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Adipocyte pyroptosis occurs in omental tumor microenvironment and is associated with chemoresistance of ovarian cancer. 网膜肿瘤微环境中出现脂肪细胞热解,与卵巢癌的化疗耐药性有关。
IF 11 2区 医学 Q1 Medicine Pub Date : 2024-06-11 DOI: 10.1186/s12929-024-01051-4
Chang-Ni Lin, Yu-Ling Liang, Hsing-Fen Tsai, Pei-Ying Wu, Lan-Yin Huang, Yu-Han Lin, Chieh-Yi Kang, Chao-Ling Yao, Meng-Ru Shen, Keng-Fu Hsu

Background: Ovarian carcinoma (OC) is a fatal malignancy, with most patients experiencing recurrence and resistance to chemotherapy. In contrast to hematogenous metastasizing tumors, ovarian cancer cells disseminate within the peritoneal cavity, especially the omentum. Previously, we reported omental crown-like structure (CLS) number is associated with poor prognosis of advanced-stage OC. CLS that have pathologic features of a dead or dying adipocyte was surrounded by several macrophages is well known a histologic hallmark for inflammatory adipose tissue. In this study, we attempted to clarify the interaction between metastatic ovarian cancer cells and omental CLS, and to formulate a therapeutic strategy for advanced-stage ovarian cancer.

Methods: A three-cell (including OC cells, adipocytes and macrophages) coculture model was established to mimic the omental tumor microenvironment (TME) of ovarian cancer. Caspase-1 activity, ATP and free fatty acids (FFA) levels were detected by commercial kits. An adipocyte organoid model was established to assess macrophages migration and infiltration. In vitro and in vivo experiments were performed for functional assays and therapeutic effect evaluations. Clinical OC tissue samples were collected for immunochemistry stain and statistics analysis.

Results: In three-cell coculture model, OC cells-derived IL-6 and IL-8 could induce the occurrence of pyroptosis in omental adipocytes. The pyroptotic adipocytes release ATP to increase macrophage infiltration, release FFA into TME, uptake by OC cells to increase chemoresistance. From OC tumor samples study, we demonstrated patients with high gasdermin D (GSDMD) expression in omental adipocytes is highly correlated with chemoresistance and poor outcome in advanced-stage OC. In animal model, by pyroptosis inhibitor, DSF, effectively retarded tumor growth and prolonged mice survival.

Conclusions: Omental adipocyte pyroptosis may contribute the chemoresistance in advanced stage OC. Omental adipocytes could release FFA and ATP through the GSDMD-mediate pyroptosis to induce chemoresistance and macrophages infiltration resulting the poor prognosis in advanced-stage OC. Inhibition of adipocyte pyroptosis may be a potential therapeutic modality in advanced-stage OC with omentum metastasis.

背景:卵巢癌(OC)是一种致命的恶性肿瘤:卵巢癌(OC)是一种致命的恶性肿瘤,大多数患者都会复发并对化疗产生抗药性。与血行转移的肿瘤不同,卵巢癌细胞会在腹腔内播散,尤其是网膜。此前,我们曾报道网膜冠状结构(CLS)的数量与晚期卵巢癌的不良预后有关。众所周知,CLS 的病理特征是一个死亡或濒死的脂肪细胞被多个巨噬细胞包围,这是炎性脂肪组织的组织学标志。在本研究中,我们试图阐明转移性卵巢癌细胞与网膜 CLS 之间的相互作用,并制定晚期卵巢癌的治疗策略:方法:建立三细胞(包括卵巢癌细胞、脂肪细胞和巨噬细胞)共培养模型,模拟卵巢癌网膜肿瘤微环境(TME)。Caspase-1活性、ATP和游离脂肪酸(FFA)水平均由商用试剂盒检测。建立了一个脂肪细胞类器官模型来评估巨噬细胞的迁移和浸润。体外和体内实验用于功能测试和疗效评估。收集临床 OC 组织样本进行免疫化学染色和统计分析:结果:在三细胞共培养模型中,OC细胞衍生的IL-6和IL-8可诱导网膜脂肪细胞发生脓毒症。嗜热脂肪细胞释放ATP增加巨噬细胞浸润,释放FFA进入TME,被OC细胞吸收增加化疗耐药性。通过对OC肿瘤样本的研究,我们发现网膜脂肪细胞中高gasdermin D(GSDMD)表达的患者与晚期OC的化疗耐药性和不良预后高度相关。在动物模型中,DSF抑制剂能有效延缓肿瘤生长,延长小鼠生存期:结论:网膜脂肪细胞的热解可能导致晚期卵巢癌患者的化疗耐药。结论:网膜脂肪细胞热解可能导致晚期 OC 的化疗抵抗,网膜脂肪细胞可通过 GSDMD 介导的热解释放 FFA 和 ATP,诱导化疗抵抗和巨噬细胞浸润,从而导致晚期 OC 预后不良。抑制脂肪细胞的嗜热可能是晚期OC网膜转移的一种潜在治疗方法。
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引用次数: 0
Correction: Excess glucose alone depress young mesenchymal stromal/stem cell osteogenesis and mitochondria activity within hours/days via NAD+/ SIRT1 axis. 更正:仅过量葡萄糖就会在数小时/数天内通过 NAD+/ SIRT1 轴抑制年轻间充质基质/干细胞的成骨和线粒体活性。
IF 11 2区 医学 Q1 Medicine Pub Date : 2024-06-07 DOI: 10.1186/s12929-024-01046-1
B Linju Yen, Li-Tzu Wang, Hsiu-Huang Wang, Chin-Pao Hung, Pei-Ju Hsu, Chia-Chi Chang, Chien-Yu Liao, Huey-Kang Sytwu, Men-Luh Yen
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引用次数: 0
The glycosylation deficiency of flavivirus NS1 attenuates virus replication through interfering with the formation of viral replication compartments. 黄病毒 NS1 的糖基化缺陷会通过干扰病毒复制区的形成来减弱病毒复制。
IF 11 2区 医学 Q1 Medicine Pub Date : 2024-06-07 DOI: 10.1186/s12929-024-01048-z
Shuhan Huang, Pan-Deng Shi, Xiao-Xuan Fan, Yang Yang, Cheng-Feng Qin, Hui Zhao, Lei Shi, Yali Ci

