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Targeting mitochondria by lipid-selenium conjugate drug results in malate/fumarate exhaustion and induces mitophagy-mediated necroptosis suppression. 通过脂质-硒结合药物靶向线粒体会导致苹果酸/富马酸耗竭,并诱导有丝分裂介导的坏死抑制。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.102424
Xing Chang, Hao Zhou, Jinlin Hu, Teng Ge, Kunyang He, Ye Chen, Rongjun Zou, Xiaoping Fan

Atherosclerosis (AS) is a chronic vascular disease primarily affecting large and medium-sized arteries and involves various complex pathological mechanisms and factors. Previous studies have demonstrated a close association between atherosclerosis and inflammatory damage, metabolic disorders, and gut microbiota. It is also closely linked to several cellular processes, such as endothelial cell pyroptosis, ferroptosis, mitophagy, mitochondrial dynamics, and mitochondrial biogenesis. Mitophagy has been recognized as a previously unexplored mechanism contributing to endothelial injury in atherosclerosis. Our study aims to further elucidate the potential relationship and mechanisms between AS-induced mitophagy dysfunction and the interaction of TMBIM6 and NDUFS4. Data from the study demonstrated that atherosclerosis in AS mice was associated with substantial activation of inflammatory and oxidative stress damage, along with a marked reduction in endothelial mitophagy expression and increased pathological mitochondrial fission, leading to mitochondrial homeostasis disruption. However, under pharmacological intervention, mitophagy levels significantly increased, pathological mitochondrial fission was notably reduced, and oxidative stress and inflammatory damage were suppressed, while necroptotic pathways in endothelial cells were significantly blocked. Interestingly, the deletion of TMBIM6 or NDUFS4 in animal models or cell lines markedly impaired the therapeutic effects of the drug, disrupting its regulation of mitophagy and mitochondrial fission, and leading to the re-emergence of inflammatory responses and oxidative stress damage. Metabolomics analysis further revealed that autophagy plays a pivotal regulatory role during drug intervention and after genetic modification of TMBIM6 and NDUFS4. The activation of autophagy (macroautophagy/mitophagy) alleviated the negative effects of mitochondrial fission and inflammatory damage induced by lipid stress in endothelial cells, a regulatory mechanism likely associated with the TMBIM6-NDUFS4 axis. Subsequent animal gene modification experiments demonstrated that knocking out TMBIM6-NDUFS4 negates the therapeutic effects of the drug on lipid-induced damage and metabolic function. In summary, our research reveals a phenotypic regulatory mechanism of endothelial cell stress damage through mitophagy, influenced by the interaction of TMBIM6 and NDUFS4. Pharmacological intervention can restore mitochondrial homeostasis in endothelial cells by regulating mitophagy via the TMBIM6-NDUFS4 pathway. This novel insight suggests that TMBIM6-NDUFS4 may serve as a key therapeutic target for atherosclerosis.

