International immunopharmacology最新文献_第4页

Corrigendum to "Betulinic acid isolated from Bacopa monniera (L.) Wettst suppresses lipopolysaccharide stimulated interleukin-6 production through modulation of nuclear factor-κB in peripheral blood mononuclear cells" [Int. Immunopharmacol. 10/8 (2010) 843-849]. 通过调节外周血单核细胞中的核因子-κB抑制脂多糖刺激的白细胞介素-6产生"[Int. Immunopharmacol.

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2024-10-25 Epub Date: 2024-08-05 DOI: 10.1016/j.intimp.2024.112648

V Viji, B Shobha, S K Kavitha, M Ratheesh, K Kripa, A Helen

引用次数: 0

Amelioration of experimental autoimmune encephalomyelitis by exogenous soluble PD-L1 is associated with restraining dendritic cell maturation and CCR7-mediated migration 外源性可溶性 PD-L1 对实验性自身免疫性脑脊髓炎的改善作用与抑制树突状细胞成熟和 CCR7 介导的迁移有关

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2024-10-18 DOI: 10.1016/j.intimp.2024.113398

Dendritic cells (DCs) orchestrate both immune activation and immune tolerance in multiple sclerosis (MS). Manipulating the phenotypes and functions of DCs to boost their tolerogenic potential is an appealing strategy for treating MS and its animal model experimental autoimmune encephalomyelitis (EAE). Programmed cell death 1 (PD-1) delivers the immunoinhibitory signals by interacting with PD-1 ligand 1 (PD-L1), which plays a critical role in maintaining immune tolerance. So far, the effects of PD-1/PD-L1 signalling activation on DCs in EAE are poorly understood. Here, the administration of soluble PD-L1 (sPD-L1) protein significantly alleviated the clinical symptoms of myelin oligodendrocyte glycoprotein (MOG)-induced EAE, and inhibited the expression of cluster of differentiation (CD)86, C-C motif chemokine receptor 7 (CCR7) as well as CCR7-mediated trafficking of splenic DCs, accompanied by enhancing their phagocytosis. The impact of sPD-L1 on the surface morphology and mechanical properties of DCs was investigated at the nanoscale, using scanning electron microscope and atomic force microscope. The treatment of sPD-L1 was found to mitigate morphological maturation and biomechanical alterations, specifically in terms of adhesion and elasticity, in bone marrow-derived DCs from EAE. Taken together, our findings suggest that application of exogenous sPD-L1 has a marked suppressive effect on the maturation and migration of DCs in EAE. PD-L1 administration may be a promising therapy for EAE and for MS in the future.

树突状细胞（DC）在多发性硬化症（MS）中协调免疫激活和免疫耐受。操纵树突状细胞的表型和功能以提高其耐受潜能是治疗多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎（EAE）的一种有吸引力的策略。程序性细胞死亡1（PD-1）通过与PD-1配体1（PD-L1）相互作用来传递免疫抑制信号，而PD-L1在维持免疫耐受方面起着至关重要的作用。迄今为止，人们对 PD-1/PD-L1 信号激活对 EAE 中直流细胞的影响还知之甚少。在这里，服用可溶性PD-L1（sPD-L1）蛋白能显著缓解髓鞘少突胶质细胞糖蛋白（MOG）诱导的EAE的临床症状，并抑制分化簇（CD）86、C-C motif趋化因子受体7（CCR7）的表达以及CCR7介导的脾脏DCs的贩运，同时增强其吞噬能力。利用扫描电子显微镜和原子力显微镜在纳米尺度上研究了 sPD-L1 对 DCs 表面形态和机械性能的影响。研究发现，sPD-L1 可减轻 EAE 骨髓源性 DCs 的形态成熟和生物力学改变，特别是在粘附性和弹性方面。综上所述，我们的研究结果表明，应用外源性 sPD-L1 对 EAE 中直流细胞的成熟和迁移有明显的抑制作用。给药 PD-L1 可能是未来治疗 EAE 和多发性硬化症的一种有前途的疗法。

