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Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by darolutamide: Prediction of in vivo drug-drug interactions 达罗鲁胺对人类 UDP-葡萄糖醛酸转移酶(UGT)的抑制:体内药物相互作用的预测
IF 4.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-13 DOI: 10.1016/j.cbi.2024.111246
Shichao Xiao, Hang Yin, Xin Lv, Zhen Wang, Lili Jiang, Yangliu Xia, Yong Liu

Darolutamide is a potent second-generation, selective nonsteroidal androgen receptor inhibitor (ARI), which has been approved by the US Food and Drug Administration (FDA) in treating castrate-resistant, non-metastatic prostate cancer (nmCRPC). Whether darolutamide affects the activity of UDP-glucuronosyltransferases (UGTs) is unknown. The purpose of the present study is to evaluate the inhibitory effect of darolutamide on recombinant human UGTs and pooled human liver microsomes (HLMs), and explore the potential for drug-drug interactions (DDIs) mediated by darolutamide through UGTs inhibition. The product formation rate of UGTs substrates with or without darolutamide was determined by HPLC or UPLC-MS/MS to estimate the inhibitory effect and inhibition modes of darolutamide on UGTs were evaluated by using the inhibition kinetics experiments. The results showed that 100 μM darolutamide exhibited inhibitory effects on most of the 12 UGTs tested. Inhibition kinetic studies of the enzyme revealed that darolutamide noncompetitively inhibited UGT1A1 and competitively inhibited UGT1A7 and 2B15, with the Ki of 14.75 ± 0.78 μM, 14.05 ± 0.42 μM, and 6.60 ± 0.08 μM, respectively. In particular, it also potently inhibited SN-38, the active metabolite of irinotecan, glucuronidation in HLMs with an IC50 value of 3.84 ± 0.46 μM. In addition, the in vitro-in vivo extrapolation (IVIVE) method was used to quantitatively predict the risk of darolutamide-mediated DDI via inhibiting UGTs. The prediction results showed that darolutamide may increase the risk of DDIs when administered in combination with substrates of UGT1A1, UGT1A7, or UGT2B15. Therefore, the combined administration of darolutamide and drugs metabolized by the above UGTs should be used with caution to avoid the occurrence of potential DDIs.

达罗鲁胺是一种强效的第二代选择性非甾体雄激素受体抑制剂(ARI),已被美国食品药品管理局(FDA)批准用于治疗对阉割有抵抗力的非转移性前列腺癌(nmCRPC)。达罗鲁胺是否会影响UDP-葡萄糖醛酸转移酶(UGTs)的活性尚不清楚。本研究旨在评估达罗鲁胺对重组人UGTs和集合人肝微粒体(HLMs)的抑制作用,并探讨达罗鲁胺通过抑制UGTs介导的药物间相互作用(DDIs)的可能性。通过HPLC或UPLC-MS/MS测定UGTs底物在有达罗鲁胺或无达罗鲁胺情况下的产物形成率,以估算达罗鲁胺对UGTs的抑制作用,并利用抑制动力学实验评估达罗鲁胺对UGTs的抑制模式。结果表明,100 μM 达罗鲁胺对所测试的 12 种 UGTs 中的大多数具有抑制作用。酶抑制动力学研究显示,达罗鲁胺对 UGT1A1 具有非竞争性抑制作用,对 UGT1A7 和 2B15 具有竞争性抑制作用,Ki 分别为 14.75 ± 0.78 μM、14.05 ± 0.42 μM 和 6.60 ± 0.08 μM。特别是,它还能有效抑制伊立替康的活性代谢产物 SN-38在 HLMs 中的葡萄糖醛酸化,IC50 值为 3.84 ± 0.46 μM。此外,还采用体外-体内外推法(IVIVE)定量预测了达罗洛胺通过抑制 UGTs 介导的 DDI 风险。预测结果显示,当达罗鲁胺与 UGT1A1、UGT1A7 或 UGT2B15 的底物联合用药时,可能会增加 DDI 风险。因此,达罗鲁胺与上述UGT代谢的药物联合用药时应谨慎,以避免出现潜在的DDIs。
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引用次数: 0
Molecular mechanisms of zinc oxide nanoparticles neurotoxicity 氧化锌纳米颗粒神经毒性的分子机制
IF 4.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-13 DOI: 10.1016/j.cbi.2024.111245
Michael Aschner , Anatoly V. Skalny , Rongzhu Lu , Airton C. Martins , Aristidis Tsatsakis , Sergey A. Miroshnikov , Abel Santamaria , Alexey A. Tinkov

