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Piceatannol promotes hepatic and renal AMPK/SIRT1/PGC-1α mitochondrial pathway in rats exposed to reserpine or gamma-radiation. 皮夏单宁能促进暴露于利血平或伽马射线的大鼠肝脏和肾脏的 AMPK/SIRT1/PGC-1α 线粒体途径。
IF 3.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2021-01-01 DOI: 10.1177/20587384211016194
Enas Mahmoud Moustafa, Engy Refaat Rashed, Rasha Refaat Rashed, Nesreen Nabil Omar

Human exposure to radio-therapeutic doses of gamma rays can produce late effects, which negatively affect cancer patients' quality of life, work prospects, and general health. This study was performed to explore the role of Piceatannol (PIC) in the process of "mitochondrial biogenesis" signaling pathway as possible management of disturbances induced in stressed animal model(s) either by gamma-irradiation (IR) or administration of reserpine (RES); as a mitochondrial complex-I inhibitor. PIC (10 mg/kg BW/day; orally) were given to rats for 7 days, after exposure to an acute dose of γ-radiation (6 Gy), or after a single reserpine injection (1 g/kg BW; sc). Compared to reserpine or γ-radiation, PIC has attenuated hepatic and renal mitochondrial oxidative stress denoted by the significant reduction in the content of lipid peroxides and NO with significant induction of SOD, CAT, GSH-PX, and GR activities. PIC has also significantly alleviated the increase of the inflammatory markers, TNF-α and IL-6 and apoptotic markers, cytochrome c, and caspase-3. The decrease of oxidative stress, inflammation, and apoptotic responses were linked to a significant amelioration in mitochondrial biogenesis demonstrated by the increased expression and proteins' tissue contents of SIRT1/p38-AMPK, PGC-1α signaling pathway. The results are substantiated by the significant amelioration in mitochondrial function verified by the higher levels of ATP content, and complex I activity, besides the improvement of hepatic and renal functions. Additionally, histopathological examinations of hepatic and renal tissues showed that PIC has modulated tissue architecture after reserpine or gamma-radiation-induced tissue damage. Piceatannol improves mitochondrial functions by regulating the oxidant/antioxidant disequilibrium, the inflammatory and apoptotic responses, suggesting its possible use as adjuvant therapy in radio-therapeutic protocols to attenuate hepatic and renal injuries.

人类暴露于放射治疗剂量的伽马射线会产生后期效应,对癌症患者的生活质量、工作前景和总体健康产生负面影响。本研究旨在探索皮夏单宁醇(PIC)在 "线粒体生物生成 "信号通路过程中的作用,以解决伽马射线照射(IR)或服用利血平(RES)(一种线粒体复合物 I 抑制剂)对受压动物模型造成的干扰。在大鼠暴露于急性剂量的γ射线(6 Gy)或注射一次利舍平(1 g/kg BW;sc)后,连续 7 天给予 PIC(10 mg/kg BW/天;口服)。与利舍平或γ-射线相比,事先知情同意可减轻肝脏和肾脏线粒体的氧化应激,表现为脂质过氧化物和 NO 含量的显著降低,以及 SOD、CAT、GSH-PX 和 GR 活性的显著提高。事先知情同意还大大缓解了炎症标志物 TNF-α 和 IL-6 以及凋亡标志物细胞色素 c 和 caspase-3 的增加。氧化应激、炎症和细胞凋亡反应的减少与线粒体生物生成的明显改善有关,这表现在 SIRT1/p38-AMPK、PGC-1α 信号通路的表达和蛋白质组织含量的增加。除了肝脏和肾脏功能的改善外,线粒体功能的显著改善也证实了这一结果,线粒体中的 ATP 含量和复合体 I 活性均有所提高。此外,对肝脏和肾脏组织的组织病理学检查表明,在利血平或伽马射线引起的组织损伤后,皮卡单宁醇能调节组织结构。皮夏单宁醇通过调节氧化剂/抗氧化剂失衡、炎症和细胞凋亡反应来改善线粒体功能,这表明皮夏单宁醇可作为放射治疗方案的辅助疗法,以减轻肝脏和肾脏损伤。
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引用次数: 0
Therapeutic effects of SKF-96365 on murine allergic rhinitis induced by OVA. SKF-96365对OVA诱发的小鼠过敏性鼻炎的治疗作用
IF 3.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2021-01-01 DOI: 10.1177/20587384211015054
Guangyi Ba, Ru Tang, Xiwen Sun, Zhipeng Li, Hai Lin, Weitian Zhang

Introduction: SKF-96365 is regarded as an inhibitor of receptor-mediated calcium ion (Ca2+) entry. The current study aimed to explore the effects of SKF-96365 on murine allergic rhinitis (AR).

