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Demystifying the impact of prenatal tobacco exposure on the placental immune microenvironment: Avoiding the tragedy of mending the fold after death 解开产前烟草暴露对胎盘免疫微环境的影响:避免死后补褶的悲剧。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-12 DOI: 10.1111/jcmm.17846
Xiaoxuan Zhao, Yuepeng Jiang, Xiao Ma, Qujia Yang, Xinyi Ding, Hanzhi Wang, Xintong Yao, Linxi Jin, Qin Zhang
Prenatal tobacco exposure (PTE) correlates significantly with a surge in adverse pregnancy outcomes, yet its pathological mechanisms remain partially unexplored. This study aims to meticulously examine the repercussions of PTE on placental immune landscapes, employing a coordinated research methodology encompassing bioinformatics, machine learning and animal studies. Concurrently, it aims to screen biomarkers and potential compounds that could sensitively indicate and mitigate placental immune disorders. In the course of this research, two gene expression omnibus (GEO) microarrays, namely GSE27272 and GSE7434, were included. Gene set enrichment analysis (GSEA) and immune enrichment investigations on differentially expressed genes (DEGs) indicated that PTE might perturb numerous innate or adaptive immune‐related biological processes. A cohort of 52 immune‐associated DEGs was acquired by cross‐referencing the DEGs with gene sets derived from the ImmPort database. A protein–protein interaction (PPI) network was subsequently established, from which 10 hub genes were extracted using the maximal clique centrality (MCC) algorithm (JUN, NPY, SST, FLT4, FGF13, HBEGF, NR0B2, AREG, NR1I2, SEMA5B). Moreover, we substantiated the elevated affinity of tobacco reproductive toxicants, specifically nicotine and nitrosamine, with hub genes through molecular docking (JUN, FGF13 and NR1I2). This suggested that these genes could potentially serve as crucial loci for tobacco's influence on the placental immune microenvironment. To further elucidate the immune microenvironment landscape, consistent clustering analysis was conducted, yielding three subtypes, where the abundance of follicular helper T cells (p < 0.05) in subtype A, M2 macrophages (p < 0.01), neutrophils (p < 0.05) in subtype B and CD8+ T cells (p < 0.05), resting NK cells (p < 0.05), M2 macrophages (p < 0.05) in subtype C were significantly different from the control group. Additionally, three pivotal modules, designated as red, blue and green, were identified, each bearing a close association with differentially infiltrated immunocytes, as discerned by the weighted gene co‐expression network analysis (WGCNA). Functional enrichment analysis was subsequently conducted on these modules. To further probe into the mechanisms by which immune‐associated DEGs are implicated in intercellular communication, 20 genes serving as ligands or receptors and connected to differentially infiltrating immunocytes were isolated. Employing a variety of machine learning techniques, including one‐way logistic regression, LASSO regression, random forest and artificial neural networks, we screened 11 signature genes from the intersection of immune‐associated DEGs and secretory protein‐encoding genes derived from the Human Protein Atlas. Notably, CCL18 and IFNA4 emerged as prospective peripheral blood markers capable of identifying PTE‐induced immune disorders. These markers demonstrated impressive predictive power, as indicated
产前烟草暴露(PTE)与不良妊娠结局的激增显著相关,但其病理机制仍部分未被探索。本研究旨在采用包括生物信息学、机器学习和动物研究在内的协调研究方法,仔细研究PTE对胎盘免疫景观的影响。同时,它旨在筛选能够敏感地指示和减轻胎盘免疫障碍的生物标志物和潜在化合物。在本研究过程中,纳入了两个基因表达综合(GEO)微阵列,即GSE27272和GSE7434。基因集富集分析(GSEA)和对差异表达基因(DEG)的免疫富集研究表明,PTE可能干扰许多先天或适应性免疫相关的生物学过程。通过将DEG与来自ImmPort数据库的基因集交叉引用,获得了52个免疫相关DEG的队列。随后建立了蛋白质-蛋白质相互作用(PPI)网络,使用最大团中心性(MCC)算法(JUN、NPY、SST、FLT4、FGF13、HBEGF、NR0B2、AREG、NR1I2、SEMA5B)从中提取10个枢纽基因。此外,我们通过分子对接证实了烟草生殖毒物,特别是尼古丁和亚硝胺,与中枢基因(JUN、FGF13和NR1I2)的亲和力升高。这表明,这些基因可能是烟草影响胎盘免疫微环境的关键基因座。为了进一步阐明免疫微环境景观,进行了一致的聚类分析,产生了三种亚型,其中卵泡辅助T细胞的丰度(p
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引用次数: 0
Therapeutic effects of medicinal plants and their constituents on lung cancer, in vitro, in vivo and clinical evidence 药用植物及其成分对癌症的治疗作用,体外、体内和临床证据。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-12 DOI: 10.1111/jcmm.17936
Arghavan Memarzia, Saeideh Saadat, Fereshteh Asgharzadeh, Sepide Behrouz, Gert Folkerts, Mohammad Hossein Boskabady

