Biochemical pharmacology最新文献_第4页

Carnitine traffic and human fertility 肉碱运输与人类生育能力

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-03 DOI: 10.1016/j.bcp.2024.116565

Carnitine is a vital molecule in human metabolism, prominently involved in fatty acid β-oxidation within mitochondria. Predominantly sourced from dietary intake, carnitine also derives from endogenous synthesis. This review delves into the complex network of carnitine transport and distribution, emphasizing its pivotal role in human fertility. Together with its role in fatty acid oxidation, carnitine modulates the acety-CoA/CoA ratio, influencing carbohydrate metabolism, lipid biosynthesis, and gene expression. The intricate regulation of carnitine homeostasis involves a network of membrane transporters, notably OCTN2, which is central in its absorption, reabsorption, and distribution. OCTN2 dysfunction, results in Primary Carnitine Deficiency (PCD), characterized by systemic carnitine depletion and severe clinical manifestations, including fertility issues. In the male reproductive system, carnitine is crucial for sperm maturation and motility. In the female reproductive system, carnitine supports mitochondrial function necessary for oocyte quality, folliculogenesis, and embryonic development. Indeed, deficiencies in carnitine or its transporters have been linked to asthenozoospermia, reduced sperm quality, and suboptimal fertility outcomes in couples. Moreover, the antioxidant properties of carnitine protect spermatozoa from oxidative stress and help in managing conditions like polycystic ovary syndrome (PCOS) and endometriosis, enhancing sperm viability and fertilization potential of oocytes. This review summarizes the key role of membrane transporters in guaranteeing carnitine homeostasis with a special focus on the implications in fertility and possible treatments of infertility and other related disorders.

肉碱是人体新陈代谢中的重要分子，主要参与线粒体内脂肪酸的β-氧化。肉碱的主要来源是膳食摄入，也可通过内源性合成获得。这篇综述深入探讨了肉碱运输和分布的复杂网络，强调了肉碱在人类生育中的关键作用。肉碱除了在脂肪酸氧化中发挥作用外，还能调节乙酰-CoA/CoA 的比例，从而影响碳水化合物代谢、脂质生物合成和基因表达。肉碱平衡的复杂调节涉及膜转运体网络，特别是 OCTN2，它是肉碱吸收、重吸收和分布的核心。OCTN2 功能障碍会导致原发性肉碱缺乏症（PCD），其特征是全身性肉碱耗竭和严重的临床表现，包括生育问题。在男性生殖系统中，肉碱对精子的成熟和活力至关重要。在女性生殖系统中，肉碱支持卵母细胞质量、卵泡生成和胚胎发育所必需的线粒体功能。事实上，肉碱或其转运体的缺乏与无精子症、精子质量下降和夫妇生育结果不理想有关。此外，肉碱的抗氧化特性可保护精子免受氧化应激，有助于控制多囊卵巢综合征（PCOS）和子宫内膜异位症等疾病，提高精子活力和卵母细胞的受精潜力。本综述总结了膜转运体在保证肉碱平衡中的关键作用，并特别关注其对生育的影响以及不孕症和其他相关疾病的可能治疗方法。

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引用次数: 0

Construction of cytochrome P450 3A and P-glycoprotein knockout rats with application in rivaroxaban-verapamil interactions 构建细胞色素 P450 3A 和 P-glycoprotein 基因敲除大鼠，并将其应用于利伐沙班与维拉帕米的相互作用。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-03 DOI: 10.1016/j.bcp.2024.116566

Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), as important metabolic enzymes and transporters, participate in the biological transformation and transport of many substances in the body. CYP3A and P-gp are closely related, with very high substrate overlap and regulation similarity, making it particularly difficult to investigate the function of one or the other individually in vivo. Rivaroxaban and verapamil are commonly used together to treat nonvalvular atrial fibrillation in clinical practice. However, this combination therapy can increase systemic exposure to rivaroxaban and the risk of major bleeding and intracranial hemorrhage. In this study, Cyp3a1/2 and Mdr1a/b quadruple gene knockout (qKO) rat model was generated and characterized for the first time. CYP3A1/2 and P-gp are completely absent in this novel rat model. Then, the qKO rat model was applied for the evaluation of the drug-drug interactions (DDI) between rivaroxaban and verapamil. The results demonstrated that CYP3A and P-gp were jointly and selectively involved in the pharmacokinetic interactions between rivaroxaban and verapamil. This study may provide useful information for understanding the role of CYP3A and P-gp in rivaroxaban-verapamil therapy and predicting the potential interaction between CYP3A and P-gp.