动脉粥样硬化(AS)是一种主要影响大、中动脉的慢性血管疾病,涉及各种复杂的病理机制和因素。以往的研究表明,动脉粥样硬化与炎症损伤、代谢紊乱和肠道微生物群密切相关。动脉粥样硬化还与多个细胞过程密切相关,如内皮细胞热噬、铁噬、有丝分裂、线粒体动力学和线粒体生物生成。有丝分裂被认为是动脉粥样硬化中导致内皮损伤的一种尚未探索的机制。我们的研究旨在进一步阐明AS诱导的有丝分裂功能障碍与TMBIM6和NDUFS4相互作用之间的潜在关系和机制。研究数据表明,AS小鼠的动脉粥样硬化与炎症和氧化应激损伤的大量激活有关,同时内皮细胞有丝分裂表达明显减少,病理性线粒体裂变增加,导致线粒体平衡紊乱。然而,在药物干预下,内皮细胞的有丝分裂水平明显提高,病理性线粒体裂变明显减少,氧化应激和炎症损伤得到抑制,同时内皮细胞的坏死通路被明显阻断。有趣的是,在动物模型或细胞系中删除 TMBIM6 或 NDUFS4 会明显削弱药物的治疗效果,破坏其对有丝分裂和线粒体分裂的调控,导致炎症反应和氧化应激损伤的再次出现。代谢组学分析进一步揭示了自噬在药物干预期间以及 TMBIM6 和 NDUFS4 基因修饰后起着关键的调控作用。自噬(大自噬/小自噬)的激活减轻了内皮细胞线粒体裂变和脂质应激诱导的炎症损伤的负面影响,这种调控机制可能与 TMBIM6-NDUFS4 轴有关。随后的动物基因修饰实验表明,敲除 TMBIM6-NDUFS4 会抵消药物对脂质诱导的损伤和代谢功能的治疗效果。总之,我们的研究揭示了通过有丝分裂对内皮细胞应激损伤的表型调控机制,该机制受 TMBIM6 和 NDUFS4 相互作用的影响。药理干预可通过 TMBIM6-NDUFS4 途径调节有丝分裂,从而恢复内皮细胞的线粒体稳态。这一新颖见解表明,TMBIM6-NDUFS4 可作为动脉粥样硬化的关键治疗靶点。
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引用次数: 0
SUMOylation modification of HNRNPK at the K422 site promotes invasion in glioblastoma. HNRNPK在K422位点的SUMO化修饰会促进胶质母细胞瘤的侵袭。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-21 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.102051
Wenguo Zhao, Jiazheng Wang, Feihu Zhao, Yaquan Li, Zhuo Li, Xingang Li, Anjing Chen

Glioblastoma multiforme (GBM) is a highly heterogeneous brain tumor with limited treatment options. Recent studies revealed cellular heterogeneity and the potential for interconversion between distinct cell types on the basis of RNA sequencing and single-cell analyses. The ability of different cell types to adapt to their surrounding environment and undergo transformation significantly complicates the study and treatment of GBM. In this study, we reveal that HNRNPK-SUMO1 expression is predominantly found in the GBM infiltration area. SUMOylation of the K422 residue of HNRNPK interferes with its DNA binding ability, thereby disrupting downstream transcription, and ultimately leading to transitions between different states of glioblastoma stem cells. Although the proneural subtype is considered to have a better prognosis, transitioning towards this state promotes tumor invasion. These findings serve as a reminder to exercise caution when considering treatments targeting specific cellular subtypes.

多形性胶质母细胞瘤(GBM)是一种高度异质性的脑肿瘤,治疗方案有限。最近的研究根据 RNA 测序和单细胞分析揭示了细胞的异质性和不同细胞类型之间相互转化的可能性。不同细胞类型能够适应周围环境并发生转化,这大大增加了 GBM 研究和治疗的复杂性。在这项研究中,我们发现 HNRNPK-SUMO1 主要在 GBM 浸润区表达。HNRNPK的K422残基的SUMO化会干扰其DNA结合能力,从而破坏下游转录,最终导致胶质母细胞瘤干细胞在不同状态之间的转换。虽然朊病毒亚型被认为预后较好,但向这种状态过渡会促进肿瘤侵袭。这些研究结果提醒我们,在考虑针对特定细胞亚型的治疗时要谨慎行事。
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引用次数: 0
Micro(nano)plastics: an Emerging Burden for Human Health. 微(纳米)塑料:人类健康的新负担。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-21 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.99556
Isabella Donisi, Antonino Colloca, Camilla Anastasio, Maria Luisa Balestrieri, Nunzia D'Onofrio

The escalation of plastic pollution represents a global environmental and health problem. Important toxic effects have been attributed to the increasing diffusion of microplastics (MPs) and nanoplastics (NPs) derived from the degradation of plastics. These particles have been ubiquitously observed in the environment, with humans being continuously exposed via ingestion, inhalation and skin contact. Nonetheless, the cellular homeostasis imbalance induced by micro- and nano- plastics (MNPs) in human health has been only recently shown, while most evidence and molecular mechanisms derived from studies in vitro and in vivo models. To date, the majority of available results testified the accumulation of MNPs in the cardiovascular, nervous, reproductive and digestive systems, and recently clear evidence about cardiovascular toxic effects of MNPs has been provided in humans. In this context, this review aims to provide a comprehensive update about the most recent studies reporting the effects of MNPs in different models, focusing on the available evidence in the main areas of study related to human health. Hopefully, this review will contribute to raise awareness about the toxicity and oxidative alteration exerted by MNPs, supporting the elaboration of new strategies to counteract plastic pandemics.