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引用次数: 0

Apigenin alleviates Sjögren’s syndrome-induced salivary gland epithelial cell ferroptosis via ERα signaling-mediated regulation of the ATF3/SLC7A1l axis 芹菜素通过ERα信号介导的ATF3/SLC7A1l轴调节缓解了Sjögren综合征诱导的唾液腺上皮细胞铁突变

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2024-10-18 DOI: 10.1016/j.intimp.2024.113409

Background

In Sjögren’s syndrome (SS)—an autoimmune disease characterized by dry mouth and eyes—salivary gland epithelial cells (SGECs) undergo ferroptosis, which disrupts their integrity and impairs saliva secretion. Apigenin, a phytoestrogen, is known to activate estrogen signalling and alleviate xerostomia in ovariectomized mice; however, its effect on SGEC survival and function in SS remains unclear. We hypothesized that apigenin alleviates SS symptoms and progression by inhibiting ferroptosis in SGECs and aimed to elucidate the underlying mechanism.

Methods

Apigenin (50 mg/kg) was orally gavaged to non-obese diabetic (NOD)/LtJ female mice (SS model); changes in SS functional indicators were analyzed using mRNA sequencing and bioinformatic analyses of submandibular glands. Interferon-gamma (IFN-γ)-stimulated SGECs were used to model SS in vitro; SGEC activity and aquaporin 5 (AQP5) expression were analyzed. Immunohistochemical staining, transmission electron microscopy, RT-qPCR, western blotting and other methods were used to verify the mechanisms.

Results

Apigenin significantly increased salivary secretion and AQP5 expression while inhibiting ferroptosis and immune infiltration in NOD mouse submandibular glands. The oxidative stress gene ATF3 was upregulated and GPX4 was downregulated in NOD mice compared to that in control group (ICR mice); however, apigenin reversed this effect. IFN-γ treatment downregulated AQP5, SLC7A11, and GPX4 expression while promoting ATF3 expression and ferroptosis, which was mitigated by apigenin. ATF3 knockdown increased SLC7A11 and GPX4 expression, inhibiting SS and ferroptosis. Furthermore, apigenin inhibited ferroptosis in SGECs through ESR1 binding to ATF3.

Conclusion

Apigenin alleviates SS by regulating SGEC ferroptosis via the ERα-regulated ATF3/SLC7A11 axis, highlighting its therapeutic potential in SS.

背景在以口干和眼干为特征的自身免疫性疾病--斯约格伦综合征（SS）中，唾液腺上皮细胞（SGEC）会发生铁突变，从而破坏其完整性并影响唾液分泌。芹菜素是一种植物雌激素，可激活雌激素信号传导，缓解卵巢切除小鼠的口干症状；但它对SS中SGEC存活和功能的影响仍不清楚。我们假设芹菜素通过抑制 SGECs 中的铁突变来减轻 SS 的症状和进展，并旨在阐明其潜在机制。方法给非肥胖糖尿病（NOD）/LtJ 雌性小鼠（SS 模型）口服芹菜素（50 mg/kg）；使用 mRNA 测序和生物信息学分析颌下腺，分析 SS 功能指标的变化。用γ干扰素（IFN-γ）刺激的SGECs在体外建立SS模型；分析SGEC的活性和水汽素5（AQP5）的表达。结果芹菜素能显著增加 NOD 小鼠颌下腺的唾液分泌和 AQP5 的表达，同时抑制铁变态反应和免疫浸润。与对照组（ICR 小鼠）相比，NOD 小鼠的氧化应激基因 ATF3 上调，GPX4 下调；但芹菜素能逆转这种效应。IFN-γ 处理下调了 AQP5、SLC7A11 和 GPX4 的表达，同时促进了 ATF3 的表达和铁变态反应，而芹菜素则减轻了这种影响。ATF3 基因敲除增加了 SLC7A11 和 GPX4 的表达，抑制了 SS 和铁突变。结论芹菜素通过ERα调控的ATF3/SLC7A11轴调节SGEC的铁突变，从而缓解了SS，突出了其在SS中的治疗潜力。

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引用次数: 0

Saroglitazar ameliorates 5- Fluorouracil-induced hepatorenal damage in rats 沙格列扎减轻 5-氟尿嘧啶诱发的大鼠肝肾损伤

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2024-10-17 DOI: 10.1016/j.intimp.2024.113407

Rationale

Hepatotoxicity and nephrotoxicity are significant adverse effects caused in cancer patients treated with 5-Flurouracil (5-FU), a pyrimidine analogue anti-metabolite anticancer drug. The purpose of this research was to evaluate the impact of PPAR α/γ agonist (Saroglitazar; SARO) on 5-FU-induced hepatorenal damage in rats.

