Chemico-Biological Interactions最新文献_第4页

ALKBH5 enhances cadmium-induced stemness enrichment and proliferation of colon cancer cells via m6A-dependent regulation of AXIN2 and activation of Wnt/β-catenin signaling ALKBH5通过m6a依赖性调节AXIN2和激活Wnt/β-catenin信号通路，增强镉诱导的结肠癌细胞干性富集和增殖。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2026-01-06 DOI: 10.1016/j.cbi.2026.111905

Jianing Hu , Shuhui Zhu , Xinze He , Bangqi Cen , Zhuangzhuang Xu , Fei Han , Kun Ding , Min Jiang , Yansu Chen , Yefei Huang

Cadmium (Cd) is a carcinogenic heavy metal with a long biological half-life that has been implicated in the development of colorectal cancer (CRC). However, the mechanisms underlying Cd-induced CRC malignancy remain incompletely understood. Cancer stem cells (CSCs), which are characterized by self-renewal, pluripotency and unlimited proliferative potential, are believed to be responsible for the initiation, progression and recurrence of CRC. The aim of this study was to investigate the long-term effects of Cd on stemness enrichment and proliferation in colon cancer cells, and to identify the key signaling pathways involved. Our results demonstrated that chronic Cd exposure enhanced sphere formation and increased the expression of stem cell-like markers (CD44, OCT4, SOX2, and NANOG) in colon cancer cells. Colony formation assays, CCK-8 assays, and xenograft models in nude mice further confirmed that Cd significantly promoted cell proliferation. Mechanistically, Cd reduced N6-methyladenosine (m6A) methylation in mRNA by upregulating the m6A demethylase ALKBH5. Knockdown of ALKBH5 attenuated Cd-induced stemness enrichment and proliferation. ALKBH5 was found to demethylate the m6A of AXIN2 mRNA, reducing IGF2BP1-mediated stabilization of AXIN2 mRNA, leading to its destabilization and reduced expression, which subsequently hyperactivated the Wnt/β-catenin signaling. These results highlight the role of the ALKBH5–m6A–AXIN2–Wnt/β-catenin axis in Cd-induced stemness and proliferation in colon cancer, offering new insights into Cd-associated CRC development.

镉（Cd）是一种具有较长生物半衰期的致癌重金属，与结直肠癌（CRC）的发展有关。然而，cd诱发的CRC恶性肿瘤的机制仍不完全清楚。肿瘤干细胞（Cancer stem cells, CSCs）具有自我更新、多能性和无限增殖潜能的特点，被认为与CRC的发生、发展和复发有关。本研究旨在探讨Cd对结肠癌细胞干细胞富集和增殖的长期影响，并确定其中的关键信号通路。我们的研究结果表明，慢性Cd暴露增强了结肠癌细胞中球体的形成，并增加了干细胞样标志物（CD44、OCT4、SOX2和NANOG）的表达。裸鼠集落形成实验、CCK-8实验和异种移植模型进一步证实了Cd显著促进细胞增殖。机制上，Cd通过上调m6A去甲基化酶ALKBH5来降低mRNA中n6 -甲基腺苷（m6A）的甲基化。敲低ALKBH5可减弱cd诱导的茎干富集和增殖。研究发现ALKBH5可以使AXIN2 mRNA的m6A去甲基化，降低igf2bp1介导的AXIN2 mRNA的稳定性，导致其不稳定和表达降低，从而过度激活Wnt/β-catenin信号。这些结果强调了ALKBH5-m6A-AXIN2-Wnt/β-catenin轴在cd诱导的结肠癌干性和增殖中的作用，为cd相关的CRC发展提供了新的见解。

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引用次数: 0

Streptomycin mitigates methylglyoxal-induced carbonyl stress through its antiglycation activity: A drug-repurposing approach for carbonyl stress-related disorder 链霉素通过其抗糖化活性减轻甲基乙二醛诱导的羰基应激：羰基应激相关疾病的药物再利用方法。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2026-01-03 DOI: 10.1016/j.cbi.2026.111901

Shin Koike , Haruka Mitsuhashi , Aoi Takahashi , Mari Ishizaki , Atsushi Kishida , Yuki Ogasawara

Advanced glycation end-products (AGEs), having multiple structures, are formed at the sites where the carbonyl groups of the reducing sugars bind to the free amino groups of the proteins through the Maillard reaction.