Methods: Intranasal SKF-96365 administration was performed on OVA induced murine AR. Serum and nasal lavage fluid (NLF) from mice were harvested to assay IgE and inflammatory cytokines using ELISA method. Inflammatory cells were counted and analyzed in NLF. Nasal mucosa tissues were collected from mice and used for HE staining, immunohistochemistry (IHC) staining, and real-time PCR detection.

Results: SKF-96365 had therapeutic effects on murine AR manifesting attenuation of sneezing, nasal rubbing, IgE, inflammatory cytokines, inflammatory cells, TRPC6 immunolabeling, and TRPC6, STIM1 and Orai1 mRNA levels in AR mice.

Conclusion: SKF-96365 could effectively alleviate the symptoms of murine AR. SKF-96365 could suppress TRPC6, STIM1, and Orai1 activities, leading to the downregulation of inflammatory cytokines and inflammatory cells in murine AR.

简介SKF-96365被认为是受体介导的钙离子(Ca2+)进入的抑制剂。本研究旨在探讨 SKF-96365 对小鼠过敏性鼻炎(AR)的影响:方法:对 OVA 诱导的小鼠过敏性鼻炎进行鼻内注射 SKF-96365。采集小鼠血清和鼻腔灌洗液(NLF),用 ELISA 方法检测 IgE 和炎性细胞因子。对鼻腔灌洗液中的炎性细胞进行计数和分析。采集小鼠鼻黏膜组织,用于 HE 染色、免疫组织化学(IHC)染色和实时 PCR 检测:结果:SKF-96365对小鼠AR有治疗作用,可减轻AR小鼠的打喷嚏、鼻摩擦、IgE、炎性细胞因子、炎性细胞、TRPC6免疫标记以及TRPC6、STIM1和Orai1 mRNA水平:结论:SKF-96365能有效缓解小鼠AR的症状。结论:SKF-96365能有效缓解小鼠AR的症状,抑制TRPC6、STIM1和Orai1的活性,导致炎性细胞因子和炎性细胞的下调。
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引用次数: 0
The p70S6K/PI3K/MAPK feedback loop releases the inhibition effect of high-dose rapamycin on rat mesangial cell proliferation. p70S6K/PI3K/MAPK反馈回路释放高剂量雷帕霉素对大鼠系膜细胞增殖的抑制作用。
IF 3.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2021-01-01 DOI: 10.1177/20587384211000544
Jihua Tian, Sijia Chang, He Ji, Taiping Huang, Haixiu Guo, Jing Kang, Yanhong Wang, Yun Zhou

Glomerular mesangial cell (MC) proliferation is one of the causative factors of glomerular diseases and one of their prominent pathological features. Rapamycin can inhibit MC proliferation and slow the progression to chronic renal fibrosis. The present study was designed to observe the role of rapamycin in MC proliferation and to explore the mechanism by which rapamycin acts on Akt and MAPK/ERK1/2 pathways in mesangial cells. MTT assay and flow cytometry were used to evaluate the proliferation and the cell cycle phase of glomerular mesangial cells respectively. The mRNA expression level of p70S6K was detected by RT-qPCR. Western blotting was performed to determine p70S6K, PI3K/Akt, and PI3K/MAPK protein expression. We found that rapamycin could reduce mesangial cell proliferation and arrest the cell cycle in the G1 phase, however the inhibition effect of 1000 nmol/L rapamycin was not higher than that in the 100 nmol/L group. The results of western blotting showed that 1000 nmol/L rapamycin more significantly inhibited the phosphorylation of p70S6K than 100 nmol/L, suggesting there should be another signaling pathway that activates the proliferation of MCs. Moreover, our results revealed that 1000 nmol/L rapamycin led to Raf1-MEK1/2-ERK pathway activation through a p70S6K-PI3K-mediated feedback loop in MCs. This study demonstrated that high-dose rapamycin leads to ERK1/2 activation through a p70S6K/PI3K/MAPK feedback loop in rat MCs, thus reducing the inhibitory effect of rapamycin on MC proliferation.