塑料污染的加剧是一个全球性的环境和健康问题。塑料降解过程中产生的微塑料(MPs)和纳米塑料(NPs)不断扩散,产生了重要的毒性影响。这些微粒在环境中无处不在,人类通过摄入、吸入和皮肤接触等方式不断接触到它们。然而,微塑料和纳米塑料(MNPs)对人体健康造成的细胞平衡失调最近才被证实,而大多数证据和分子机制都来自体外和体内模型研究。迄今为止,大多数现有结果都证明了 MNPs 在心血管、神经、生殖和消化系统中的蓄积,最近还提供了有关 MNPs 对人类心血管毒性影响的明确证据。在此背景下,本综述旨在全面更新报告 MNPs 在不同模型中影响的最新研究,重点关注与人类健康相关的主要研究领域的现有证据。希望本综述有助于提高人们对 MNPs 的毒性和氧化作用的认识,从而支持制定应对塑料流行病的新策略。
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引用次数: 0
New insights into non-small cell lung cancer bone metastasis: mechanisms and therapies. 非小细胞肺癌骨转移的新见解:机制与疗法。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-21 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.100960
Man Xue, Li Ma, Pengpeng Zhang, Hui Yang, Zhaoxia Wang

Bone metastasis is a common cause of death in patients with non-small cell lung cancer (NSCLC), with approximately 30-40% of NSCLC patients eventually developing bone metastases. Bone metastasis, especially the occurrence of skeletal-related events (SREs), significantly reduces overall survival (OS) and quality of life (QoL) in patients. Although bone-targeting agents (BTAs) have been shown to reduce SREs and improve QoL in NSCLC patients with bone metastases, the prognosis for these patients remains poor. Understanding the underlying molecular pathways of bone metastasis is crucial for the development of novel therapeutic approaches. Bone metastasis is a complex, multistep process that involves interactions between tumor cells and the bone microenvironment. The bone microenvironment provides a fertile soil for tumor cells, and crosstalk among various signaling pathways and secreted factors also plays a role in regulating the occurrence and progression of bone metastasis in NSCLC. In this article, we provide a comprehensive review of the process, regulatory mechanisms, and clinical treatment in NSCLC bone metastasis, with the hope of assisting with clinical treatment.

骨转移是非小细胞肺癌(NSCLC)患者的常见死因,大约 30%-40% 的 NSCLC 患者最终会发生骨转移。骨转移,尤其是骨骼相关事件(SRE)的发生,大大降低了患者的总生存率(OS)和生活质量(QoL)。尽管骨靶向药物(BTAs)已被证明可以减少骨转移 NSCLC 患者的 SREs 并改善 QoL,但这些患者的预后仍然很差。了解骨转移的潜在分子途径对于开发新型治疗方法至关重要。骨转移是一个复杂的多步骤过程,涉及肿瘤细胞与骨微环境之间的相互作用。骨微环境为肿瘤细胞提供了肥沃的土壤,各种信号通路和分泌因子之间的串联也在调控 NSCLC 骨转移的发生和进展中发挥着作用。本文对NSCLC骨转移的过程、调控机制和临床治疗进行了全面综述,希望对临床治疗有所帮助。
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引用次数: 0
AIMP1-Derived Peptide Secreted from Hair Follicle Stem Cells Promotes Hair Growth by Activating Dermal Papilla Cells. 毛囊干细胞分泌的 AIMP1 衍生肽通过激活真皮乳头细胞促进毛发生长
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-21 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.101127
YounHa Kim, Sang Bum Kim, Ho Lee, Doyeun Kim, Soon Sun Bak, Ina Yoon, Seongmin Cho, Seung Jae Jeong, Yoon Jeon, Jina Kim, Ji-Hee Kim, Soohwan Oh, Khas-Erdene Battogtokh, Min Chul Park, Young Kwan Sung, Sunghoon Kim

