GRP78

Grp78
  • 文章类型: Journal Article
    本研究旨在探讨抗糖尿病药物二甲双胍对卵母细胞细胞质组织的作用。从成年雌性瑞士白化病小鼠中收集生小泡(GV)期卵母细胞,并在各种实验组-对照中进行体外成熟(IVM)。车辆控制(0.3%乙醇),二甲双胍(50μg/mL),高糖高脂(HGHL,10mM葡萄糖;150μM棕榈酸;乙醇中的75μM硬脂酸和200μM油酸),和HGHL补充二甲双胍。分析了中期II(MII)卵母细胞的脂质积累,线粒体和内质网(ER)的分布模式,氧化和ER应激,肌动蛋白丝组织,皮质颗粒分布模式,纺锤体组织和染色体排列。在HGHL组中观察到早期极体挤出。然而,与对照组相比,实验组在24小时的成熟率没有显着差异。HGHL条件表现出明显更高水平的氧化应激,ER压力,不良的肌动蛋白丝组织,增加脂质积累,改变线粒体分布,纺锤异常,与对照相比,染色体错位。除主轴组织外,在HGHL条件下补充二甲双胍改善了所有参数(对ER和肌动蛋白分布模式无意义)。这些结果表明,除了纺锤体组织外,二甲双胍在培养基中的暴露有助于改善高血糖和高脂血症诱导的细胞质异常。鉴于纺锤体组织在卵母细胞成熟和减数分裂恢复过程中正确的染色体分离中的关键作用,二甲双胍在这方面的局限性的影响值得仔细评估和进一步调查。
    The present study aimed to investigate the role of antidiabetic drug metformin on the cytoplasmic organization of oocytes. Germinal vesicle (GV) stage oocytes were collected from adult female Swiss albino mice and subjected to in vitro maturation (IVM) in various experimental groups- control, vehicle control (0.3% ethanol), metformin (50 μg/mL), high glucose and high lipid (HGHL, 10 mM glucose; 150 μM palmitic acid; 75 μM stearic acid and 200 μM oleic acid in ethanol), and HGHL supplemented with metformin. The metaphase II (MII) oocytes were analyzed for lipid accumulation, mitochondrial and endoplasmic reticulum (ER) distribution pattern, oxidative and ER stress, actin filament organization, cortical granule distribution pattern, spindle organization and chromosome alignment. An early polar body extrusion was observed in the HGHL group. However, the maturation rate at 24 h did not differ significantly among the experimental groups compared to the control. The HGHL conditions exhibited significantly higher levels of oxidative stress, ER stress, poor actin filament organization, increased lipid accumulation, altered mitochondrial distribution, spindle abnormalities, and chromosome misalignment compared to the control. Except for spindle organization, supplementation of metformin to the HGHL conditions improved all the parameters (non-significant for ER and actin distribution pattern). These results show that metformin exposure in the culture media helped to improve the hyperglycemia and hyperlipidemia-induced cytoplasmic anomalies except for spindle organization. Given the crucial role of spindle organization in proper chromosome segregation during oocyte maturation and meiotic resumption, the implications of metformin\'s limitations in this aspect warrant careful evaluation and further investigation.
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  • 文章类型: Preprint
    在这里,我们报告了联合对甲苯磺酸盐索拉非尼的单中心2期临床试验的结果,丙戊酸,和西地那非治疗复发性高级别胶质瘤患者(NCT01817751)。临床毒性为1级和2级,黄斑丘疹的毒性为3级(6.4%)。对于所有可评估的患者,中位无进展生存期为3.65个月,总生存期(OS)为10.0个月.有有希望的证据显示临床活动和益处。在33个可评估的患者中,低蛋白质水平的伴侣GRP78(HSPA5)与更好的OS显著相关(p<0.0026)。PDGFRα的表达与OS之间的相关性接近显著性(p<0.0728)。目前有五名患者的平均OS为73.6个月,并且仍然存活。这是第一个将GRP78表达与OS显着相关的治疗性干预胶质母细胞瘤试验。我们的数据表明,对甲苯磺酸盐索拉非尼的组合,丙戊酸,在复发的神经胶质瘤人群中,西地那非需要额外的临床开发。
    Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma (NCT01817751). Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p < 0.0026). A correlation between the expression of PDGFRα and OS approached significance (p < 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.