The accumulation of AGEs, which are generated when carbonyl compounds produced in the process of glucose metabolism react with proteins, is involved in various carbonyl stress-related diseases. Meanwhile, guanidine compounds, represented by aminoguanidine, have possibilities as a scavenger that inhibits AGE formation by directly reacting with carbonyl compounds. We here focused on existing drugs with a guanidine-like structure and estimated the reactivity of nine drugs, including aminoguanidine, with methylglyoxal (MGO), a glucose metabolite, to assess their potential application to carbonyl stress-induced diseases. Considering the results of the two screening methods, we concentrated on streptomycin, which exhibited stable scavenging activity, and evaluated its inhibitory effect on the MGO-induced AGE formation in proteins in vitro. Furthermore, the effects of streptomycin on carbonyl protein accumulation in the cells and the MGO-induced cytotoxicity were investigated to elucidate the cytoprotective potential against glycation. The results revealed that streptomycin added to the culture medium with MGO suppressed the MGO-induced carbonylation of intracellular proteins and exerted a protective effect by alleviating the toxicity of MGO in a study using human-derived neuroblastoma SH-SY5Y. These findings suggest that the clinically available streptomycin has a potential to be utilized for carbonyl stress-related diseases as a repurposing drug.

晚期糖基化终产物（AGEs）具有多种结构，是在还原糖的羰基通过美拉德反应与蛋白质的游离氨基结合的位点形成的。葡萄糖代谢过程中产生的羰基化合物与蛋白质发生反应时产生的AGEs积累与各种羰基应激相关疾病有关。同时，以氨基胍为代表的胍类化合物有可能通过与羰基化合物直接反应来抑制AGE的形成。本研究聚焦于现有的胍类结构药物，并估计了包括氨基胍在内的九种药物与葡萄糖代谢物甲基乙二醛（MGO）的反应性，以评估它们在羰基应激诱导疾病中的潜在应用。考虑到两种筛选方法的结果，我们将重点放在具有稳定清除活性的链霉素上，并在体外评估其对mgo诱导的蛋白质AGE形成的抑制作用。此外，我们还研究了链霉素对细胞中羰基蛋白积累的影响以及mgo诱导的细胞毒性，以阐明其对糖基化的细胞保护潜力。在SH-SY5Y人源性神经母细胞瘤的研究中，结果显示在MGO培养基中加入链霉素可以抑制MGO诱导的细胞内蛋白的羰基化，并通过减轻MGO的毒性发挥保护作用。这些发现表明，临床上可用的链霉素有潜力作为一种再利用药物用于羰基应激相关疾病。

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引用次数: 0

The expanding frontiers of gallic acid: From dual chemistry and pharmacology to innovative technological applications 没食子酸的扩展前沿：从双重化学和药理学到创新技术应用。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2026-01-03 DOI: 10.1016/j.cbi.2026.111899

Woo Hyun Park

Gallic acid (3,4,5-trihydroxybenzoic acid), a phenolic compound of botanical origin, exhibits a historically significant role within the annals of traditional pharmacopeia and is currently garnering substantial academic attention for its multifaceted utility in contemporary scientific and technological spheres. In this treatise, a comprehensive synthesis of multidisciplinary insights is presented, wherein the dual redox behavior of gallic acid—characterized by its function as an antioxidant through radical scavenging and metal coordination, or alternatively as a pro-oxidant via Fenton-type reactions and the depletion of intracellular glutathione (GSH)—is established as the primary conceptual framework for its functional versatility. The pharmacological dimensions investigated herein comprise anti-inflammatory activities mediated by the inhibition of NF-κB and mitogen-activated protein kinase (MAPK) pathways; selective antineoplastic cytotoxicity facilitated by the generation of reactive oxygen species (ROS) and subsequent induction of apoptosis; metabolic regulation attained through the activation of AMPK and PPAR-γ; and neuroprotection enabled via the modulation of GSK3β–Nrf2 signaling. Notwithstanding its extensive therapeutic potential, the clinical translation of gallic acid is currently impeded by its classification as a Biopharmaceutics Classification System (BCS) Class III compound, reflecting a sub-optimal pharmacokinetic profile. Strategic interventions, including molecular derivatization and nanotechnology-based delivery architectures, are evaluated as means to circumvent these physiological barriers. Furthermore, this review delineates innovative applications in active packaging, environmental remediation, and the nascent frontier of metal–phenolic networks (MPNs). Through the integration of these disparate research trajectories, an AI-driven and sustainable roadmap is proposed to fully harness the redox duality of gallic acid in both biomedical and industrial implementations.