Background: Flavivirus is a challenge all over the world. The replication of flavivirus takes place within membranous replication compartments (RCs) derived from endoplasmic reticulum (ER). Flavivirus NS1 proteins have been proven essential for the formation of viral RCs by remodeling the ER. The glycosylation of flavivirus NS1 proteins is important for viral replication, yet the underlying mechanism remains unclear.

Methods: HeLa cells were used to visualize the ER remodeling effects induced by NS1 expression. ZIKV replicon luciferase assay was performed with BHK-21 cells. rZIKV was generated from BHK-21 cells and the plaque assay was done with Vero Cells. Liposome co-floating assay was performed with purified NS1 proteins from 293T cells.

Results: We found that the glycosylation of flavivirus NS1 contributes to its ER remodeling activity. Glycosylation deficiency of NS1, either through N-glycosylation sites mutations or tunicamycin treatment, compromises its ER remodeling activity and interferes with viral RCs formation. Disruption of NS1 glycosylation results in abnormal aggregation of NS1, rather than reducing its membrane-binding activity. Consequently, deficiency in NS1 glycosylation impairs virus replication.

Conclusions: In summary, our results highlight the significance of NS1 glycosylation in flavivirus replication and elucidate the underlying mechanism. This provides a new strategy for combating flavivirus infections.

背景:黄病毒是全世界面临的一个挑战。黄病毒的复制是在内质网(ER)的膜复制区(RC)内进行的。事实证明,黄病毒 NS1 蛋白通过重塑 ER 对病毒 RC 的形成至关重要。黄病毒 NS1 蛋白的糖基化对病毒复制很重要,但其潜在机制仍不清楚。用 BHK-21 细胞进行 ZIKV 复制荧光素酶检测,用 Vero 细胞生成 rZIKV 并进行斑块检测。用 293T 细胞纯化的 NS1 蛋白进行脂质体共浮游实验:结果:我们发现黄病毒 NS1 的糖基化有助于其 ER 重塑活性。通过N-糖基化位点突变或使用曲安奈德处理,NS1的糖基化缺陷会损害其ER重塑活性并干扰病毒RC的形成。NS1 糖基化的破坏会导致 NS1 异常聚集,而不是降低其膜结合活性。因此,NS1糖基化缺陷会损害病毒复制:总之,我们的研究结果强调了NS1糖基化在黄病毒复制中的重要性,并阐明了其潜在机制。这为抗击黄病毒感染提供了一种新策略。
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引用次数: 0
Osteosarcoma in a ceRNET perspective. 从 ceRNET 角度看骨肉瘤。
IF 11 2区 医学 Q1 Medicine Pub Date : 2024-06-05 DOI: 10.1186/s12929-024-01049-y
Nicola Mosca, Nicola Alessio, Alessandra Di Paola, Maria Maddalena Marrapodi, Umberto Galderisi, Aniello Russo, Francesca Rossi, Nicoletta Potenza

Osteosarcoma (OS) is the most prevalent and fatal type of bone tumor. It is characterized by great heterogeneity of genomic aberrations, mutated genes, and cell types contribution, making therapy and patients management particularly challenging. A unifying picture of molecular mechanisms underlying the disease could help to transform those challenges into opportunities.This review deeply explores the occurrence in OS of large-scale RNA regulatory networks, denominated "competing endogenous RNA network" (ceRNET), wherein different RNA biotypes, such as long non-coding RNAs, circular RNAs and mRNAs can functionally interact each other by competitively binding to shared microRNAs. Here, we discuss how the unbalancing of any network component can derail the entire circuit, driving OS onset and progression by impacting on cell proliferation, migration, invasion, tumor growth and metastasis, and even chemotherapeutic resistance, as distilled from many studies. Intriguingly, the aberrant expression of the networks components in OS cells can be triggered also by the surroundings, through cytokines and vesicles, with their bioactive cargo of proteins and non-coding RNAs, highlighting the relevance of tumor microenvironment. A comprehensive picture of RNA regulatory networks underlying OS could pave the way for the development of innovative RNA-targeted and RNA-based therapies and new diagnostic tools, also in the perspective of precision oncology.