细胞色素 P450 3A（CYP3A）和 P 糖蛋白（P-gp）作为重要的代谢酶和转运体，参与了许多物质在体内的生物转化和转运。CYP3A 和 P-gp 关系密切，底物重叠和调控相似度极高，因此在体内单独研究二者的功能尤为困难。在临床实践中，利伐沙班和维拉帕米通常一起用于治疗非瓣膜性心房颤动。然而，这种联合疗法会增加利伐沙班的全身暴露，增加大出血和颅内出血的风险。本研究首次建立了Cyp3a1/2和Mdr1a/b四重基因敲除（qKO）大鼠模型，并对其进行了表征。在这种新型大鼠模型中，CYP3A1/2 和 P-gp 基因完全缺失。然后，将 qKO 大鼠模型用于评估利伐沙班和维拉帕米之间的药物相互作用（DDI）。结果表明，CYP3A和P-gp共同选择性地参与了利伐沙班和维拉帕米之间的药代动力学相互作用。这项研究可为了解 CYP3A 和 P-gp 在利伐沙班-维拉帕米治疗中的作用以及预测 CYP3A 和 P-gp 之间的潜在相互作用提供有用信息。

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引用次数: 0

Sex differences in the metabolic activation of and platelet response to vicagrel in mice: Androgen as a key player 小鼠体内维卡格雷的代谢激活和血小板反应的性别差异：雄激素是关键因素

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-02 DOI: 10.1016/j.bcp.2024.116564

As a biological variable, sex influences the metabolism of and/or response to certain drugs. Vicagrel is being developed as an investigational new drug in China; however, it is unknown whether sex could affect its metabolic activation and platelet responsiveness. This study aimed to determine whether such differences could exist, and to elucidate the mechanisms involved. Orchiectomized (ORX) or ovariectomized (OVX) mouse models were used to investigate the effects of androgens or estrogens on the metabolic activation of and platelet response to vicagrel. Plasma vicagrel active metabolite H4 concentrations, platelet inhibition of vicagrel, and protein levels of intestinal hydrolases Aadac and Ces2 were measured, respectively. Further, p38-MAPK signaling pathway was enriched, whose role was determined using SB202190. Results showed that female mice exhibited significantly elevated systemic exposure of H4 and enhanced platelet responses to vicagrel than males, and that protein expression levels of Aadac and Ces2 differed by sex. OVX mice exhibited less changes than sham mice. ORX mice exhibited increases in protein levels of intestinal hydrolases, systemic exposure of H4, and platelet inhibition of vicagrel, but dihydrotestosterone (DHT) reversed these changes in ORX mice and suppressed these changes in OVX mice. Phosphorylated p38 levels were reduced in female or ORX mice but increased in ORX mice by DHT. SB202190 reversed DHT-induced changes observed in ORX mice. We concluded that sex differences exist in metabolic activation of and platelet response to vicagrel in mice through elevation of p38 phosphorylation by androgens, suggesting sex-based vicagrel dosage adjustments for patient care.