没食子酸（3,4,5-三羟基苯甲酸）是一种植物来源的酚类化合物，在传统药典年鉴中具有重要的历史意义，目前因其在当代科学和技术领域的多方面用途而获得了大量的学术关注。在这篇论文中，提出了多学科见解的综合综合，其中没食子酸的双重氧化还原行为-其特征是通过自由基清除和金属配位作为抗氧化剂的功能，或者通过芬顿型反应和细胞内谷胱甘肽（GSH）的消耗作为促氧化剂-被建立为其功能多功能性的主要概念框架。本文研究的药理学维度包括通过抑制NF-κB和丝裂原活化蛋白激酶（MAPK）途径介导的抗炎活性；活性氧（ROS）的产生和随后的细胞凋亡诱导促进了选择性抗肿瘤细胞毒性；通过激活AMPK和PPAR-γ实现代谢调节；并通过调节GSK3β-Nrf2信号通路实现神经保护。尽管没食子酸具有广泛的治疗潜力，但它目前被分类为生物制药分类系统（BCS） III类化合物，这反映了它的次优药代动力学特征，这阻碍了它的临床转化。战略干预措施，包括分子衍生化和基于纳米技术的递送架构，被评估为规避这些生理障碍的手段。此外，本文综述了活性包装、环境修复和金属酚网络（mpn）的创新应用。通过整合这些不同的研究轨迹，提出了一个人工智能驱动的可持续路线图，以充分利用没食子酸在生物医学和工业应用中的氧化还原二元性。

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引用次数: 0

Melatonin suppresses glycolysis and coordinately disrupts DNA repair via targeting the YAP1-NAMPT signaling in breast cancer 褪黑素通过靶向乳腺癌中的YAP1-NAMPT信号通路抑制糖酵解并协调破坏DNA修复。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2026-01-02 DOI: 10.1016/j.cbi.2026.111900

Yi-Wen Lai , Cheng-Ying Chu , Zei-Wei Liu , Hsin-Ying Lu , Chi-Ching Lee , Mei-Hsiang Lin , Cheng-Wei Lin

Triple-negative breast cancer (TNBC) is characterized by aggressive behavior and high recurrence rates, contributing to poor prognoses of TNBC patients. However, the lack of appropriate molecular targets limits the effectiveness of current antineoplastic therapies. Therefore, effective therapeutic strategies are urgently needed. Melatonin (N-acetyl-5-methoxytryptamine) has shown a broad spectrum of anticancer activities, but its potential for treating TNBC remains elusive. In this study, we discovered that melatonin suppressed the growth and invasiveness of TNBC cells through downregulating glycolytic capacity in association with inhibition of Yes-associated protein 1 (YAP1) signaling. Notably, melatonin suppressed expression of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme participated in nicotinamide adenine dinucleotide (NAD) turnover and contributes to protein poly(ADP)-ribosylation (PARylation). As a result, melatonin potentiated DNA damage and elevated apoptosis. Furthermore, it is found that melatonin suppressed NAMPT expression via inhibition of YAP1. Moreover, downregulation of glycolysis decreased protein PARylation levels and increased DNA damage accumulation, suggesting that melatonin suppresses the crosstalk between glycolysis and DNA repair signaling. Combined treatment with melatonin and Olaparib, an inhibitor of the major conductor of protein PARylation, poly(ADP-ribose) polymerase (PARP), showed additive inhibitory effects on breast cancer proliferation compared to their single treatment. These findings demonstrated that melatonin may be a promising agent for targeting YAP1-mediated glycolysis and DNA repair in breast cancer for enhancing the therapeutic efficacy of Olaparib in TNBC patients.

三阴性乳腺癌（TNBC）具有侵袭性行为和高复发率的特点，导致TNBC患者预后不良。然而，缺乏合适的分子靶点限制了当前抗肿瘤治疗的有效性。因此，迫切需要有效的治疗策略。褪黑素（n -乙酰-5-甲氧基色胺）已显示出广泛的抗癌活性，但其治疗TNBC的潜力尚不明确。在这项研究中，我们发现褪黑素通过下调糖酵解能力和抑制yes相关蛋白1 （YAP1）信号传导来抑制TNBC细胞的生长和侵袭性。值得注意的是，褪黑激素抑制了烟酰胺磷酸核糖基转移酶（NAMPT）的表达，这是一种参与烟酰胺腺嘌呤二核苷酸（NAD）转换的酶，并有助于蛋白质聚(ADP)-核糖基化（PARylation）。结果，褪黑素增强了DNA损伤和细胞凋亡。此外，褪黑素通过抑制YAP1抑制NAMPT的表达。此外，糖酵解的下调降低了蛋白PARylation水平，增加了DNA损伤积累，表明褪黑激素抑制糖酵解和DNA修复信号之间的串扰。与单独治疗相比，褪黑素和奥拉帕尼联合治疗对乳腺癌增殖有累加性抑制作用。奥拉帕尼是蛋白质PARylation的主要载体，聚（adp -核糖）聚合酶（PARP）的抑制剂。这些发现表明，褪黑激素可能是靶向yap1介导的乳腺癌糖酵解和DNA修复的有希望的药物，可以提高奥拉帕尼对TNBC患者的治疗效果。

