Biochemical pharmacology最新文献_第7页

Proteomic and cytokine profiling of a CTRP8-RXFP1 glioma mouse model CTRP8-RXFP1胶质瘤小鼠模型的蛋白质组学和细胞因子分析。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116722

Thatchawan Thanasupawat , Yared Pages Mejia , Santhosh S. Anandhan , Yaxiong Guo , Jasneet Tiwana , Adline Fernando , Aleksandra Glogowska , Talia Shafai , Simone daSilva , Nimrat Kaur , Farhana Begum , Rene Zahedi , Sabine Hombach-Klonisch , Thomas Klonisch

Glioblastoma (GB) is the most prevalent and aggressive primary brain tumor with fatal outcome due to a lack of effective treatments. We previously identified C1q-tumor necrosis factor-related protein 8 (CTRP8), a new member of the adiponectin family, as a novel agonist of the relaxin family peptide receptor 1 (RXFP1) and showed that the CTRP8-RXFP1 ligand-receptor system facilitates increased invasiveness and chemoresistance in GB cells. In the present study, we have investigated the role of the CTRP8-RXFP1 signaling axis in glioma progression using an orthotopic mouse model xenografted with human U251 glioma cells stably expressing CTRP8 and RXFP1. Our results demonstrate that this in-vivo U251-CTRP8/RXFP1 glioma model promoted the formation of aggressive, highly proliferative glioma that resulted in significantly shorter survival times of xenografted mice. CTRP8/RXFP1 xenografts showed strongly elevated mitotic activity, increased expression of cathepsin B at the migrating front and promoted a pro-inflammatory tumor microenvironment characterized by a strong upregulation of cytokines, among them eotaxin-2 and-3, interleukin (IL)-6, IL-18 and others. Proteomic analysis of xenografted mouse brain identified both human and mouse proteome signatures unique to CTRP8/RXFP1 xenografts compared to U251 xenografts. In conclusion, our results suggest that co-expression of CTRP8 and RXFP1 promotes signaling pathways that generate unique tissue proteomic and inflammatory cytokine signatures which promote glioma aggressiveness. The CTRP-RXFP1 signaling pathway may represent an effective therapeutic target for the treatment of fast-progressing and currently untreatable GB.

胶质母细胞瘤（GB）是最普遍和侵袭性的原发性脑肿瘤，由于缺乏有效的治疗而导致致命的结局。我们之前发现c1q -肿瘤坏死因子相关蛋白8 （CTRP8）是脂联素家族的新成员，是松弛素家族肽受体1 （RXFP1）的一种新型激动剂，并表明CTRP8-RXFP1配体受体系统促进了GB细胞的侵袭性和化疗耐药的增加。在本研究中，我们通过移植稳定表达CTRP8和RXFP1的人U251胶质瘤细胞的原位小鼠模型，研究了CTRP8-RXFP1信号轴在胶质瘤进展中的作用。我们的研究结果表明，这种体内U251-CTRP8/RXFP1胶质瘤模型促进了侵袭性、高增殖胶质瘤的形成，导致异种移植小鼠的生存时间显著缩短。CTRP8/RXFP1异种移植物有丝分裂活性明显升高，迁移前沿组织蛋白酶B的表达增加，促进了以细胞因子（eotaxin-2和3、白细胞介素(IL)-6、IL-18等）强烈上调为特征的促炎肿瘤微环境。异种鼠脑移植的蛋白质组学分析鉴定出与U251异种移植物相比，CTRP8/RXFP1异种移植物特有的人和小鼠蛋白质组特征。总之，我们的研究结果表明，CTRP8和RXFP1的共同表达促进了产生独特的组织蛋白质组学和炎症细胞因子特征的信号通路，从而促进了胶质瘤的侵袭性。CTRP-RXFP1信号通路可能是治疗快速进展且目前无法治疗的GB的有效靶点。

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引用次数: 0

CircDUSP16 mediates the effect of triple-negative breast cancer in pirarubicin via the miR-1224-3p/TFDP2 axis CircDUSP16通过miR-1224-3p/TFDP2轴介导吡柔比星对三阴性乳腺癌的影响。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116719

Dexian Wei , Fan Zhang , Min Li , Zhimin Fan , Jiulong Ma , Jiahua Ji , Sennan Qiao , Peng Huang , Wenqing Zhang , Kaiqi Fan , Lu Li , Wentao Zheng , Xiangjun Li , Liqun Ren