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  • 文章类型: Journal Article
    背景:新生血管形成对于肿瘤组织的生长和进展至关重要。GRP78经常在各种癌症中过表达,并被认为是促血管生成因子。
    目的:本研究旨在研究GRP78的表达水平,并测试与血管生成标志物的显著关系,VEGF,CD31
    方法:在本研究中,我们回顾性收集了94例NSCLC患者的石蜡包埋NSCLC组织样本(71例腺癌和23例鳞状细胞癌).VEGF的表达,通过免疫组织化学测定CD31和GRP78。
    结果:在65和74例中观察到VEGF和GRP78的高表达水平,分别。36名患者表达高CD31水平。腺癌表达三种蛋白的水平高于鳞状细胞癌(p值<0.05)。此外,VEGF和CD31的表达水平(p值=0.001)与VEGF和GRP78的表达水平(p值=0.028)之间存在统计学上显著的相关性.
    结论:在大多数研究样品中发现了GRP78过表达。VEGF和GRP78之间的正相关可能表明GRP78在肺癌中的促血管生成作用。此外,VEGF和CD31表达水平呈正相关,提示VEGF可能与CD31协同促进NSCLC血管生成.
    Neovascularization is essential for the growth and progression of tumor tissues. GRP78 is frequently overexpressed in various cancers and has been suggested as a proangiogenic factor.
    This study aimed to investigate the expression levels of GRP78 and to test for significant relationships with the angiogenic markers, VEGF, and CD31.
    In this study, paraffin-embedded NSCLC tissue samples (71 adenocarcinomas and 23 squamous cell carcinoma) were retrospectively collected from 94 patients with NSCLC. The expressions of VEGF, CD31, and GRP78 were determined by immunohistochemistry.
    High expression levels of VEGF and GRP78 were observed in 65 and 74 cases, respectively. Thirty-six patients expressed high CD31 levels. Adenocarcinomas expressed higher levels of the three proteins than squamous cell carcinomas (p-value < 0.05). Moreover, a statistically significant association was found between the expression levels of VEGF and CD31 (p-value = 0.001) and VEGF and GRP78 (p-value=0.028).
    GRP78 overexpression was revealed in most of the investigated samples. The positive association between VEGF and GRP78 may indicate the proangiogenic role of GRP78 in lung cancer. Moreover, the positive association between VEGF and CD31 expression levels suggests that VEGF may cooperate with CD31 to promote angiogenesis in NSCLC.