The most common type of cancer in the world is lung cancer. Traditional treatments have an important role in cancer therapy. In the present review, the most recent findings on the effects of medicinal plants and their constituents or natural products (NP) in treating lung cancer are discussed. Empirical studies until the end of March 2022 were searched using the appropriate keywords through the databases PubMed, Science Direct and Scopus. The extracts and essential oils tested were all shown to effect lung cancer by several mechanisms including decreased tumour weight and volume, cell viability and modulation of cytokine. Some plant constituents increased expression of apoptotic proteins, the proportion of cells in the G2/M phase and subG0/G1 phase, and Cyt c levels. Also, natural products (NP) activate apoptotic pathways in lung cancer cell including p-JNK, Akt/mTOR, PI3/ AKT and Bax, Bcl2, but suppressed AXL phosphorylation. Plant-derived substances altered the cell morphology, reduced cell migration and metastasis, oxidative marker production, p-eIF2α and GRP78, IgG, IgM levels and reduced leukocyte counts, LDH, GGT, 5′NT and carcinoembryonic antigen (CEA). Therefore, medicinal plant extracts and their constituents could have promising therapeutic value for lung cancer, especially if used in combination with ordinary anti-cancer drugs.

世界上最常见的癌症是癌症。传统疗法在癌症治疗中具有重要作用。本文综述了药用植物及其成分或天然产物(NP)治疗肺癌的最新研究成果。截至2022年3月底的实证研究使用适当的关键词通过PubMed、Science Direct和Scopus数据库进行搜索。测试的提取物和精油都显示出通过多种机制影响癌症,包括降低肿瘤重量和体积、细胞活力和调节细胞因子。一些植物成分增加了凋亡蛋白的表达、G2/M期和亚G0/G1期细胞的比例以及Cyt-c水平。此外,天然产物(NP)激活癌症细胞中的凋亡途径,包括p-JNK、Akt/mTOR、PI3/Akt和Bax、Bcl2,但抑制AXL磷酸化。植物来源的物质改变了细胞形态,减少了细胞迁移和转移、氧化标记物产生、p-eIF2α和GRP78、IgG、IgM水平,并减少了白细胞计数、LDH、GGT、5'NT和癌胚抗原(CEA)。因此,药用植物提取物及其成分对癌症具有很好的治疗价值,特别是与普通抗癌药物联合使用。
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引用次数: 1
Combinations of EGFR and MET inhibitors reduce proliferation and invasiveness of mucosal melanoma cells EGFR和MET抑制剂的组合降低了粘膜黑色素瘤细胞的增殖和侵袭性。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-07 DOI: 10.1111/jcmm.17935
Aleksandra Simiczyjew, Justyna Wądzyńska, Magdalena Kot, Marcin Ziętek, Rafał Matkowski, Mai P. Hoang, Piotr Donizy, Dorota Nowak

Mucosal melanoma (MM) is a very rare and aggressive type of cancer for which immunotherapy or targeted therapy such as BRAF/MEK inhibitors, used in cutaneous melanoma, usually fail. Due to our earlier experience showing the high effectiveness of epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (MET) inhibitors in reducing the activation of the MAPK and PI3K/AKT signalling pathways, we aim to test whether these drugs would also be effective for mucosal melanoma. Cells representing two commercially available mucosal melanoma cell lines (GAK and HMVII) and one cell line obtained from a patient's vaginal melanoma were treated with MET or EGFR inhibitors, or combinations of these agents. The dual-inhibitor treatment strategy resulted in a decrease of cell proliferation, migration and invasion. Moreover, combinations of inhibitors led to reduction of pEGFR/EGFR and pMET/MET ratio and downregulation of PI3K/AKT and MEK/ERK1/2-based signalling pathways. Our findings indicate a potential therapeutic strategy based on EGFR and MET inhibitors in mucosal melanoma, which should be further evaluated in vivo and in clinical experiments. They also suggest that targeting multiple receptor tyrosine kinases may block signalling crosstalk and possibly delay the appearance of resistance to kinase inhibitors in mucosal melanoma cells.