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引用次数: 0

N-homocysteinylation of ferritin and associated changes in iron metabolism as potential drivers of vascular endothelial dysfunction in hyperhomocysteinemia 铁蛋白的n -同型半胱氨酸化和铁代谢的相关变化是高同型半胱氨酸血症中血管内皮功能障碍的潜在驱动因素。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-29 DOI: 10.1016/j.cbi.2025.111890

Andzelika Borkowska , Ulana Juhas , Szczepan Olszewski , Joanna Reczkowicz , Pawel Wityk , Banu Akdogan , Hans Zischka , Jedrzej Antosiewicz

Hyperhomocysteinemia contributes to various diseases, including cardiovascular and neurodegenerative disorders. While previous research indicates iron's role in hyperhomocysteinemia, the underlying molecular interactions remain poorly understood. Our previous study demonstrated that homocysteine significantly increases ferritin levels, linked to disruptions in the Akt-FOXO3a pathway, though the reasons for these increases are unclear. In the present study, we investigated these mechanisms, evidencing that homocysteine thiolactone (HcyT) similarly increases the levels of Ferritin L and H in HUVEC, but not in SH-SY5Y cells. This ferritin upregulation was accompanied by elevations labile iron pools. Furthermore, in cells exposed to HcyT, there was an increase in proteins responsible for exporting iron, such as ferroportin and APP. Additionally, intracellular iron chaperones, such as PCBP1 and PCBP2, were significantly dysregulated, while the level of the transferrin receptor—the protein responsible for importing iron into the cell—was decreased. These results suggest a compensatory protective response to iron accumulation in HcyT-treated cells. Pre-incubating with H₂O₂ increased cellular sensitivity to HcyT-induced toxic effects, providing indirect evidence for the involvement of an iron-dependent cell death mechanism in endothelial cells HUVEC. We discovered that HcyT triggers the process of N-homocysteinylation of ferritin H, which most likely impairs its function. This explains the steady increase in ferritin and LIP levels in the studied cell model. In conclusion, we are the first to demonstrate that HcyT disrupt iron metabolism at multiple levels, including storage, export, import, and intracellular transport. Our findings indicate that these disturbances are caused by N-homocysteinylation of ferritin.

高同型半胱氨酸血症会导致各种疾病，包括心血管和神经退行性疾病。虽然先前的研究表明铁在高同型半胱氨酸血症中的作用，但潜在的分子相互作用仍然知之甚少。我们之前的研究表明，同型半胱氨酸显著增加铁蛋白水平，这与Akt-FOXO3a通路的中断有关，尽管这些增加的原因尚不清楚。在本研究中，我们研究了这些机制，证明了同型半胱氨酸硫内酯（HcyT）类似地增加了HUVEC中铁蛋白L和H的水平，但在SH-SY5Y细胞中没有。这种铁蛋白上调伴随着不稳定铁池的升高。此外，在暴露于HcyT的细胞中，负责输出铁的蛋白质（如铁转运蛋白（FPN）和APP）增加。此外，细胞内铁伴侣（如PCBP1和PCBP2）显著失调，而负责将铁输入细胞的转铁蛋白受体水平下降。这些结果表明，代偿性保护反应铁积累在hcyt处理的细胞。用H2O2预孵育增加了细胞对hcyt诱导的毒性作用的敏感性，为内皮细胞HUVEC中铁依赖性细胞死亡机制的参与提供了间接证据。我们发现HcyT触发铁蛋白H的n -同型半胱氨酸化过程，这很可能损害其功能。这解释了在研究的细胞模型中铁蛋白和LIP水平的稳定增长。总之，我们是第一个证明HcyT在多个水平上破坏铁代谢，包括储存、输出、输入和细胞内运输。我们的研究结果表明，这些干扰是由铁蛋白的n -同型半胱氨酸化引起的。