Zinc oxide nanoparticles (ZnONPs) are widely used in industry and biomedicine. A growing body of evidence demonstrates that ZnONPs exposure may possess toxic effects to a variety of tissues, including brain. Therefore, the objective of the present review was to summarize existing evidence on neurotoxic effects of ZnONPs and discuss the underlying molecular mechanisms. The existing laboratory data demonstrate that both in laboratory rodents and other animals ZnONPs exposure results in a significant accumulation of Zn in brain and nervous tissues, especially following long-term exposure. As a result, overexposure to ZnONPs causes oxidative stress and cell death, both in neurons and glial cells, by induction of apoptosis, necrosis and ferroptosis. In addition, ZnONPs may induce neuroinflammation through the activation of nuclear factor kappa B (NF-κB), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and lipoxygenase (LOX) signaling pathways. ZnONPs exposure is associated with altered cholinergic, dopaminergic, serotoninergic, as well as glutamatergic and γ-aminobutyric acid (GABA)-ergic neurotransmission, thus contributing to impaired neuronal signal transduction. Cytoskeletal alterations, as well as impaired autophagy and mitophagy also contribute to ZnONPs-induced brain damage. It has been posited that some of the adverse effects of ZnONPs in brain are mediated by altered microRNA expression and dysregulation of gut-brain axis. Furthermore, in vivo studies have demonstrated that ZnONPs exposure induced anxiety, motor and cognitive deficits, as well as adverse neurodevelopmental outcome. At the same time, the relevance of ZnONPs-induced neurotoxicity and its contribution to pathogenesis of neurological diseases in humans are still unclear. Further studies aimed at estimation of hazards of ZnONPs to human brain health and the underlying molecular mechanisms are warranted.

氧化锌纳米粒子(ZnONPs)被广泛应用于工业和生物医学领域。越来越多的证据表明,接触纳米氧化锌可能会对包括大脑在内的多种组织产生毒性效应。因此,本综述旨在总结有关 ZnONPs 神经毒性效应的现有证据,并讨论其潜在的分子机制。现有的实验室数据表明,无论是实验室啮齿动物还是其他动物,接触壬基氧化锌都会导致锌在大脑和神经组织中大量蓄积,尤其是在长期接触之后。因此,过量接触壬基膦酸锌会导致氧化应激,并通过诱导细胞凋亡、坏死和铁突变,导致神经元和神经胶质细胞死亡。此外,ZnONPs 还可能通过激活核因子卡巴 B(NF-κB)、细胞外信号调节激酶(ERK)、p38 丝裂原活化蛋白激酶(MAPK)和脂氧合酶(LOX)信号通路诱发神经炎症。接触 ZnONPs 会改变胆碱能、多巴胺能、5-羟色胺能以及谷氨酸能和γ-氨基丁酸(GABA)能神经传递,从而导致神经元信号转导受损。细胞骨架改变以及自噬和有丝分裂功能受损也是锰锌诱发脑损伤的原因之一。有研究认为,ZnONPs 对大脑的一些不良影响是由微核糖核酸(microRNA)表达的改变和肠脑轴的失调介导的。此外,体内研究表明,暴露于 ZnONPs 会诱发焦虑、运动和认知障碍以及不良的神经发育结果。同时,ZnONPs 诱导的神经毒性及其对人类神经系统疾病发病机制的影响仍不清楚。有必要开展进一步的研究,以估算壬基酚锌盐对人类大脑健康的危害及其潜在的分子机制。
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引用次数: 0
Telomerase reverse transcriptase protects against diabetic kidney disease by promoting AMPK/PGC-1a-regulated mitochondrial energy homeostasis 端粒酶逆转录酶通过促进由 AMPK/PGC-1a 调节的线粒体能量平衡来预防糖尿病肾病
IF 4.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-13 DOI: 10.1016/j.cbi.2024.111238
Nan Ma, Chengye Xu, Yan Wang, Kexin Cui, Hongyu Kuang

Disordered glucose and lipid metabolism, coupled with disturbed mitochondrial bioenergetics, are pivotal in the initiation and development of diabetic kidney disease (DKD). While the essential role of telomerase reverse transcriptase (TERT) in regulating mitochondrial function in the cardiovascular system has been recognized, its specific function in maintaining mitochondrial homeostasis in DKD remains unclear. This study aimed to explore how TERT regulates mitochondrial function and the underlying mechanisms. In vitro, human renal proximal tubular HK-2 cells exposed to high glucose/high fat (HG/HF) presented significant downregulation of TERT and AMPK dephosphorylation. This led to decreased ATP production, altered NAD+/NADH ratios, reduced mitochondrial complex activities, increased mitochondrial dysfunction, lipid accumulation, and reactive oxygen species (ROS) production. Knockdown of TERT (si-TERT) further exacerbated mitochondrial dysfunction, decreased mitochondrial membrane potential, and lowered levels of cellular oxidative phosphorylation and glycolysis, as determined via a Seahorse X24 flux analyzer. Conversely, mitochondrial dysfunction was significantly alleviated after pcDNA-TERT plasmid transfection and adeno-associated virus (AAV) 9-TERT gene therapy in vivo. Notably, treatment with an AMPK inhibitor, activator, and si-PGC-1a (peroxisome proliferator-activated receptor γ coactivator-1α), resulted in mitochondrial dysfunction and decreased expression of genes related to energy metabolism and mitochondrial biogenesis. Our findings reveal that TERT protects mitochondrial function and homeostasis by partially activating the AMPK/PGC-1a signaling pathway. These results establish a crucial foundation for understanding TERT's critical role inmitochondrial regulation and its protective effect on DKD.