粘膜黑色素瘤(MM)是一种非常罕见和侵袭性的癌症类型,用于皮肤黑色素瘤的免疫疗法或靶向治疗(如BRAF/MEK抑制剂)通常失败。由于我们早期的经验表明,表皮生长因子受体(EGFR)和肝细胞生长因子受体抑制剂在减少MAPK和PI3K/AKT信号通路激活方面具有高效性,我们旨在测试这些药物是否也对粘膜黑色素瘤有效。用MET或EGFR抑制剂或这些药物的组合处理代表两种市售粘膜黑色素瘤细胞系(GAK和HMVII)和一种从患者阴道黑色素瘤获得的细胞系的细胞。双重抑制剂治疗策略导致细胞增殖、迁移和侵袭减少。此外,抑制剂的组合导致pEGFR/EGFR和pMET/MET比率的降低以及PI3K/AKT和MEK/ERK1/2基信号通路的下调。我们的研究结果表明,基于EGFR和MET抑制剂的粘膜黑色素瘤潜在治疗策略,应在体内和临床实验中进一步评估。他们还表明,靶向多种受体酪氨酸激酶可能阻断信号串扰,并可能延迟粘膜黑色素瘤细胞对激酶抑制剂产生耐药性。
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引用次数: 0
The role of regulatory T cells in the pathogenesis of acute kidney injury 调节性T细胞在急性肾损伤发病机制中的作用。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-04 DOI: 10.1111/jcmm.17771
Xiaoyou Liu, Jianmin Hu, Guorong Liao, Ding Liu, Song Zhou, Jie Zhang, Jun Liao, Zefeng Guo, Yuzhu Li, Siqiang Yang, Shichao Li, Hua Chen, Ying Guo, Min Li, Lipei Fan, Liuyang Li, Ming Zhao, Yongguang Liu

The incidence of acute kidney injury (AKI) is on the rise and is associated with high mortality; however, there are currently few effective treatments. Moreover, the relationship between Tregs and other components of the immune microenvironment (IME) in the pathogenesis of AKI remains unclear. We downloaded four publicly accessible AKI datasets, GSE61739, GSE67401, GSE19130, GSE81741, GSE19288 and GSE106993 from the gene expression omnibus (GEO) database. Additionally, we gathered two kidney single-cell sequencing (scRNA-seq) samples from the Department of Organ Transplantation at Zhujiang Hospital of Southern Medical University to investigate chronic kidney transplant rejection (CKTR). Moreover, we also collected three samples of normal kidney tissue from GSE131685. By analysing the differences in immune cells between the AKI and Non-AKI groups, we discovered that the Non-AKI group contained a significantly greater number of Tregs than the AKI group. Additionally, the activation of signalling pathways, such as inflammatory molecules secretion, immune response, glycolytic metabolism, NOTCH, FGF, NF-κB and TLR4, was significantly greater in the AKI group than in the Non-AKI group. Additionally, analysis of single-cell sequencing data revealed that Tregs in patients with chronic kidney rejection and in normal kidney tissue have distinct biology, including immune activation, cytokine production, and activation fractions of signalling pathways such as NOTCH and TLR4. In this study, we found significant differences in the IME between AKI and Non-AKI, including differences in Tregs cells and activation levels of biologically significant signalling pathways. Tregs were associated with lower activity of signalling pathways such as inflammatory response, inflammatory molecule secretion, immune activation, glycolysis.