Triple-negative breast cancer (TNBC) is an aggressive molecular subtype of breast cancer characterized by a high recurrence rate, poor prognosis, and elevated mortality. Identifying novel molecular targets is crucial for developing more effective therapeutic strategies against TNBC. Recent studies have highlighted the role of circular RNAs (circRNAs) in the progression of TNBC. In this study, we identified and validated that circDUSP16 (hsa_circ_0003855) is significantly upregulated in TNBC cells, tissues, and plasma exosomes. Functional assays in vitro demonstrated that overexpression of circDUSP16 promoted the proliferation, migration and invasion of TNBC cells, weathers circDUSP16 knockdown exerted the opposite effect. In vivo studies confirmed that circDUSP16 knockdown can inhibit tumor growth. Using bioinformatics analysis, circDUSP16/miR-1224-3p/TFDP2 pathway was predicted and cascaded. Mechanistically, circDUSP16 was shown to promote the progression of TNBC via the miR-1224-3p/TFDP2 axis. Additionally, THP, a commonly used anthracycline chemotherapy drug, was found to downregulate circDUSP16, suggesting that its therapeutic effects on TNBC may be mediated through circDUSP16/miR-1224-3p/TFDP2 pathway. Our findings suggest that circDUSP16 is a promising biomarker and potential therapeutic target for TNBC.

三阴性乳腺癌（TNBC）是一种具有侵袭性的乳腺癌分子亚型，其特点是复发率高、预后差、死亡率高。确定新的分子靶点对于制定更有效的治疗策略至关重要。最近的研究强调了环状rna （circRNAs）在TNBC进展中的作用。在这项研究中，我们发现并验证了circDUSP16 （hsa_circ_0003855）在TNBC细胞、组织和血浆外泌体中显著上调。体外功能实验表明，过表达circDUSP16可促进TNBC细胞的增殖、迁移和侵袭，而敲低circDUSP16则相反。体内研究证实，circDUSP16敲低可抑制肿瘤生长。利用生物信息学分析，预测circDUSP16/miR-1224-3p/TFDP2通路并进行级联。机制上，circDUSP16被证明通过miR-1224-3p/TFDP2轴促进TNBC的进展。此外，研究发现蒽环类化疗常用药物THP下调circDUSP16，提示其对TNBC的治疗作用可能通过circDUSP16/miR-1224-3p/TFDP2途径介导。我们的研究结果表明circDUSP16是一种有前景的生物标志物和潜在的TNBC治疗靶点。

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引用次数: 0

Harnessing nuclear receptors to modulate hepatic stellate cell activation for liver fibrosis resolution 利用核受体调节肝星状细胞活化以解决肝纤维化。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116730

Yaxin Sun , Xiaoyan Yuan , Zhenhua Hu , Yuanyuan Li

With the recent approval of Resmetirom as the first drug targeting nuclear receptors for metabolic dysfunction-associated steatohepatitis (MASH), there is promising way to treat MASH-associated liver fibrosis. However, liver fibrosis can arise from various pathogenic factors, and effective treatments for fibrosis due to other causes remain elusive. The activation of hepatic stellate cells (HSCs) represents a central link in the pathogenesis of hepatic fibrosis. Therefore, harnessing nuclear receptors to modulate HSC activation may be an effective approach to resolving the complex liver fibrosis caused by various factors. In this comprehensive review, we systematically explore the structure and physiological functions of nuclear receptors, shedding light on their multifaceted roles in HSC activation. Recent advancements in drug development targeting nuclear receptors are discussed, providing insights into their potential as rational and effective therapeutic targets for modulating HSC activation in the context of liver fibrosis. By elucidating the intricate interplay between nuclear receptors and HSC activation, this review contributes to the discovery of new nuclear receptor targets in HSCs for resolving hepatic fibrosis.

随着remetirom最近被批准作为首个靶向核受体治疗代谢功能障碍相关脂肪性肝炎（MASH）的药物，有了治疗MASH相关肝纤维化的有希望的方法。然而，肝纤维化可由多种致病因素引起，对其他原因引起的纤维化的有效治疗仍然难以捉摸。肝星状细胞（HSCs）的激活是肝纤维化发病机制的中心环节。因此，利用核受体调控HSC活化可能是解决多种因素导致的复杂肝纤维化的有效途径。在这篇全面的综述中，我们系统地探讨了核受体的结构和生理功能，揭示了它们在HSC激活中的多方面作用。本文讨论了靶向核受体的药物开发的最新进展，提供了它们作为肝纤维化背景下调节HSC激活的合理和有效的治疗靶点的潜力。通过阐明核受体与HSC活化之间复杂的相互作用，本综述有助于发现HSC中解决肝纤维化的新核受体靶点。