葡萄糖和脂质代谢紊乱,再加上线粒体生物能紊乱,是糖尿病肾病(DKD)发病和发展的关键因素。虽然端粒酶逆转录酶(TERT)在调节心血管系统线粒体功能中的重要作用已得到公认,但它在维持糖尿病肾病线粒体平衡中的具体功能仍不清楚。本研究旨在探讨TERT如何调控线粒体功能及其内在机制。在体外,暴露于高糖/高脂(HG/HF)条件下的人肾近曲小管 HK-2 细胞出现了 TERT 的显著下调和 AMPK 的去磷酸化。这导致 ATP 生成减少、NAD+/NADH 比率改变、线粒体复合物活性降低、线粒体功能障碍增加、脂质积累和活性氧(ROS)生成。通过海马 X24 通量分析仪测定,敲除 TERT(si-TERT)会进一步加剧线粒体功能障碍、降低线粒体膜电位、降低细胞氧化磷酸化和糖酵解水平。相反,在体内进行 pcDNA-TERT 质粒转染和腺相关病毒(AAV)9-TERT 基因治疗后,线粒体功能障碍明显缓解。值得注意的是,使用 AMPK 抑制剂、激活剂和 si-PGC-1a(过氧化物酶体增殖激活受体 γ 辅激活剂-1α)治疗会导致线粒体功能障碍以及能量代谢和线粒体生物生成相关基因的表达减少。我们的研究结果表明,TERT 可通过部分激活 AMPK/PGC-1a 信号通路来保护线粒体功能和稳态。这些结果为理解 TERT 在线粒体调控中的关键作用及其对 DKD 的保护作用奠定了重要基础。
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引用次数: 0
Association of genetic variants in CYP3A5, DRD2 and NK1R with opioid overdose CYP3A5、DRD2 和 NK1R 基因变异与阿片类药物过量的关系
IF 4.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-12 DOI: 10.1016/j.cbi.2024.111242
Joshua Lambert , Dan Petrovitch , Katie P. Himes , Caroline E. Freiermuth , Robert S. Braun , Jennifer L. Brown , Jason J. Bischof , Michael S. Lyons , Brittany E. Punches , Andrew K. Littlefield , David F. Kisor , Jon E. Sprague

In 2023, 3651 Ohioans died because of an opioid overdose. Of those opioid overdoses, 3579 (98%) of which were attributed to fentanyl. We evaluated the association between 180 candidate single nucleotide polymorphisms (SNPs) and self-reported, nonfatal opioid overdose history from a prospective sample of 1301 adult patients (≥18 years of age) seen in three urban emergency departments in Ohio. Candidate SNPs included 120 related to the dopamine reward pathway and 60 related to pharmacokinetics. Of the 821 patients who reported having been exposed to opioids in their lifetime, 95 (11.6%) also reported having experienced an opioid-related overdose. Logistic regression, adjusting for age and biologic sex, was used to characterize the association between each SNP and opioid overdose, correcting for multiple comparisons. Three SNPs, located in three different genes were associated with opioid overdose: increased odds with CYP3A5 (rs776746) and DRD2 (rs4436578), and decreased odds with NKIR (rs6715729). Homozygotic CYP3A5 (rs776746) had the highest adjusted odds ratio (OR) of 6.96 (95% CI [2.45, 29.23]) and homozygotic NK1R (rs6715729) had the lowest OR of 0.28 (95% CI [0.14, 0.54). Given that CYP3A5 (rs776746) has been associated with increased plasma concentrations of fentanyl, rs776746 could potentially be utilized as a prognostic risk indicator for the potential of an opioid overdose. NK1R regulates the expression of the neurokinin-1 receptor, a regulator of respiration and NK1R (rs6715729) represents a novel genetic marker for a decreased risk of opioid overdose risk.