肾小球系膜细胞(Glomerular mesangial cell, MC)增生是肾小球疾病的病因之一,也是肾小球疾病的突出病理特征之一。雷帕霉素可抑制MC增殖,减缓慢性肾纤维化的进展。本研究旨在观察雷帕霉素对肾小球系膜细胞增殖的作用,并探讨雷帕霉素作用于系膜细胞Akt和MAPK/ERK1/2通路的机制。采用MTT法和流式细胞术分别观察肾小球系膜细胞的增殖和细胞周期。RT-qPCR检测p70S6K mRNA表达水平。Western blotting检测p70S6K、PI3K/Akt和PI3K/MAPK蛋白的表达。我们发现雷帕霉素可以降低系膜细胞的增殖,使细胞周期停留在G1期,但1000 nmol/L雷帕霉素的抑制作用并不高于100 nmol/L组。western blotting结果显示,1000 nmol/L的雷帕霉素比100 nmol/L的雷帕霉素对p70S6K磷酸化的抑制作用更显著,提示可能存在另一条激活MCs增殖的信号通路。此外,我们的研究结果显示,1000 nmol/L的雷帕霉素通过p70s6k - pi3k介导的反馈回路在MCs中激活Raf1-MEK1/2-ERK通路。本研究表明,在大鼠MCs中,高剂量雷帕霉素通过p70S6K/PI3K/MAPK反馈回路激活ERK1/2,从而降低雷帕霉素对MCs增殖的抑制作用。
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引用次数: 2
Dedifferentiated liposarcoma with abrupt transition of low-grade and high-grade dedifferentiation: A rare case report. 低级别和高级别去分化突然转变的去分化脂肪肉瘤1例罕见报告。
IF 3.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2021-01-01 DOI: 10.1177/20587384211048565
Yang Wen, Xianglei He, Ming Zhao

Dedifferentiated liposarcoma is a unique subtype of liposarcoma, which has obvious histological heterogeneity. In affected patients, the condition typically manifests as the dedifferentiation of high-grade histological morphology, but it may also manifest as the dedifferentiation of low-grade histological morphology. In some cases, unique histological or immunophenotypic characteristics are observed. We describe, herein, a rare case of dedifferentiated liposarcoma, in which the high-grade and low-grade dedifferentiated components coexisted with a relatively sharp transition in pathology.

去分化脂肪肉瘤是一种独特的脂肪肉瘤亚型,具有明显的组织学异质性。在受影响的患者中,病情通常表现为高级别组织形态的去分化,但也可能表现为低级别组织形态的去分化。在某些情况下,观察到独特的组织学或免疫表型特征。我们在此描述一例罕见的去分化脂肪肉瘤,其中高级别和低级别去分化成分共存,病理上发生了相对急剧的转变。
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引用次数: 2
Curative role of mesenchymal stromal cells in chronic pancreatitis: Modulation of MAPK and TGF-β1/SMAD factors. 间充质基质细胞在慢性胰腺炎中的治疗作用:MAPK和TGF-β1/SMAD因子的调节作用
IF 3.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2021-01-01 DOI: 10.1177/20587384211054036
Hager S Taha, Enas M Moustafa, Fatma Sm Moawed, Marwa Ga Hegazy

Background and objective: Living organisms respond to physical, chemical, and biological threats with a potent inflammatory response which alters organ cell signaling and leads to dysfunction. We evaluated the therapeutic effect of bone marrow-based mesenchymal stromal cell (BM-MSC) transplanted in rats to preserve tissue integrity and to restore homeostasis and function in the pancreatitis experimental pattern.

Methods: This study involved 40 adult male Wister rats. Repeated L-arginine injections caused chronic pancreatitis (CP), leading to the development of pancreatic damage and shifting the intracellular signaling pathways. Rats were then infused with BM-MSC labeled with PKH26 fluorescent linker dye for 12 weeks.

Results: Cell-surface indicators of BM-MSCs such as CD 90 and CD29 were expressed with the lack of CD34 expression. BM-MSC treatment considerably improved the alterations induced in a series of inflammatory markers, including IL-18, TNF-α, CRP, PGE2, and MCP-1. Furthermore, improvement was found in digestive enzymes and lipid profile with amelioration in myeloperoxidase activity. BM-MSC treatment also regulated the (TGF-/p-38MPAK/SMAD2/3) signaling factors that enhances repair of damaged pancreatic tissue, confirmed by reversed alteration of histopathological examination.

Conclusion: our results further bring to light the promise of cell transplant therapy for chronic pancreatitis.

背景和目的:生物体在应对物理、化学和生物威胁时会产生强烈的炎症反应,从而改变器官细胞信号传导并导致功能障碍。我们评估了骨髓间充质干细胞(BM-MSC)移植到大鼠体内对保护组织完整性、恢复胰腺炎实验模式的稳态和功能的治疗效果:本研究涉及 40 只成年雄性 Wister 大鼠。反复注射 L-精氨酸会引起慢性胰腺炎(CP),导致胰腺损伤和细胞内信号通路的改变。然后用标记有 PKH26 荧光连接染料的骨髓间充质干细胞为大鼠输注 12 周:结果:BM-间充质干细胞的细胞表面指标(如 CD 90 和 CD29)均有表达,但缺乏 CD34 表达。BM-MSC 治疗大大改善了一系列炎症指标的变化,包括 IL-18、TNF-α、CRP、PGE2 和 MCP-1。此外,消化酶和血脂状况也有所改善,髓过氧化物酶活性也有所改善。BM-间充质干细胞治疗还能调节(TGF-/p-38MPAAK/SMAD2/3)信号传导因子,从而增强受损胰腺组织的修复,组织病理学检查的逆转性改变也证实了这一点。
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引用次数: 0
Natural killer cell deficiency experiences higher risk of sepsis after critical intracerebral hemorrhage. 自然杀伤细胞缺乏症在严重脑出血后发生败血症的风险更高。
IF 3.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2021-01-01 DOI: 10.1177/20587384211056495
Yu Feng, Qian Wu, Tingbao Zhang, Jincao Chen, Xiaohui Wu