作为一种生物变量，性别会影响某些药物的代谢和/或对药物的反应。维卡格雷是中国正在研发的新药，但性别是否会影响其代谢活化和血小板反应性尚属未知。本研究旨在确定是否存在这种差异，并阐明其中的机制。研究采用睾丸切除（ORX）或卵巢切除（OVX）小鼠模型，探讨雄激素或雌激素对维卡格雷代谢活化和血小板反应的影响。实验分别测定了血浆中的维卡格雷活性代谢物H4浓度、血小板对维卡格雷的抑制作用以及肠水解酶Aadac和Ces2的蛋白水平。此外，还丰富了 p38-MAPK 信号通路，并使用 SB202190 确定了其作用。结果表明，与雄性小鼠相比，雌性小鼠全身H4暴露量明显升高，血小板对vicagrel的反应增强，Aadac和Ces2的蛋白表达水平因性别而异。与假小鼠相比，卵巢切除小鼠的变化较小。ORX小鼠的肠水解酶蛋白水平、H4的全身暴露和血小板对vicagrel的抑制均有所增加，但二氢睾酮（DHT）逆转了ORX小鼠的这些变化，抑制了OVX小鼠的这些变化。磷酸化的 p38 水平在雌性或 ORX 小鼠中降低，但在 ORX 小鼠中因 DHT 而升高。SB202190 逆转了在 ORX 小鼠中观察到的 DHT 诱导的变化。我们得出结论：通过雄激素使 p38 磷酸化水平升高，小鼠体内维卡格雷的代谢激活和血小板对维卡格雷的反应存在性别差异，这表明在患者护理中应根据性别调整维卡格雷的剂量。

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引用次数: 0

PCSK9 inhibitor attenuates cardiac fibrosis in reperfusion injury rat by suppressing inflammatory response and TGF-β1/Smad3 pathway PCSK9抑制剂通过抑制炎症反应和TGF-β1/Smad3通路减轻再灌注损伤大鼠的心脏纤维化

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-01 DOI: 10.1016/j.bcp.2024.116563

Progressive cardiac fibrosis, a hallmark of heart failure, remains poorly understood regarding Proprotein convertase subtilisin/kexin type 9 (PCSK9) ’s role. This study aims to elucidate PCSK9′s involvement in cardiac fibrosis. After ischemia/reperfusion (I/R) injury surgery in rats, PCSK9 inhibitors were used to examine their effects on the transforming growth factor-β1 (TGF-β1)/small mother against decapentaplegic 3 (Smad3) pathway and inflammation. Elevated PCSK9, TGF-β1, and Smad3 levels were observed in cardiac tissues post-I/R injury, indicating fibrosis. PCSK9 inhibition reduced pro-fibrotic protein expression, protecting the heart and mitigating I/R-induced damage and fibrosis. Additionally, it ameliorated cardiac inflammation and reduced post-myocardial infarction (MI) size, improving cardiac function and slowing heart failure progression. PCSK9 inhibitors significantly attenuate myocardial fibrosis induced by I/R via the TGF-β1/Smad3 pathway.

进行性心脏纤维化是心力衰竭的标志之一，但人们对PCSK9（Protein convertase subtilisin/kexin type 9）的作用仍然知之甚少。本研究旨在阐明PCSK9在心脏纤维化中的作用。在对大鼠进行缺血再灌注（I/R）损伤手术后，使用PCSK9抑制剂检测其对转化生长因子-β1（TGF-β1）/小母抗癸型截瘫因子3（Smad3）通路和炎症的影响。在I/R损伤后的心脏组织中观察到PCSK9、TGF-β1和Smad3水平升高，表明心脏纤维化。抑制 PCSK9 可减少促纤维化蛋白的表达，从而保护心脏，减轻 I/R 引起的损伤和纤维化。此外，它还能改善心脏炎症，缩小心肌梗死（MI）后的面积，改善心脏功能，减缓心力衰竭的进展。PCSK9抑制剂能明显减轻I/R通过TGF-β1/Smad3途径诱导的心肌纤维化。

引用次数: 0

Corrigendum to “Autophagy contributes to dasatinib-induced myeloid differentiation of human acute myeloid leukemia cells” [Biochem. Pharmacol. 89/1 (2014) 74–85] 自噬作用有助于达沙替尼诱导的人类急性髓性白血病细胞髓系分化》[Biochem. Pharmacol. 89/1 (2014) 74-85]的更正。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-01 DOI: 10.1016/j.bcp.2024.116553