急性肾损伤(AKI)的发病率呈上升趋势,并与高死亡率有关;然而,目前很少有有效的治疗方法。此外,Tregs和免疫微环境(IME)的其他成分在AKI发病机制中的关系尚不清楚。我们从基因表达综合数据库(GEO)下载了四个可公开访问的AKI数据集,即GSE61739、GSE67401、GSE19130、GSE81741、GSE1 9288和GSE106993。此外,我们从南方医科大学珠江医院器官移植科收集了两份肾脏单细胞测序(scRNA-seq)样本,以研究慢性肾移植排斥反应(CKTR)。此外,我们还从GSE131685中采集了三份正常肾组织样本。通过分析AKI组和非AKI组之间免疫细胞的差异,我们发现非AKI的Treg数量明显多于AKI组。此外,信号通路的激活,如炎症分子分泌、免疫反应、糖酵解代谢、NOTCH、FGF、NF-κB和TLR4,在AKI组中显著高于非AKI组。此外,对单细胞测序数据的分析显示,慢性肾排斥反应患者和正常肾组织中的Tregs具有不同的生物学特性,包括免疫激活、细胞因子产生以及NOTCH和TLR4等信号通路的激活部分。在这项研究中,我们发现AKI和非AKI之间的IME存在显著差异,包括Tregs细胞和生物重要信号通路激活水平的差异。Tregs与炎症反应、炎症分子分泌、免疫激活、糖酵解等信号通路活性较低有关。
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引用次数: 0
Design and preclinical testing of an anti-CD41 CAR T cell for the treatment of acute megakaryoblastic leukaemia 用于治疗急性巨核细胞白血病的抗CD41 CAR T细胞的设计和临床前测试。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-04 DOI: 10.1111/jcmm.17810
Adrian Bogdan Tigu, Catalin Sorin Constantinescu, Patric Teodorescu, David Kegyes, Raluca Munteanu, Richard Feder, Mareike Peters, Ioana Pralea, Cristina Iuga, Diana Cenariu, Andra Marcu, Alina Tanase, Anca Colita, Rares Drula, Jon Thor Bergthorsson, Victor Greiff, Delia Dima, Cristina Selicean, Ioana Rus, Mihnea Zdrenghea, Diana Gulei, Gabriel Ghiaur, Ciprian Tomuleasa

Acute megakaryoblastic leukaemia (AMkL) is a rare subtype of acute myeloid leukaemia (AML) representing 5% of all reported cases, and frequently diagnosed in children with Down syndrome. Patients diagnosed with AMkL have low overall survival and have poor outcome to treatment, thus novel therapies such as CAR T cell therapy could represent an alternative in treating AMkL. We investigated the effect of a new CAR T cell which targets CD41, a specific surface antigen for M7-AMkL, against an in vitro model for AMkL, DAMI Luc2 cell line. The performed flow cytometry evaluation highlighted a percentage of 93.8% CAR T cells eGFP-positive and a limited acute effect on lowering the target cell population. However, the interaction between effector and target (E:T) cells, at a low ratio, lowered the cell membrane integrity, and reduced the M7-AMkL cell population after 24 h of co-culture, while the cytotoxic effect was not significant in groups with higher E:T ratio. Our findings suggest that the anti-CD41 CAR T cells are efficient for a limited time spawn and the cytotoxic effect is visible in all experimental groups with low E:T ratio.

急性巨核细胞白血病(AMkL)是一种罕见的急性髓细胞白血病(AML)亚型,占所有报告病例的5%,经常在唐氏综合征儿童中诊断。被诊断为AMkL的患者总体生存率较低,治疗效果较差,因此CAR T细胞治疗等新疗法可能是治疗AMkL中的一种替代方案。我们研究了一种靶向CD41(M7 AMkL的特异性表面抗原)的新CAR T细胞对AMkL体外模型DAMI Luc2细胞系的影响。进行的流式细胞术评估强调了93.8%的CAR T细胞eGFP阳性的百分比,以及降低靶细胞群的有限急性作用。然而,效应细胞和靶细胞(E:T)之间的相互作用,在低比率下,降低了细胞膜的完整性,并在24小时后减少了M7 AMkL细胞群 h,而在具有较高E:T比率的组中细胞毒性作用不显著。我们的研究结果表明,抗CD41 CAR T细胞在有限的时间内是有效的,并且在低E:T比率的所有实验组中都可以看到细胞毒性作用。
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引用次数: 1
Effects of blocking CD24 and CD47 ‘don't eat me’ signals in combination with rituximab in mantle-cell lymphoma and chronic lymphocytic leukaemia 阻断CD24和CD47“不吃我”信号与利妥昔单抗联合治疗套细胞淋巴瘤和慢性淋巴细胞白血病的效果。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-31 DOI: 10.1111/jcmm.17868
Andrea Aroldi, Mario Mauri, Daniele Ramazzotti, Matteo Villa, Federica Malighetti, Valentina Crippa, Federica Cocito, Chiara Borella, Elisa Bossi, Carolina Steidl, Chiara Scollo, Claudia Voena, Roberto Chiarle, Luca Mologni, Rocco Piazza, Carlo Gambacorti-Passerini

