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Opioid-Based Haptens: Development of Immunotherapy 基于阿片类的aptens:开发免疫疗法
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-16 DOI: 10.3390/ijms25147781
S. Hosztafi, A. R. Galambos, István Köteles, D. Karádi, Susanna Fürst, M. Al-Khrasani
Over the past decades, extensive preclinical research has been conducted to develop vaccinations to protect against substance use disorder caused by opioids, nicotine, cocaine, and designer drugs. Morphine or fentanyl derivatives are small molecules, and these compounds are not immunogenic, but when conjugated as haptens to a carrier protein will elicit the production of antibodies capable of reacting specifically with the unconjugated hapten or its parent compound. The position of the attachment in opioid haptens to the carrier protein will influence the specificity of the antiserum produced in immunized animals with the hapten–carrier conjugate. Immunoassays for the determination of opioid drugs are based on the ability of drugs to inhibit the reaction between drug-specific antibodies and the corresponding drug–carrier conjugate or the corresponding labelled hapten. Pharmacological studies of the hapten–carrier conjugates resulted in the development of vaccines for treating opioid use disorders (OUDs). Immunotherapy for opioid addiction includes the induction of anti-drug vaccines which are composed of a hapten, a carrier protein, and adjuvants. In this review we survey the design of opioid haptens, the development of the opioid radioimmunoassay, and the results of immunotherapy for OUDs.
过去几十年来,人们进行了广泛的临床前研究,以开发疫苗,预防阿片类药物、尼古丁、可卡因和特制药物引起的药物使用障碍。吗啡或芬太尼衍生物都是小分子,这些化合物不具有免疫原性,但当它们作为合剂与载体蛋白结合时,就会激发抗体的产生,这种抗体能够与未结合的合剂或其母体化合物发生特异性反应。阿片触价素与载体蛋白的连接位置会影响使用触价素-载体共轭物免疫动物产生的抗血清的特异性。测定阿片类药物的免疫测定是基于药物抑制药物特异性抗体与相应的药物载体共轭物或相应的标记杂蛋白之间反应的能力。通过对合蛋白-载体共轭物的药理学研究,开发出了用于治疗阿片类药物使用障碍(OUDs)的疫苗。治疗阿片类药物成瘾的免疫疗法包括诱导注射由合蛋白、载体蛋白和佐剂组成的抗毒疫苗。在这篇综述中,我们将对阿片合剂的设计、阿片放射免疫测定法的开发以及阿片类药物成瘾免疫疗法的成果进行调查。
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引用次数: 0
New Modifiable Risk Factors Influencing Coronary Artery Disease Severity 影响冠状动脉疾病严重程度的新可调节风险因素
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-16 DOI: 10.3390/ijms25147766
Kamila Florek, Maja Kübler, Magdalena Górka, Piotr Kübler
Cardiovascular diseases (CVDs) remain the leading cause of death worldwide with coronary artery disease (CAD) being the first culprit in this group. In terms of CAD, not only its presence but also its severity plays a role in the patient’s treatment and prognosis. CAD complexity can be assessed with the indicator named the SYNTAX score (SS). A higher SS is associated with major adverse cardiovascular event (MACE) occurrence in short- and long-term observations. Hence, the risk factors affecting CAD severity based on SS results may help lower the risk among patients with already developed CAD to reduce their impact on coronary atherosclerosis progression. The well-established risk factors of CAD are consistent with those associated with the coronary plaque burden. However, recently, it was shown that new indicators exist, which we present in this paper, that significantly contribute to CAD complexity such as inflammatory parameters, C-reactive protein (CRP), ratios based on blood smear results, and uric acid. Moreover, microbiota alteration, vitamin D deficiency, and obstructive sleep apnea (OSA) also predicted CAD severity. However, sometimes, certain indicators were revealed as significant only in terms of chronic coronary syndromes (CCSs) or specific acute coronary syndromes (ACSs). Importantly, there is a need to apply the interdisciplinary and translational approach to the novel CAD severity risk assessment to maximize the impact of secondary prevention among patients at risk of coronary atherosclerosis progression.