Hair follicle stem cells (HFSCs) and dermal papilla cells (DPCs) are crucial in the biogenesis and maintenance of hair follicles (HFs). This study demonstrated that a fragment derived from aminoacyl-tRNA synthetase-interacting multifunctional protein1 (AIMP1) secreted from HFSCs activated DPCs and maintained HF homeostasis. A histological analysis revealed that AIMP1 levels in HF decreased with hair loss. Hair regrowth in AIMP1-induced mice was faster than in non-induced mice. Deletion mapping revealed 41 amino acids (TN41, aa 6-46) as the active region of AIMP1. The N-terminal peptide fragment of AIMP1 generated by MMP1 was secreted from Wnt-treated HFSCs to activate DPCs. TN41 activated Akt and ERK, increased β-catenin, and enhanced DPC activation. TN41 promoted hair shaft elongation in cultured human HFs and improved the hair-inducing activity of cultured DPC spheroids. Our findings suggest that the AIMP1 fragment secreted from HFSCs stimulates active hair regrowth through activating DPCs.

毛囊干细胞(HFSCs)和真皮乳头细胞(DPCs)对毛囊(HFs)的生物生成和维持至关重要。这项研究证明,从毛囊干细胞分泌的氨基酰-tRNA合成酶-相互作用多功能蛋白1(AIMP1)中提取的片段能激活真皮乳头细胞,维持毛囊的平衡。组织学分析表明,HF 中的 AIMP1 水平随着脱发而降低。AIMP1诱导小鼠的毛发再生速度快于非诱导小鼠。缺失图谱显示 41 个氨基酸(TN41,aa 6-46)是 AIMP1 的活性区。由 MMP1 生成的 AIMP1 N 端多肽片段从 Wnt 处理的高频间充质干细胞中分泌出来,激活 DPCs。TN41 激活了 Akt 和 ERK,增加了 β-catenin,并增强了 DPC 的激活。TN41 可促进培养的人类 HF 的毛干伸长,并提高培养的 DPC 球体的毛发诱导活性。我们的研究结果表明,高频间充质干细胞分泌的 AIMP1 片段可通过激活 DPC 刺激毛发再生。
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引用次数: 0
Mechanistic study of celastrol-mediated inhibition of proinflammatory activation of macrophages in IgA nephropathy via down-regulating ECM1. 通过下调 ECM1 抑制 IgA 肾病巨噬细胞促炎激活的机理研究
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-21 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.99738
Juanyong Zhao, Haiyang Liu, Qian Chen, Ming Xia, Lili Wan, Weihong Yu, Chenxi Liu, Xiaomiao Hao, Chengyuan Tang, Guochun Chen, Yu Liu, Fang Yuan, Hong Liu

Increasing evidence suggests that the mononuclear/macrophage system is vital in amplifying the inflammatory cascade in IgA Nephropathy (IgAN). However, the pathogenic mechanism of macrophages in IgAN and targeted treatment strategies still need to be explored. This study found that botanical triterpene celastrol (CLT) effectively alleviated renal lesions, M1-like macrophage infiltration, inflammatory factors production, and improved renal function in IgAN mice. We found that the renal macrophages of IgAN patients had high expression of ECM1, a crucial molecule involved in macrophage inflammatory polarization, positively correlated with the IgAN clinical severity. In murine macrophage Raw 264.7 cells, CLT inhibited macrophage M1-like polarization and the output of TNF-α and IL-6 by downregulating the ECM1/STAT5 pathway. Mechanistically, molecular docking, CESTA, and immunoprecipitation verified that CLT directly bound to ECM1 and increased the ubiquitination of ECM1. Collectively, these results illustrated that CLT inhibited proinflammatory macrophage in IgAN by directly targeting ECM1 to promote ubiquitination degradation of ECM1. Therefore, this study may provide a theoretical basis for exploring the pathogenesis of IgAN and identifying new perspectives for targeted therapy of IgAN.