Mantle-cell lymphoma (MCL) is a B-cell non-Hodgkin Lymphoma (NHL) with a poor prognosis, at high risk of relapse after conventional treatment. MCL-associated tumour microenvironment (TME) is characterized by M2-like tumour-associated macrophages (TAMs), able to interact with cancer cells, providing tumour survival and resistance to immuno-chemotherapy. Likewise, monocyte-derived nurse-like cells (NLCs) present M2-like profile and provide proliferation signals to chronic lymphocytic leukaemia (CLL), a B-cell malignancy sharing with MCL some biological and phenotypic features. Antibodies against TAMs targeted CD47, a ‘don't eat me’ signal (DEMs) able to quench phagocytosis by TAMs within TME, with clinical effectiveness when combined with Rituximab in pretreated NHL. Recently, CD24 was found as valid DEMs in solid cancer. Since CD24 is expressed during B-cell differentiation, we investigated and identified consistent CD24 in MCL, CLL and primary human samples. Phagocytosis increased when M2-like macrophages were co-cultured with cancer cells, particularly in the case of paired DEMs blockade (i.e. anti-CD24 + anti-CD47) combined with Rituximab. Similarly, unstimulated CLL patients-derived NLCs provided increased phagocytosis when DEMs blockade occurred. Since high levels of CD24 were associated with worse survival in both MCL and CLL, anti-CD24-induced phagocytosis could be considered for future clinical use, particularly in association with other agents such as Rituximab.

套细胞淋巴瘤(MCL)是一种B细胞非霍奇金淋巴瘤(NHL),预后不良,常规治疗后复发风险高。MCL-相关肿瘤微环境(TME)的特征是M2-样肿瘤相关巨噬细胞(TAM),能够与癌症细胞相互作用,提供肿瘤存活率和对免疫化疗的抵抗力。同样,单核细胞衍生的护士样细胞(NLCs)呈现M2样特征,并向慢性淋巴细胞白血病(CLL)提供增殖信号,慢性淋巴细胞白血病是一种B细胞恶性肿瘤,与MCL具有一些生物学和表型特征。针对TAM的抗体靶向CD47,这是一种“不吃我”的信号(DEM),能够抑制TME内TAM的吞噬作用,在预处理的NHL中与利妥昔单抗联合时具有临床有效性。最近,CD24被发现在实体癌症中是有效的DEMs。由于CD24在B细胞分化过程中表达,我们研究并鉴定了MCL、CLL和原代人类样本中一致的CD24。当M2-样巨噬细胞与癌症细胞共同培养时,吞噬作用增加,特别是在配对DEMs阻断(即抗CD24)的情况下 + 抗CD47)与利妥昔单抗组合。类似地,当DEMs阻断发生时,未刺激的CLL患者来源的NLCs提供了增加的吞噬作用。由于高水平的CD24与MCL和CLL中较差的生存率相关,抗CD24诱导的吞噬作用可被考虑用于未来的临床应用,特别是与其他药物如利妥昔单抗联合使用。
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引用次数: 0
Effects of early exercise on cardiac function and lipid metabolism pathway in heart failure 早期运动对心力衰竭患者心功能和脂质代谢途径的影响。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-31 DOI: 10.1111/jcmm.17908
Sérgio Luiz Borges de Souza, Gustavo Augusto Ferreira Mota, Vitor Loureiro da Silva, Danielle Fernandes Vileigas, Paula Grippa Sant'Ana, Cristina Schmitt Gregolin, Rebeca Lopes Figueira, Sabrina Setembre Batah, Alexandre Todorovic Fabro, Gilson Masahiro Murata, Silmeia Garcia Zanati Bazan, Marina Politi Okoshi, Antonio Carlos Cicogna

We employed an early training exercise program, immediately after recovery from surgery, and before severe cardiac hypertrophy, to study the underlying mechanism involved with the amelioration of cardiac dysfunction in aortic stenosis (AS) rats. As ET induces angiogenesis and oxygen support, we aimed to verify the effect of exercise on myocardial lipid metabolism disturbance. Wistar rats were divided into Sham, trained Sham (ShamT), AS and trained AS (AST). The exercise consisted of 5-week sessions of treadmill running for 16 weeks. Statistical analysis was conducted by anova or Kruskal–Wallis test and Goodman test. A global correlation between variables was also performed using a two-tailed Pearson's correlation test. AST rats displayed a higher functional capacity and a lower cardiac remodelling and dysfunction when compared to AS, as well as the myocardial capillary rarefaction was prevented. Regarding metabolic properties, immunoblotting and enzymatic assay raised beneficial effects of exercise on fatty acid transport and oxidation pathways. The correlation assessment indicated a positive correlation between variables of angiogenesis and FA utilisation, as well as between metabolism and echocardiographic parameters. In conclusion, early exercise improves exercise tolerance and attenuates cardiac structural and functional remodelling. In parallel, exercise attenuated myocardial capillary and lipid metabolism derangement in rats with aortic stenosis-induced heart failure.