Methods

Male rats were randomly assigned to four groups: control, 5-FU, 5-FU + SARO (2 mg/kg), and 5-FU + SARO (4 mg/kg). Rats received 75 mg/kg 5-FU intraperitoneally once weekly for three weeks. Saroglitazar (2 and 4 mg/kg/day) was orally supplied by oral syringe for three consecutive weeks. On day 22, rats were euthanized and their livers and kidneys were subjected to morphological, biochemical, histological, and immunohistochemical analysis.

Results

Saroglitazar treatment significantly decreased serum liver and kidney function biomarkers. In addition, it successfully modulated liver and kidney levels of inflammatory mediators and markers (NF-κB P65, TNF-α, cleaved caspase-1, IL-1β and p-p38 MAPK) and oxidative stress-related parameters (MDA, GSH, SOD, Keap1, Nrf-2 and HO-1) in a dose dependent manner. Furthermore, SARO could attenuate 5-FU-induced activation of cleaved caspase-3 as well as improved histopathological examination of both liver and kidney tissues. Significance: Saroglitazar may be a viable therapy option for 5-FU toxicity as it halts the interaction network of NF-kB and Nrf2 signaling pathways and apoptosis.

理由肝毒性和肾毒性是癌症患者使用嘧啶类似物抗代谢抗癌药物 5-氟尿嘧啶（5-FU）治疗时产生的严重不良反应。本研究的目的是评估 PPAR α/γ 激动剂（沙格列扎；SARO）对 5-FU 诱导的大鼠肝肾损伤的影响。方法将雄性大鼠随机分为四组：对照组、5-FU 组、5-FU + SARO 组（2 毫克/千克）和 5-FU + SARO 组（4 毫克/千克）。大鼠每周一次腹腔注射 75 毫克/千克 5-FU，连续注射三周。沙格列扎尔（2 毫克和 4 毫克/千克/天）通过口服注射器连续口服三周。第 22 天，对大鼠实施安乐死，并对其肝脏和肾脏进行形态学、生物化学、组织学和免疫组化分析。此外，它还以剂量依赖的方式成功调节了肝脏和肾脏的炎症介质和标志物（NF-κB P65、TNF-α、裂解的卡巴酶-1、IL-1β和p-p38 MAPK）以及氧化应激相关参数（MDA、GSH、SOD、Keap1、Nrf-2和HO-1）的水平。此外，SARO 还能减轻 5-FU 诱导的裂解 Caspase-3 活化，并改善肝脏和肾脏组织的组织病理学检查。意义重大：Saroglitazar 可以阻止 NF-kB 和 Nrf2 信号通路的相互作用网络和细胞凋亡，因此可能是治疗 5-FU 毒性的一种可行疗法。

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引用次数: 0

Sphingosine kinase 1 counteracts chemosensitivity and immune evasion in diffuse large B cell lymphoma cells via the PI3K/AKT/PD-L1 axis 鞘氨醇激酶 1 通过 PI3K/AKT/PD-L1 轴抵消弥漫大 B 细胞淋巴瘤细胞的化疗敏感性和免疫逃避作用

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2024-10-17 DOI: 10.1016/j.intimp.2024.113361

Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive neoplasm of lymphatic system that represent 38–58 % of non-Hodgkin lymphoma. Chemoresistance and immune escape constitute the major obstacles to the treatment of patients. Sphingosine kinase 1 (SphK1) is involved in multiple processes of cancer. Up to now, little research focuses on its function in DLBCL. In the current research, GEPIA and human Protein Atlas databases confirmed high expression of SphK1 in DLBCL tissues. Analogously, increased expression of SphK1 were determined in DLBCL tissues and cells. Intriguingly, knockdown of SphK1 suppressed DLBCL cell viability and increased chemosensitivity to doxorubicin by decreasing cell viability and increasing caspase-3 activity. Reversely, SphK1 elevation facilitated cancer cell resistance to doxorubicin. Furthermore, loss of SphK1 increased the productions of inflammatory cytokine IFN-γ and TNF-α, but reduced IL-10 levels in co-culture model of CD8 + T cells and DLBCL cells. Importantly, SphK1 knockdown enhanced T cell cytotoxicity to DLBCL cells, while its elevation restrained the ability of T cells to kill cancer cells. Concomitantly, targeting SphK1 enhanced the percentage of CD8 + T cells and attenuated co-culture-evoked CD8 + T cell apoptosis, indicating the important roles in T cell escape. Mechanically, SphK1 overexpression enhanced and its knockdown suppressed activation of the PI3K/AKT/PD-L1 pathway. After blockage of this pathway by its antagonist, the beneficial effects of SpHK1 on chemoresistance and immune escape were abrogated. In vivo, targeting SphK1 inhibited tumor growth and enhanced the anti-tumor efficacy of doxorubicin in DLBCL xenograft tumor, concomitant with the inhibition of the PI3K/AKT/PD-L1 signaling. Collectively, SphK1 knockdown counteracted chemoresistance and immune escape from T cell killing by inhibiting the PI3K/AKT/PD-L1 pathway. Therefore, targeting SphK1 may represent a promising therapeutic strategy for overcoming chemoresistance and immune escape in DLBCL.

弥漫大B细胞淋巴瘤（DLBCL）是一种侵袭性极强的淋巴系统肿瘤，占非霍奇金淋巴瘤的38-58%。化疗抗药性和免疫逃逸是治疗患者的主要障碍。鞘氨醇激酶 1（SphK1）参与了癌症的多个过程。迄今为止，很少有研究关注它在DLBCL中的功能。在目前的研究中，GEPIA和人类蛋白质图谱数据库证实了SphK1在DLBCL组织中的高表达。同样，在 DLBCL 组织和细胞中也发现了 SphK1 的高表达。耐人寻味的是，敲除 SphK1 会抑制 DLBCL 细胞的活力，并通过降低细胞活力和增加 caspase-3 活性来增加细胞对多柔比星的化疗敏感性。反之，SphK1 的升高会促进癌细胞对多柔比星的耐药性。此外，在CD8 + T细胞和DLBCL细胞共培养模型中，SphK1缺失会增加炎症细胞因子IFN-γ和TNF-α的产生，但会降低IL-10的水平。重要的是，SphK1的敲除增强了T细胞对DLBCL细胞的细胞毒性，而其升高则抑制了T细胞杀死癌细胞的能力。同时，靶向 SphK1 可提高 CD8 + T 细胞的比例，并减轻共培养诱发的 CD8 + T 细胞凋亡，这表明 SphK1 在 T 细胞逃逸中发挥着重要作用。在机制上，SphK1 的过表达增强了 PI3K/AKT/PD-L1 通路的激活，而其敲除则抑制了该通路的激活。在通过其拮抗剂阻断该通路后，SpHK1对化疗抗性和免疫逃逸的有益作用被削弱。在体内，在抑制PI3K/AKT/PD-L1信号传导的同时，靶向SphK1可抑制肿瘤生长，并增强多柔比星在DLBCL异种移植瘤中的抗肿瘤疗效。总之，通过抑制PI3K/AKT/PD-L1通路，敲除SphK1可抵消化疗耐药性和T细胞杀伤的免疫逃逸。因此，靶向SphK1可能是克服DLBCL化疗耐药和免疫逃逸的一种有前途的治疗策略。