越来越多的证据表明,单核/巨噬细胞系统在扩大 IgA 肾病(IgAN)的炎症级联过程中起着至关重要的作用。然而,巨噬细胞在 IgAN 中的致病机制和靶向治疗策略仍有待探索。本研究发现,植物三萜类化合物西司他醇(CLT)能有效缓解IgAN小鼠的肾脏病变、M1样巨噬细胞浸润、炎症因子产生,并改善肾功能。我们发现,IgAN 患者肾脏巨噬细胞中参与巨噬细胞炎症极化的关键分子 ECM1 高表达,与 IgAN 临床严重程度呈正相关。在小鼠巨噬细胞 Raw 264.7 细胞中,CLT 通过下调 ECM1/STAT5 通路,抑制巨噬细胞 M1 样极化以及 TNF-α 和 IL-6 的输出。从机理上讲,分子对接、CESTA 和免疫沉淀验证了 CLT 可直接与 ECM1 结合并增加 ECM1 的泛素化。综上所述,这些结果表明,CLT通过直接靶向ECM1促进ECM1泛素化降解,从而抑制了IgAN中的促炎巨噬细胞。因此,本研究可为探索 IgAN 的发病机制提供理论依据,并为 IgAN 的靶向治疗提供新的视角。
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引用次数: 0
Overcoming Barriers in Photodynamic Therapy Harnessing Nanogenerators Strategies. 利用纳米发电机策略克服光动力疗法的障碍。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.100317
Yi Zhou, Pingjin Zou, Xingmin Chen, Ping Chen, Min Shi, Jinyi Lang, Meihua Chen

Photodynamic therapy (PDT) represents a targeted approach for cancer treatment that employs light and photosensitizers (PSs) to induce the generation of reactive oxygen species (ROS). However, PDT faces obstacles including insufficient PS localization, limited light penetration, and treatment resistance. A potential solution lies in nanogenerators (NGs), which function as self-powered systems capable of generating electrical energy. Recent progress in piezoelectric and triboelectric NGs showcases promising applications in cancer research and drug delivery. Integration of NGs with PDT holds the promise of enhancing treatment efficacy by ensuring sustained PS illumination, enabling direct electrical control of cancer cells, and facilitating improved drug administration. This comprehensive review aims to augment our comprehension of PDT principles, explore associated challenges, and underscore the transformative capacity of NGs in conjunction with PDT. By harnessing NG technology alongside PDT, significant advancement in cancer treatment can be realized. Herein, we present the principal findings and conclusions of this study, offering valuable insights into the integration of NGs to overcome barriers in PDT.

光动力疗法(PDT)是一种利用光和光敏剂(PS)诱导活性氧(ROS)生成的癌症靶向治疗方法。然而,PDT 面临着 PS 定位不足、光穿透力有限和治疗阻力等障碍。潜在的解决方案在于纳米发电机(NGs),它是一种能够产生电能的自供电系统。压电纳米发电机和三电纳米发电机的最新进展表明,它们在癌症研究和药物输送方面的应用前景广阔。将 NG 与 PDT 相结合,有望通过确保持续的 PS 照明、实现对癌细胞的直接电控制以及改进给药方式来提高治疗效果。本综述旨在加深我们对光导疗法原理的理解,探讨相关的挑战,并强调伍德灯与光导疗法结合的变革能力。通过将 NG 技术与光动力疗法结合使用,可以实现癌症治疗的重大进步。在此,我们将介绍这项研究的主要发现和结论,并就如何整合 NG 以克服 PDT 的障碍提出宝贵的见解。
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引用次数: 0
Breast cancer-derived CAV1 promotes lung metastasis by regulating integrin α6β4 and the recruitment and polarization of tumor-associated neutrophils. 乳腺癌来源的 CAV1 通过调节整合素 α6β4 以及肿瘤相关中性粒细胞的招募和极化促进肺转移。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.94153
Qing Lin, Siwen Zong, Yi Wang, Youjia Zhou, Keqin Wang, Fuxiu Shi, Jiayang Wang, Mingrui Feng, Wenting Luo, Lifang Zhang, Hui Lin, Lixia Xiong