骨肉瘤(Osteosarcoma,OS)是最常见、最致命的骨肿瘤。它的特点是基因组畸变、突变基因和细胞类型贡献的巨大异质性,使得治疗和患者管理特别具有挑战性。本综述深入探讨了操作系统中出现的大规模 RNA 调控网络,即 "竞争性内源性 RNA 网络"(ceRNET),其中不同的 RNA 生物型,如长非编码 RNA、环状 RNA 和 mRNA 可通过竞争性结合到共享的 microRNA 上,从而在功能上相互作用。在此,我们将讨论任何一个网络组件的失衡如何使整个电路脱轨,并通过影响细胞增殖、迁移、侵袭、肿瘤生长和转移甚至化疗耐药性来驱动 OS 的发生和发展,这一点已在许多研究中得到了提炼。耐人寻味的是,OS 细胞中网络成分的异常表达也可由周围环境通过细胞因子和囊泡及其生物活性蛋白和非编码 RNA 触发,这凸显了肿瘤微环境的相关性。从精准肿瘤学的角度来看,全面了解操作系统所依赖的 RNA 调控网络可为开发创新的 RNA 靶向疗法和基于 RNA 的疗法以及新的诊断工具铺平道路。
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引用次数: 0
Immunoglobulin and T cell receptor repertoire changes induced by a prototype vaccine against Chagas disease in naïve rhesus macaques. 原型恰加斯病疫苗诱导天真猕猴体内免疫球蛋白和 T 细胞受体谱系发生变化。
IF 11 2区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1186/s12929-024-01050-5
Eric Dumonteil, Weihong Tu, Hans Desale, Kelly Goff, Preston Marx, Jaime Ortega-Lopez, Claudia Herrera

Background: A vaccine against Trypanosoma cruzi, the agent of Chagas disease, would be an excellent additional tool for disease control. A recombinant vaccine based on Tc24 and TSA1 parasite antigens was found to be safe and immunogenic in naïve macaques.

Methods: We used RNA-sequencing and performed a transcriptomic analysis of PBMC responses to vaccination of naïve macaques after each vaccine dose, to shed light on the immunogenicity of this vaccine and guide the optimization of doses and formulation. We identified differentially expressed genes and pathways and characterized immunoglobulin and T cell receptor repertoires.

Results: RNA-sequencing analysis indicated a clear transcriptomic response of PBMCs after three vaccine doses, with the up-regulation of several immune cell activation pathways and a broad non-polarized immune profile. Analysis of the IgG repertoire showed that it had a rapid turnover with novel IgGs produced following each vaccine dose, while the TCR repertoire presented several persisting clones that were expanded after each vaccine dose.

Conclusions: These data suggest that three vaccine doses may be needed for optimum immunogenicity and support the further evaluation of the protective efficacy of this vaccine.

背景:针对南美锥虫病病原体--克鲁斯锥虫的疫苗将是控制疾病的又一绝佳工具。研究发现,基于 Tc24 和 TSA1 寄生虫抗原的重组疫苗在天真猕猴体内安全且具有免疫原性:方法:我们使用 RNA 测序技术,对天真猕猴接种每剂疫苗后的 PBMC 反应进行了转录组学分析,以揭示该疫苗的免疫原性并指导剂量和配方的优化。我们确定了不同表达的基因和通路,并描述了免疫球蛋白和 T 细胞受体的特征:结果:RNA 序列分析表明,接种三剂疫苗后,PBMC 发生了明显的转录组反应,几种免疫细胞活化通路上调,出现了广泛的非极化免疫特征。对 IgG 重排的分析表明,每次接种疫苗后都会产生新的 IgG,其更新速度很快,而 TCR 重排则出现了几个持续存在的克隆,每次接种疫苗后这些克隆都会扩大:这些数据表明,可能需要接种三剂疫苗才能获得最佳免疫原性,并支持进一步评估该疫苗的保护效力。
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引用次数: 0
Revolution in sepsis: a symptoms-based to a systems-based approach? 败血症的革命:从基于症状的方法到基于系统的方法?
IF 9 2区 医学 Q1 CELL BIOLOGY Pub Date : 2024-05-30 DOI: 10.1186/s12929-024-01043-4
Geoffrey P Dobson, Hayley L Letson, Jodie L Morris