心血管疾病(CVDs)仍然是导致全球死亡的主要原因,而冠状动脉疾病(CAD)则是其中的罪魁祸首。就 CAD 而言,其存在与否以及严重程度都会对患者的治疗和预后产生影响。CAD 的复杂程度可以用 SYNTAX 评分(SS)这一指标来评估。在短期和长期观察中,SS 越高,主要不良心血管事件(MACE)的发生率就越高。因此,根据SS评分结果确定影响CAD严重程度的风险因素,有助于降低已患CAD患者的风险,减少其对冠状动脉粥样硬化进展的影响。已确立的 CAD 危险因素与冠状动脉斑块负荷相关的危险因素是一致的。然而,最近有研究表明,我们在本文中介绍的一些新指标,如炎症参数、C 反应蛋白(CRP)、基于血涂片结果的比率和尿酸等,对 CAD 的复杂性有显著影响。此外,微生物群改变、维生素 D 缺乏和阻塞性睡眠呼吸暂停(OSA)也能预测 CAD 的严重程度。不过,有时某些指标仅对慢性冠状动脉综合征(CCS)或特定急性冠状动脉综合征(ACS)有显著意义。重要的是,有必要将跨学科和转化方法应用到新型的冠状动脉粥样硬化严重程度风险评估中,以最大限度地提高冠状动脉粥样硬化进展风险患者的二级预防效果。
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引用次数: 0
Association of Glutathione Transferase M1, T1, P1 and A1 Gene Polymorphism and Susceptibility to IgA Vasculitis 谷胱甘肽转移酶 M1、T1、P1 和 A1 基因多态性与 IgA 血管炎易感性的关系
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-16 DOI: 10.3390/ijms25147777
Ana Juras, Kristina Crkvenac Gornik, M. Held, M. Šestan, D. Turudic, M. Šapina, S. Srsen, Sanda Huljev Frković, M. Frković, A. Gagro, M. Jelušić
Endothelial cell injury is a hallmark of IgA vasculitis (IgAV), possibly associated with various factors, including oxidative stress. Certain single nucleotide polymorphisms (SNPs) of glutathione S-transferases (GST) genes have been shown to increase susceptibility to oxidative stress. The objective of our study was to evaluate the gene polymorphisms of GSTM1, GSTT1, GSTP1, and GSTA1 in patients with IgAV. DNA was extracted from the blood of 124 children with IgAV and 168 age-matched healthy controls. A higher frequency of the GSTM1 null genotype was observed in patients with gastrointestinal (GI) system involvement compared to those without GI system involvement (51.5% vs. 28.6%, p = 0.011). Additionally, the GSTM1 null genotype was less prevalent (30.8% vs. 69.2%, p = 0.032), while the GSTP1 Val/Val genotype was significantly more prevalent in patients who developed urogenital complications (scrotal swelling) during the course of the disease (60% vs. 40%, p = 0.039). This study is the first to suggest an association between GSTM1 and GSTP1 polymorphisms and various phenotypes observed during the clinical course of IgAV in the pediatric population. However, it was performed on a national and likely single ethnic cohort, too small for definitive conclusions, so larger studies are needed to confirm this association.