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引用次数: 0

Implications of early-life BPS-induced thyroid disruption on adult female reproductive disorders 早期bps诱导的甲状腺功能紊乱对成年女性生殖障碍的影响。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-29 DOI: 10.1016/j.cbi.2025.111891

Lina Chouchene, Mariem Ben Rhouma, Sana Boughammoura, Imed Messaoudi, Kaouthar Kessabi

Reproductive disorders have become a growing public health concern, with early-life environmental exposures increasingly recognized as critical determinants of long-term reproductive outcomes. Among emerging endocrine disruptors, bisphenol S (BPS) raises concern due to its potential to interfere with hormone signaling during sensitive developmental windows. This study examined whether prenatal BPS exposure affects reproductive outcomes in adulthood through maternal thyroid disruption. Pregnant rats were exposed to BPS and the thyroid hormone receptor (THR) antagonist (AT 1–850). Key parameters studied included body weight, ovarian function (puberty onset, estrous cyclicity, histology, hormone levels), oxidative status, and oocyte development gene expression. Our findings support a model in which maternal thyroid disruption during critical developmental stages leads to long-term alterations in ovarian function and architecture, significantly impacting female reproductive health. This disruption is further corroborated by the striking similarity between the effects observed with BPS exposure and those induced by the THR antagonist, suggesting a common underlying mechanism. Despite a normal oxidative status, reproductive disturbances emerged as early pubertal onset, with accelerated vaginal opening and earlier first estrous. Irregular estrous cycles were noted, with prolonged estrus and metestrus phases. Folliculogenesis was impaired, marked by the accumulation of primordial, primary, and atretic follicles, and a blockade in progression to the secondary stage. Oocyte development was also altered, evidenced by elevated FIGLα and H1FOO expression. These disruptions were associated with hormonal imbalance, particularly decreased E2 levels. Altogether, these outcomes suggest that early-life BPS exposure compromises female reproductive function and efficiency in adulthood through maternal thyroid disruption.

生殖疾病已成为一个日益严重的公共卫生问题，生命早期的环境暴露日益被认为是长期生殖结果的关键决定因素。在新兴的内分泌干扰物中，双酚S （BPS）引起了人们的关注，因为它有可能干扰敏感发育窗口期的激素信号。本研究考察了产前BPS暴露是否会通过母体甲状腺功能紊乱影响成年后的生殖结果。怀孕大鼠分别暴露于BPS和甲状腺激素受体拮抗剂（AT 1-850）。研究的关键参数包括体重、卵巢功能（青春期开始、发情周期、组织学、激素水平）、氧化状态和卵母细胞发育基因表达。我们的研究结果支持一种模型，即在关键发育阶段，母体甲状腺功能紊乱导致卵巢功能和结构的长期改变，显著影响女性生殖健康。BPS暴露和THR拮抗剂诱导的效果之间惊人的相似性进一步证实了这种破坏，这表明存在共同的潜在机制。尽管氧化状态正常，但生殖障碍出现在青春期早期，阴道开放加速，第一次发情提前。不规律的发情周期被注意到，与发情和流星期延长。卵泡发生受损，表现为原始卵泡、原发卵泡和闭锁卵泡的积累，并在进展到继发性阶段时被阻断。卵母细胞发育也发生改变，FIGLα和H1FOO表达升高。这些破坏与荷尔蒙失衡有关，尤其是E2水平下降。总之，这些结果表明，早年接触BPS会通过母体甲状腺功能紊乱而损害女性成年后的生殖功能和效率。

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引用次数: 0

Structural diversity of aldehydes determines covalent versus non-covalent inhibition mechanisms against steroid 5α-reductase type 1: Species-specific differences and preliminary structure-activity relationships 醛的结构多样性决定了对类固醇5α-还原酶1型的共价和非共价抑制机制：物种特异性差异和初步的构效关系。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-22 DOI: 10.1016/j.cbi.2025.111888

Junying Chen , Shufang Qi , Zijian Lin , Haonan Fang , Putian Zhang , Wanyu Li , Ren-shan Ge , Yiyan Wang