Severe infection and sepsis are medical emergencies. High morbidity and mortality are linked to CNS dysfunction, excessive inflammation, immune compromise, coagulopathy and multiple organ dysfunction. Males appear to have a higher risk of mortality than females. Currently, there are few or no effective drug therapies to protect the brain, maintain the blood brain barrier, resolve excessive inflammation and reduce secondary injury in other vital organs. We propose a major reason for lack of progress is a consequence of the treat-as-you-go, single-nodal target approach, rather than a more integrated, systems-based approach. A new revolution is required to better understand how the body responds to an infection, identify new markers to detect its progression and discover new system-acting drugs to treat it. In this review, we present a brief history of sepsis followed by its pathophysiology from a systems' perspective and future opportunities. We argue that targeting the body's early immune-driven CNS-response may improve patient outcomes. If the barrage of PAMPs and DAMPs can be reduced early, we propose the multiple CNS-organ circuits (or axes) will be preserved and secondary injury will be reduced. We have been developing a systems-based, small-volume, fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat sepsis and endotoxemia. Our early studies indicate that ALM therapy shifts the CNS from sympathetic to parasympathetic dominance, maintains cardiovascular-endothelial glycocalyx coupling, reduces inflammation, corrects coagulopathy, and maintains tissue O2 supply. Future research will investigate the potential translation to humans.

严重感染和败血症是医疗急症。高发病率和高死亡率与中枢神经系统功能障碍、过度炎症、免疫受损、凝血功能障碍和多器官功能障碍有关。男性的死亡风险似乎高于女性。目前,保护大脑、维持血脑屏障、消除过度炎症和减少其他重要器官二次损伤的有效药物疗法很少或根本没有。我们认为,缺乏进展的一个主要原因是 "随治随走 "的单一节点目标方法,而不是更加综合、基于系统的方法。我们需要一场新的革命,以更好地了解人体如何对感染做出反应,确定检测感染进展的新标记物,并发现治疗感染的新系统作用药物。在这篇综述中,我们将简要介绍败血症的历史,然后从系统的角度介绍其病理生理学和未来的机遇。我们认为,针对机体早期免疫驱动的中枢神经系统反应可能会改善患者的预后。如果能在早期减少 PAMPs 和 DAMPs 的冲击,我们认为多个中枢神经系统-器官回路(或轴)将会得到保护,继发性损伤也会减少。我们一直在开发一种基于系统的小容量液体疗法,包括腺苷、利多卡因和镁(ALM),用于治疗败血症和内毒素血症。我们的早期研究表明,ALM疗法能使中枢神经系统从交感神经主导转向副交感神经主导,维持心血管-内皮糖萼耦合,减轻炎症反应,纠正凝血病变,并维持组织的氧气供应。未来的研究将探讨将这种疗法应用于人体的可能性。
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引用次数: 0
Development of a highly effective combination monoclonal antibody therapy against Herpes simplex virus. 开发抗单纯疱疹病毒的高效单克隆抗体联合疗法。
IF 11 2区 医学 Q1 Medicine Pub Date : 2024-05-28 DOI: 10.1186/s12929-024-01045-2
Narges Seyfizadeh, David Kalbermatter, Thomas Imhof, Moritz Ries, Christian Müller, Leonie Jenner, Elisabeth Blumenschein, Alexandra Yendrzheyevskiy, Frank Grün, Kevin Moog, Daniel Eckert, Ronja Engel, Philipp Diebolder, Mohamed Chami, Jürgen Krauss, Torsten Schaller, Michaela Arndt

Background: Infections with Herpes simplex virus (HSV)-1 or -2 usually present as mild chronic recurrent disease, however in rare cases can result in life-threatening conditions with a large spectrum of pathology. Monoclonal antibody therapy has great potential especially to treat infections with virus resistant to standard therapies. HDIT101, a humanized IgG targeting HSV-1/2 gB was previously investigated in phase 2 clinical trials. The aim of this study was to develop a next-generation therapy by combining different antiviral monoclonal antibodies.

Methods: A lymph-node derived phage display library (LYNDAL) was screened against recombinant gB from Herpes simplex virus (HSV) -1 and HDIT102 scFv was selected for its binding characteristics using bio-layer interferometry. HDIT102 was further developed as fully human IgG and tested alone or in combination with HDIT101, a clinically tested humanized anti-HSV IgG, in vitro and in vivo. T-cell stimulating activities by antigen-presenting cells treated with IgG-HSV immune complexes were analyzed using primary human cells. To determine the epitopes, the cryo-EM structures of HDIT101 or HDIT102 Fab bound to HSV-1F as well as HSV-2G gB protein were solved at resolutions < 3.5 Å.