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  • 文章类型: Journal Article
    乳腺癌(BC)在世界范围内普遍存在,是女性死亡的主要原因。然而,细胞表面葡萄糖调节蛋白78(cs-GRP78)在几种类型的癌症和病原体感染中过表达。这项研究检查了FDA批准的两种著名的BC药物作为GRP78的BC治疗方法。第一种类型包括基于细胞周期蛋白的激酶4/6的抑制剂,包括abemaciclib,palbociclib,ribociclib,和dinaciclib。此外,衣霉素,和阿霉素,这是早期和晚期BC最有效的抗癌药物之一,对GRP78进行了测试。由于(-)-表半乳糖儿茶素没食子酸酯抑制GRP78,其也被评估(用作阳性对照)。因此,使用分子动力学模拟方法,这项研究旨在研究靶向GRP78的优势,GRP78代表了一种有希望的癌症治疗方案.鉴于计算药物反应预测模型的最新进展,这项研究旨在检查GRP78靶向的益处,这代表了一种有前途的癌症治疗方案,利用分子对接和分子动力学模拟相结合的方法。模拟蛋白质(50ns)与药物对接,然后进行了100ns的第二轮动力学模拟。之后,在模拟期间,每个络合物的结合自由能从30到100ns计算。这些发现证明了abemaciclib的疗效,ribociclib,和衣霉素与GRP78的核苷酸结合域结合,为阐明这些药物与过表达GRP78的癌症(和其他应激)细胞之间的相互作用模式铺平了道路。由RamaswamyH.Sarma沟通。
    Breast cancer (BC) is prevalent worldwide and is a leading cause of death among women. However, cell-surface glucose-regulated protein 78 (cs-GRP78) is overexpressed in several types of cancer and during pathogen infections. This study examines two well-known BC drugs approved by the FDA as BC treatments to GRP78. The first type consists of inhibitors of cyclin-based kinases 4/6, including abemaciclib, palbociclib, ribociclib, and dinaciclib. In addition, tunicamycin, and doxorubicin, which are among the most effective anticancer drugs for early and late-stage BC, are tested against GRP78. As (-)-epiGallocatechin gallate inhibits GRP78, it is also being evaluated (used as positive control). Thus, using molecular dynamics simulation approaches, this study aims to examine the advantages of targeting GRP78, which represents a promising cancer therapy regime. In light of recent advances in computational drug response prediction models, this study aimed to examine the benefits of GRP78 targeting, which represents a promising cancer therapy regime, by utilizing combined molecular docking and molecular dynamics simulation approaches. The simulated protein (50 ns) was docked with the drugs, then a second round of dynamics simulation was performed for 100 ns. After that, the binding free energies were calculated from 30 to 100 ns for each complex during the simulation period. These findings demonstrate the efficacy of abemaciclib, ribociclib, and tunicamycin in binding to the nucleotide-binding domain of the GRP78, paving the way for elucidating the mode of interactions between these drugs and cancer (and other stressed) cells that overexpress GRP78.Communicated by Ramaswamy H. Sarma.
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  • 文章类型: Journal Article
    未经批准:2019年冠状病毒病(COVID-19)相关的毛霉菌病(CAM)在2021年成为印度的公共卫生问题。然而,关于发病率的信息,CAM的表现和预后仍然很少。
    UNASSIGNED:这项研究描述了100例病例,这些病例是在Chandrapur(SPAROS)研究中接受手术治疗的COVID后急性侵袭性真菌性犀眶鼻窦炎,一项对Chandrapur地区诊断为CAM的患者进行的前瞻性观察性随访研究,印度。使用四个输入变量的两步聚类分析-入院时的血糖,糖尿病状态,糖皮质激素暴露和COVID-19的严重程度-用于定义三个不同的CAM簇。
    UNASSIGNED:普通人群中CAM的发生率为7.1例/1000例COVID-19住院患者。76%和55%的病例存在类固醇暴露和先前存在的糖尿病,分别。在18天的中位随访中,只有两人死亡,93例病例稳定。糖皮质激素,特别是甲基强的松龙,似乎沉淀了CAM。重症监护病房的入院似乎预示着手术范围较小。
    未经证实:确定了三种CAM亚型:COVID-19相关糖尿病和毛霉菌病,COVID-19相关的经典毛霉菌病,和COVID-19诱导的毛霉菌病。基于严重急性呼吸综合征冠状病毒-2和葡萄糖调节蛋白的动力学,提出了CAM假设。
    未经证实:临床特征,CAM的自然病程和发病机制与前COVID时代的毛霉菌病不同。希望这种分类在CAM管理中有用。
    UNASSIGNED: Coronavirus disease 2019 (COVID-19)-associated mucormycosis (CAM) became a public health problem in India in 2021. However, information about the incidence, presentation and prognosis of CAM remains sparse.