引用次数: 0

The thienopyridine A-769662 and benzimidazole 991 inhibit human TASK-3 potassium channels in an AMPK-independent manner 噻吩并吡啶 A-769662 和苯并咪唑 991 以不依赖于 AMPK 的方式抑制人类 TASK-3 钾通道。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-01 DOI: 10.1016/j.bcp.2024.116562

Heteromeric Tandem pore domain Acid Sensitive (TASK)-1/3 channels are critical to oxygen-sensing by carotid body type 1 cells, where hypoxia-induced inhibition of TASK-3 and/or TASK-1/3 potassium currents leads to voltage-gated calcium entry, exocytotic transmitter release and increases in carotid body afferent input responses that initiate corrective changes in breathing patterns. It was proposed that, in response to hypoxia, the AMP–activated protein kinase (AMPK) might directly phosphorylate and inhibit TASK channels, in particular TASK–3, but studies on rat type I cells questioned this view. However, sequence alignment identified a putative AMPK recognition motif in human (h) TASK-3, but not hTASK–1, with Ser⁵⁵ representing a potential phosphorylation site. We therefore studied the effects of five different AMPK activators on recombinant hTASK–3 potassium channels expressed in human embryonic kidney (HEK)–293 cells. Two structurally unrelated AMPK activators, the thienopyridine A–769662 (100–500 µM) and the benzimidazole 991 (3–30 µM) inhibited hTASK–3 currents in a concentration–dependent manner, while the 4-azabenzimidazole MK–8722 (3–30 µM) partially inhibited hTASK–3 at concentrations above those required for maximal AMPK activation. By contrast, the 4-azabenzimidazole, BI-9774 (10–100 µM; a closely related analogue of MK8722) and the pro-drug AICA-riboside (1 mM; metabolised to ZMP, an AMP-mimetic) had no significant effect on hTASK–3 currents at concentrations sufficient to maximally activate AMPK. Importantly, A–769662 (300 µM) also inhibited hTASK–3 channel currents in HEK–293 cells that stably over-expressed an AMPK–β1 subunit mutant (S108A) that renders AMPK insensitive to activators that bind to the Allosteric Drug and Metabolite site, such as A–769662. We therefore identify A–769662 and 991 as novel hTASK–3 channel inhibitors and provide conclusive evidence that AMPK does not regulate hTASK–3 channel currents.

异构串联孔域酸敏感（TASK）-1/3 通道对颈动脉体 1 型细胞的氧传感至关重要，缺氧诱导的 TASK-3 和/或 TASK-1/3 钾电流抑制会导致电压门控钙离子进入、外渗递质释放以及颈动脉体传入输入反应的增加，从而引发呼吸模式的纠正变化。有人提出，在应对缺氧时，AMP 激活蛋白激酶（AMPK）可能会直接磷酸化并抑制 TASK 通道，尤其是 TASK-3，但对大鼠 I 型细胞的研究对这一观点提出了质疑。然而，序列比对在人类（h）TASK-3（而非 hTASK-1）中发现了一个潜在的 AMPK 识别基序，其中 Ser55 是一个潜在的磷酸化位点。因此，我们研究了五种不同的 AMPK 激活剂对在人胚胎肾（HEK）-293 细胞中表达的重组 hTASK-3 钾通道的影响。两种结构不相关的 AMPK 激活剂--噻吩并吡啶 A-769662 （100-500 µM）和苯并咪唑 991（3-30 µM）以浓度依赖的方式抑制了 hTASK-3 电流，而 4-氮杂苯并咪唑 MK-8722（3-30 µM）在超过最大 AMPK 激活所需的浓度时部分抑制了 hTASK-3。相比之下，4-氮杂苯并咪唑 BI-9774（10-100 µM；MK8722 的近亲类似物）和原药 AICA 核苷（1 mM；代谢为 ZMP，一种 AMP 模拟物）在足以最大程度激活 AMPK 的浓度下对 hTASK-3 电流没有显著影响。重要的是，A-769662（300 µM）还抑制了稳定过表达 AMPK-β1 亚基突变体（S108A）的 HEK-293 细胞中的 hTASK-3 通道电流，这种突变体使 AMPK 对与异位药物和代谢物位点结合的激活剂（如 A-769662）不敏感。因此，我们确定 A-769662 和 991 为新型 hTASK-3 通道抑制剂，并提供了确凿证据，证明 AMPK 并不调节 hTASK-3 通道电流。