Results: HDIT102 Fab showed strong binding to HSV-1F gB with Kd of 8.95 × 10-11 M and to HSV-2G gB with Kd of 3.29 × 10-11 M. Neutralization of cell-free virus and inhibition of cell-to-cell spread were comparable between HDIT101 and HDIT102. Both antibodies induced internalization of gB from the cell surface into acidic endosomes by binding distinct epitopes in domain I of gB and compete for binding. CryoEM analyses revealed the ability to form heterogenic immune complexes consisting of two HDIT102 and one HDIT101 Fab bound to one gB trimeric molecule. Both antibodies mediated antibody-dependent phagocytosis by antigen presenting cells which stimulated autologous T-cell activation. In vivo, the combination of HDIT101 and HDIT102 demonstrated synergistic effects on survival and clinical outcome in immunocompetent BALB/cOlaHsd mice.

Conclusion: This biochemical and immunological study showcases the potential of an effective combination therapy with two monoclonal anti-gB IgGs for the treatment of HSV-1/2 induced disease conditions.

背景:单纯疱疹病毒(HSV)-1 或-2 感染通常表现为轻微的慢性复发性疾病,但在极少数情况下会导致危及生命的病症,病理范围广泛。单克隆抗体疗法具有巨大的潜力,尤其是在治疗对标准疗法耐药的病毒感染方面。HDIT101是一种针对HSV-1/2 gB的人源化IgG,曾在2期临床试验中进行过研究。本研究的目的是通过结合不同的抗病毒单克隆抗体开发下一代疗法:方法:针对来自单纯疱疹病毒(HSV)-1 的重组 gB 筛选了淋巴结衍生噬菌体展示文库(LYNDAL),并使用生物层干涉测量法筛选出具有结合特性的 HDIT102 scFv。HDIT102 被进一步开发为全人源 IgG,并单独或与经过临床测试的人源化抗 HSV IgG HDIT101 联合进行了体外和体内测试。使用原代人体细胞分析了经 IgG-HSV 免疫复合物处理的抗原递呈细胞的 T 细胞刺激活性。为了确定表位,对 HDIT101 或 HDIT102 Fab 与 HSV-1F 以及 HSV-2G gB 蛋白结合的冷冻电镜结构进行了解析:HDIT102 Fab与HSV-1F gB的结合力很强,Kd为8.95 × 10-11 M,与HSV-2G gB的结合力为3.29 × 10-11 M。这两种抗体通过结合 gB 结构域 I 中的不同表位并竞争结合,诱导 gB 从细胞表面内化到酸性内体。冷冻电镜分析表明,两种抗体都能形成由两个 HDIT102 和一个 HDIT101 Fab 与一个 gB 三聚体分子结合的异源免疫复合物。这两种抗体都能介导抗原呈递细胞进行抗体依赖性吞噬,从而刺激自体 T 细胞活化。在体内,HDIT101和HDIT102的组合对免疫功能正常的BALB/cOlaHsd小鼠的存活率和临床结果具有协同作用:这项生化和免疫学研究展示了两种单克隆抗 IgG 有效联合治疗 HSV-1/2 诱发疾病的潜力。
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引用次数: 0
USP9X-mediated REV1 deubiquitination promotes lung cancer radioresistance via the action of REV1 as a Rad18 molecular scaffold for cystathionine γ-lyase. USP9X介导的REV1去泛素化通过REV1作为胱硫醚γ-赖氨酸酶的Rad18分子支架的作用促进肺癌放射抗性。
IF 11 2区 医学 Q1 Medicine Pub Date : 2024-05-28 DOI: 10.1186/s12929-024-01044-3
Yunshang Chen, Xue Feng, Zilong Wu, Yongqiang Yang, Xinrui Rao, Rui Meng, Sheng Zhang, Xiaorong Dong, Shuangbing Xu, Gang Wu, Xiaohua Jie

Background: Radioresistance is a key clinical constraint on the efficacy of radiotherapy in lung cancer patients. REV1 DNA directed polymerase (REV1) plays an important role in repairing DNA damage and maintaining genomic stability. However, its role in the resistance to radiotherapy in lung cancer is not clear. This study aims to clarify the role of REV1 in lung cancer radioresistance, identify the intrinsic mechanisms involved, and provide a theoretical basis for the clinical translation of this new target for lung cancer treatment.

Methods: The effect of targeting REV1 on the radiosensitivity was verified by in vivo and in vitro experiments. RNA sequencing (RNA-seq) combined with nontargeted metabolomics analysis was used to explore the downstream targets of REV1. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify the content of specific amino acids. The coimmunoprecipitation (co-IP) and GST pull-down assays were used to validate the interaction between proteins. A ubiquitination library screening system was constructed to investigate the regulatory proteins upstream of REV1.

