CAR-T cells.Conclusions Cytotoxic activity of BCMA CAR-γδT targeting at BCMA in vitro was significantly enhanced,which is expected to serve as a novel allogeneic γδT cell product for cell a-doptive immunotherapy of multiple myeloma.

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Bone marrow-derived mesenchymal stem cells relieve the adverse effects of simulated microgravity on mouse cerebral cortex

Jintao GONG ; Jianwei LI ; Yuheng LI ; Qian LI ; Chunhua ZHAO

Basic & Clinical Medicine.2024;44(6):772-778. doi:10.16352/j.issn.1001-6325.2024.06.0772

Objective To explore the protective effects and the underlying mechanisms of bone marrow mesenchymal stem cells(BMSCs)on the brain in microgravity environment.Methods The physiological effects of microgravity were simulated with the hindlimb unloading(HU)mouse model.The animals were divided into 3 groups:the control group(wild-type mice),the hindlimb unloading(HU)group,and the BMSCs treatment group,with six in each.RT-qPCR was adopted to determine the expression levels of pro-inflammatory cytokines(Il-6,Il-1β and Tnf-α)in the cerebral cortex;immunohistochemistry was performed to evaluate the proportions of microglia(IBA-positive)and astrocytes(GFAP-positive);Western blot was used to measure the expression levels of apoptosis-and senescence-related molecules(BAX,BCL-2,p21,and p53).Results Compared with wild-type mice,the expression levels of Il-6,Il-1β and Tnf-α in the cerebral cortex of HU mice were significantly increased(P＜0.05),the expression level of BAX,p21 and p53 was also significantly increased(P＜0.05).However,the expression level of BCL-2 protein were significantly decreased(P＜0.05).The proportion of micro-glia(IBA1 positive)and astrocytes(GFAP positive)was increased(P＜0.05);After BMSCs treatment,the expression level of Il-1β in the cerebral cortex of HU mice was significantly decreased(P＜0.05),the expression levels of BAX,p21 and p53 were significantly decreased(P＜0.05),and the expression level of BCL-2 protein was significantly increased(P＜0.05).The proportion of microglia(IBA1 positive)and astrocytes(GFAP posi-tive)decreased(P＜0.05).Conclusions BMSCs potentially relieve the detrimental effects of simulated micro-gravity on mouse brain by inhibiting inflammation,apoptosis and cellular senescence.

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Dynamic transcriptomic analysis of macrophages infected with Salmonella typhimurium

Boyuan SONG ; Xueli WU ; Xueyuan LI ; Lisha WANG ; Yang CHEN

Basic & Clinical Medicine.2024;44(6):779-785. doi:10.16352/j.issn.1001-6325.2024.06.0779

Objective To comprehensively understand the dynamic transcriptional landscape during infection through investigating the temporal molecular changes in macrophages RAW 264.7 upon infection with Salmonella typhimurium SL1344.Methods Macrophages RAW 264.7 were infected with Salmonella typhimurium SL1344,and cell samples were collected at 0 h,8 h,and 16 h for RNA-sequencing(RNA-seq).Upstream and downstream analyses of the transcriptome data including differential gene expression,clustering,functional annotation,and mo-lecular network studies were conducted to elucidate the signaling pathways changes in macrophages.Results Infec-ted macrophages exhibited significant morphological and transcriptional changes.Differential gene analysis identified significant upregulation and downregulation patterns.Clustering revealed six gene clusters involving various signaling pathways,such as immune response,membrane transport,and lipid catabolic process.Conclusions Macrophages dynamically respond to Salmonella typhimurium infection,displaying distinct temporal gene expression patterns.The coordinated activation of immune response,membrane transport,and lipid catabolic process pathways implies a multifaceted cellular adaptation to external infections,providing essential insights into the molecular mechanisms of macrophage response to Salmonella typhimurium infection.

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Small molecule compounds improve the targeted differentiation efficiency of cerebral organoids from pluripotent stem cells

Wanwan ZHU ; Jinjuan ZHOU ; Jianbo XIU

Basic & Clinical Medicine.2024;44(6):786-792. doi:10.16352/j.issn.1001-6325.2024.06.0786