内皮细胞损伤是 IgA 血管炎(IgAV)的一个特征,可能与包括氧化应激在内的各种因素有关。谷胱甘肽 S-转移酶(GST)基因的某些单核苷酸多态性(SNPs)已被证明会增加对氧化应激的易感性。我们的研究旨在评估 IgAV 患者中 GSTM1、GSTT1、GSTP1 和 GSTA1 的基因多态性。我们从 124 名 IgAV 患儿和 168 名年龄匹配的健康对照者的血液中提取了 DNA。与未受累于胃肠道系统的患者相比,受累于胃肠道系统的患者中出现 GSTM1 空基因型的频率更高(51.5% 对 28.6%,P = 0.011)。此外,GSTM1 空基因型的发病率较低(30.8% 对 69.2%,p = 0.032),而 GSTP1 Val/Val 基因型在病程中出现泌尿生殖系统并发症(阴囊肿胀)的患者中发病率明显更高(60% 对 40%,p = 0.039)。这项研究首次提出了 GSTM1 和 GSTP1 多态性与儿童 IgAV 临床病程中观察到的各种表型之间的关联。然而,这项研究是在全国范围内进行的,而且可能是在单一种族的队列中进行的,规模太小,无法得出明确的结论,因此需要更大规模的研究来证实这种关联。
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引用次数: 0
Integrated Metabolomics and Transcriptomics Analyses of the Biosynthesis of Arbutin and 6′-O-Caffeoylarbutin in Vaccinium dunalianum Cell Suspension Cultures Fed with Hydroquinone 用对苯二酚喂养的越橘细胞悬浮培养物中熊果苷和 6′-O-Caffeoylarbutin 生物合成的代谢组学和转录组学综合分析
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-16 DOI: 10.3390/ijms25147760
Churan Li, Boxiao Wu, Weihua Wang, Xiaoqin Yang, Yun Liu, Guolei Zhu, Si-da Xie, Qian Jiang, Yong Ding, Yingjun Zhang, Ping Zhao, Lihua Zou
Arbutin and 6′-O-caffeoylarbutin (CA) from Vaccinium dunalianum Wight are known for their ability to inhibit melanin synthesis. To boost the production of arbutin and CA, precursor feeding with hydroquinone (HQ) was studied in V. dunalianum suspension cells. The effect of HQ on the biosynthesis of arbutin and CA in the suspension cells was investigated using high-performance liquid chromatography (HPLC), and possible molecular mechanisms were analyzed using metabolomics and transcriptomics analyses. HPLC analysis only showed that the addition of HQ significantly enhanced arbutin synthesis in cells, peaking at 15.52 ± 0.28 mg·g−1 after 0.5 mmol·L−1 HQ treatment for 12 h. Subsequently, metabolomics identified 78 differential expression metabolites (DEMs), of which arbutin and CA were significantly up-regulated metabolites. Moreover, transcriptomics found a total of 10,628 differential expression genes (DEGs). The integrated transcriptomics and metabolomics revealed that HQ significantly enhanced the expression of two arbutin synthase (AS) genes (Unigene0063512 and Unigene0063513), boosting arbutin synthesis. Additionally, it is speculated that CA was generated from arbutin and 3,4,5-tricaffeoylquinic acid catalyzed by caffeoyl transferase, with Unigene0044545, Unigene0043539, and Unigene0017356 as potentially associated genes with CA synthesis. These findings indicate that the precursor feeding strategy offers a promising approach for the mass production of arbutin and CA in V. dunalianum suspension cells and provides new insights for CA biosynthesis in V. dunalianum.