2023 年,俄亥俄州有 3651 人死于阿片类药物过量。在这些阿片类药物过量患者中,有 3579 人(98%)死于芬太尼。我们从俄亥俄州三个城市急诊科就诊的 1301 名成年患者(年龄≥18 岁)的前瞻性样本中评估了 180 个候选单核苷酸多态性 (SNP) 与自我报告的非致命性阿片类药物过量史之间的关联。候选 SNP 包括 120 个与多巴胺奖赏途径相关的 SNP 和 60 个与药代动力学相关的 SNP。在 821 名报告在其一生中接触过阿片类药物的患者中,有 95 人(11.6%)还报告经历过与阿片类药物相关的用药过量。在对年龄和生物性别进行调整后,采用逻辑回归法来描述每个 SNP 与阿片类药物过量之间的关系,并对多重比较进行校正。位于三个不同基因中的三个 SNP 与阿片类药物过量有关:CYP3A5(rs776746)和 DRD2(rs4436578)的几率增加,而 NKIR(rs6715729)的几率降低。同卵 CYP3A5 (rs776746)的调整比值比 (OR) 最高,为 6.96(95% CI [2.45,29.23]),同卵 NK1R (rs6715729)的调整比值比 (OR) 最低,为 0.28(95% CI [0.14,0.54])。鉴于 CYP3A5(rs776746)与芬太尼血浆浓度升高有关,rs776746 有可能被用作潜在阿片类药物过量的预后风险指标。NK1R 可调节神经激肽-1 受体(呼吸调节器)的表达,NK1R(rs6715729)是降低阿片类药物过量风险的新型遗传标记。
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引用次数: 0
Ovatodiolide inhibits endometrial cancer stemness via reactive oxygen species-mediated DNA damage and cell cycle arrest 卵泡二内酯通过活性氧介导的 DNA 损伤和细胞周期停滞抑制子宫内膜癌干细胞的形成
IF 4.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-12 DOI: 10.1016/j.cbi.2024.111244
Chun-Yu Chen , Yu-Zhen Ye , Yu-Hao Huang , Yew-Min Tzeng , Ranal Gurbanov , Wen-Ling Wang , Wen-Wei Chang

Endometrial cancer (EC) is a common gynecological cancer worldwide, often associated with a poor prognosis after recurrence or metastasis. Ovatodiolide (OVA) is a macrocyclic diterpenoid derived from Anisomeles indica that shows anticancer effects in various malignancies. This study aimed to evaluate the cytotoxic effects of OVA on EC cell proliferation and cancer stem cell (CSC) activity and explore its underlying molecular mechanisms. OVA treatment dose-dependently reduced the viability and colony formation of three EC cell lines (AN3CA, HEC-1A, and EMC6). It induced G2/M phase cell cycle arrest, associated with decreased cell division cycle 25C (CDC25C) expression and reduced activation of cyclin-dependent kinases 1 (CDK1) and 2 (CDK2). OVA also increased reactive oxygen species (ROS) production and DNA damage, activating the DNA damage-sensitive cell cycle checkpoint kinases 1 (CHK1) and 2 (CHK2) and upregulating the DNA damage marker γ-H2A.X variant histone (H2AX). It also suppressed the activation of mechanistic target of rapamycin kinase (mTOR) and nuclear factor kappa B (NF-κB) and downregulated glutathione peroxidase 1 (GPX1), an antioxidant enzyme counteracting oxidative stress. Moreover, OVA reduced the self-renewal capacity of CSCs, reducing the expression of key stemness proteins Nanog homeobox (NANOG) and octamer-binding transcription factor 4 (OCT4). The ROS inhibitor N-acetylcysteine attenuated the anti-proliferative and anti-CSC effects of OVA. Our findings suggest that OVA acts via ROS generation, leading to oxidative stress and DNA damage, culminating in cell cycle arrest and the suppression of CSC activity in EC. Therefore, OVA is a promising therapeutic agent for EC, either as a standalone treatment or an adjunct to existing therapies.

子宫内膜癌(EC)是全球常见的妇科癌症,复发或转移后往往预后不良。Ovatodiolide (OVA)是从茴芹中提取的一种大环二萜类化合物,对多种恶性肿瘤有抗癌作用。本研究旨在评估 OVA 对 EC 细胞增殖和癌症干细胞(CSC)活性的细胞毒性作用,并探索其潜在的分子机制。OVA处理可剂量依赖性地降低三种EC细胞系(AN3CA、HEC-1A和EMC6)的活力和集落形成。它诱导 G2/M 期细胞周期停滞,与细胞分裂周期 25C (CDC25C)表达减少和细胞周期蛋白依赖性激酶 1(CDK1)和 2(CDK2)活化减少有关。OVA 还增加了活性氧(ROS)的产生和 DNA 损伤,激活了对 DNA 损伤敏感的细胞周期检查点激酶 1(CHK1)和 2(CHK2),并上调了 DNA 损伤标记物 γ-H2A.X 变异组蛋白(H2AX)。它还抑制了雷帕霉素激酶机制靶点(mTOR)和核因子卡巴B(NF-κB)的激活,并下调了谷胱甘肽过氧化物酶1(GPX1),这是一种对抗氧化应激的抗氧化酶。此外,OVA还降低了CSC的自我更新能力,减少了关键干性蛋白Nanog同源框(NANOG)和八聚体结合转录因子4(OCT4)的表达。ROS抑制剂N-乙酰半胱氨酸减弱了OVA的抗增殖和抗CSC作用。我们的研究结果表明,OVA通过产生ROS发挥作用,导致氧化应激和DNA损伤,最终导致细胞周期停滞并抑制EC中CSC的活性。因此,OVA是一种很有前景的治疗EC的药物,既可以作为一种独立的治疗方法,也可以作为现有疗法的辅助手段。
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引用次数: 0
Inhibition of 5-alpha reductase attenuates cardiac oxidative damage in obese and aging male rats via the enhancement of antioxidants and the p53 protein suppression 通过增强抗氧化剂和抑制 p53 蛋白,抑制 5-α 还原酶可减轻肥胖和衰老雄性大鼠的心脏氧化损伤
IF 4.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1016/j.cbi.2024.111240
Nattayaporn Apaijai , Hiranya Pintana , Thiraphat Saengmearnuparp , Apisek Kongkaew , Busarin Arunsak , Titikorn Chunchai , Siriporn C. Chattipakorn , Nipon Chattipakorn