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引用次数: 0

The TFEB activator clomiphene citrate ameliorates lipid metabolic syndrome pathology by activating lipophagy and lipolysis TFEB激活剂克罗米芬柠檬酸盐通过激活脂肪吞噬和脂肪分解来改善脂质代谢综合征病理。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116694

Lu Li , Jieru Lin , Chunhuan Huang , Jiamiao Liu , Yi Yuan , Zhenxing Liu , Yuyin Li , Wei Li , Aipo Diao

The balance between lipid synthesis and lipid catabolism is critical to maintain energy homeostasis. Lipophagy and lipolysis are two important pathways for lipid selective catabolism. Defects in lipophagy and lipolysis are linked to lipid metabolic diseases. Transcription factor EB (TFEB) is a master regulator of autophagy and lysosome biogenesis, as well as lipid metabolism by promoting expression of genes encoding fat catabolic lipases. Therefore, targeting TFEB provides a novel potential strategy for the treatment of lipid metabolic diseases. In this study, we showed that the TFEB activator clomiphene citrate (CC) activated the autophagy-lysosome and lipolysis pathways, and promoted degradation of lipid droplets induced by the free fatty acids oleate and palmitate in HepG2 cells. Moreover, CC treatment promoted lipid catabolism and attenuated obesity, restored lipid levels, blood glucose levels and insulin resistance, hepatocellular injury and hepatic steatosis, as well as liver inflammation in the HFD fed mice. In addition, we found that En-CC, a trans-isomer of CC, displayed less toxicity and more efficient activation of TFEB. Consistent with CC, En-CC treatment improved lipid metabolic syndrome pathology. These findings demonstrate that CC promotes clearance of lipids and ameliorates HFD-induced lipid metabolic syndrome pathology through activating TFEB-mediated lipophagy and lipolysis, indicating that CC has the potential to be used to treat lipid metabolic diseases.

脂质合成和脂质分解代谢之间的平衡对维持能量稳态至关重要。脂食和脂解是脂质选择性分解代谢的两种重要途径。脂质吞噬和脂质分解缺陷与脂质代谢疾病有关。转录因子EB （TFEB）是自噬和溶酶体生物发生以及脂质代谢的主要调节因子，通过促进编码脂肪分解代谢脂肪酶的基因的表达。因此，靶向TFEB为脂质代谢疾病的治疗提供了一种新的潜在策略。在本研究中，我们发现TFEB激活剂克罗米芬柠檬酸（CC）激活了HepG2细胞自噬溶酶体和脂解途径，促进了游离脂肪酸油酸和棕榈酸诱导的脂滴降解。此外，CC处理促进脂质分解代谢，减轻肥胖，恢复脂质水平，血糖水平和胰岛素抵抗，肝细胞损伤和肝脂肪变性，以及肝脏炎症。此外，我们发现CC的反式异构体En-CC毒性更小，对TFEB的激活效率更高。与CC一致，En-CC治疗改善了脂质代谢综合征病理。这些发现表明，CC通过激活tfeb介导的脂质吞噬和脂质分解，促进脂质清除，改善hfd诱导的脂质代谢综合征病理，表明CC具有用于治疗脂质代谢疾病的潜力。

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引用次数: 0

Breakthroughs in nanoparticle-based strategies for pancreatic cancer therapy 基于纳米颗粒的胰腺癌治疗策略的突破。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116685

Sara Escalera-Anzola , Maria Rosado , Yuchen Yang , Daniel Parra-Sanchez , Carolina San Pedro-Liberal , Pilar Acedo

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide, mainly due to its high heterogeneity, resistance to therapy and late diagnosis, with a 5-year survival rate of less than 10%. This dismal prognosis has promoted strategies to develop more effective treatments. Nanoparticle-based strategies have emerged, in the last decades, as a great opportunity because they can enhance drug delivery and promote controlled release, presenting lower side effects than conventional therapeutic regimens. Moreover, nanoparticles can often be modified to target specific cells or to achieve a sustained release of the drugs into the tumor. However, very few nanoparticle-based therapies are clinically approved. Concretely for pancreatic cancer treatment only two nanoformulations have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) so far. Clinical translation of nanoparticles remains a challenge for modern medicine, and in particular for pancreatic cancer therapy, because of the complexity of the disease, and a lack of studies been performed in clinically relevant in vitro and in vivo models. In this review, we have summarized the most recent clinical trials using nanoparticle-based formulations in PDAC, giving a small context of the diverse types of nanoparticles employed and the most recent advancements in the field.