    UNASSIGNED: This study describes 100 cases from the Surgically treated Post COVID Acute invasive fungal Rhino-Orbital Sinusitis in Chandrapur (SPAROS) study, a prospective observational follow-up study of patients with CAM diagnosed in Chandrapur district, India. Two-step cluster analysis using four input variables - blood glucose on admission, diabetes status, glucocorticoid exposure and severity of COVID-19 - was used to define three distinct CAM clusters.
    UNASSIGNED: The incidence of CAM in the general population was 7.1 cases/1000 patients hospitalized with COVID-19. Steroid exposure and pre-existing diabetes were present in 76% and 55% of cases, respectively. At median follow-up of 18 days, only two deaths had been recorded, while 93 cases were stable. Glucocorticoids, particularly methylprednisolone, seemed to precipitate CAM. Admission to the intensive care unit appeared to be predictive of less extensive surgery.
    UNASSIGNED: Three subtypes of CAM were identified: COVID-19-associated diabetes and mucormycosis, COVID-19-associated classical mucormycosis, and COVID-19-induced mucormycosis. A CAM hypothesis was proposed based on the dynamics of severe acute respiratory syndrome coronavirus-2 and glucose regulated protein.
    UNASSIGNED: The clinical characteristics, natural course and pathogenesis of CAM differ from mucormycosis in the pre-COVID era. It is hoped that this classification will be useful in CAM management.
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  • 文章类型: Journal Article
    Background: The different waves of SARS-CoV-2 infection have strained hospital resources and, notably, intensive care units (ICUs). Identifying patients at risk of developing a critical condition is essential to correctly refer patients to the appropriate structure and to spare limited resources. The soluble form of RAGE (sRAGE), the endoplasmic stress response and its surrogates, GRP78 and VEGF-A, may be interesting markers. Methods: This was a prospective monocenter cohort study of adult patients admitted to the ICU for severe COVID-19 pneumonia. The plasma levels of sRAGE, GRP78 and VEGF-A were measured within the first 24 h. Patients were classified as critical if they further needed vasopressor therapy, renal replacement therapy, or invasive mechanical ventilation, or died during their ICU stay, and were otherwise classified as not critical. Results: A total of 98 patients were included and 39 developed a critical condition. Critical patients presented higher sRAGE (626 [450−1043] vs. 227 [137−404] pg/mL, p < 0.0001), interleukin-6 (43 [15−112] vs. 11 [5−20] pg/mL, p < 0.0001), troponin T (17 [9−39] vs. 10 [6−18] pg/mL, p = 0.003) and NT-pro-BNP (321 [118−446] vs. 169 [63−366] pg/mL, p = 0.009) plasma levels. No difference was observed for VEGF-A and GRP78. The variables independently associated with worsening in the ICU were sRAGE (1.03 [1.01−1.05] per 10 pg/mL) and age (1.7 [1.2−2.4] per 5 years). An sRAGE value of 449.5 pg/mL predicted worsening with a sensitivity of 77% and a specificity of 80%. Conclusion: sRAGE may allow the identification of patients at risk of developing a critical form of COVID-19 pneumonia, and thus may be useful to correctly refer patients to the appropriate structure of care.
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  • 文章类型: Journal Article
    背景:新冠肺炎感染于2020年3月11日被世卫组织宣布为全球大流行。已知GRP78蛋白参与多种病毒的入侵。我们目前的研究试图为新冠肺炎患者GRP78蛋白水平的变化提供一些见解,Covid-19(+)肺炎,与正常人群相比,CT阴性的Covid-19感染病例更多。
    方法:42例Covid-19(-)肺炎患者;72例Covid-19感染患者(30例肺炎,42例CT阴性患者)和30例无已知疾病的患者(对照组)在临床和放射学评估后纳入研究。通过市售的酶联免疫吸附测定(ELISA)试剂盒测量受试者的血清GRP78水平。
    结果:发现新冠肺炎感染组的GRP78水平显著高于新冠肺炎(-)肺炎组和对照组(分别为p=0.031和p=0.0001)。Covid-19(-)肺炎之间没有显着差异,就GRP78水平而言,Covid-19(+)肺炎和CT阴性Covid19感染组(p=0.09)。此外,Covid-19(-)肺炎组的GRP78水平显著高于对照组(p=0.0001).