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引用次数: 0

Isovalerylspiramycin I suppresses small cell lung cancer proliferation via ATR/CHK1 mediated DNA damage response and PERK/eIF2α/ATF4/CHOP mediated ER stress 异戊酰螺霉素 I 通过 ATR/CHK1 介导的 DNA 损伤反应和 PERK/eIF2α/ATF4/CHOP 介导的 ER 应激抑制小细胞肺癌的增殖。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-29 DOI: 10.1016/j.bcp.2024.116557

Small cell lung cancer (SCLC) urgently needs new therapeutic approaches. We found that the antibiotic-derived compound Isovalerylspiramycin I (ISP-I) has potent anti-tumor activity against SCLC cell lines H1048 and DMS53 both in vitro and in vivo. ISP-I induced apoptosis, G2/M phase cell cycle arrest, and mitochondrial respiratory chain dysfunction in both cell lines. Comprehensive RNA sequencing revealed that the anti-SCLC effects of ISP-I were primarily attributed to ATR/CHK1-mediated DNA damage response and PERK/eIF2α/ATF4/CHOP-mediated ER stress. Importantly, the induction of DNA damage, ER stress, and apoptosis by ISP-I was mitigated by the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC), underscoring the critical role of ROS in the anti-SCLC mechanism of ISP-I. Moreover, ISP-I treatment induced immunogenic cell death (ICD) in SCLC cells, as evidenced by increased adenosine triphosphate (ATP) secretion, elevated release of high-mobility group box 1 (HMGB1), and enhanced exposure of calreticulin (CRT) on the cell surface. Additionally, network pharmacology analysis, combined with cellular thermal shift assay (CETSA) and cycloheximide (CHX) chase experiments, demonstrated that ISP-I acted as a ligand for apurinic/apyrimidinic endonuclease 1 (APEX1) and promoted its degradation, leading to the accumulation of ROS. In conclusion, our findings elucidate the multifaceted mechanisms underlying the anti-cancer effects of ISP-I, highlighting its potential as a promising therapeutic candidate for SCLC treatment.

小细胞肺癌（SCLC）迫切需要新的治疗方法。我们发现，抗生素衍生化合物异戊酰螺霉素 I（ISP-I）在体外和体内对小肺癌细胞株 H1048 和 DMS53 均有很强的抗肿瘤活性。ISP-I 可诱导两种细胞株出现细胞凋亡、G2/M 期细胞周期停滞和线粒体呼吸链功能障碍。综合 RNA 测序显示，ISP-I 的抗SCLC 作用主要归因于 ATR/CHK1 介导的 DNA 损伤反应和 PERK/eIF2α/ATF4/CHOP 介导的 ER 应激。重要的是，活性氧（ROS）清除剂N-乙酰-L-半胱氨酸（NAC）减轻了ISP-I对DNA损伤、ER应激和细胞凋亡的诱导作用，强调了ROS在ISP-I抗SCLC机制中的关键作用。此外，ISP-I还能诱导SCLC细胞的免疫原性细胞死亡（ICD），三磷酸腺苷（ATP）分泌增加、高迁移率基团框1（HMGB1）释放增加以及细胞表面钙网蛋白（CRT）暴露增加都证明了这一点。此外，网络药理学分析结合细胞热转移试验（CETSA）和环己亚胺（CHX）追逐实验证明，ISP-I 是嘌呤/近嘧啶内切酶 1（APEX1）的配体，能促进其降解，从而导致 ROS 的积累。总之，我们的研究结果阐明了ISP-I抗癌作用的多方面机制，凸显了它作为一种治疗SCLC的候选药物的潜力。

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引用次数: 0

Aspirin increases estrogen levels in the placenta to prevent preeclampsia by regulating placental metabolism and transport function 阿司匹林可增加胎盘中的雌激素水平，通过调节胎盘代谢和运输功能来预防子痫前期。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-27 DOI: 10.1016/j.bcp.2024.116561