Lung metastasis in breast cancer (BC) patients is one of the main reasons for their high mortality rate. The most prevalent BC small extracellular vesicles (sEVs receptor, integrin α6β4, has been found to interact with surfactant-associated protein (SFTPC) in lung epithelial cells, making BC more likely to metastasize to the lung. Tumor-associated neutrophils (TANs) play an essential role in BC lung metastasis as a component of the lung pre-metastatic niche (PMN) with two sides. It has been demonstrated that Toll-like Receptor4 (TLR4) can participate in signaling, such as NF-B and NLRP3, to facilitate tumor metastasis. A cellular membrane structural protein called caveolin-1 (CAV1) is associated with BC's proliferation, metastasis, and immunological control. According to our previous research, CAV1 on BC-derived sEVs facilitates the formation of the lung PMN by enhancing tenascin-C (TnC) secretion in lung fibroblasts to promote the deposition of ECM, by increasing the expression of PMN marker genes and inflammatory chemokines in lung epithelial cells, and by supporting N2-type polarization of lung macrophages via inhibiting the PTEN/CCL2/VEGF-A axis. More research is needed to determine how sEVs-mediated CAV1 facilitates BC-targeted metastasis to the lungs. By creating a stable-translocating cell line that stably interfered with CAV1 and a mouse model of BC lung metastasis, we investigated how sEVs-mediated CAV1 promotes BC lung metastasis and TAN recruitment and polarization in vivo and in vitro. In this study, we showed that CAV1 increases the likelihood that BC lung metastasis would occur by controlling the expression of integrin α6β4 and via boosting TANs recruitment and polarization through activating the TLR4-NF-B-IL-6/CCL2 and TLR4/NF-B/NLRP3 signaling pathways. According to our findings, CAV1 regulates integrin α6β4 and modulates TLR4 signaling, both of which are critical for BC lung metastasis. This finding may open new avenues for BC lung metastasis prevention and treatment.

乳腺癌(BC)患者的肺转移是其死亡率高的主要原因之一。研究发现,乳腺癌最常见的细胞外小泡(sEVs)受体--整合素α6β4与肺上皮细胞中的表面活性物质相关蛋白(SFTPC)相互作用,使乳腺癌更容易转移到肺部。肿瘤相关中性粒细胞(TANs)作为肺转移前生态位(PMN)的组成部分,在BC肺转移中扮演着至关重要的角色,具有两面性。有研究表明,Toll样受体4(Toll-like Receptor4,TLR4)可参与NF-B和NLRP3等信号转导,促进肿瘤转移。一种名为洞穴素-1(CAV1)的细胞膜结构蛋白与 BC 的增殖、转移和免疫控制有关。根据我们之前的研究,BC衍生的sEVs上的CAV1通过增强肺成纤维细胞中tenascin-C(TnC)的分泌来促进ECM的沉积,通过增加肺上皮细胞中PMN标记基因和炎性趋化因子的表达,以及通过抑制PTEN/CCL2/VEGF-A轴来支持肺巨噬细胞的N2型极化,从而促进肺PMN的形成。要确定 sEVs 介导的 CAV1 如何促进 BC 向肺部转移,还需要更多的研究。通过创建稳定干扰 CAV1 的稳定转移细胞系和 BC 肺转移小鼠模型,我们研究了 sEVs 介导的 CAV1 如何促进 BC 肺转移以及 TAN 在体内和体外的招募和极化。在这项研究中,我们发现CAV1通过控制整合素α6β4的表达,以及通过激活TLR4-NF-B-IL-6/CCL2和TLR4/NF-B/NLRP3信号通路来促进TANs的招募和极化,从而增加了BC肺转移发生的可能性。根据我们的研究结果,CAV1能调节整合素α6β4和TLR4信号转导,而这两种信号转导对BC肺转移至关重要。这一发现可能会为预防和治疗卡介苗肺转移开辟新的途径。
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引用次数: 0
Targeting PLCG2 Suppresses Tumor Progression, Orchestrates the Tumor Immune Microenvironment and Potentiates Immune Checkpoint Blockade Therapy for Colorectal Cancer. 靶向 PLCG2 可抑制肿瘤进展、协调肿瘤免疫微环境并增强结直肠癌免疫检查点阻断疗法的疗效。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.98200
Xueliang Zhou, Joshua Lin, Yanfei Shao, Huang Zheng, Yi Yang, Shuchun Li, Xiaodong Fan, Hiju Hong, Zhihai Mao, Pei Xue, Sen Zhang, Jing Sun