来自 Vaccinium dunalianum Wight 的熊果苷和 6′-O-caffeoylarbutin (CA) 因其抑制黑色素合成的能力而闻名。为了提高熊果苷和 CA 的产量,研究人员在杜梨悬浮细胞中用对苯二酚(HQ)喂养前体。使用高效液相色谱法(HPLC)研究了 HQ 对悬浮细胞中熊果苷和 CA 生物合成的影响,并使用代谢组学和转录组学分析了可能的分子机制。高效液相色谱分析结果表明,添加 HQ 能显著提高细胞中熊果苷的合成,在 0.5 mmol-L-1 HQ 处理 12 小时后,合成量达到峰值 15.52 ± 0.28 mg-g-1。此外,转录组学共发现了 10628 个差异表达基因(DEGs)。综合转录组学和代谢组学发现,HQ 能显著提高两个熊果苷合成酶(AS)基因(Unigene0063512 和 Unigene0063513)的表达,促进熊果苷的合成。此外,推测 CA 是由熊果苷和 3,4,5 三咖啡酰奎宁酸在咖啡酰转移酶的催化下生成的,Unigene0044545、Unigene0043539 和 Unigene0017356 可能与 CA 的合成有关。这些发现表明,前体喂养策略为在杜仲悬浮细胞中大量生产熊果苷和 CA 提供了一种可行的方法,并为杜仲的 CA 生物合成提供了新的见解。
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引用次数: 0
Tumor Necrosis Factor-Alpha: Ally and Enemy in Protean Cutaneous Sceneries 肿瘤坏死因子-α:蛋白皮肤病的盟友与敌人
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-16 DOI: 10.3390/ijms25147762
K. Pocino, Valeria Carnazzo, A. Stefanile, V. Basile, Cristina Guerriero, M. Marino, D. Rigante, Umberto Basile
Skin is the forestage for a series of many-sided functions of tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine with staggering versatility and sizable implications for tissue homeostasis, immune responses, angiogenesis, apoptosis, local and systemic inflammation. An aberrant TNF-α-mediated crosstalk has been linked to the pathogenesis of acute and chronic skin inflammatory diseases, and indeed, TNF-α dysregulation can contribute to the development and progression of psoriasis, vitiligo, local damage following exposition to ultraviolet light radiations, cutaneous lupus erythematosus, and acne vulgaris. Therapies that target TNF-α are conspicuously used in the treatment of different skin disorders, aiming to modulate the in vivo immune functions triggered by many cutaneous cells, including keratinocytes, mast cells, or Langerhans cells, and reduce inflammation taking place within the skin. Herein, we focus on the key relationships between TNF-α and distinct skin non-neoplastic inflammatory or physiologic conditions, showing that a natural induction of TNF-α may have a protective significance but that TNF-α overproduction may be harmful or even lethal. Many questions remain unraveled in the therapeutic practice, and caution should be exercised due to eventual backlashes exerted by TNF-α in maintaining skin health or in provoking skin disease.
皮肤是肿瘤坏死因子-α(TNF-α)一系列多方面功能的 "森林",TNF-α是一种促炎细胞因子,具有惊人的多功能性,对组织稳态、免疫反应、血管生成、细胞凋亡、局部和全身炎症具有重大影响。TNF-α介导的异常串扰与急性和慢性皮肤炎症性疾病的发病机制有关,事实上,TNF-α失调可导致牛皮癣、白癜风、紫外线照射后的局部损伤、皮肤红斑狼疮和寻常痤疮的发生和发展。针对 TNF-α 的疗法被广泛用于治疗各种皮肤疾病,旨在调节由角质形成细胞、肥大细胞或朗格汉斯细胞等多种皮肤细胞引发的体内免疫功能,减轻皮肤内部的炎症反应。在此,我们将重点关注TNF-α与不同的皮肤非肿瘤性炎症或生理状况之间的关键关系,表明TNF-α的自然诱导可能具有保护意义,但TNF-α的过度产生可能有害甚至致命。在治疗实践中仍有许多问题有待解决,由于TNF-α在维持皮肤健康或诱发皮肤疾病方面最终会产生反作用,因此应谨慎行事。
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引用次数: 0
Cellular and Molecular Biology of Mitochondria in Chronic Obstructive Pulmonary Disease 慢性阻塞性肺病线粒体的细胞和分子生物学研究
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-16 DOI: 10.3390/ijms25147780
Chin-Ling Li, Shih-Feng Liu
Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by enduring airflow limitation and chronic inflammation. Growing evidence highlights mitochondrial dysfunction as a critical factor in COPD development and progression. This review explores the cellular and molecular biology of mitochondria in COPD, focusing on structural and functional changes, including alterations in mitochondrial shape, behavior, and respiratory chain complexes. We discuss the impact on cellular signaling pathways, apoptosis, and cellular aging. Therapeutic strategies targeting mitochondrial dysfunction, such as antioxidants and mitochondrial biogenesis inducers, are examined for their potential to manage COPD. Additionally, we consider the role of mitochondrial biomarkers in diagnosis, evaluating disease progression, and monitoring treatment efficacy. Understanding the interplay between mitochondrial biology and COPD is crucial for developing targeted therapies to slow disease progression and improve patient outcomes. Despite advances, further research is needed to fully elucidate mitochondrial dysfunction mechanisms, discover new biomarkers, and develop targeted therapies, aiming for comprehensive disease management that preserves lung function and enhances the quality of life for COPD patients.