Background: Lymphopenia is common in intracerebral hemorrhage (ICH) and may predispose to severe infections such as sepsis. However, what specific kind of lymphocytes subsets decreases is still unclear. We investigated the impact of lymphocytes subsets on post-critical ICH infections and mortality.

Methods: Consecutive ICH patients (admitted to a single center between January 2017 and January 2018) were prospectively assessed to evaluate the following main parameters: peripheral blood lymphocytes, infections, and clinical scores. Predicting factors of sepsis were measured using multivariate Logistic regressions analysis. A Kaplan-Meier survival curve was performed to compare the mortality between septic and nonseptic patients. Survival status was evaluated by multivariate Cox regression analysis.

Results: In total, 112 critical ICH cases were enrolled including 29 septic patients. Total counts of lymphocytes decreased accordingly with reduced lymphocyte subsets, especially natural killer (NK) cells and CD8+T lymphocytes after ICH. Septic patients had a higher incidence of pneumonia, a longer length of stay, higher 90-day mortality, and worse long-term outcomes. Multivariate Logistic regression analysis showed venous catheterization, high APACHE-II score (>15), low GCS score (3-5), and NK cells percentages on admission were independently associated with ensuing sepsis. After sepsis, the percentages of CD4+T and NK cells percentages decreased, CD8+T cells increased followed by a significantly decreased CD4/CD8 ratio. Bloodstream infection alone directly affected the survival status of patients with sepsis.

Conclusions: Critical ICH patients underwent immune dysfunction and NK cells deficiency could favor nosocomial threatening sepsis after ICH.

背景:淋巴细胞减少症在脑出血(ICH)中很常见,并可能导致严重感染,如败血症。然而,具体哪种淋巴细胞亚群减少尚不清楚。我们研究了淋巴细胞亚群对急性脑出血后感染和死亡率的影响。方法:前瞻性评估连续ICH患者(2017年1月至2018年1月入住单一中心),评估以下主要参数:外周血淋巴细胞,感染和临床评分。脓毒症的预测因素采用多因素Logistic回归分析。采用Kaplan-Meier生存曲线比较脓毒症和非脓毒症患者的死亡率。采用多变量Cox回归分析评估患者的生存状况。结果:共纳入脑出血危重患者112例,其中感染性疾病患者29例。脑出血后淋巴细胞总数相应减少,淋巴细胞亚群减少,尤其是自然杀伤细胞(NK)和CD8+T淋巴细胞。脓毒症患者有较高的肺炎发病率、较长的住院时间、较高的90天死亡率和较差的长期预后。多因素Logistic回归分析显示,入院时静脉置管、高APACHE-II评分(>15)、低GCS评分(3-5)和NK细胞百分比与随后的脓毒症独立相关。脓毒症后,CD4+T细胞百分比和NK细胞百分比降低,CD8+T细胞百分比升高,CD4/CD8比值明显降低。单纯血液感染直接影响脓毒症患者的生存状况。结论:危重脑出血患者发生免疫功能障碍和NK细胞缺乏可能导致脑出血后发生院内威胁性败血症。
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引用次数: 3
The role of the sphingosine axis in immune regulation: A dichotomy in the anti-inflammatory effects between sphingosine kinase 1 and sphingosine kinase 2-dependent pathways. 鞘氨醇轴在免疫调节中的作用:鞘氨醇激酶1和鞘氨醇激酶2依赖通路之间抗炎作用的二分法。
IF 3.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2021-01-01 DOI: 10.1177/20587384211053274
Yuval Ishay, Dvorah Rotnemer-Golinkin, Yaron Ilan