    结论:这项前瞻性病例对照研究表明,与新冠肺炎和对照组相比,新冠肺炎感染期间血清GRP78水平显著升高。随着SARS-CoV-2病毒与GRP78蛋白之间的联系越来越清楚,这种关联可能会成为治疗目标。
    BACKGROUND: Covid-19 infection was declared a global pandemic by WHO on March 11, 2020. GRP78 protein is known to be involved in the intrusion of numerous viruses. Our current study tries to provide some insight into the variation of GRP78 protein levels in patients with Covid-19 (-) pneumonia, Covid-19 (+) pneumonia, and CT negative Covid-19 infection in comparison to the normal population through a larger number of cases.
    METHODS: 42 patients who have Covid-19 (-) pneumonia; 72 patients who have Covid-19 infection (30 pneumonia,42 CT negative patients) and 30 patient who have no known diseases (control group) have included in the study after the clinical and radiological evaluation. Serum GRP78 levels of the subjects were measured through a commercially available enzyme-linked immunosorbent assay (ELISA) kit.
    RESULTS: The GRP78 level was found to be significantly higher in the Covid-19 infection group than both Covid-19 (-) pneumonia and control group (p = 0.031 and p = 0.0001, respectively).No significant difference was evident between Covid-19 (-) pneumonia, Covid-19 (+) pneumonia and CT negative Covid 19 infection groups with respect to GRP78 levels (p = 0.09). In addition, the GRP78 levels were significantly higher in the Covid-19 (-) pneumonia group than the control group (p = 0.0001).
    CONCLUSIONS: This prospective case-control study reveals that the serum GRP78 levels significantly increased during Covid-19 infection in comparison to both the Covid-19 (-) pneumonia and the control group. As the association between SARS-CoV-2 virus and GRP78 protein is revealed more clearly, this association may come to the fore as a therapeutic target.
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  • 文章类型: Comparative Study
    目的:一种新型人类冠状病毒,命名为SARS-COV-2,最近在世界各地造成数千人死亡。内质网应激在疾病的发生发展中起着重要作用。
    方法:我们旨在研究SARS-COV-2感染患者与肺炎患者的ER应激标志物之间的关系。共有9例患者(4例诊断为肺炎,5例诊断为SARS-COV-2感染)因肺炎和SARS-COV-2症状入院。纳入18名无任何已知慢性或急性疾病和药物使用的健康个体作为健康对照组。血清人葡萄糖调节蛋白78(GRP78),采用酶联免疫吸附试验(ELISA)检测血清人C/EBP同源蛋白(CHOP)和血清人磷酸化细胞外信号调节激酶(PERK)水平。
    结果:发现与其他组的个体相比,SARS-COV-2阳性病例中的GRP78水平明显更高。与其他组相比,SARS-COV-2阳性组的血清GRP-78水平中位数在统计学上明显更高(p=0.0003)。SARS-COV-2阳性肺炎病例的血清PERK水平在统计学上显着升高(p=0.046)。
    结论:显示GRP78与SARS-COV-2感染之间存在关联。尽管对少数患者进行了调查,这些结果将对SARS-COV-2的未来治疗具有重要意义。
    OBJECTIVE: A novel human coronavirus, named SARS-COV-2, has recently caused thousands of deaths all around the world. Endoplasmic reticulum (ER) stress plays an important role in the development of diseases.