慢性阻塞性肺病(COPD)是一种进行性呼吸系统疾病,其特征是持久的气流受限和慢性炎症。越来越多的证据表明,线粒体功能障碍是慢性阻塞性肺病发展和恶化的关键因素。本综述探讨慢性阻塞性肺病线粒体的细胞和分子生物学,重点关注结构和功能变化,包括线粒体形状、行为和呼吸链复合物的改变。我们讨论了线粒体对细胞信号通路、细胞凋亡和细胞衰老的影响。我们研究了针对线粒体功能障碍的治疗策略,如抗氧化剂和线粒体生物生成诱导剂,以了解它们在控制慢性阻塞性肺病方面的潜力。此外,我们还考虑了线粒体生物标志物在诊断、评估疾病进展和监测治疗效果方面的作用。了解线粒体生物学与慢性阻塞性肺病之间的相互作用对于开发靶向疗法以减缓疾病进展和改善患者预后至关重要。尽管取得了进展,但仍需进一步研究,以全面阐明线粒体功能障碍机制、发现新的生物标记物和开发靶向疗法,从而实现全面的疾病管理,保护慢性阻塞性肺病患者的肺功能并提高其生活质量。
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引用次数: 0
De Novo DNM1L Mutation in a Patient with Encephalopathy, Cardiomyopathy and Fatal Non-Epileptic Paroxysmal Refractory Vomiting 一名患有脑病、心肌病和致命性非癫痫性阵发性难治性呕吐的患者体内的新DNM1L突变
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-16 DOI: 10.3390/ijms25147782
B. Berti, D. Verrigni, A. Nasca, M. Di Nottia, Daniela Leone, A. Torraco, T. Rizza, E. Bellacchio, A. Legati, C. Palermo, S. Marchet, C. Lamperti, A. Novelli, Eugenio Maria Mercuri, E. Bertini, Marika Pane, Daniele Ghezzi, R. Carrozzo
Mitochondrial fission and fusion are vital dynamic processes for mitochondrial quality control and for the maintenance of cellular respiration; they also play an important role in the formation and maintenance of cells with high energy demand including cardiomyocytes and neurons. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family that is responsible for the fission of mitochondria; it is ubiquitous but highly expressed in the developing neonatal heart. De novo heterozygous pathogenic variants in the DNM1L gene have been previously reported to be associated with neonatal or infantile-onset encephalopathy characterized by hypotonia, developmental delay and refractory epilepsy. However, cardiac involvement has been previously reported only in one case. Next-Generation Sequencing (NGS) was used to genetically assess a baby girl characterized by developmental delay with spastic–dystonic, tetraparesis and hypertrophic cardiomyopathy of the left ventricle. Histochemical analysis and spectrophotometric determination of electron transport chain were performed to characterize the muscle biopsy; moreover, the morphology of mitochondria and peroxisomes was evaluated in cultured fibroblasts as well. Herein, we expand the phenotype of DNM1L-related disorder, describing the case of a girl with a heterozygous mutation in DNM1L and affected by progressive infantile encephalopathy, with cardiomyopathy and fatal paroxysmal vomiting correlated with bulbar transitory abnormal T2 hyperintensities and diffusion-weighted imaging (DWI) restriction areas, but without epilepsy. In patients with DNM1L mutations, careful evaluation for cardiac involvement is recommended.