Results: Targeting REV1 could enhance the radiosensitivity in vivo, while this effect was not obvious in vitro. RNA sequencing combined with nontargeted metabolomics revealed that the difference result was related to metabolism, and that the expression of glycine, serine, and threonine (Gly/Ser/Thr) metabolism signaling pathways was downregulated following REV1 knockdown. LC-MS/MS demonstrated that REV1 knockdown results in reduced levels of these three amino acids and that cystathionine γ-lyase (CTH) was the key to its function. REV1 enhances the interaction of CTH with the E3 ubiquitin ligase Rad18 and promotes ubiquitination degradation of CTH by Rad18. Screening of the ubiquitination compound library revealed that the ubiquitin-specific peptidase 9 X-linked (USP9X) is the upstream regulatory protein of REV1 by the ubiquitin-proteasome system, which remodels the intracellular Gly/Ser/Thr metabolism.

Conclusion: USP9X mediates the deubiquitination of REV1, and aberrantly expressed REV1 acts as a scaffolding protein to assist Rad18 in interacting with CTH, promoting the ubiquitination and degradation of CTH and inducing remodeling of the Gly/Ser/Thr metabolism, which leads to radioresistance. A novel inhibitor of REV1, JH-RE-06, was shown to enhance lung cancer cell radiosensitivity, with good prospects for clinical translation.

背景:放射抗性是制约肺癌患者放疗疗效的关键临床因素。REV1 DNA 定向聚合酶(REV1)在修复 DNA 损伤和维持基因组稳定性方面发挥着重要作用。然而,它在肺癌放疗耐药中的作用尚不明确。本研究旨在阐明REV1在肺癌放射治疗耐药性中的作用,确定其内在机制,为肺癌治疗新靶点的临床转化提供理论依据:方法:通过体内和体外实验验证了靶向REV1对放射敏感性的影响。RNA测序(RNA-seq)结合非靶向代谢组学分析用于探索REV1的下游靶点。液相色谱-串联质谱(LC-MS/MS)用于量化特定氨基酸的含量。共免疫沉淀(co-IP)和 GST 下拉实验用于验证蛋白质之间的相互作用。构建了泛素化文库筛选系统,以研究REV1上游的调控蛋白:结果:靶向REV1可以提高体内的放射敏感性,而在体外这种效果并不明显。RNA测序结合非靶向代谢组学发现,差异结果与代谢有关,REV1敲除后,甘氨酸、丝氨酸和苏氨酸(Gly/Ser/Thr)代谢信号通路的表达下调。LC-MS/MS证明,REV1敲除会导致这三种氨基酸的水平降低,而胱硫醚γ-赖氨酸酶(CTH)是其功能的关键。REV1能增强CTH与E3泛素连接酶Rad18的相互作用,并促进Rad18对CTH的泛素化降解。对泛素化化合物库的筛选发现,泛素特异性肽酶9 X-连锁(USP9X)是REV1通过泛素-蛋白酶体系统的上游调控蛋白,它重塑了细胞内Gly/Ser/Thr的代谢:USP9X介导REV1的去泛素化,异常表达的REV1作为支架蛋白协助Rad18与CTH相互作用,促进CTH的泛素化和降解,诱导Gly/Ser/Thr代谢重塑,从而导致放射抗性。研究表明,REV1的新型抑制剂JH-RE-06能增强肺癌细胞的放射敏感性,具有良好的临床应用前景。
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引用次数: 0
Tumor necrosis factor-inducible gene 6 protein and its derived peptide ameliorate liver fibrosis by repressing CD44 activation in mice with alcohol-related liver disease. 肿瘤坏死因子诱导基因 6 蛋白及其衍生肽可抑制 CD44 在酒精相关肝病小鼠体内的激活,从而改善肝纤维化。
IF 9 2区 医学 Q1 Medicine Pub Date : 2024-05-24 DOI: 10.1186/s12929-024-01042-5
Jinsol Han, Chanbin Lee, Hayeong Jeong, Seunghee Jeon, Myunggyo Lee, Haeseung Lee, Yung Hyun Choi, Youngmi Jung

Background: Alcohol-related liver disease (ALD) is a major health concern worldwide, but effective therapeutics for ALD are still lacking. Tumor necrosis factor-inducible gene 6 protein (TSG-6), a cytokine released from mesenchymal stem cells, was shown to reduce liver fibrosis and promote successful liver repair in mice with chronically damaged livers. However, the effect of TSG-6 and the mechanism underlying its activity in ALD remain poorly understood.

Methods: To investigate its function in ALD mice with fibrosis, male mice chronically fed an ethanol (EtOH)-containing diet for 9 weeks were treated with TSG-6 (EtOH + TSG-6) or PBS (EtOH + Veh) for an additional 3 weeks.

Results: Severe hepatic injury in EtOH-treated mice was markedly decreased in TSG-6-treated mice fed EtOH. The EtOH + TSG-6 group had less fibrosis than the EtOH + Veh group. Activation of cluster of differentiation 44 (CD44) was reported to promote HSC activation. CD44 and nuclear CD44 intracellular domain (ICD), a CD44 activator which were upregulated in activated HSCs and ALD mice were significantly downregulated in TSG-6-exposed mice fed EtOH. TSG-6 interacted directly with the catalytic site of MMP14, a proteolytic enzyme that cleaves CD44, inhibited CD44 cleavage to CD44ICD, and reduced HSC activation and liver fibrosis in ALD mice. In addition, a novel peptide designed to include a region that binds to the catalytic site of MMP14 suppressed CD44 activation and attenuated alcohol-induced liver injury, including fibrosis, in mice.