胰腺导管腺癌（Pancreatic ductal adencarcinoma， PDAC）是世界范围内最致命的癌症之一，主要原因是其异质性高、耐药和诊断晚，5年生存率不到10%。这种惨淡的预后促进了开发更有效治疗方法的策略。在过去的几十年里，基于纳米颗粒的策略作为一个巨大的机遇出现了，因为它们可以增强药物传递和促进控制释放，比传统治疗方案的副作用更小。此外，纳米颗粒通常可以修饰为针对特定细胞或实现药物持续释放到肿瘤中。然而，很少有基于纳米颗粒的治疗方法被临床批准。到目前为止，美国食品和药物管理局（FDA）和欧洲药品管理局（EMA）只批准了两种具体用于胰腺癌治疗的纳米制剂。纳米颗粒的临床转化仍然是现代医学的一个挑战，特别是胰腺癌治疗，因为疾病的复杂性，以及缺乏在临床相关的体外和体内模型中进行的研究。在这篇综述中，我们总结了最近在PDAC中使用纳米颗粒为基础的配方的临床试验，给出了不同类型纳米颗粒的使用背景和该领域的最新进展。

{"title":"Breakthroughs in nanoparticle-based strategies for pancreatic cancer therapy","authors":"Sara Escalera-Anzola , Maria Rosado , Yuchen Yang , Daniel Parra-Sanchez , Carolina San Pedro-Liberal , Pilar Acedo","doi":"10.1016/j.bcp.2024.116685","DOIUrl":"10.1016/j.bcp.2024.116685","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide, mainly due to its high heterogeneity, resistance to therapy and late diagnosis, with a 5-year survival rate of less than 10%. This dismal prognosis has promoted strategies to develop more effective treatments. Nanoparticle-based strategies have emerged, in the last decades, as a great opportunity because they can enhance drug delivery and promote controlled release, presenting lower side effects than conventional therapeutic regimens. Moreover, nanoparticles can often be modified to target specific cells or to achieve a sustained release of the drugs into the tumor. However, very few nanoparticle-based therapies are clinically approved. Concretely for pancreatic cancer treatment only two nanoformulations have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) so far. Clinical translation of nanoparticles remains a challenge for modern medicine, and in particular for pancreatic cancer therapy, because of the complexity of the disease, and a lack of studies been performed in clinically relevant <em>in vitro</em> and <em>in vivo</em> models. In this review, we have summarized the most recent clinical trials using nanoparticle-based formulations in PDAC, giving a small context of the diverse types of nanoparticles employed and the most recent advancements in the field.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"232 ","pages":"Article 116685"},"PeriodicalIF":5.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hyperlipidemia impairs bone repair and regeneration via miR-193a-3p/STMN1/PI3K/Akt axis 高脂血症通过miR-193a-3p/STMN1/PI3K/Akt轴损害骨修复和再生。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116693

Jiaming Shang , Zechuan Li , Anquan Ma , Tiantian Zhu , Gaoqiang Ma , Houda Gui , Huiping Ren , Baiyu Sun , Wenhao Wang , Xi Wang , Chenghang Liu , Chuanhua Li , Zhifeng Wang , Jing Lan

Hyperlipidemia, a metabolic disease characterized by excessive blood lipid, disturbs bone metabolism by shifting cell fate of bone marrow stromal cells (BMSCs) towards adipogenic differentiation, thus resulting in poor bone regeneration and osseointegration of implants. Among numerous factors affecting hyperlipidemic bone metabolism, non-coding RNAs play an essential role in post-transcriptional regulation. Our previous study has shown that miR-193a-3p levels were elevated in hyperlipidemia, which hindered implant osseointegration and BMSCs function. However, the downstream targets and pathways of miR-193a-3p warrant further investigation. In this study, we identified STMN1 as the target of miR-193a-3p by miRNA databases and validated their interaction through dual luciferase reporter assays. Models of hyperlipidemia were established in vitro using a high-fat medium and in vivo with a high-fat diet to study these molecular interactions. Besides, miRNA array and PCR analyses confirmed the level of miR-193a and STMN1 in both rats with hyperlipidemia and high-fat-cultured BMSCs. Calvarial defects were used to evaluate STMN1′s impact on bone repair and regeneration. As a result, miR-193a-3p levels were highly elevated in hyperlipidemic conditions, whereas the STMN1 levels were reduced sharply. The elevated miR-193a targeted STMN1 and disabled it from activating the PI3K/Akt pathway, thus resulting in delayed bone repair and poor bone regeneration. Additionally, common lipid-lowering drug simvastatin blunted hyperlipidemia’s adverse effect on this axis. Our findings underscore the miR-193a-3p/STMN1/PI3K/Akt axis as a novel and promising therapeutic target for hyperlipidemic osteopenia, offering insights into the molecular mechanisms underlying bone metabolism disorders in hyperlipidemia and paving the way for innovative treatments.