我们采用早期训练锻炼计划,在手术后立即恢复,在严重心肌肥大之前,研究改善主动脉狭窄(AS)大鼠心功能障碍的潜在机制。由于ET诱导血管生成和氧支持,我们旨在验证运动对心肌脂质代谢紊乱的影响。Wistar大鼠分为Sham、训练Sham(ShamT)、AS和训练AS(AST)。这项运动包括为期5周的16次跑步机跑步 周。统计分析采用方差分析或Kruskal-Wallis检验和Goodman检验。变量之间的全局相关性也使用双尾Pearson相关检验进行。与AS相比,AST大鼠表现出更高的功能能力和更低的心脏重塑和功能障碍,并且防止了心肌毛细血管稀疏。关于代谢特性,免疫印迹和酶测定提出了运动对脂肪酸转运和氧化途径的有益影响。相关性评估表明,血管生成和FA利用的变量之间以及代谢和超声心动图参数之间存在正相关。总之,早期运动可以提高运动耐受性,减轻心脏结构和功能的重塑。同时,运动减轻了主动脉瓣狭窄诱发心力衰竭大鼠的心肌毛细血管和脂质代谢紊乱。
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引用次数: 0
Ion channels and transporters regulate nutrient absorption in health and disease 离子通道和转运体调节健康和疾病中的营养吸收
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-28 DOI: 10.1111/jcmm.17853
Xianmin Lu, Chen Luo, Jiangbo Wu, Ya Deng, Xingyi Mu, Ting Zhang, Xiaoxu Yang, Qi Liu, Zhuo Li, Siqi Tang, Yanxia Hu, Qian Du, Jingyu Xu, Rui Xie

Ion channels and transporters are ubiquitously expressed on cell membrane, which involve in a plethora of physiological process such as contraction, neurotransmission, secretion and so on. Ion channels and transporters is of great importance to maintaining membrane potential homeostasis, which is essential to absorption of nutrients in gastrointestinal tract. Most of nutrients are electrogenic and require ion channels and transporters to absorb. This review summarizes the latest research on the role of ion channels and transporters in regulating nutrient uptake such as K+ channels, Ca2+ channels and ion exchangers. Revealing the mechanism of ion channels and transporters associated with nutrient uptake will be helpful to provide new methods to diagnosis and find potential targets for diseases like diabetes, inflammatory bowel diseases, etc. Even though some of study still remain ambiguous and in early stage, we believe that ion channels and transporters will be novel therapeutic targets in the future.

离子通道和转运体在细胞膜上广泛表达,参与细胞收缩、神经传递、分泌等多种生理过程。离子通道和转运体对维持细胞膜电位稳态具有重要意义,对营养物质在胃肠道的吸收至关重要。大多数营养物质是电致的,需要离子通道和转运体来吸收。本文综述了钾离子通道、钙离子通道和离子交换体等离子通道和转运体在调控养分吸收中的作用。揭示与营养摄取相关的离子通道和转运体的机制将有助于为糖尿病、炎症性肠病等疾病的诊断和发现潜在靶点提供新的方法。尽管一些研究仍处于早期阶段,但我们相信离子通道和转运体将在未来成为新的治疗靶点。
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引用次数: 1
Androgen receptor agonist and antagonist reduce response of cytokine-induced killer cells on prostate cancer cells 雄激素受体激动剂和拮抗剂降低细胞因子诱导的杀伤细胞对前列腺癌症细胞的反应。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-28 DOI: 10.1111/jcmm.17923
Thanakorn Pungsrinont, Margret Ann Schneider, Aria Baniahmad