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引用次数: 0

Palmatine alleviates inflammation and modulates ferroptosis against dextran sulfate sodium (DSS)-induced ulcerative colitis 巴马汀能缓解炎症并调节铁蛋白沉积，对抗右旋糖酐硫酸钠（DSS）诱导的溃疡性结肠炎

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2024-10-17 DOI: 10.1016/j.intimp.2024.113396

UC, also known as ulcerative colitis, is an inflammatory bowel disease that is chronic and nonspecific. Palmatine (PAL), a natural alkaloid active ingredient, has demonstrated predominant protective effects on UC. In spite of this, PAL on UC is unclear in terms of its underlying mechanisms. Thus, this study aimed to investigate its effects and mechanism. By inducing rats with 5 % dextran sulfate sodium (DSS), an in vivo model of UC was developed. and then oral PAL administration. In vitro viability of NCM460 cells was measured using Cell Counting Kit-8. An enzyme-linked immunosorbent assay was used to determine the levels of inflammatory factores. The levels of oxidative stress parameters were also assessed, and the expression level of cyclooxygenase-2 (COX-2), acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), NF-E2-related factor 2(Nrf2), phospho-Nrf2, and heme oxygenase-1 (HO-1) was detected by Western blot. An iron kit was employed to measure iron content in cells and colonic tissues. Results indicated that PAL treatment significantly improved UC in rats, as shown by reduced disease activity index scores and increased colon length, which decreased IL-18, IL-1β, IL-6, TNF-α, MDA, NO, and LDH levels, but increased GSH level in DSS-induced rats and NCM460 cells. Further, PAL treatment markedly decreased COX-2, ACSL4, Nrf2, and HO-1 expression levels while increasing that of GPX4 and phospho-Nrf2. Furthermore, PAL inhibited the iron overload in the cells and colonic tissues. PAL may protect against UC by inhibiting the inflammatory response, oxidative stress, iron load, and suppressing ferroptosis pathway.

UC 又称溃疡性结肠炎，是一种慢性非特异性炎症性肠病。帕马汀（PAL）是一种天然生物碱活性成分，对溃疡性结肠炎有显著的保护作用。尽管如此，PAL 对 UC 的潜在机制尚不清楚。因此，本研究旨在探讨其作用和机制。通过用 5% 右旋糖酐硫酸钠（DSS）诱导大鼠，建立了 UC 体内模型，然后口服 PAL。使用细胞计数试剂盒 8 测定 NCM460 细胞的体外存活率。使用酶联免疫吸附试验确定炎症因子的水平。还评估了氧化应激参数的水平，并通过 Western 印迹法检测了环氧化酶-2 (COX-2)、酰基-CoA 合成酶长链家族成员 4 (ACSL4)、谷胱甘肽过氧化物酶 4 (GPX4)、NF-E2 相关因子 2 (Nrf2)、磷酸化 Nrf2 和血红素加氧酶-1 (HO-1) 的表达水平。采用铁试剂盒检测细胞和结肠组织中的铁含量。结果表明，PAL 治疗能明显改善大鼠的 UC，表现为疾病活动指数评分降低和结肠长度增加，降低了 DSS 诱导的大鼠和 NCM460 细胞中的 IL-18、IL-1β、IL-6、TNF-α、MDA、NO 和 LDH 水平，但增加了 GSH 水平。此外，PAL 处理明显降低了 COX-2、ACSL4、Nrf2 和 HO-1 的表达水平，同时提高了 GPX4 和 phospho-Nrf2 的表达水平。此外，PAL 还能抑制细胞和结肠组织中的铁超载。PAL可通过抑制炎症反应、氧化应激、铁负荷和抑制铁变态反应途径来预防UC。

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引用次数: 0

Human umbilical mesenchymal stem cell-derived exosomes alleviate bone destruction and regulate bone immunity via the aryl hydrocarbon receptor to treat rheumatoid arthritis 人脐间充质干细胞衍生的外泌体通过芳基烃受体缓解骨破坏并调节骨免疫，从而治疗类风湿性关节炎

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2024-10-17 DOI: 10.1016/j.intimp.2024.113340

Objective

Rheumatoid arthritis (RA) can lead to joint deformity, loss of function, and even disability. Bone erosion is a common cause of disability in individuals with RA; bone resorption by osteoclasts (OCs) and bone immunity by regulatory T cells (Tregs) play key roles in this process. Human umbilical mesenchymal stem cells (HUMSCs) can be used to treat RA; however, the regulation of Tregs and OCs by HUMSCs and their therapeutic effects on RA have not been fully elucidated. This study aimed to reveal the effects of exosomes derived from HUMSCs carrying miRNA-150-5p on Tregs and OCs in individuals with RA and to provide innovative evidence for the ability of HUMSCs to alleviate RA.