Steroid 5α-reductase type 1 (SRD5A1) plays a crucial role in neurosteroid biosynthesis, and its inhibition by environmental chemicals may disrupt brain function. This study systematically evaluated the inhibitory effects of thirteen structurally diverse aldehydes on human and rat SRD5A1 activity using microsomal enzyme assays, surface plasmon resonance (SPR) binding, cellular experiments, and computational analyses. Three aldehydes significantly inhibited human SRD5A1: o-phthalaldehyde (OPA, IC₅₀ = 2.74 μM), benzaldehyde (BEA, IC₅₀ = 45.97 μM), and cinnamaldehyde (CNA, IC₅₀ = 67.85 μM). Remarkable mechanistic differences were revealed through SPR analysis: OPA demonstrated covalent binding with incomplete dissociation (K_D = 2.16 μM), while BEA showed complete dissociation characteristic of non-covalent binding (K_D = 35.1 μM). All active compounds exhibited mixed/noncompetitive inhibition mechanisms. Species-specific differences were observed, with only OPA showing cross-species activity against rat SRD5A1. Cellular experiments revealed different potency patterns, with CNA demonstrating the strongest cellular effects despite weaker enzyme inhibition. Molecular docking revealed that OPA forms covalent bonds with Cys124 through Michael addition (−6.52 kcal/mol), while BEA and CNA rely on non-covalent interactions. DTT rescue experiments confirmed the covalent nature of OPA inhibition and the non-covalent mechanisms of BEA. OPA also uniquely affected NADPH binding kinetics, indicating its binding site spans both substrate and cofactor regions. 3D-QSAR modeling of non-covalent inhibitors identified hydrogen bond acceptor and hydrophobic features as critical for inhibition. These findings demonstrate that aldehyde structural diversity-particularly the presence of dual versus single aldehyde groups, determines both binding mechanisms and inhibitory potency, with important implications for environmental health risk assessment.

类固醇5α-还原酶1型（SRD5A1）在神经类固醇生物合成中起着至关重要的作用，环境化学物质对其的抑制可能会破坏大脑功能。本研究通过微粒体酶测定、表面等离子体共振（SPR）结合、细胞实验和计算分析，系统地评估了13种结构不同的醛对人和大鼠SRD5A1活性的抑制作用。邻苯二醛（OPA, IC50 = 2.74 μM）、苯甲醛（BEA, IC50 = 45.97 μM）和肉桂醛（CNA, IC50 = 67.85 μM）对人SRD5A1有显著抑制作用。通过SPR分析，发现了显著的机制差异：OPA表现为不完全解离的共价结合（KD = 2.16 μM），而BEA表现为完全解离的非共价结合（KD = 35.1 μM）。所有活性化合物均表现出混合/非竞争性抑制机制。观察到物种特异性差异，只有OPA对大鼠SRD5A1具有跨物种活性。细胞实验显示了不同的效价模式，CNA表现出最强的细胞效应，尽管酶抑制较弱。分子对接发现，OPA与Cys124通过Michael加成（-6.52 kcal/mol）形成共价键，而BEA和CNA则通过非共价相互作用形成共价键。DTT拯救实验证实了OPA抑制的共价性质和BEA的非共价机制。OPA还独特地影响NADPH结合动力学，表明其结合位点跨越底物和辅因子区域。非共价抑制剂的3D-QSAR模型确定了氢键受体和疏水特征是抑制的关键。这些发现表明，醛结构的多样性，特别是双醛与单醛基团的存在，决定了结合机制和抑制效力，对环境健康风险评估具有重要意义。

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引用次数: 0

Dexamethasone regulates the SIRT1/NF-κB signaling pathway in neonatal rats with bronchopulmonary dysplasia to counteract NLRP3-inflammasome-induced pyroptosis and oxidative stress 地塞米松调节新生支气管肺发育不良大鼠SIRT1/NF-κB信号通路，对抗nlrp3炎性小体诱导的焦亡和氧化应激

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-17 DOI: 10.1016/j.cbi.2025.111882

Shaohua Wang , Mengyao Fan , Zhenzhuang Zou , Jian Deng

Bronchopulmonary dysplasia (BPD) is a lung disease that affects premature infants. This study explored the effects of dexamethasone (DXM) in BPD and the potential involvement of NLRP3 inflammasome and the SIRT1/NF-κB pathway in this process. In vitro, we transfected alveolar epithelial type II (AECII) cells with shRNA SIRT1 and SIRT1 Vector and subjected them to lipopolysaccharide (LPS) and DXM treatments under hyperoxic conditions. In vivo, we used prenatal intraamniotic-LPS injection followed by postnatal hyperoxia exposure to establish a rat model of BPD. CCK8 viability assay, Caspase 3/7 activity, and TUNEL staining were used to detect cell apoptosis. Also, ELISA, ROS staining and the oxidative stress-related enzymes were used to evaluate inflammation-related proteins expression and oxidative stress. HE staining was used for histopathological analysis, whereas qRT-PCR and Western blot were used for gene expression analysis. Our results indicated that DXM counteracts the dysregulated expression of SIRT1 caused by LPS. Moreover, DXM regulated the SIRT1/NF-κB axis to reverse the LPS-induced changes in viability, oxidative stress, and apoptosis of ACEII cells, and inflammation- and oxidative stress-related protein expression, demonstrating that DXM decreases inflammation in BPD through the SIRT1/NF-κB pathway and inhibits the NLRP3 inflammasome-induced pyroptosis, providing a new therapeutic strategy for this disease.