Background: Sphingosine kinase has been identified as playing a central role in the immune cascade, being a common mediator in the cellular response to a variety of signals. The different effects of sphingosine kinase 1 and 2 (SphK1 and SphK2, respectively) activity have not been completely characterized. Aim: To determine the different roles played by SphK1 and SphK2 in the regulation of immune-mediated disorders. Methods: Nine groups of mice were studied. Concanavalin A (ConA) injection was used to induce immune-mediated hepatitis. Mice were treated with SphK1 inhibitor (termed SphK-I) and SphK2 inhibitor (termed ABC294640), prior to ConA injection, and effects of treatment on liver enzymes, subsets of T lymphocytes, and serum levels of cytokines were observed. Results: While liver enzyme elevation was ameliorated by administration of SphK1 inhibitor, SphK2 inhibitor-treated mice did not show this tendency. A marked decrease in expression of CD25+ T-cells and Foxp+ T-cells was observed in mice treated with a high dose of SphK1 inhibitor. Alleviation of liver damage was associated with a statistically significant reduction of serum IFNγ levels in mice treated with SphK1 inhibitor and not in those treated with SphK2 inhibitor. Conclusions: Early administration of SphK1 inhibitor in a murine model of immune-mediated hepatitis alleviated liver damage and inflammation with a statistically significant reduction in IFN-γ levels. The data support a dichotomy in the anti-inflammatory effects of SphK1 and SphK2, and suggests that isoenzyme-directed therapies can improve the effect of targeting these pathways.

背景:鞘氨醇激酶已被确定在免疫级联中发挥核心作用,是细胞对各种信号反应的常见介质。鞘氨醇激酶1和2(分别为SphK1和SphK2)活性的不同作用尚未完全表征。目的:确定SphK1和SphK2在免疫介导的疾病调节中的不同作用。方法:对9组小鼠进行实验研究。刀豆球蛋白A(ConA)注射液用于诱导免疫介导的肝炎。在ConA注射之前,用SphK1抑制剂(称为SphK-I)和SphK2抑制剂(称称为ABC294640)治疗小鼠,并观察治疗对肝酶、T淋巴细胞亚群和血清细胞因子水平的影响。结果:虽然SphK1抑制剂可改善肝酶升高,但SphK2抑制剂治疗的小鼠没有表现出这种趋势。在用高剂量SphK1抑制剂处理的小鼠中观察到CD25+T细胞和Foxp+T细胞的表达显著降低。在用SphK1抑制剂治疗的小鼠中,肝损伤的减轻与血清IFNγ水平的统计学显著降低有关,而在用Sph K2抑制剂治疗的鼠中则没有。结论:在免疫介导的肝炎小鼠模型中早期给予SphK1抑制剂减轻了肝损伤和炎症,IFN-γ水平显著降低。数据支持SphK1和SphK2抗炎作用的二分法,并表明同工酶导向疗法可以提高靶向这些途径的效果。
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引用次数: 0
A nano based approach to alleviate cisplatin induced nephrotoxicity. 减轻顺铂引起的肾毒性的纳米方法。
IF 3.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2021-01-01 DOI: 10.1177/20587384211066441
Lobna M Anees, Gehan R Abdel-Hamid, Ahmed A Elkady

Background and objective: Cisplatin, an effective drug against cancer, commonly induces nephrotoxicity; limiting its therapeutic efficacy and application. In this study, Cisplatin NanoComposite (Cis NC) was formulated successfully from irradiated chitosan coated Cisplatin and MgO nanoparticles (CHIT/Cis/MgO NPs) to promote cisplatin release in a more sustained manner to improve therapeutic efficacy via the reduction of its nephrotoxicity. To compare the relative induced renal toxicity of cisplatin with Cisplatin NanoComposite, histological and biochemical mechanisms underlying nephrotoxicity were investigated.

Methods: Thirty rats were equally separated to three groups, first group received saline injections and adjusted as the control group, the second group was injected intra-peritoneal with cisplatin 0.64 mg/kg b. wt./day for 6 weeks, the third group was injected intra-peritoneal with Cis NC 5.75 mg/kg b. wt. daily for 6 weeks.

Results: Cisplatin-induced renal functional impairment and histopathological damages in the kidney; also, cisplatin disrupted the balance of the redox system in renal tissue, stimulated the inflammatory reactions in the kidney via triggering signal transducer and activator of transcription-1 (STAT1) dependent pathways. Moreover, Cisplatin-induced activation of mammalian target of rapamycin mTOR and inactivation of AMPK/PI3K/Akt signal pathway, and was coupled with induction of p53 activity and the executioner caspase3 to induce apoptotic renal cell death. On the other hand, Cis NC exerted a minimal stimulatory effect on apoptotic and inflammatory signal cascade with negligible renal functional and morphological alterations.

Conclusion: We postulated that Cis NC may be a valued possible drug to decrease the cytotoxicity of cisplatin thus reserves the renal function and structure.