Methods

First, we used collagen-induced arthritis (CIA) model mice to verify the efficacy of miR-150-5p^mimic-Exos and explored their effects on bone erosion in mouse joints and on Tregs in the lymph nodes. Subsequently, miR-150-5p^mimic-Exos and the aryl hydrocarbon receptor (AhR) inhibitor CH223191 were used in in vitro OCs, Tregs, and OC-Treg coculture systems to determine whether miR-150-5p^mimic-Exos regulate bone immune microenvironment homeostasis via AhR.

Results

Treatment with miR-150-5p^mimic-Exos effectively alleviated bone damage to the ankle and knee joints in CIA model mice, inhibited OC differentiation, activated the immunosuppressive function of Tregs, and regulated bone immunity by increasing the expression of AhR/CYP1A1 signalling pathway genes such as Ahr, Arnt, Ahrr, Cyp1a1/1a2 and Cyp1b1 in OCs and Tregs. By coculturing Tregs and OCs, the ability of the miR-150-5p^mimic-Exos to inhibit OC differentiation was further strengthened.

Conclusions

This study confirmed that miR-150-5p^mimic-Exos can reduce bone destruction in mice with CIA. We first showed that miR-150-5p^mimic-Exos acted on a Treg-OC coculture system to alleviate bone erosion and regulate bone immunity. This study is expected to provide new ideas for the treatment of RA.

目的类风湿性关节炎（RA）可导致关节畸形、功能丧失甚至残疾。骨侵蚀是类风湿关节炎患者致残的常见原因；破骨细胞（OCs）的骨吸收和调节性 T 细胞（Tregs）的骨免疫在这一过程中发挥着关键作用。人脐间充质干细胞（HUMSCs）可用于治疗RA；然而，HUMSCs对Tregs和OCs的调控及其对RA的治疗效果尚未完全阐明。本研究旨在揭示携带 miRNA-150-5p 的 HUMSCs 外泌体对 RA 患者 Tregs 和 OCs 的影响，并为 HUMSCs 缓解 RA 的能力提供创新性证据。方法首先，我们使用胶原诱导的关节炎（CIA）模型小鼠验证了 miR-150-5pmimic-Exos 的疗效，并探讨了它们对小鼠关节骨侵蚀和淋巴结中 Tregs 的影响。随后，miR-150-5pmimic-Exos和芳基烃受体（AhR）抑制剂CH223191被用于体外OCs、Tregs和OC-Treg共培养系统，以确定miR-150-5pmimic-Exos是否通过AhR调控骨免疫微环境稳态。结果 miR-150-5pmimic-Exos能有效缓解CIA模型小鼠踝关节和膝关节的骨损伤，抑制OC分化，激活Tregs的免疫抑制功能，并通过增加OC和Tregs中Ahr、Arnt、Ahrr、Cyp1a1/1a2和Cyp1b1等AhR/CYP1A1信号通路基因的表达来调节骨免疫。本研究证实，miR-150-5pmimic-Exos 可减少 CIA 小鼠的骨破坏。我们首次发现，miR-150-5pmimic-Exos 在 Treg-OC 协同培养系统中能减轻骨侵蚀并调节骨免疫。这项研究有望为治疗RA提供新思路。

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引用次数: 0

Modified mRNA-based gene editing reveals sarcomere-based regulation of gene expression in human induced-pluripotent stem cell-derived cardiomyocytes 基于修饰 mRNA 的基因编辑揭示了人类诱导多能干细胞衍生心肌细胞中基于肌节的基因表达调控机制