In aging and metabolic syndrome oxidative stress is a causative factor in the cardiovascular pathology. Upregulation of 5-⍺ reductase is associated with cardiac hypertrophy but how inhibition of 5-⍺ reductase affects cardiometabolic function during oxidative damage under those conditions is unclear. Our hypothesis was that Finasteride (Fin), a 5-⍺ reductase inhibitor, promotes an antioxidant response, leading to an improvement in cardiac function in obese and aging rats. Male rats were divided into 3 groups including normal diet (ND) fed rats, ND-fed rats treated with d-galactose (D-gal) to induce aging, and high-fat diet (HFD) fed rats to induce obesity. Rats received their assigned diet or D-gal for 18 weeks. At week 13, rats in each group were divided into 2 subgroups and received either a vehicle or Fin (5 mg/kg/day, oral gavage). Cardiometabolic and molecular parameters were subsequently investigated. Both D-gal and HFD successfully induced cardiometabolic dysfunction, oxidative stress, mitochondrial dysfunction, and DNA fragmentation. Fin treatment did not affect metabolic disturbances; however, it reduced cardiac sympathovagal imbalance, cardiac dysfunction through the inhibition of oxidative stress and promoted antioxidants, resulting in reduced p53 protein levels and DNA fragmentation. Surprisingly, Fin induced insulin resistance in ND-fed rats. Fin effectively improved cardiac function in both models by enhancing antioxidant levels, suppressing oxidative stress and DNA fragmentation. However, Fin treatment did not confer any beneficial effects on metabolic status. Fin administration effectively improved cardiac sympathovagal balance and cardiac function in rats with oxidative damage induced by either D-gal or HFD.

在衰老和代谢综合征中,氧化应激是心血管病变的一个致病因素。5-⍺还原酶的上调与心脏肥大有关,但抑制5-⍺还原酶如何在这些条件下的氧化损伤过程中影响心脏代谢功能尚不清楚。我们的假设是,5-⍺还原酶抑制剂非那雄胺(Fin)能促进抗氧化反应,从而改善肥胖和衰老大鼠的心脏功能。雄性大鼠被分为三组,包括正常饮食(ND)喂养的大鼠、用d-半乳糖(D-gal)处理ND喂养的大鼠以诱导衰老,以及用高脂饮食(HFD)喂养的大鼠以诱导肥胖。大鼠接受指定饮食或 D-gal 治疗 18 周。第 13 周时,每组大鼠被分成 2 个亚组,分别接受药物或 Fin(5 毫克/千克/天,口服)治疗。随后对大鼠的心脏代谢和分子参数进行了研究。D-gal 和 HFD 都成功诱导了心脏代谢功能障碍、氧化应激、线粒体功能障碍和 DNA 断裂。然而,通过抑制氧化应激和促进抗氧化,Fin治疗并没有影响代谢紊乱;但它减少了心脏交感神经失衡和心脏功能障碍,导致p53蛋白水平和DNA片段减少。令人惊讶的是,Fin 会诱导 ND 喂养大鼠的胰岛素抵抗。芬通过提高抗氧化剂水平、抑制氧化应激和DNA片段化,有效改善了这两种模型的心脏功能。然而,翅素治疗并未对代谢状态产生任何有益影响。在 D-gal 或 HFD 诱导氧化损伤的大鼠中,服用 Fin 能有效改善心脏交感神经平衡和心脏功能。
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引用次数: 0
Cardioprotection of Canagliflozin, Dapagliflozin, and Empagliflozin: Lessons from preclinical studies Canagliflozin、Dapagliflozin 和 Empagliflozin 的心脏保护作用:临床前研究的启示。
IF 4.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-06 DOI: 10.1016/j.cbi.2024.111229
Rayla Rodrigues Soares , Larissa Freitas Viggiani , Juliano Moreira Reis Filho , Julliane V. Joviano-Santos