Background: Tumor progression and limited benefits of immune checkpoint blockade (ICB) therapy have been two major challenges in the clinical management of colorectal cancer (CRC). The objective of our research was to explore the role of PLCG2 in CRC progression, tumor microenvironment, and potentiating ICB therapy. Methods: Based on bioinformatics analysis and a prospective clinical observational study, the expression, prognostic significance, and clinical relevance of PLCG2 in CRC were unveiled. The single-cell and spatial transcriptome revealed the role of PLCG2 in shaping the heterogeneity of the CRC tumor microenvironment. The biological function of PLCG2 was validated by in vivo and in vitro experiments. The underlying mechanisms were elucidated by RNA-seq, western blotting, qRT-PCR, and multicolor immunofluorescence. The multiplex immunohistochemistry and flow cytometry were adopted to clarify the immunomodulatory role of PLCG2 in facilitating CRC immune escape. The translational value of targeting PLCG2 to potentiate the efficacy of ICB therapy and synergistic therapy to improve prognosis was explored in the preclinical animal models. Results: In CRC, PLCG2 exhibited high expression levels and was strongly associated with poor prognosis and advanced clinicopathological characteristics of patients. The single-cell transcriptome shed light on its important role in cell communication and the development and differentiation of immune cells. The spatial transcriptome described the spatial distribution of PLCG2 in CRC tissues. Further mechanistic analysis demonstrated that PLCG2 could promote proliferation, invasion, metastasis, epithelial-mesenchymal transition, and cell cycle regulation and inhibit apoptosis of CRC cells via the Akt-mTOR pathway activation. Furthermore, PLCG2 was found to contribute greatly to the immunosuppressive microenvironment and enhanced immune escape as it significantly suppressed the infiltration and functional activation of CD8+ T cells and promoted the infiltration of Treg cells as well as PD-1 and PD-L1 expression. Meanwhile, knockdown of PLCG2 could potentiate the efficacy of ICB therapy. Conclusion: In summary, we have identified for the first time that PLCG2 could be considered a precise biomarker and promising therapeutic target for predicting CRC prognosis, optimizing individualized treatment, reversing CRC immune escape, and overcoming resistance to ICB therapy.

背景:肿瘤进展和免疫检查点阻断疗法(ICB)疗效有限一直是结直肠癌(CRC)临床治疗的两大挑战。我们的研究旨在探索 PLCG2 在 CRC 进展、肿瘤微环境和 ICB 治疗中的作用。研究方法基于生物信息学分析和前瞻性临床观察研究,揭示了 PLCG2 在 CRC 中的表达、预后意义和临床相关性。单细胞和空间转录组揭示了 PLCG2 在形成 CRC 肿瘤微环境异质性中的作用。体内和体外实验验证了PLCG2的生物学功能。通过RNA-seq、Western印迹、qRT-PCR和多色免疫荧光阐明了其潜在机制。采用多重免疫组化和流式细胞术阐明了 PLCG2 在促进 CRC 免疫逃逸中的免疫调节作用。在临床前动物模型中探讨了靶向 PLCG2 的转化价值,以增强 ICB 治疗和协同治疗的疗效,改善预后。研究结果在 CRC 中,PLCG2 表现出高表达水平,并与患者的不良预后和晚期临床病理特征密切相关。单细胞转录组揭示了 PLCG2 在细胞通讯以及免疫细胞的发育和分化中的重要作用。空间转录组描述了 PLCG2 在 CRC 组织中的空间分布。进一步的机理分析表明,PLCG2可通过激活Akt-mTOR通路促进CRC细胞的增殖、侵袭、转移、上皮-间质转化和细胞周期调控,并抑制细胞凋亡。此外,研究还发现 PLCG2 能显著抑制 CD8+ T 细胞的浸润和功能活化,促进 Treg 细胞的浸润以及 PD-1 和 PD-L1 的表达,从而对免疫抑制性微环境和增强免疫逃逸起到重要作用。同时,敲除 PLCG2 可增强 ICB 治疗的疗效。结论综上所述,我们首次发现 PLCG2 可被视为预测 CRC 预后、优化个体化治疗、逆转 CRC 免疫逃逸和克服 ICB 治疗耐药性的精确生物标志物和有前景的治疗靶点。
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引用次数: 0
Harnessing the Anti-Inflammatory Properties of Polyphenols in the Treatment of Inflammatory Bowel Disease. 利用多酚的抗炎特性治疗炎症性肠病。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.98107
Diego Liviu Boaru, Oscar Fraile-Martinez, Diego De Leon-Oliva, Cielo Garcia-Montero, Patricia De Castro-Martinez, Alejandro Miranda-Gonzalez, Miguel A Saez, Leticia Muñon-Zamarron, Elisa Castillo-Ruiz, Silvestra Barrena-Blázquez, Rafael Cañonez-Zafra, Miguel Ángel Alvarez-Mon, Maria V Toledo-Lobo, Ana M Minaya-Bravo, Laura Lopez-Gonzalez, Raul Diaz-Pedrero, Jose V Saz, Agustin Albillos, Melchor Alvarez-Mon, Luis G Guijarro, Miguel A Ortega