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2024-10-17 DOI: 10.1016/j.intimp.2024.113378

Mutations in genes coding sarcomere components are the major causes of human inherited cardiomyopathy. Genome editing is widely applied to genetic modification of human pluripotent stem cells (hPSCs) before hPSCs were differentiated into cardiomyocytes to model cardiomyopathy. Whether genetic mutations influence the early hPSC differentiation process or solely the terminally differentiated cardiomyocytes during cardiac pathogenesis remains challenging to distinguish. To solve this problem, here we harnessed chemically modified mRNA (modRNA) and synthetic single-guide RNA to develop an efficient genome editing approach in hPSC-derived cardiomyocytes (hPSC-CMs). We showed that modRNA-based CRISPR/Cas9 mutagenesis of TNNT2, the coding gene for cardiac troponin T, results in sarcomere disassembly and contractile dysfunction in hPSC-CMs. These structural and functional phenotypes were associated with profound downregulation of oxidative phosphorylation genes and upregulation of cardiac stress markers NPPA and NPPB. These data confirmed that sarcomeres regulate gene expression in hPSC-CMs and highlighted the RNA technology as a powerful tool to achieve stage-specific genome editing during hPSC differentiation.

编码肌节成分的基因突变是导致人类遗传性心肌病的主要原因。基因组编辑被广泛应用于人类多能干细胞（hPSCs）的基因修饰，然后再将hPSCs分化成心肌细胞，以建立心肌病模型。在心脏发病过程中，基因突变是影响了早期的 hPSC 分化过程，还是仅仅影响了终末分化的心肌细胞，目前仍难以区分。为了解决这个问题，我们利用化学修饰 mRNA（modRNA）和合成单导 RNA 开发了一种高效的 hPSC 衍生心肌细胞（hPSC-CMs）基因组编辑方法。我们发现，基于 modRNA 的 CRISPR/Cas9 诱变 TNNT2（心肌肌钙蛋白 T 的编码基因）会导致 hPSC-CMs 中的肌节解体和收缩功能障碍。这些结构和功能表型与氧化磷酸化基因的深度下调和心脏应激标志物 NPPA 和 NPPB 的上调有关。这些数据证实了肌节可调控 hPSC-CMs 中的基因表达，并强调了 RNA 技术是在 hPSC 分化过程中实现阶段特异性基因组编辑的有力工具。

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引用次数: 0

Corilagin inhibits human cytomegalovirus infection and replication via activating the cGAS-STING signaling pathway in vitro and in vivo 柯里拉京通过激活体外和体内 cGAS-STING 信号通路抑制人类巨细胞病毒感染和复制

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2024-10-17 DOI: 10.1016/j.intimp.2024.113401

Aim

The existence of human cytomegalovirus (HCMV) is extremely widespread, causing serious diseases in patients with low immune function. The purpose of this study is to explore the efficacy and mechanism of Corilagin in the control of CMV infection, in order to provide scientific basis for the control of CMV infection.

Methods

Our study employed an animal model in Balb/c mice, infected with MCMV, alongside cellular models in HFF cells and THP-1 cells, stimulated with HCMV. The expression of cGAS-STING signaling pathway molecules was detected in liver tissue, lung tissue, serum, cells and cell supernatant. The liver function and histopathological changes of mice were evaluated.

Results

In vivo and in vitro experiments showed that Corilagin significantly inhibits CMV levels and attenuates pathological damage in liver and lung tissues in vivo, and similarly inhibits viral load in cells in vitro. Corilagin promotes the expression levels of STING and its downstream molecules in vivo and in vitro. Inhibition/down-regulation of STING significantly promotes CMV replication, on the contrary, activation/up-regulation of STING inhibits CMV replication, and Corilagin also promotes the expression levels of molecules related to the cGAS-STING signaling pathway in the above cases.

Conclusion

Corilagin could effectively inhibit the infection and replication of CMV in vitro and in vivo, which may be through the activation of cGAS-STING signaling pathway.