    METHODS: We aimed to to investigate the relationship between ER stress markers in patients infected with SARS-COV-2 and patients with pneumonia. A total of 9 patients (4 patients diagnosed with pneumonia and 5 patients diagnosed with SARS-COV-2 infection) who admitted to the emergency Department with symptoms of pneumonia and SARS-COV-2 were included in the study. A total of 18 healthy individuals without any known chronic or acute disease and drug use were included as the healthy control group. Serum human glucose regulated protein 78 (GRP78), serum human C/EBP homologous protein (CHOP) and serum human phospho extracellular signal regulated kinase (PERK) levels were measured using enzyme-linked immunosorbent assay (ELISA).
    RESULTS: GRP78 levels were found to be significantly higher in SARS-COV-2 positive cases compared to individuals in other groups. Serum GRP-78 level median value was statistically significantly higher in SARS-COV-2-positive group compared to the other groups (p=0.0003). Serum PERK level was statistically significantly higher in SARS-COV-2-positive pneumonia cases (p=0.046).
    CONCLUSIONS: An association was shown between GRP78 and SARS-COV-2 infection. Although a small number of patients was investigated, these results will be important and guide future treatments of SARS-COV-2.
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  • 文章类型: Journal Article
    OBJECTIVE: The purpose of this study was to determine the value of the endoplasmic reticulum (ER) stress markers glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and PERK in predicting the success of cardiopulmonary resuscitation (CPR) or post-CPR survival.
    METHODS: Non-traumatic out-of-hospital CA patients were included in this prospective, nested case-control study. Standard CPR and post-resuscitative care were applied. Levels of ER stress markers were measured at presentation and were investigated to determine whether they might constitute a marker predicting return of spontaneous circulation (ROSC) or sustained ROSC, and of 24-h, and 1 and 3-month survival.
    RESULTS: Fifty-two out of 99 non-traumatic CA patients were enrolled. ROSC was determined at a level of 25%, sustained ROSC at 23%, 24-h survival at 7%, and 1- and 3-month survival at 4.6%. No difference was determined in terms of ER stress markers between patients with and without ROSC or sustained ROSC. Only PERK levels were higher in surviving patients than non-surviving subjects in terms of 24-h survival (p = 0.01). Otherwise, no stress markers differed between surviving and non-surviving patients at any survival time point.
    CONCLUSIONS: ER stress markers are of no value in determining establishment of ROSC or sustained ROSC, success of CPR, or survival. Only PERK levels may be valuable in terms of 24-h survival.
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  • 文章类型: Journal Article
    OBJECTIVE: This phase I clinical study (NCT01415297) evaluated the safety, tolerability, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of IT-139 (formerly NKP-1339) monotherapy in patients with advanced solid tumours. IT-139, sodium trans-(tetrachlorobis(1H-indazole)ruthenate(III)), is a novel small molecule that suppresses the stress induction of GRP78 in tumour cells. GRP78 is a key regulator of misfolded protein processing, and its upregulation in tumours is associated with intrinsic and drug-induced resistance.
    METHODS: Forty-six patients with advanced solid tumours refractory to treatment received intravenous infusions of IT-139 on days 1, 8 and 15 for every 28 days, and doses were evaluated across nine cohorts at 20, 40, 80, 160, 320, 420, 500, 625 and 780 mg/m2.
    RESULTS: Overall, IT-139 was well tolerated. The treatment-emergent adverse events (AEs) occurring in ≥20% of patients were nausea, fatigue, vomiting, anaemia and dehydration. The majority of patients had AEs that were ≤grade 2, regardless of relationship with the study drug. Of the total 38 efficacy-evaluable patients, one patient with a carcinoid tumour achieved a durable partial response. Nine additional patients achieved stable disease . The MTD was determined to be 625 mg/m2. IT-139 exhibited first-order linear pharmacokinetics.
    CONCLUSIONS: IT-139 demonstrated a manageable safety profile at the MTD and modest anti-tumour activity in this study of patients with solid tumours refractory to treatment. The lack of dose-limiting haematological toxicity and the absence of neurotoxicity position IT-139 well for use in combination with a broad spectrum of anticancer drugs.
    BACKGROUND: NCT01415297.
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