Clinical and preclinical studies have elucidated the favorable effects of Inhibitors of Sodium-Glucose Cotransporter-2 (iSGLT2) in patients and animal models with type 2 diabetes. Notably, these inhibitors have shown significant benefits in reducing hospitalizations and mortality among patients with heart failure. However, despite their incorporation into clinical practice for indications beyond diabetes, the decision-making process regarding their use often lacks a systematic approach. The selection of iSGLT2 remains arbitrary, with only a limited number of studies simultaneously exploring the different classes of them. Currently, no unique guideline establishes their application in both clinical and basic research. This review delves into the prevalent use of iSGLT2 in animal models previously subjected to induced cardiac stress. We have compiled key findings related to cardioprotection across various animal models, encompassing diverse dosages and routes of administration. Beyond their established role in diabetes management, iSGLT2 has demonstrated utility as agents for safeguarding heart health and cardioprotection can be class-dependent among the iSGLT2. These findings may serve as valuable references for other researchers. Preclinical studies play a pivotal role in ensuring the safety of novel compounds or treatments for potential human use. By assessing side effects, toxicity, and optimal dosages, these studies offer a robust foundation for informed decisions, identifying interventions with the highest likelihood of success and minimal risk to patients. The insights gleaned from preclinical studies, which play a crucial role in highlighting areas of knowledge deficiency, can guide the exploration of novel mechanisms and strategies involving iSGLT2.

临床和临床前研究阐明了钠-葡萄糖共转运体-2(iSGLT2)抑制剂对 2 型糖尿病患者和动物模型的有利影响。值得注意的是,这些抑制剂在降低心力衰竭患者的住院率和死亡率方面效果显著。然而,尽管这些抑制剂已被纳入临床实践,用于糖尿病以外的适应症,但有关其使用的决策过程往往缺乏系统的方法。对 iSGLT2 的选择仍然很随意,只有数量有限的研究同时对不同类别的 iSGLT2 进行了探讨。目前,在临床和基础研究中还没有确定应用 iSGLT 的独特指南。这篇综述深入探讨了 iSGLT2 在先前受到诱导心脏应激的动物模型中的普遍应用。我们汇编了各种动物模型中与心脏保护相关的主要发现,包括不同的剂量和给药途径。iSGLT2 除了在糖尿病管理中的既定作用外,还显示出其作为保护心脏健康的药物的效用,而且 iSGLT2 的心脏保护作用可能是类依赖性的。这些发现可为其他研究人员提供有价值的参考。临床前研究在确保可能用于人类的新型化合物或治疗方法的安全性方面发挥着关键作用。通过评估副作用、毒性和最佳剂量,这些研究为做出明智的决定奠定了坚实的基础,确定了最有可能成功且对患者风险最小的干预措施。临床前研究在突显知识不足领域方面发挥着至关重要的作用,从临床前研究中获得的见解可以为探索涉及 iSGLT2 的新机制和策略提供指导。
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引用次数: 0
The CYP3A inducer dexamethasone affects the pharmacokinetics of sunitinib by accelerating its metabolism in rats CYP3A 诱导剂地塞米松通过加速舒尼替尼在大鼠体内的代谢,影响舒尼替尼的药代动力学。
IF 4.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.cbi.2024.111228
Guang-rong Lu , Rui-zhen Wang , Xin-yu Zhao , Jun-er Xu , Cheng-ke Huang , Wei Sun , Rui-jie Chen , Zhe Wang

Sunitinib, a novel anti-tumor small molecule targeting VEGFR, is prescribed for advanced RCC and GISTs. Sunitinib is primarily metabolized by the CYP3A enzyme. It is well-known that dexamethasone serves as a potent inducer of this enzyme system. Nonetheless, the effect of dexamethasone on sunitinib metabolism remains unclear. This study examined the effect of dexamethasone on the pharmacokinetics of sunitinib and its metabolite N-desethyl sunitinib in rats. The plasma levels of both compounds were measured using UHPLC-MS/MS. Pharmacokinetic parameters and metabolite ratio values were calculated. Compare to control group, the low-dose dexamethasone group and high-dose dexamethasone group decreased the AUC(0-t) values of sunitinib by 47 % and 45 %, respectively. Meanwhile, the AUC(0-t) values of N-desethyl sunitinib were increased by 2.2-fold and 2.4-fold in low-dose dexamethasone group and high-dose dexamethasone group, respectively. The CL values for sunitinib were both approximately 45 % higher in the two dexamethasone groups. Remarkably, metabolite ratio values increased over 5-fold in both low-dose dexamethasone group and high-dose dexamethasone group, indicating a significant enhancement of sunitinib metabolism by dexamethasone. Moreover, the total levels of sunitinib and its metabolite are also significantly increased. The impact of interactions on sunitinib metabolism, as observed with CYP3A inducers such as dexamethasone, is a crucial consideration for clinical practice. To optimize the dosage and prevent adverse drug events, therapeutic drug monitoring can be employed to avoid the toxicity from such interactions.