线粒体分裂和融合是线粒体质量控制和维持细胞呼吸的重要动态过程;它们在心肌细胞和神经元等高能量需求细胞的形成和维持过程中也发挥着重要作用。DNM1L(dynamin-1 like)基因编码 DRP1 蛋白,这是一种进化保守的 dynamin 家族成员,负责线粒体的裂变;它无处不在,但在发育中的新生儿心脏中高表达。据报道,DNM1L 基因的新发杂合致病变体与新生儿或婴儿期发病的脑病有关,这些脑病的特征是肌张力低下、发育迟缓和难治性癫痫。然而,此前仅有一例报告了心脏受累。研究人员利用下一代测序技术(NGS)对一名女婴进行了基因评估,该女婴患有发育迟缓伴痉挛性肌张力障碍、四肢瘫痪和左心室肥厚性心肌病。对肌肉活检组织进行了组织化学分析,并对电子传递链进行了分光光度测定;此外,还对培养成纤维细胞中线粒体和过氧化物酶体的形态进行了评估。在此,我们扩展了DNM1L相关疾病的表型,描述了一例DNM1L杂合子突变的女孩,她患有进行性婴儿脑病,伴有心肌病和致命的阵发性呕吐,与球部短暂性异常T2高密度和弥散加权成像(DWI)限制区相关,但没有癫痫。建议对 DNM1L 基因突变患者进行心脏受累的仔细评估。
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引用次数: 0
Platelet Contribution and Endothelial Activation and Stress Index-Potential Mortality Predictors in Traumatic Brain Injury 创伤性脑损伤的潜在死亡率预测因素--血小板贡献、内皮活化和压力指数
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-16 DOI: 10.3390/ijms25147763
A. Băetu, Liliana Mirea, Cristian Cobilinschi, I. Grințescu, I. Grințescu
Coagulopathy and traumatic brain injury (TBI) are complexly intertwined. In isolated TBI, coagulopathy may contribute to hemorrhagic lesion development, progression, or recurrence, as it may lead to a particular pattern of coagulopathy called TBI-induced coagulopathy (TBI-IC). We performed a retrospective and descriptive evaluation of 63 patients admitted to the Emergency Clinical Hospital Bucharest with the diagnosis of moderate/severe brain injury. In addition to demographic data, all included patients had a complete paraclinical evaluation that included rotational thromboelastometric (ROTEM) blood-clot analysis. The platelet component (PLTEM) and the endotheliopathy activation and stress index score (EASIX) were calculated. These parameters were presented comparatively according to survival at 30 days and helped define the two study groups: survivors and non-survivors at 30 days. The contribution of platelets to clot strength is derived from maximum clot elasticity (MCE) and maximum clot firmness (MCF). MCE is defined as (MCF × 100)/(100 − MCF), and PLTEM is defined as EXTEM MCE—FIBTEM MCE. EASIX is a novel biomarker recently studied in TBI patients, calculated according to the following formula: lactate dehydrogenase (U/L) × creatinine (mg/dL)/platelets (109 cells/L). Regarding the demographic data, there were no significant differences between the survivors and non-survivors. All ROTEM parameters related to clot amplitude (A5, A10, A20, MCF in EXTEM and FIBTEM channels) were higher in the group of patients who survived. Also, PLTEM was decreased in the group of deceased patients (89.71 ± 22.86 vs. 132.3 ± 16.56 p < 0.0001). The cut-off point determined with the ROC curve is 114.10, with a sensitivity of 94.74% and a specificity of 93.18%, for the detection of the negative prognosis (death at 30 days). The EASIX score was significantly higher in the patients who survived the traumatic event, with a median difference value of 1.15 (p < 0.0001). The ROC analysis of this biomarker highlights a cut-off point of 2.12, with a sensitivity of 88.64% and a specificity of 94.74% (AUC = 0.95, p < 0.0001), for the prediction of mortality. The comparative analysis of the two studied markers was performed using the Cox proportional hazard ratio and highlighted the greater influence that PLTEM has on survival time (b value = −0.05, p < 0.0001) compared to EASIX (b value = 0.49, p = 0.0026). The present retrospective study indicates the potential of the TBI-IC reflecting parameters PLTEM and EASIX as markers of mortality prognosis. Larger prospective studies are needed to confirm their combined prognostic value and use in decision-making and reduction in the burden of disease by adequate allocation of resources in a personalized and timely manner.