Preeclampsia is a unique multisystem progressive disease during pregnancy, which seriously endangers the health of pregnant women and fetuses. In clinical practice, aspirin is recommended for the prevention of preeclampsia, but the mechanism by which aspirin prevents preeclampsia has not yet been revealed. This report comprehensively evaluates the effects of aspirin on the expression and activity of placental metabolic enzymes and transporters. We found that after aspirin administration, only the expression of organic anion transporter 4 (OAT4) in the placenta showed a significant increase at both mRNA and protein levels, consistent with the results in JAR cells. Meanwhile, studies on the metabolic enzyme activity in the placenta showed a high upregulation of CYP19A1 activity. Subsequently, significant increases in endogenous substrates of OAT4 and CYP19A1 (dehydroepiandrosterone sulfate (DHEAS) and androstenedione) as well as estrone were detected in placental tissue. In summary, aspirin enhances the transport of DHEAS through OAT4 and promotes the metabolism of androstenedione through CYP19A1, thereby increasing estrogen levels in the placenta. This may be the mechanism by which aspirin prevents preeclampsia and maintains pregnancy by regulating the metabolism and transport function of the placenta.

子痫前期是妊娠期一种特殊的多系统进行性疾病，严重危害孕妇和胎儿的健康。在临床实践中，阿司匹林被推荐用于预防子痫前期，但阿司匹林预防子痫前期的机制尚未揭示。本报告全面评估了阿司匹林对胎盘代谢酶和转运体的表达和活性的影响。我们发现，服用阿司匹林后，只有有机阴离子转运体 4（OAT4）在胎盘中的表达在 mRNA 和蛋白水平上有显著增加，这与在 JAR 细胞中的结果一致。同时，对胎盘中代谢酶活性的研究表明，CYP19A1 的活性有较高的上调。随后，在胎盘组织中检测到 OAT4 和 CYP19A1 的内源性底物（硫酸脱氢表雄酮（DHEAS）和雄烯二酮）以及雌酮明显增加。总之，阿司匹林可通过 OAT4 增强 DHEAS 的运输，并通过 CYP19A1 促进雄烯二酮的代谢，从而增加胎盘中的雌激素水平。这可能是阿司匹林通过调节胎盘的代谢和转运功能来预防子痫前期和维持妊娠的机制。

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引用次数: 0

Curcumol effectively improves obesity through GDF15 induction via activation of endoplasmic reticulum stress response 姜黄醇通过激活内质网应激反应诱导 GDF15，从而有效改善肥胖症。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-27 DOI: 10.1016/j.bcp.2024.116560

The escalating prevalence of obesity presents a formidable global health challenge, underscoring the imperative for efficacious pharmacotherapeutic interventions. However, current anti-obesity medications often exhibit limited efficacy and adverse effects, necessitating the exploration of alternative therapeutic approaches. Growth differentiation factor 15 (GDF15) has emerged as a promising target for obesity management, given its crucial role in appetite control and metabolic regulation. In this study, we aimed to investigate the efficacy of curcumol, a sesquiterpene compound derived from plants of the Zingiberaceae family, in obesity treatment. Our findings demonstrate that curcumol effectively induces the expression of GDF15 through the activation of the endoplasmic reticulum stress pathway. To confirm the role of GDF15 as a critical target for curcumol’s function, we compared the effects of curcumol in wild-type mice and Gdf15-knockout mice. Using a high-fat diet-induced obese murine model, we observed that curcumol led to reduced appetite and altered dietary preferences mediated by GDF15. Furthermore, chronic curcumol intervention resulted in promising anti-obesity effects. Additionally, curcumol administration improved glucose tolerance and lipid metabolism in the obese mice. These findings highlight the potential of curcumol as a GDF15 inducer and suggest innovative strategies for managing obesity and its associated metabolic disorders. In conclusion, our study provides evidence for the efficacy of curcumol in obesity treatment by inducing GDF15 expression. The identified effects of curcumol on appetite regulation, dietary preferences, glucose tolerance, and lipid metabolism emphasize its potential as a therapeutic agent for combating obesity and related metabolic disorders.