舒尼替尼是一种靶向血管内皮生长因子受体的新型抗肿瘤小分子药物,可用于晚期 RCC 和 GIST 的治疗。舒尼替尼主要通过 CYP3A 酶代谢。众所周知,地塞米松是该酶系统的强效诱导剂。然而,地塞米松对舒尼替尼代谢的影响仍不清楚。本研究考察了地塞米松对大鼠体内舒尼替尼及其代谢物 N-去乙基舒尼替尼的药代动力学的影响。采用超高效液相色谱-质谱/质谱法测定了这两种化合物的血浆水平。计算了药代动力学参数和代谢物比值。与对照组相比,小剂量地塞米松组和大剂量地塞米松组的舒尼替尼的AUC(0-t)值分别降低了47%和45%。同时,N-去乙基舒尼替尼的AUC(0-t)值在小剂量地塞米松组和大剂量地塞米松组分别增加了2.2倍和2.4倍。两个地塞米松组中舒尼替尼的CL值均高出约45%。值得注意的是,低剂量地塞米松组和高剂量地塞米松组的代谢物比值均增加了5倍以上,这表明地塞米松显著增强了舒尼替尼的代谢。此外,舒尼替尼及其代谢物的总含量也明显增加。在使用地塞米松等 CYP3A 诱导剂时观察到的相互作用对舒尼替尼代谢的影响是临床实践的一个重要考虑因素。为了优化用药剂量和预防药物不良事件,可以采用治疗药物监测来避免此类相互作用带来的毒性。
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引用次数: 0
Human Urinary Kallidinogenase improves vascular endothelial injury by activating the Nrf2/HO-1 signaling pathway 人尿液凯利苷原酶通过激活 Nrf2/HO-1 信号通路改善血管内皮损伤
IF 4.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.cbi.2024.111230
Xiong Zhang , Jiaying Yang , Yini Lu , Yi Liu , Tianyin Wang , Feng Yu

Vascular endothelial injury is closely related to the progression of various cardio-cerebrovascular diseases. Whether Human Urinary Kallidinogenase (HUK) has a protective effect on endothelial injury remains unclear. This study established an in vivo model of rat common carotid artery intima injury and an in vitro model of human umbilical vein endothelial cell (HUVECs) injury induced by hydrogen peroxide (H2O2). To explore the protective effect and mechanism of HUK on endothelial injury. In vivo, HUK can reduce the hyperplasia and lumen stenosis of rat common carotid artery after intimal injury, and promote the fluorescence expression of vWF in the common carotid artery. HUK also activated the Nrf2/HO-1 signaling pathway in rat common carotid artery tissue to reduce endothelial damage. In vitro, HUK can inhibit the H2O2-induced decline in HUVECs activity, improve the migration ability of HUVECs induced by H2O2, inhibit the apoptosis and necrosis of HUVECs and the generation of ROS, and regulate the expression of VEGFA, ET-1 and eNOS proteins related to endothelial function in cells. The Nrf2/HO-1 signaling pathway is activated, and the HO-1 specific inhibitor zinc porphyrin (ZnPP) can partially reverse the protective effect of HUK on H2O2-induced HUVECs injury in terms of cell migration, necrosis and oxidative stress. The Nrf2/HO-1 signaling pathway plays an important role in the regulation of migration, necrosis and oxidative stress of HUVECs cells. HUK has a protective effect on vascular endothelial injury. HUK can inhibit oxidative stress and apoptotic necrosis by activating Nrf2/HO-1 signaling pathway.

血管内皮损伤与各种心脑血管疾病的进展密切相关。人尿凯利苷原酶(HUK)是否对血管内皮损伤有保护作用尚不清楚。本研究建立了过氧化氢(H2O2)诱导的大鼠颈总动脉内膜损伤体内模型和人脐静脉内皮细胞(HUVECs)损伤体外模型。探讨 HUK 对内皮损伤的保护作用及其机制。在体内,HUK能减轻大鼠颈总动脉内膜损伤后的增生和管腔狭窄,促进颈总动脉中vWF的荧光表达。HUK还能激活大鼠颈总动脉组织中的Nrf2/HO-1信号通路,减轻内皮损伤。在体外,HUK 能抑制 H2O2 诱导的 HUVECs 活性下降,改善 H2O2 诱导的 HUVECs 迁移能力,抑制 HUVECs 的凋亡和坏死以及 ROS 的产生,调节细胞中与内皮功能相关的 VEGFA、ET-1 和 eNOS 蛋白的表达。Nrf2/HO-1信号通路被激活,HO-1特异性抑制剂卟啉锌(ZnPP)能部分逆转HUK对H2O2诱导的HUVECs损伤在细胞迁移、坏死和氧化应激方面的保护作用。Nrf2/HO-1信号通路在调控HUVECs细胞迁移、坏死和氧化应激中发挥重要作用。HUK 对血管内皮损伤有保护作用。HUK能通过激活Nrf2/HO-1信号通路抑制氧化应激和细胞凋亡坏死。
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引用次数: 0
A derivative of honokiol HM568 has an anti-neuroinflammatory effect in Parkinson's disease Honokiol的一种衍生物HM568对帕金森病有抗神经炎症作用。
IF 4.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-04 DOI: 10.1016/j.cbi.2024.111212
Changfeng Zhong , Changmei Wang , Wei Li , Wenyuan Li , Xuemei Chen , Jieqing Guo , Yifan Feng , Xia Wu