背景和目的:顺铂是一种有效的抗癌药物,但通常会诱发肾毒性,从而限制其疗效和应用。本研究利用辐照壳聚糖包覆顺铂和氧化镁纳米颗粒(CHIT/Cis/MgO NPs)成功配制了顺铂纳米复合材料(Cis NC),以更持久的方式促进顺铂的释放,通过降低其肾毒性来提高疗效。为了比较顺铂与顺铂纳米复合材料的相对肾毒性,研究了肾毒性的组织学和生化机制:将30只大鼠平均分为三组,第一组接受生理盐水注射并调整为对照组,第二组腹腔注射顺铂0.64 mg/kg体重/天,连续6周,第三组腹腔注射顺铂纳米复合材料5.75 mg/kg体重/天,连续6周:结果:顺铂诱导肾功能损害和肾组织病理学损伤;顺铂还破坏了肾组织氧化还原系统的平衡,通过信号转导和激活转录-1(STAT1)依赖途径刺激肾脏炎症反应。此外,顺铂还能诱导哺乳动物雷帕霉素靶标 mTOR 的激活和 AMPK/PI3K/Akt 信号通路的失活,并与 p53 活性和 caspase3 执行器的诱导相结合,诱导肾细胞凋亡。另一方面,顺式数控对细胞凋亡和炎症信号级联的刺激作用很小,肾功能和形态学改变可以忽略不计:我们推测顺式 NC 可能是一种有价值的药物,可以降低顺铂的细胞毒性,从而保护肾功能和结构。
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引用次数: 0
Splenic CD4+ and CD8+ T-cells highly expressed PD-1 and Tim-3 in cirrhotic patients with HCV infection and portal hypertension. HCV感染合并门静脉高压症肝硬化患者脾CD4+和CD8+ t细胞高表达PD-1和Tim-3。
IF 3.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2021-01-01 DOI: 10.1177/20587384211061051
Na Huang, Rui Zhou, Haiyan Chen, Shu Zhang, Jun Li, Wei Wei, Jin Sun, Song Ren, Baohua Li, Hong Deng, Jun Yang, Fanpu Ji, Zongfang Li

Introduction: The spleen plays an important role in regulating the immune response to infectious pathogens. T-cells dysfunction and exhaustion have been reported in patients with hepatitis B/C virus (HBV/HCV) infection, which contributes to persistent virus infection. The aims of this study were to investigate spleen-related evidence of immunosuppression and immune tolerance in HCV cirrhotic patients with portal hypertension (PH). Methods: The expression of programmed cell death 1 (PD-1), T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) and its ligand PD-L1/2, and Galectin-9 in the spleens and livers of HCV cirrhotic patients (n = 15) was analyzed using real-time PCR and immunohistochemistry. Flow cytometry was used to evaluate the expression of PD-1 and Tim-3 on splenic T-cells and the peripheral blood T-cells before and after splenectomy (n = 8). Results: Spleens from patients with PH showed significantly increased mRNA levels of PD-L2, Tim-3, Galectin-9, CD80, and CD86, and decreased levels of CD28 compared to control spleens (spleens removed due to traumatic injury) (all p < 0.05). Additionally, protein expression of inhibitory signaling molecules was significantly increased in both the spleens and livers of cirrhotic patients compared with controls (all p < 0.05). Peripheral blood and splenic CD4+ and CD8+ T-cells also expressed higher protein levels of PD-1, Tim-3, and CTLA-4 in cirrhotic patients as compared with healthy controls (all p < 0.05). The proportion of PD-1+CD4+T lymphocytes (26.2% ± 7.12% vs. 21.0% ± 9.14%, p = 0.0293) and Tim-3+CD8+ T lymphocytes (9.4% ± 3.04% vs. 6.0% ± 2.24%, p = 0.0175) in peripheral blood decreased followed splenectomy. Conclusion: The CD4+ and CD8+ T-cells in spleen and peripheral blood highly expressed PD-1 and Tim-3 in HCV-infected and cirrhotic patients with portal hypertension. Highly expressed PD-1 and Tim-3 in peripheral blood T-lymphocytes can be partly reversed following splenectomy.