凝血病与创伤性脑损伤(TBI)复杂地交织在一起。在孤立的创伤性脑损伤中,凝血功能障碍可能会导致出血性病变的发生、发展或复发,因为它可能会导致一种特殊的凝血功能障碍模式,即创伤性脑损伤诱发凝血功能障碍(TBI-IC)。我们对布加勒斯特临床急诊医院收治的 63 名诊断为中度/重度脑损伤的患者进行了回顾性和描述性评估。除人口统计学数据外,所有患者都接受了完整的临床旁评估,包括旋转血栓弹性测定(ROTEM)血凝分析。计算了血小板成分(PLTEM)和内皮病变激活和压力指数评分(EASIX)。这些参数根据 30 天后的存活率进行比较,有助于界定两个研究组:30 天后的存活者和非存活者。血小板对血凝块强度的贡献来自最大血凝块弹性(MCE)和最大血凝块坚固性(MCF)。MCE定义为(MCF × 100)/(100 - MCF),PLTEM定义为EXTEM MCE-FIBTEM MCE。EASIX 是最近在创伤性脑损伤患者中研究的一种新型生物标志物,计算公式如下:乳酸脱氢酶(U/L)×肌酐(mg/dL)/血小板(109 个细胞/L)。在人口统计学数据方面,幸存者和非幸存者之间没有显著差异。所有与血块振幅有关的 ROTEM 参数(A5、A10、A20、EXTEM 和 FIBTEM 通道中的 MCF)在存活患者组中都较高。此外,PLTEM 在死亡患者组中也有所下降(89.71 ± 22.86 vs. 132.3 ± 16.56 p < 0.0001)。根据 ROC 曲线确定的临界点为 114.10,检测阴性预后(30 天后死亡)的灵敏度为 94.74%,特异度为 93.18%。在创伤事件后存活的患者中,EASIX 评分明显较高,中位差值为 1.15(P < 0.0001)。对该生物标志物进行的 ROC 分析表明,预测死亡率的临界点为 2.12,灵敏度为 88.64%,特异度为 94.74%(AUC = 0.95,p < 0.0001)。使用 Cox 比例危险比对两种标记物进行了比较分析,结果显示,与 EASIX(b 值 = 0.49,p = 0.0026)相比,PLTEM 对生存时间的影响更大(b 值 = -0.05,p < 0.0001)。本回顾性研究表明,反映 TBI-IC 的参数 PLTEM 和 EASIX 有可能成为死亡率预后的指标。需要进行更大规模的前瞻性研究,以确认这两个指标的综合预后价值,并将其用于决策,通过个性化和及时的充分资源分配来减轻疾病负担。
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引用次数: 0
(E)-2-Benzylidenecyclanones: Part XIX. Reaction of (E)-2-(4′-X-Benzylidene)-1-tetralones with Cellular Thiols: Comparison of Thiol Reactivities of Open-Chain Chalcones and Their Six- and Seven-Membered Cyclic Analogs (E)-2-亚苄基环酮:第十九部分。(E)-2-(4′-X-亚苄基)-1-四氢萘酮与细胞硫醇的反应:开链查耳酮及其六元和七元环状类似物的硫醇反应活性比较
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-16 DOI: 10.3390/ijms25147773
Fatemeh Kenari, Zoltán Pintér, S. Molnár, I. Borges, A. Camargo, H. Napolitano, P. Perjési
Non-enzyme-catalyzed thiol addition onto the α,β-unsaturated carbonyl system is associated with several biological effects. Kinetics and diastereoselectivity of non-enzyme catalyzed nucleophilic addition of reduced glutathione (GSH) and N-acetylcysteine (NAC) to the six-membered cyclic chalcone analogs 2a and 2b were investigated at different pH values (pH 3.2, 7.4 and 8.0). The selected compounds displayed in vitro cancer cell cytotoxicity (IC50) of different orders of magnitude. The chalcones intrinsically reacted with both thiols under all incubation conditions. The initial rates and compositions of the final mixtures depended both on the substitution and the pH. The stereochemical outcome of the reactions was evaluated using high-pressure liquid chromatography with UV detection (HPLC-UV). The structures of the formed thiol-conjugates and the retro-Michael products (Z)-2a and (Z)-2b were confirmed by high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Frontier molecular orbitals and the Fukui function calculations were carried out to investigate their effects on the six-membered cyclic analogs. Data were compared with those obtained with the open-chain (1) and the seven-membered (3) analogs. The observed reactivities do not directly relate to the difference in in vitro cancer cell cytotoxicity of the compounds.