Conclusions: These results demonstrate that TSG-6 attenuates alcohol-induced liver damage and fibrosis by blocking CD44 cleavage to CD44ICD and suggest that TSG-6 and TSG-6-mimicking peptide could be used as therapeutics for ALD with fibrosis.

背景:酒精相关肝病(ALD)是全球关注的主要健康问题,但目前仍缺乏治疗ALD的有效疗法。肿瘤坏死因子诱导基因6蛋白(TSG-6)是间充质干细胞释放的一种细胞因子,已被证明可减少肝纤维化并促进慢性损伤肝脏的小鼠成功修复肝脏。然而,TSG-6在ALD中的作用及其机制仍不甚明了:为了研究TSG-6在伴有肝纤维化的ALD小鼠中的功能,长期喂食含乙醇(EtOH)食物9周的雄性小鼠再接受TSG-6(EtOH + TSG-6)或PBS(EtOH + Veh)治疗3周:结果:以TSG-6处理的小鼠喂食EtOH后,EtOH处理小鼠的严重肝损伤明显减轻。EtOH+TSG-6组的肝纤维化程度低于EtOH+Veh组。据报道,分化簇 44(CD44)的激活可促进造血干细胞的活化。CD44和核CD44胞内结构域(ICD)是CD44激活剂,在活化的造血干细胞和ALD小鼠中上调,而在喂食EtOH的TSG-6暴露小鼠中则显著下调。TSG-6与MMP14(一种能裂解CD44的蛋白水解酶)的催化位点直接相互作用,抑制了CD44裂解为CD44ICD,减少了ALD小鼠的造血干细胞活化和肝纤维化。此外,一种新型多肽的设计包含了一个与MMP14催化位点结合的区域,它能抑制CD44的活化,减轻酒精诱导的小鼠肝损伤,包括肝纤维化:这些结果表明,TSG-6可通过阻断CD44裂解为CD44ICD来减轻酒精诱导的肝损伤和纤维化,并表明TSG-6和TSG-6模拟肽可用作治疗ALD伴纤维化的药物。
{"title":"Tumor necrosis factor-inducible gene 6 protein and its derived peptide ameliorate liver fibrosis by repressing CD44 activation in mice with alcohol-related liver disease.","authors":"Jinsol Han, Chanbin Lee, Hayeong Jeong, Seunghee Jeon, Myunggyo Lee, Haeseung Lee, Yung Hyun Choi, Youngmi Jung","doi":"10.1186/s12929-024-01042-5","DOIUrl":"10.1186/s12929-024-01042-5","url":null,"abstract":"<p><strong>Background: </strong>Alcohol-related liver disease (ALD) is a major health concern worldwide, but effective therapeutics for ALD are still lacking. Tumor necrosis factor-inducible gene 6 protein (TSG-6), a cytokine released from mesenchymal stem cells, was shown to reduce liver fibrosis and promote successful liver repair in mice with chronically damaged livers. However, the effect of TSG-6 and the mechanism underlying its activity in ALD remain poorly understood.</p><p><strong>Methods: </strong>To investigate its function in ALD mice with fibrosis, male mice chronically fed an ethanol (EtOH)-containing diet for 9 weeks were treated with TSG-6 (EtOH + TSG-6) or PBS (EtOH + Veh) for an additional 3 weeks.</p><p><strong>Results: </strong>Severe hepatic injury in EtOH-treated mice was markedly decreased in TSG-6-treated mice fed EtOH. The EtOH + TSG-6 group had less fibrosis than the EtOH + Veh group. Activation of cluster of differentiation 44 (CD44) was reported to promote HSC activation. CD44 and nuclear CD44 intracellular domain (ICD), a CD44 activator which were upregulated in activated HSCs and ALD mice were significantly downregulated in TSG-6-exposed mice fed EtOH. TSG-6 interacted directly with the catalytic site of MMP14, a proteolytic enzyme that cleaves CD44, inhibited CD44 cleavage to CD44ICD, and reduced HSC activation and liver fibrosis in ALD mice. In addition, a novel peptide designed to include a region that binds to the catalytic site of MMP14 suppressed CD44 activation and attenuated alcohol-induced liver injury, including fibrosis, in mice.</p><p><strong>Conclusions: </strong>These results demonstrate that TSG-6 attenuates alcohol-induced liver damage and fibrosis by blocking CD44 cleavage to CD44ICD and suggest that TSG-6 and TSG-6-mimicking peptide could be used as therapeutics for ALD with fibrosis.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11127441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093543","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
Characterization of the genetic variation and evolutionary divergence of the CLEC18 family. CLEC18 家族遗传变异和进化分化的特征。
IF 11 2区 医学 Q1 Medicine Pub Date : 2024-05-20 DOI: 10.1186/s12929-024-01034-5
Che-Mai Chang, Wei-Chiao Chang, Shie-Liang Hsieh

Background: The C-type lectin family 18 (CLEC18) with lipid and glycan binding capabilities is important to metabolic regulation and innate immune responses against viral infection. However, human CLEC18 comprises three paralogous genes with highly similar sequences, making it challenging to distinguish genetic variations, expression patterns, and biological functions of individual CLEC18 paralogs. Additionally, the evolutionary relationship between human CLEC18 and its counterparts in other species remains unclear.