脾脏在调节机体对感染性病原体的免疫应答中起着重要作用。乙型/丙型肝炎病毒(HBV/HCV)感染患者中有t细胞功能障碍和衰竭的报道,这是导致持续病毒感染的原因。本研究的目的是探讨HCV肝硬化合并门脉高压(PH)患者免疫抑制和免疫耐受的脾相关证据。方法:采用实时荧光定量PCR和免疫组化技术,分析15例HCV肝硬化患者脾脏和肝脏中程序性细胞死亡1 (PD-1)、t细胞免疫球蛋白结构域和粘蛋白结构域含分子-3 (Tim-3)及其配体PD-L1/2、半乳糖凝集素-9的表达。采用流式细胞术检测PD-1、Tim-3在脾切除术前后脾脏及外周血t细胞上的表达情况(n = 8)。结果:PH患者脾脏中PD-L2、Tim-3、半凝集素-9、CD80、CD86 mRNA表达水平与对照组(创伤性脾切除)相比显著升高(p < 0.05), CD28 mRNA表达水平显著降低(p < 0.05)。肝硬化患者脾脏和肝脏抑制信号分子蛋白表达均显著高于对照组(p < 0.05)。肝硬化患者外周血和脾CD4+和CD8+ t细胞表达的PD-1、Tim-3和CTLA-4蛋白水平也高于健康对照组(均p < 0.05)。脾切除术后外周血PD-1+CD4+T淋巴细胞比例(26.2%±7.12%比21.0%±9.14%,p = 0.0293)和Tim-3+CD8+ T淋巴细胞比例(9.4%±3.04%比6.0%±2.24%,p = 0.0175)降低。结论:hcv感染和肝硬化门静脉高压症患者脾和外周血CD4+和CD8+ t细胞高表达PD-1和Tim-3。脾切除术后外周血t淋巴细胞高表达的PD-1和Tim-3可部分逆转。
{"title":"Splenic CD4<sup>+</sup> and CD8<sup>+</sup> T-cells highly expressed PD-1 and Tim-3 in cirrhotic patients with HCV infection and portal hypertension.","authors":"Na Huang,&nbsp;Rui Zhou,&nbsp;Haiyan Chen,&nbsp;Shu Zhang,&nbsp;Jun Li,&nbsp;Wei Wei,&nbsp;Jin Sun,&nbsp;Song Ren,&nbsp;Baohua Li,&nbsp;Hong Deng,&nbsp;Jun Yang,&nbsp;Fanpu Ji,&nbsp;Zongfang Li","doi":"10.1177/20587384211061051","DOIUrl":"https://doi.org/10.1177/20587384211061051","url":null,"abstract":"<p><p><b>Introduction:</b> The spleen plays an important role in regulating the immune response to infectious pathogens. T-cells dysfunction and exhaustion have been reported in patients with hepatitis B/C virus (HBV/HCV) infection, which contributes to persistent virus infection. The aims of this study were to investigate spleen-related evidence of immunosuppression and immune tolerance in HCV cirrhotic patients with portal hypertension (PH). <b>Methods:</b> The expression of programmed cell death 1 (PD-1), T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) and its ligand PD-L1/2, and Galectin-9 in the spleens and livers of HCV cirrhotic patients (<i>n</i> = 15) was analyzed using real-time PCR and immunohistochemistry. Flow cytometry was used to evaluate the expression of PD-1 and Tim-3 on splenic T-cells and the peripheral blood T-cells before and after splenectomy (<i>n</i> = 8). <b>Results:</b> Spleens from patients with PH showed significantly increased mRNA levels of PD-L2, Tim-3, Galectin-9, CD80, and CD86, and decreased levels of CD28 compared to control spleens (spleens removed due to traumatic injury) (all <i>p</i> < 0.05). Additionally, protein expression of inhibitory signaling molecules was significantly increased in both the spleens and livers of cirrhotic patients compared with controls (all <i>p</i> < 0.05). Peripheral blood and splenic CD4<sup>+</sup> and CD8<sup>+</sup> T-cells also expressed higher protein levels of PD-1, Tim-3, and CTLA-4 in cirrhotic patients as compared with healthy controls (all <i>p</i> < 0.05). The proportion of PD-1<sup>+</sup>CD4<sup>+</sup>T lymphocytes (26.2% ± 7.12% vs. 21.0% ± 9.14%, <i>p</i> = 0.0293) and Tim-3<sup>+</sup>CD8<sup>+</sup> T lymphocytes (9.4% ± 3.04% vs. 6.0% ± 2.24%, <i>p</i> = 0.0175) in peripheral blood decreased followed splenectomy. <b>Conclusion:</b> The CD4<sup>+</sup> and CD8<sup>+</sup> T-cells in spleen and peripheral blood highly expressed PD-1 and Tim-3 in HCV-infected and cirrhotic patients with portal hypertension. Highly expressed PD-1 and Tim-3 in peripheral blood T-lymphocytes can be partly reversed following splenectomy.</p>","PeriodicalId":14046,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":"35 ","pages":"20587384211061051"},"PeriodicalIF":3.5,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2d/9f/10.1177_20587384211061051.PMC8725229.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39742756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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: 1
Liquiritigenin enhances cyclic adenosine monophosphate production to mitigate inflammation in dendritic cells. 利尿素增强环磷酸腺苷的产生以减轻树突状细胞的炎症。
IF 3.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2021-01-01 DOI: 10.1177/20587384211038098
Mingming Qin, Aili Guo, Feng Li, Fuxiang Zhang, Meirong Bi, Yamin Zhang, Weiwei Zhu

Objective: This study aims to dissect the mechanism of traditional Chinese medicinal herbs against asthma; we chose to first focus on the main chemical components of licorice to investigate their contribution to asthmatic inflammation inhibition.