支气管肺发育不良是一种影响早产儿的肺部疾病。本研究探讨了地塞米松（DXM）在BPD中的作用，以及NLRP3炎性体和SIRT1/NF-κB通路在这一过程中的潜在参与。在体外，我们用shRNA SIRT1和SIRT1载体转染肺泡上皮II型（AECII）细胞，并在高氧条件下对其进行脂多糖（LPS）和DXM处理。在体内，我们采用产前羊膜内lps注射和产后高氧暴露建立大鼠BPD模型。CCK8活力测定、Caspase 3/7活性、TUNEL染色检测细胞凋亡。ELISA、ROS染色及氧化应激相关酶检测炎症相关蛋白表达及氧化应激水平。组织病理学分析采用HE染色，基因表达分析采用qRT-PCR和Western blot。我们的研究结果表明，ddxm可以抵消LPS引起的SIRT1表达失调。此外，DXM调节SIRT1/NF-κ b轴，逆转lps诱导的ACEII细胞活力、氧化应激、凋亡以及炎症和氧化应激相关蛋白表达的变化，表明DXM通过SIRT1/NF-κ b途径降低BPD炎症，抑制NLRP3炎症小体诱导的焦亡，为该疾病的治疗提供了新的策略。

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引用次数: 0

Celastrol induces cardiotoxicity by directly targeting AMOTL2 and inhibiting YAP1/PGC-1α/TFAM-dependent mitochondrial biogenesis Celastrol通过直接靶向AMOTL2和抑制YAP1/PGC-1α/ tfam依赖的线粒体生物发生诱导心脏毒性。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-16 DOI: 10.1016/j.cbi.2025.111885

Huiying Shang , Hongbo Cheng , Wei Zhou , Xianglin Tang , Weiye Han , Xiaotong Zhang , Chengrong Xiao , Yehui Gao , Xian Liu , Yue Gao

Celastrol is a promising therapeutic candidate for cancers, metabolic diseases, and autoimmune disorders. However, recent studies demonstrated consecutive administration of celastrol at anticancer doses may induce severe heart injuries, which significantly limited its clinical translation. This study aimed to investigate the cellular target and potential mechanism underlying celastrol-induced cardiotoxicity. Consecutive i.p. injection of celastrol for 14 days induces cardiotoxicity in mice, as evidenced by reduced heart-to-body weight ratio, decreased cardiac output and stroke volume, and increased serum cardiac enzymes and proinflammatory cytokine levels in heart tissues. At the cellular level, celastrol triggered mitochondrial dysfunction and promoted cardiomyocyte apoptosis through activation of the mitochondrial pathway, as evidenced by altered B-Cell Lymphoma 2/Bcl-2-Associated X Protein (Bax/Bcl-2) ratio and expression of Cysteinyl aspartate specific proteinase 3 (caspase-3). Mechanistically, we identified Angiomotin-Like Protein 2 (AMOTL2) as a direct cellular target of celastrol using activity-based protein profiling (ABPP). Celastrol-AMOTL2 binding initiated a signaling cascade through Hippo pathway activation, promoting Yes-Associated Protein 1 (YAP1) phosphorylation and subsequent degradation. Knockdown of AMOTL2 by short hairpin RNA attenuated celastrol-induced cardiomyocyte apoptosis by enhancing YAP1 expression and mitochondrial biogenesis. These findings demonstrate that celastrol induces cardiotoxicity by directly targeting AMOTL2 and disrupting YAP1/PGC-1α/TFAM-dependent mitochondrial biogenesis.