Despite many advances, prostate cancer (PCa) is still the second most frequently diagnosed cancer and fifth leading cause of cancer death in men worldwide. So far, the promising field of onco-immunology has not yet provided a satisfactory treatment option for PCa. Here we show that the ex vivo expansion and activation of cytokine-induced killer (CIK) cells isolated from primary peripheral blood mononuclear cells induce immune-mediated apoptosis in both human PCa LNCaP and C4-2 cells. Interestingly, pretreating LNCaP and C4-2 cells with either androgen or the androgen receptor (AR) antagonist enzalutamide mediates resistance to this immunogenic attack. This is associated with a reduction of both total cell loss and apoptosis levels suggesting one possible mechanism blunting onco-immunological activity. The data also suggest that secreted factors from AR ligand-treated PCa cell suppress lymphocyte proliferation. Further, we analysed immune-mediated killing activity using conditioned media from LNCaP and C4-2 treated cells. The obtained data suggest that the conditioned media from PCa treated cells does not influence a measurable lymphocyte-mediated apoptosis. However, analysing clonal expansion of activated lymphocytes, the androgen-derived conditioned media suppresses lymphocyte proliferation/expansion suggesting inhibition of onco-immunological activity by pretreatment of PCa cells with AR ligands.

尽管取得了许多进展,但癌症(PCa)仍然是全球第二常见的癌症,也是癌症死亡的第五大原因。到目前为止,肿瘤免疫学领域还没有为前列腺癌提供令人满意的治疗选择。在这里,我们发现从原代外周血单核细胞分离的细胞因子诱导的杀伤细胞(CIK)的离体扩增和激活在人PCa-LNCaP和C4-2细胞中诱导免疫介导的凋亡。有趣的是,用雄激素或雄激素受体(AR)拮抗剂恩扎鲁胺预处理LNCaP和C4-2细胞介导对这种免疫原性攻击的抵抗。这与总细胞损失和细胞凋亡水平的降低有关,这表明一种可能的机制削弱了肿瘤免疫活性。数据还表明,来自AR配体处理的PCa细胞的分泌因子抑制淋巴细胞增殖。此外,我们使用LNCaP和C4-2处理的细胞的条件培养基分析了免疫介导的杀伤活性。所获得的数据表明,来自PCa处理的细胞的条件培养基不影响可测量的淋巴细胞介导的细胞凋亡。然而,分析活化淋巴细胞的克隆扩增,雄激素衍生的条件培养基抑制淋巴细胞增殖/扩增,这表明通过用AR配体预处理PCa细胞来抑制肿瘤免疫活性。
{"title":"Androgen receptor agonist and antagonist reduce response of cytokine-induced killer cells on prostate cancer cells","authors":"Thanakorn Pungsrinont,&nbsp;Margret Ann Schneider,&nbsp;Aria Baniahmad","doi":"10.1111/jcmm.17923","DOIUrl":"10.1111/jcmm.17923","url":null,"abstract":"<p>Despite many advances, prostate cancer (PCa) is still the second most frequently diagnosed cancer and fifth leading cause of cancer death in men worldwide. So far, the promising field of onco-immunology has not yet provided a satisfactory treatment option for PCa. Here we show that the ex vivo expansion and activation of cytokine-induced killer (CIK) cells isolated from primary peripheral blood mononuclear cells induce immune-mediated apoptosis in both human PCa LNCaP and C4-2 cells. Interestingly, pretreating LNCaP and C4-2 cells with either androgen or the androgen receptor (AR) antagonist enzalutamide mediates resistance to this immunogenic attack. This is associated with a reduction of both total cell loss and apoptosis levels suggesting one possible mechanism blunting onco-immunological activity. The data also suggest that secreted factors from AR ligand-treated PCa cell suppress lymphocyte proliferation. Further, we analysed immune-mediated killing activity using conditioned media from LNCaP and C4-2 treated cells. The obtained data suggest that the conditioned media from PCa treated cells does not influence a measurable lymphocyte-mediated apoptosis. However, analysing clonal expansion of activated lymphocytes, the androgen-derived conditioned media suppresses lymphocyte proliferation/expansion suggesting inhibition of onco-immunological activity by pretreatment of PCa cells with AR ligands.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"27 19","pages":"2970-2982"},"PeriodicalIF":5.3,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.17923","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10111181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Environmental-relevant bisphenol A exposure promotes ovarian cancer stemness by regulating microRNA biogenesis 环境相关双酚A暴露通过调节microRNA生物发生促进卵巢癌的发生
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-23 DOI: 10.1111/jcmm.17920
Sophia S. N. Lam, Zeyu Shi, Carman K. M. Ip, Chris K. C. Wong, Alice S. T. Wong