Parkinson's disease (PD) is the fastest growing neurodegenerative disease in the world at present. Neuroinflammation plays an important role in Parkinson's disease. In our study, we initially screened magnolol/honokiol derivatives synthesized by our group for their potential anti-neuroinflammatory properties. This was done using LPS-activated BV-2 microglial cell and MPP + -induced PC-12 cell models. Most of derivatives had increased anti-inflammatory activities and decreased toxicities compared to raw materials. Then, compounds were scored with inflammatory factors IL-1β, TNF-α and IL-6 by molecular docking in silico. Our studies revealed the strongest binding compound HM568 which binds with honokiol and metformin. Furthermore, HM568 showed no acute toxicity in mice through acute toxicity. And it is stable under high temperature, high humidity and strong light irradiation. Combining cell experiments and computer results, HM568 was considered for further in vivo pharmacological validations. Intraperitoneal injection administration of MPTP into C57BL/6 mice was utilized as Parkinson's animal model. Results showed that administration of HM568 for 14 days in MPTP-PD mice led to a significant alleviation in weight loss and movement disorders. Further HM568 could significantly down-regulate the expression levels of inflammatory factors IL-1β, IL-6 and TNF-α in brain tissue of the mouse model, reduce the level of caspase-3 and the ratio of Bcl-2/Bax, and up-regulate the level of transforming factor TGF-β, thus producing anti-apoptosis and anti-neuroinflammatory effects on neuronal cells. In terms of pathological features, HM568 could reduce the infiltration of neuronal cells and alleviate the development of lesions, promote the transformation of microglia from M1 negative phenotype to M2 type, and reverse the reduction of TH-positive immune cells in mouse neurons induced by MPTP. The administration of HM568 could reduce the abnormal accumulation of α-syn, and thus produce neuroprotective effect on MPTP-PD mice. Cell experiments, molecular docking and animal experiments thus depict HM568 as a promising agent to delay neuronal degeneration in PD, and its mechanism is related to anti-neuroinflammation.

帕金森病(PD)是目前世界上发展最快的神经退行性疾病。神经炎症在帕金森病中扮演着重要角色。在我们的研究中,我们首先筛选了我们小组合成的 magnolol/honokiol 衍生物,以确定其潜在的抗神经炎特性。我们使用 LPS 激活的 BV-2 微神经胶质细胞和 MPP + 诱导的 PC-12 细胞模型进行了筛选。与原材料相比,大多数衍生物的抗炎活性增强,毒性降低。然后,通过分子对接对化合物与炎症因子 IL-1β、TNF-α 和 IL-6 进行了硅学评分。我们的研究发现了结合力最强的化合物 HM568,它能与 honokiol 和二甲双胍结合。此外,通过急性毒性测试,HM568 对小鼠无急性毒性。而且在高温、高湿和强光照射下也很稳定。结合细胞实验和计算机结果,HM568 被考虑用于进一步的体内药理验证。以 C57BL/6 小鼠为帕金森病动物模型,腹腔注射 MPTP。结果表明,给 MPTP-PD 小鼠注射 HM568 14 天后,体重减轻和运动障碍明显缓解。此外,HM568还能显著下调炎症因子IL-1β、IL-6和TNF-α在模型小鼠脑组织中的表达水平,降低Caspase-3水平和Bcl-2/Bax比值,上调转化因子TGF-β水平,从而对神经细胞产生抗凋亡和抗神经炎症作用。在病理特征方面,HM568 可以减少神经元细胞的浸润,缓解病变的发展,促进小胶质细胞从 M1 阴性表型向 M2 型转化,逆转 MPTP 诱导的小鼠神经元 TH 阳性免疫细胞的减少。服用HM568可以减少α-syn的异常积累,从而对MPTP-PD小鼠产生神经保护作用。因此,细胞实验、分子对接和动物实验表明,HM568是一种有望延缓帕金森病神经元变性的药物,其机制与抗神经炎症有关。
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引用次数: 0
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Chemico-Biological Interactions
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