雷公藤红素是治疗癌症、代谢疾病和自身免疫性疾病的有前途的候选药物。然而，最近的研究表明，连续服用抗癌剂量的雷公藤红素可能会导致严重的心脏损伤，这大大限制了其临床应用。本研究旨在探讨celastrol诱导心脏毒性的细胞靶点和潜在机制。小鼠连续腹腔注射雷公藤红素14天可引起心脏毒性，表现为心体比降低，心输出量和脑卒中量减少，心脏组织血清心肌酶和促炎细胞因子水平升高。在细胞水平上，celastrol通过激活线粒体途径触发线粒体功能障碍，促进心肌细胞凋亡，这可以通过改变b细胞淋巴瘤2/Bcl-2相关X蛋白（Bax/Bcl-2）比例和天冬氨酸半胱氨酸特异性蛋白酶3 （caspase-3）的表达来证明。在机制上，我们利用基于活性的蛋白谱（ABPP）鉴定出血管运动素样蛋白2 （AMOTL2）是celastrol的直接细胞靶点。Celastrol-AMOTL2结合通过Hippo通路激活启动信号级联，促进Yes-Associated Protein 1 （YAP1）磷酸化和随后的降解。短发夹RNA敲低AMOTL2可通过增强YAP1表达和线粒体生物发生来减弱celastrol诱导的心肌细胞凋亡。这些发现表明，celastrol通过直接靶向AMOTL2和破坏YAP1/PGC-1α/ tfam依赖的线粒体生物发生来诱导心脏毒性。

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引用次数: 0

Subchronic co-exposure to dibutyl phthalate and benzo(a)pyrene exacerbates renal inflammation and fibrosis in rat: Crosstalk between tubular epithelial cells and fibroblasts 亚慢性共暴露于邻苯二甲酸二丁酯和苯并(a)芘加剧大鼠肾炎症和纤维化：小管上皮细胞和成纤维细胞之间的串扰

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions

Pub Date : 2025-12-16 DOI: 10.1016/j.cbi.2025.111887

Jing Chen , Jixing He , Changzhu Long , Zenglin Li , Yanli Cen , Yining Liu , Wenyan Chen , Baojun Sun , Mingdan You , Guanghong Yang

Dibutyl phthalate (DBP) and benzo(a)pyrene (BaP) are commonly organic pollutants that have been simultaneously detected in environmental media, posing a significant risk to human health. However, the precise impacts and underlying mechanisms of subchronic co-exposure to DBP and BaP on the kidney remain incompletely comprehended. In this research, we evaluated the combined impact of DBP and BaP on the kidney in vivo and in vitro models. The findings exhibited that subchronic co-exposure to environmental concentrations of DBP and BaP engendered more severe inflammation and renal fibrosis than single exposure. Mechanistically, DBP and BaP co-exposure may activate the renin-angiotensin system (RAS) signaling through fibroblast growth factor 23 (FGF-23), potentially damaging renal tubular epithelial cells (RTECs). The injured RTECs further produced significant amounts of pro-inflammatory and pro-fibrotic factors, which activate surrounding fibroblasts, leading to excessive extracellular matrix (ECM) deposition and ultimately renal fibrosis. Notably, knockdown FGF-23 alleviated activation of the RAS signaling, as well as ECM production and deposition induced by DBP and BaP subchronic co-exposure. Collectively, our results indicated that DBP and BaP co-exposure may activate fibroblasts via FGF-23 activation of RAS signaling in RTECs, thereby accelerating the development of renal fibrosis.

邻苯二甲酸二丁酯（DBP）和苯并(a)芘（BaP）是在环境介质中同时检测到的常见有机污染物，对人类健康构成重大风险。然而，亚慢性DBP和BaP共同暴露对肾脏的确切影响和潜在机制仍不完全清楚。在本研究中，我们在体内和体外模型中评估了DBP和BaP对肾脏的联合影响。研究结果显示，亚慢性DBP和BaP环境浓度共同暴露比单一暴露产生更严重的炎症和肾纤维化。从机制上讲，DBP和BaP共同暴露可能通过成纤维细胞生长因子23 （FGF-23）激活肾素-血管紧张素系统（RAS）信号，潜在地损害肾小管上皮细胞（RTECs）。损伤的rtec进一步产生大量的促炎和促纤维化因子，这些因子激活周围的成纤维细胞，导致过度的细胞外基质（ECM）沉积，最终导致肾纤维化。值得注意的是，敲除FGF-23可减轻RAS信号的激活，以及DBP和BaP亚慢性共暴露诱导的ECM的产生和沉积。总之，我们的研究结果表明，DBP和BaP共同暴露可能通过FGF-23激活rtec中的RAS信号来激活成纤维细胞，从而加速肾纤维化的发展。

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引用次数: 0