Objective To optimize the conditions and improve the efficiency for the differentiation of pluripotent stem cells(PSCs)into cerebral organoids.Methods Based on the induction differentiation system for inducing hu-man embryonic stem cells(hESCs)H9 towards cerebral organoids,a combination of small molecule compounds was added to the developmental stage of neural progenitor cells in the early stage of cerebral organoid differentia-tion,and the efficiency of neural progenitor cell formation,apoptosis and differentiation into neurons in cerebral or-ganoids in the differentiation stage were observed through morphology,the expression of marker genes was detected by RT-qPCR and the effect of small molecule compound combination on cerebral organoids was comprehensively evaluated.Results At the critical stage of neural progenitor cell development(1 d-14 d)of cerebral organoids,dorsomorphine,A83-01,GSK-3β inhibitor CHIR99021 and SMAD inhibitor SB-431542 were successively added to the medium.It could significantly increase the expression of marker genes in the neural progenitor cell stage,promote the formation of specific neural tube-like structures and reduce apoptosis in the central region of cerebral organoids.Conclusions By using the combination of four small molecule compounds,the formation efficiency in early cerebral organoids can be significantly improved,apoptosis in cerebral organoids can be reduced,neuronal formation can be promoted,and tissue structure heterogeneity in the culture process can be reduced.

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Effects of intraperitoneal injection of busulfan on metabolic characteristics of spermatogonial stem cells

Zhixin YU ; Xinyu MANG ; Dingfeng ZOU ; Shiying MIAO ; Wei SONG ; Kai LI

Basic & Clinical Medicine.2024;44(6):793-799. doi:10.16352/j.issn.1001-6325.2024.06.0793

Objective To establish a mouse model treated with busulfan and to investigate its effects on the metabo-lism of spermatogonial stem cells(SSCs)of mouse testis.Methods C57BL/6J male mice with age of 8 weeks were injected with 10 mg/kg of busulfan intraperitoneally,then Thy1 positive cells were selected by immunomagnetic beads on day 0,day 5 and day 10 and followed by identification for purity and metabolomic analysis.Results The testis weight ratio decreased and the tissue structure of testis was damaged(P＜0.05).Based on the results of principal component analysis(PCA)and partial least squares discriminant analysis(PLS-DA),there were signifi-cant metabolic differences between the sample groups treated for 0 d,5 d and 10 d.A total of 89 differential metabolites were identified including glutathione(GSH),arginine and unsaturatedfatty acids(UFAs),and their important metabolic pathways involved glycerophospholipid metabolism,arginine and proline metabolism.Conclu-sions Affecting the specific metabolic pathway may result in obvious reproductive toxicity and lead to decrease of testicular weight as well as tissue structure damage in mice.Metabolomic analysis showed that the potential repro-ductive toxicity mechanism of SSCs may be related to the metabolic pathways such as lipid metabolism,arginine and proline metabolism.

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Bioinformatics analysis of differential expression of CD44 in glioblastomas and cell experimental validation

Xu SUN ; Shunshun LI ; Dianheng WANG ; Zhenfeng WANG

Basic & Clinical Medicine.2024;44(6):800-808. doi:10.16352/j.issn.1001-6325.2024.06.0800

Objective To investigate the clinical significance of the differential expression of CD44 in glioblastoma(GBM),and the enrichment of related pathways combined with U87 cell verification.Methods Differential ex-pression and Cox analysis were used to find potential differences in CD44 expression between tumor patients and healthy people as shown by pancancer transcriptome and hazard ratio(HR).Immunoinfiltration and stem-cell re-lated scores of GBM patients with high and low CD44 expression groups were compared and the differences be-tween immune cell subsets,and their correlation with CD44 were further analyzed.Pathway enrichment of differen-tially expressed genes in high and low CD44 expression groups for GBM patients was performed.Over-expression(OE),knockdown(KD)and knockout(KO)of CD44 in U87 cells was done by constructing and packaging lenti-virus and using the electroribonucleoprotein complex;CD44 immunofluorescence staining was performed on U87 and U87 CD44 OE cells.The activity and apoptosis of U87 cells were detected by knocking down CD44 and the mi-gration and invasion ability of U87 cells were detected by knocking down CD44.Results The expression of CD44 in GBM patients was higher than that in healthy people(P＜0.05)and HR＞1.GBM patients with high CD44 ex-pression had higher stromal cell and immunoinfiltration scores,and GBM patients with high and low CD44 expres-sion had significant differences in the ratio of dendritic cells,CD4+memory T cells and regulatory T cells,all posi-tively correlated with CD44 expression(P＜0.05).Differential gene enrichment in GBM patients with high and low CD44 expression was further associated with pathways related to cell migration and apoptosis(P＜0.05).Experi-ments using U87 cells showed that CD44 was normally localized in the cell membrane,but for CD44 OE it accumu-lated in the cytoplasm.CD44 KD can lead to a decrease in cell viability,increased in cell apoptosis,with the cell migration and invasion ability of CD44 KO also decreasing(P＜0.05).Conclusions Low expression of CD44 can decrease viability,migration and invasion of U87 cells and promote apoptosis rate of U87 cells,which leads to the deterioration of GBM and is a related factor potentially affecting the prognosis of GBM patients.

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