目的人类巨细胞病毒（HCMV）的存在极为广泛，对免疫功能低下的患者造成严重的疾病。本研究的目的是探讨柯里拉京在控制巨细胞病毒感染中的疗效和机制，为控制巨细胞病毒感染提供科学依据。方法我们的研究采用了感染 MCMV 的 Balb/c 小鼠动物模型，以及 HFF 细胞和 THP-1 细胞在 HCMV 刺激下的细胞模型。在肝组织、肺组织、血清、细胞和细胞上清液中检测了 cGAS-STING 信号通路分子的表达。结果体内和体外实验表明，柯里拉京能显著抑制体内肝脏和肺组织中 CMV 的水平并减轻病理损伤，同样也能抑制体外细胞中的病毒载量。在体内和体外，Corilagin 可促进 STING 及其下游分子的表达水平。结论Corilagin可有效抑制CMV在体外和体内的感染和复制，这可能是通过激活cGAS-STING信号通路实现的。

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引用次数: 0

The IL-1β/STAT1 Axis inhibits STAT3 function via Sequestration of the transcriptional activator GLIS2, leading to postoperative vascular dysfunction IL-1β/STAT1 轴通过封闭转录激活因子 GLIS2 抑制 STAT3 功能，导致术后血管功能障碍

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2024-10-17 DOI: 10.1016/j.intimp.2024.113372

Surgery-induced endothelial dysfunction is crucial in thrombus formation, driven by the release of inflammatory mediators due to surgical trauma. The STAT family, known for amplifying inflammatory responses via cytokine activation, plays an unclear role in the signaling mechanisms from surgery to molecular activation, and their regulatory effects on inflammation vary. This study aimed to identify key signaling pathways responsible for vascular dysfunction post-surgery and to discover potential targets for predicting or preventing thrombosis. To explore this, endothelial cells were co-cultured with post-surgical trauma serum and analyzed using various assays. Bioinformatics analysis linked surgical trauma with pathways involving thrombosis, interleukins, cytokines, and STAT signaling. Elevated inflammatory mediators were observed in mouse serum post-surgical trauma, with IL-6 activating STAT3 to enhance endothelial proliferation, while IL-1β activated STAT1, inhibiting STAT3′s effects. Gli-similar 2 (GLIS2), a novel coactivator of STAT3, was found to regulate STAT transcription. STAT1, however, inhibited GLIS2′s interaction with STAT3, suppressing STAT3′s role in endothelial proliferation. The study concludes that IL-1β-triggered STAT1 activation impedes GLIS2-STAT3 interaction, reducing STAT3′s transcriptional activity and leading to endothelial dysfunction, presenting new targets for preventing post-surgical trauma endothelial dysfunction and thrombosis.

手术创伤导致的炎症介质释放是血栓形成的关键因素，而手术诱发的内皮功能障碍则是血栓形成的关键因素。STAT 家族因通过激活细胞因子放大炎症反应而闻名，但在从手术到分子激活的信号机制中扮演的角色尚不明确，而且它们对炎症的调节作用也各不相同。本研究旨在确定导致手术后血管功能障碍的关键信号通路，并发现预测或预防血栓形成的潜在靶点。为了探讨这一问题，研究人员将内皮细胞与手术后创伤血清共同培养，并使用各种检测方法进行分析。生物信息学分析将手术创伤与涉及血栓形成、白细胞介素、细胞因子和 STAT 信号转导的通路联系起来。在手术创伤后的小鼠血清中观察到炎症介质升高，IL-6激活STAT3以增强内皮增殖，而IL-1β激活STAT1，抑制STAT3的作用。研究发现，Gli-similar 2（GLIS2）是 STAT3 的一种新型辅助激活剂，可调节 STAT 的转录。然而，STAT1 会抑制 GLIS2 与 STAT3 的相互作用，从而抑制 STAT3 在内皮增殖中的作用。研究认为，IL-1β触发的STAT1活化会阻碍GLIS2-STAT3的相互作用，降低STAT3的转录活性，导致内皮功能障碍，为预防手术创伤后内皮功能障碍和血栓形成提供了新的靶点。

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引用次数: 0