Bisphenol A (BPA) is a ubiquitous environmental xenobiotic impacting millions of people worldwide. BPA has long been proposed to promote ovarian carcinogenesis, but the detrimental mechanistic target remains unclear. Cancer stem cells (CSCs) are considered as the trigger of tumour initiation and progression. Here, we show for the first time that nanomolar (environmentally relevant) concentration of BPA can markedly increase the formation and expansion of ovarian CSCs concomitant. This effect is observed in both oestrogen receptor (ER)-positive and ER-defective ovarian cancer cells, suggesting that is independent of the classical ERs. Rather, the signal is mediated through alternative ER G-protein-coupled receptor 30 (GPR30), but not oestrogen-related receptor α and γ. Moreover, we report a novel role of BPA in the regulation of Exportin-5 that led to dysregulation of microRNA biogenesis through miR-21. The use of GPR30 siRNA or antagonist to inhibit GPR30 expression or activity, respectively, resulted in significant inhibition of ovarian CSCs. Similarly, the CSCs phenotype can be reversed by expression of Exportin-5 siRNA. These results identify for the first time non-classical ER and microRNA dysregulation as novel mediators of low, physiological levels of BPA function in CSCs that may underlie its significant tumour-promoting properties in ovarian cancer.

双酚A (BPA)是一种无处不在的环境外源性物质,影响着全世界数百万人。长期以来,人们一直认为双酚a会促进卵巢癌的发生,但其有害的机制目标尚不清楚。肿瘤干细胞(CSCs)被认为是肿瘤发生和发展的触发因素。在这里,我们首次表明,纳摩尔(环境相关)浓度的双酚a可以显著增加卵巢csc伴随物的形成和扩张。在雌激素受体(ER)阳性和ER缺陷的卵巢癌细胞中都观察到这种作用,表明它独立于经典的ER。相反,该信号是通过替代ER g蛋白偶联受体30 (GPR30)介导的,而不是雌激素相关受体α和γ。此外,我们报道了双酚a在调节export -5中的新作用,该作用通过miR-21导致microRNA生物发生失调。分别使用GPR30 siRNA或拮抗剂抑制GPR30的表达或活性,可显著抑制卵巢CSCs。同样,CSCs的表型也可以通过表达Exportin-5 siRNA来逆转。这些结果首次确定了非经典ER和microRNA失调是CSCs中低生理水平双酚a功能的新介质,可能是其在卵巢癌中显著促肿瘤特性的基础。
{"title":"Environmental-relevant bisphenol A exposure promotes ovarian cancer stemness by regulating microRNA biogenesis","authors":"Sophia S. N. Lam,&nbsp;Zeyu Shi,&nbsp;Carman K. M. Ip,&nbsp;Chris K. C. Wong,&nbsp;Alice S. T. Wong","doi":"10.1111/jcmm.17920","DOIUrl":"10.1111/jcmm.17920","url":null,"abstract":"<p>Bisphenol A (BPA) is a ubiquitous environmental xenobiotic impacting millions of people worldwide. BPA has long been proposed to promote ovarian carcinogenesis, but the detrimental mechanistic target remains unclear. Cancer stem cells (CSCs) are considered as the trigger of tumour initiation and progression. Here, we show for the first time that nanomolar (environmentally relevant) concentration of BPA can markedly increase the formation and expansion of ovarian CSCs concomitant. This effect is observed in both oestrogen receptor (ER)-positive and ER-defective ovarian cancer cells, suggesting that is independent of the classical ERs. Rather, the signal is mediated through alternative ER G-protein-coupled receptor 30 (GPR30), but not oestrogen-related receptor α and γ. Moreover, we report a novel role of BPA in the regulation of Exportin-5 that led to dysregulation of microRNA biogenesis through miR-21. The use of GPR30 siRNA or antagonist to inhibit GPR30 expression or activity, respectively, resulted in significant inhibition of ovarian CSCs. Similarly, the CSCs phenotype can be reversed by expression of Exportin-5 siRNA. These results identify for the first time non-classical ER and microRNA dysregulation as novel mediators of low, physiological levels of BPA function in CSCs that may underlie its significant tumour-promoting properties in ovarian cancer.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"27 18","pages":"2792-2803"},"PeriodicalIF":5.3,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.17920","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10577160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Journal of Cellular and Molecular Medicine
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