Methods: Production of cellular nucleotide molecules such as cAMP, cGMP, and cGAMP was examined by using enzyme-linked immunosorbent assay (ELISA). Enzyme-encoding genes were tested in vitro using quantitative real-time PCR and protein level was detected by Western blotting analysis. In addition, co-culturing of murine dendritic cells together with T cells was conducted to examine the expression of cytokine genes and host immune response.

Results: We found that one of the components within licorice, named liquiritigenin (LR), could efficiently enhance cAMP production in different cell lines. The augmentation of such molecules was linked to the high expression of cAMP synthesis genes and repressed expression of cAMP breaking down genes. In addition, the downstream immune response was also alleviated by the increase in cAMP levels by LR, suggesting the great potential of this molecule against inflammation. Subsequent immunological tests showed that LR could efficiently inhibit the expression of several cytokines and alter the NF-κB pathway and T cell polarization.

Conclusion: Altogether, we have identified a promising antiasthmatic agent LR that could exhibit immunosuppressive function by elevating the cAMP level.

目的:探讨中药抗哮喘的作用机制;我们选择首先关注甘草的主要化学成分来研究它们对哮喘炎症抑制的贡献。方法:采用酶联免疫吸附法(ELISA)检测细胞中cAMP、cGMP、cGAMP等核苷酸分子的产生。采用实时荧光定量PCR法检测酶编码基因,Western blotting法检测蛋白水平。此外,将小鼠树突状细胞与T细胞共培养,检测细胞因子基因的表达和宿主免疫反应。结果:甘草中有一种名为利尿原素(liquiritigenin, LR)的成分能有效促进不同细胞系中cAMP的生成。这些分子的增加与cAMP合成基因的高表达和cAMP分解基因的抑制表达有关。此外,LR增加cAMP水平也减轻了下游的免疫反应,表明该分子具有抗炎症的巨大潜力。随后的免疫学试验表明,LR能有效抑制多种细胞因子的表达,改变NF-κB通路和T细胞极化。结论:总之,我们已经确定了一种很有前途的平喘药LR,它可以通过提高cAMP水平来发挥免疫抑制作用。
{"title":"Liquiritigenin enhances cyclic adenosine monophosphate production to mitigate inflammation in dendritic cells.","authors":"Mingming Qin,&nbsp;Aili Guo,&nbsp;Feng Li,&nbsp;Fuxiang Zhang,&nbsp;Meirong Bi,&nbsp;Yamin Zhang,&nbsp;Weiwei Zhu","doi":"10.1177/20587384211038098","DOIUrl":"https://doi.org/10.1177/20587384211038098","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to dissect the mechanism of traditional Chinese medicinal herbs against asthma; we chose to first focus on the main chemical components of licorice to investigate their contribution to asthmatic inflammation inhibition.</p><p><strong>Methods: </strong>Production of cellular nucleotide molecules such as cAMP, cGMP, and cGAMP was examined by using enzyme-linked immunosorbent assay (ELISA). Enzyme-encoding genes were tested <i>in vitro</i> using quantitative real-time PCR and protein level was detected by Western blotting analysis. In addition, co-culturing of murine dendritic cells together with T cells was conducted to examine the expression of cytokine genes and host immune response.</p><p><strong>Results: </strong>We found that one of the components within licorice, named liquiritigenin (LR), could efficiently enhance cAMP production in different cell lines. The augmentation of such molecules was linked to the high expression of cAMP synthesis genes and repressed expression of cAMP breaking down genes. In addition, the downstream immune response was also alleviated by the increase in cAMP levels by LR, suggesting the great potential of this molecule against inflammation. Subsequent immunological tests showed that LR could efficiently inhibit the expression of several cytokines and alter the NF-κB pathway and T cell polarization.</p><p><strong>Conclusion: </strong>Altogether, we have identified a promising antiasthmatic agent LR that could exhibit immunosuppressive function by elevating the cAMP level.</p>","PeriodicalId":14046,"journal":{"name":"International Journal of Immunopathology and Pharmacology","volume":"35 ","pages":"20587384211038098"},"PeriodicalIF":3.5,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c7/d1/10.1177_20587384211038098.PMC8728780.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39750271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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: 4
期刊
International Journal of Immunopathology and Pharmacology
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