Methods: To identify the sequence variation and evolutionary divergence of human CLEC18 paralogs, we conducted a comprehensive analysis using various resources, including human and non-human primate reference genome assemblies, human pangenome assemblies, and long-read-based whole-genome and -transcriptome sequencing datasets.

Results: We uncovered paralogous sequence variants (PSVs) and polymorphic variants (PVs) of human CLEC18 proteins, and identified distinct signatures specific to each CLEC18 paralog. Furthermore, we unveiled a novel segmental duplication for human CLEC18A gene. By comparing CLEC18 across human and non-human primates, our research showed that the CLEC18 paralogy probably occurred in the common ancestor of human and closely related non-human primates, and the lipid-binding CAP/SCP/TAPS domain of CLEC18 is more diverse than its glycan-binding CTLD. Moreover, we found that certain amino acids alterations at variant positions are exclusive to human CLEC18 paralogs.

Conclusions: Our findings offer a comprehensive profiling of the intricate variations and evolutionary characteristics of human CLEC18.

背景:C 型凝集素家族 18(CLEC18)具有脂质和糖结合能力,对新陈代谢调节和抵御病毒感染的先天性免疫反应非常重要。然而,人类 CLEC18 包括三个具有高度相似序列的旁系基因,这使得区分各个 CLEC18 旁系基因的遗传变异、表达模式和生物功能具有挑战性。此外,人类 CLEC18 与其他物种同类基因之间的进化关系仍不清楚:为了确定人类 CLEC18 准同源物的序列变异和进化分化,我们利用各种资源进行了综合分析,包括人类和非人灵长类参考基因组组装、人类泛基因组组装以及基于长读数的全基因组和转录组测序数据集:结果:我们发现了人类 CLEC18 蛋白的旁系序列变异(PSVs)和多态变异(PVs),并确定了每个 CLEC18 旁系的特异特征。此外,我们还发现了人类 CLEC18A 基因的一个新的片段重复。通过比较人类和非人灵长类中的CLEC18,我们的研究表明,CLEC18旁系亲属可能发生在人类和近亲非人灵长类的共同祖先中,而且CLEC18的脂质结合CAP/SCP/TAPS结构域比其糖类结合CTLD更多样化。此外,我们还发现某些氨基酸在变异位置上的改变是人类 CLEC18 准同源物所独有的:我们的研究结果全面剖析了人类 CLEC18 的复杂变异和进化特征。
{"title":"Characterization of the genetic variation and evolutionary divergence of the CLEC18 family.","authors":"Che-Mai Chang, Wei-Chiao Chang, Shie-Liang Hsieh","doi":"10.1186/s12929-024-01034-5","DOIUrl":"10.1186/s12929-024-01034-5","url":null,"abstract":"<p><strong>Background: </strong>The C-type lectin family 18 (CLEC18) with lipid and glycan binding capabilities is important to metabolic regulation and innate immune responses against viral infection. However, human CLEC18 comprises three paralogous genes with highly similar sequences, making it challenging to distinguish genetic variations, expression patterns, and biological functions of individual CLEC18 paralogs. Additionally, the evolutionary relationship between human CLEC18 and its counterparts in other species remains unclear.</p><p><strong>Methods: </strong>To identify the sequence variation and evolutionary divergence of human CLEC18 paralogs, we conducted a comprehensive analysis using various resources, including human and non-human primate reference genome assemblies, human pangenome assemblies, and long-read-based whole-genome and -transcriptome sequencing datasets.</p><p><strong>Results: </strong>We uncovered paralogous sequence variants (PSVs) and polymorphic variants (PVs) of human CLEC18 proteins, and identified distinct signatures specific to each CLEC18 paralog. Furthermore, we unveiled a novel segmental duplication for human CLEC18A gene. By comparing CLEC18 across human and non-human primates, our research showed that the CLEC18 paralogy probably occurred in the common ancestor of human and closely related non-human primates, and the lipid-binding CAP/SCP/TAPS domain of CLEC18 is more diverse than its glycan-binding CTLD. Moreover, we found that certain amino acids alterations at variant positions are exclusive to human CLEC18 paralogs.</p><p><strong>Conclusions: </strong>Our findings offer a comprehensive profiling of the intricate variations and evolutionary characteristics of human CLEC18.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11103991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065414","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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