Inflammatory bowel disease (IBD) encompasses a spectrum of chronic inflammatory conditions affecting the gastrointestinal tract, notably ulcerative colitis (UC) and Crohn's disease (CD). Both UC and CD result from the interplay between genetic and environmental factors that trigger an exacerbated immune response against gut microorganisms, leading to non-resolving inflammatory damage in the mucosa of specific zones in the intestine. Despite extensive research, current treatments often entail invasive interventions with considerable adverse effects on patient well-being. Consequently, there is a pressing need to find alternative and complementary therapeutic strategies aimed at ameliorating chronic inflammation and restoring intestinal barrier integrity. Polyphenols are plant-based compounds formed naturally or as semi-synthetic/synthetic derivatives with proven health-promoting effects and translational applications in a broad spectrum of chronic diseases. Preclinical models of IBD largely support the efficacy of a broad variety of polyphenols due to their well-documented antioxidant and modulatory properties on the immune system and gut microbiota. Likewise, a growing number of studies using distinct types of polyphenols are being conducted in humans, although more efforts are still warranted. In the present review, the main polyphenols investigated in vitro and in vivo models of IBD will be summarized, as well as the available trials or observational data accessible in humans. Finally, the role of polyphenols in the clinical context of IBDs, along with the main problematics regarding their translational issues and concerns will be discussed, including bioavailability, their inclusion in healthy dietary patterns and foods, interaction with other drugs, and other important points to be addressed by future research.

炎症性肠病(IBD)包括一系列影响胃肠道的慢性炎症,尤其是溃疡性结肠炎(UC)和克罗恩病(CD)。溃疡性结肠炎和克罗恩病都是遗传和环境因素相互作用的结果,这些因素会引发针对肠道微生物的免疫反应加剧,导致肠道特定区域粘膜的炎症损伤无法缓解。尽管进行了广泛的研究,但目前的治疗方法往往需要进行侵入性干预,对患者的健康造成相当大的不利影响。因此,迫切需要找到替代和辅助治疗策略,以改善慢性炎症并恢复肠道屏障的完整性。多酚是天然形成或作为半合成/合成衍生物的植物性化合物,其促进健康的作用已得到证实,并可转化应用于多种慢性疾病。IBD 的临床前模型在很大程度上支持多种多酚的功效,因为它们对免疫系统和肠道微生物群的抗氧化和调节特性已得到充分证明。同样,越来越多的研究正在人体中使用不同类型的多酚类物质,但仍需做出更多努力。在本综述中,将总结在 IBD 体外和体内模型中研究的主要多酚,以及在人体中可用的试验或观察数据。最后,将讨论多酚在 IBD 临床中的作用,以及有关其转化的主要问题和关注点,包括生物利用度、将其纳入健康饮食模式和食品、与其他药物的相互作用,以及未来研究需要解决的其他重要问题。
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