α、β-不饱和羰基系统上的非酶催化硫醇加成与多种生物效应有关。在不同的 pH 值(pH 3.2、7.4 和 8.0)下,研究了还原型谷胱甘肽(GSH)和 N-乙酰半胱氨酸(NAC)与六元环查耳酮类似物 2a 和 2b 的非酶催化亲核加成的动力学和非对映选择性。所选化合物显示出不同数量级的体外癌细胞毒性(IC50)。在所有培养条件下,查耳酮都会与两种硫醇发生固有反应。最终混合物的初始速率和组成取决于取代和 pH 值。反应的立体化学结果通过紫外检测高压液相色谱法(HPLC-UV)进行了评估。高压液相色谱-质谱法(HPLC-MS)确认了所形成的硫醇共轭物和逆迈克尔产物 (Z)-2a 和 (Z)-2b 的结构。对前沿分子轨道和 Fukui 函数进行了计算,以研究它们对六元环状类似物的影响。数据与开链 (1) 和七元 (3) 类似物的数据进行了比较。观察到的反应活性与化合物在体外癌细胞毒性方面的差异没有直接关系。
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引用次数: 0
Dementia after Ischemic Stroke, from Molecular Biomarkers to Therapeutic Options 缺血性中风后痴呆,从分子生物标记物到治疗方案
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-16 DOI: 10.3390/ijms25147772
Vikalpa Dammavalam, Deborah Rupert, Marcos Lanio, Zhaosheng Jin, Neil A Nadkarni, Stella E. Tsirka, Sergio D. Bergese
Ischemic stroke is a leading cause of disability worldwide. While much of post-stroke recovery is focused on physical rehabilitation, post-stroke dementia (PSD) is also a significant contributor to poor functional outcomes. Predictive tools to identify stroke survivors at risk for the development of PSD are limited to brief screening cognitive tests. Emerging biochemical, genetic, and neuroimaging biomarkers are being investigated in an effort to unveil better indicators of PSD. Additionally, acetylcholinesterase inhibitors, NMDA receptor antagonists, dopamine receptor agonists, antidepressants, and cognitive rehabilitation are current therapeutic options for PSD. Focusing on the chronic sequelae of stroke that impair neuroplasticity highlights the need for continued investigative trials to better assess functional outcomes in treatments targeted for PSD.
缺血性中风是导致全球残疾的主要原因。虽然中风后的康复主要集中在身体康复方面,但中风后痴呆(PSD)也是导致功能障碍的重要原因。用于识别有发生 PSD 风险的中风幸存者的预测工具仅限于简短的筛查认知测试。目前正在研究新出现的生化、遗传和神经影像生物标志物,以揭示更好的 PSD 指标。此外,乙酰胆碱酯酶抑制剂、NMDA 受体拮抗剂、多巴胺受体激动剂、抗抑郁药和认知康复也是目前治疗 PSD 的选择。重点关注损害神经可塑性的中风慢性后遗症,突出了继续开展调查试验的必要性,以更好地评估针对 PSD 治疗的功能结果。
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International Journal of Molecular Sciences
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