肥胖症的发病率不断攀升，给全球健康带来了严峻的挑战，这凸显了采取有效的药物治疗干预措施的必要性。然而，目前的抗肥胖药物往往显示出有限的疗效和不良反应，因此有必要探索其他治疗方法。鉴于生长分化因子 15（GDF15）在食欲控制和新陈代谢调节中的关键作用，它已成为肥胖症治疗的一个有希望的靶点。在这项研究中，我们旨在研究姜黄醇（一种从姜科植物中提取的倍半萜化合物）在肥胖症治疗中的疗效。我们的研究结果表明，姜黄醇能通过激活内质网应激途径有效诱导 GDF15 的表达。为了证实 GDF15 是姜黄醇发挥作用的关键靶点，我们比较了姜黄醇对野生型小鼠和 Gdf15 基因敲除小鼠的影响。通过使用高脂饮食诱导的肥胖小鼠模型，我们观察到姜黄醇在 GDF15 的介导下降低了食欲并改变了饮食偏好。此外，长期姜黄醇干预还具有良好的抗肥胖效果。此外，姜黄醇还能改善肥胖小鼠的葡萄糖耐量和脂质代谢。这些发现凸显了姜黄醇作为 GDF15 诱导剂的潜力，并提出了控制肥胖及其相关代谢紊乱的创新策略。总之，我们的研究为姜黄醇通过诱导 GDF15 表达治疗肥胖症提供了证据。姜黄醇对食欲调节、饮食偏好、葡萄糖耐量和脂质代谢的作用得到了确认，这凸显了姜黄醇作为抗击肥胖和相关代谢紊乱的治疗药物的潜力。

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引用次数: 0

Hydrogen sulfide mitigates mitochondrial dysfunction and cellular senescence in diabetic patients: Potential therapeutic applications 硫化氢可减轻糖尿病患者的线粒体功能障碍和细胞衰老：潜在的治疗应用。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-25 DOI: 10.1016/j.bcp.2024.116556

Diabetes induces a pro-aging state characterized by an increased abundance of senescent cells in various tissues, heightened chronic inflammation, reduced substance and energy metabolism, and a significant increase in intracellular reactive oxygen species (ROS) levels. This condition leads to mitochondrial dysfunction, including elevated oxidative stress, the accumulation of mitochondrial DNA (mtDNA) damage, mitophagy defects, dysregulation of mitochondrial dynamics, and abnormal energy metabolism. These dysfunctions result in intracellular calcium ion (Ca²⁺) homeostasis disorders, telomere shortening, immune cell damage, and exacerbated inflammation, accelerating the aging of diabetic cells or tissues. Hydrogen sulfide (H₂S), a novel gaseous signaling molecule, plays a crucial role in maintaining mitochondrial function and mitigating the aging process in diabetic cells. This article systematically explores the specific mechanisms by which H₂S regulates diabetes-induced mitochondrial dysfunction to delay cellular senescence, offering a promising new strategy for improving diabetes and its complications.

糖尿病会诱发一种促衰老状态，其特征是各种组织中衰老细胞的数量增加、慢性炎症加剧、物质和能量代谢降低以及细胞内活性氧（ROS）水平显著增加。这种情况会导致线粒体功能障碍，包括氧化应激升高、线粒体 DNA（mtDNA）损伤积累、有丝分裂缺陷、线粒体动力学失调和能量代谢异常。这些功能障碍会导致细胞内钙离子（Ca2+）平衡失调、端粒缩短、免疫细胞损伤和炎症加剧，从而加速糖尿病细胞或组织的衰老。硫化氢（H2S）是一种新型气体信号分子，在维持线粒体功能和缓解糖尿病细胞衰老过程中发挥着至关重要的作用。本文系统地探讨了 H2S 调节糖尿病诱导的线粒体功能障碍以延缓细胞衰老的具体机制，为改善糖尿病及其并发症提供了一种前景广阔的新策略。

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