高脂血症是一种以血脂过高为特征的代谢性疾病，它通过改变骨髓基质细胞（BMSCs）的细胞命运向成脂分化而扰乱骨代谢，从而导致骨再生和植入物骨整合不良。在影响高脂血症骨代谢的众多因素中，非编码rna在转录后调控中发挥着重要作用。我们之前的研究表明，miR-193a-3p水平在高脂血症中升高，这阻碍了种植体骨整合和BMSCs的功能。然而，miR-193a-3p的下游靶点和通路还有待进一步研究。在本研究中，我们通过miRNA数据库确定了STMN1是miR-193a-3p的靶标，并通过双荧光素酶报告基因试验验证了它们的相互作用。在体外用高脂培养基和体内用高脂饮食分别建立了高脂血症模型，以研究这些分子相互作用。此外，miRNA阵列和PCR分析证实了miR-193a和STMN1在高脂血症大鼠和高脂肪培养的骨髓间充质干细胞中的表达水平。采用颅骨缺损评价STMN1对骨修复和再生的影响。结果，miR-193a-3p水平在高脂血症中高度升高，而STMN1水平急剧降低。升高的miR-193a靶向STMN1，使其无法激活PI3K/Akt通路，从而导致骨修复延迟和骨再生不良。此外，常见的降脂药物辛伐他汀可以减弱高脂血症对该轴的不良影响。我们的研究结果强调了miR-193a-3p/STMN1/PI3K/Akt轴作为高脂血症骨质减少的一个新的和有前途的治疗靶点，为高脂血症骨代谢紊乱的分子机制提供了见解，并为创新治疗铺平了道路。

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引用次数: 0

1α,25(OH)2D3 improves 17β-estradiol secretion and potentially alleviates endoplasmic reticulum stress in muskrat granulosa cells 1α,25(OH)2D3改善小鼠颗粒细胞17β-雌二醇分泌，可能减轻内质网应激。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116696

Wenjing Lu, Xinjing Shi, Yuning Liu, Haolin Zhang, Zhengrong Yuan, Yingying Han, Qiang Weng

Vitamin D₃ plays an essential regulatory role in female reproduction. However, the studies on the correlation between vitamin D₃ and muskrat reproduction are limited. This study aims to determine the role of the active form of vitamin D₃, 1α,25-dihydroxytamin D₃ [1α,25(OH)₂D₃], on muskrat ovarian granulosa cells (MGCs). The results showed that vitamin D receptor (VDR) was prominently localized in MGCs and 1α,25(OH)₂D₃ supplementation increased VDR signaling of MGCs. Meanwhile, 10 nM of 1α,25(OH)₂D₃ stimulated MGCs to secrete 17β-estradiol and enhanced the mRNA expression of steroidogenic enzymes. 1α,25(OH)₂D₃ also remarkably down-regulated MGCs endoplasmic reticulum stress according to the expression of GRP78, p-PERK, ATF4, and CHOP. In addition, RNA-seq analysis revealed that 10 nM of 1α,25(OH)₂D₃ activated the PI3K/Akt/mTOR and TNF pathways that contributed to the inhibition of MGCs apoptosis. Taken together, these findings suggest that 1α,25(OH)₂D₃-induced VDR signaling improves 17β-estradiol secretion and potentially alleviate MGCs endoplasmic reticulum stress through the PERK-ATF4-CHOP pathway.

维生素D3在女性生殖中起着重要的调节作用。然而，关于维生素D3与麝鼠繁殖之间关系的研究还很有限。本研究旨在确定活性形式维生素D3, 1α，25-二羟胺D3 [1α，25(OH)2D3]对麝鼠卵巢颗粒细胞（MGCs）的作用。结果表明，维生素D受体（VDR）明显定位于MGCs中，补充1α，25(OH)2D3增加了MGCs的VDR信号转导。同时，10 nM的1α，25(OH)2D3刺激MGCs分泌17β-雌二醇，增强了甾体生成酶mRNA的表达。1α,25(OH)2D3也通过表达GRP78、p-PERK、ATF4和CHOP显著下调MGCs内质网应激。此外，RNA-seq分析显示，10 nM的1α，25(OH)2D3激活了抑制MGCs凋亡的PI3K/Akt/mTOR和TNF通路。综上所述，这些发现表明，1α,25(OH) 2d3诱导的VDR信号可改善17β-雌二醇分泌，并可能通过PERK-ATF4-CHOP途径缓解MGCs内质网应激。

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引用次数: 0

Targeting AhR suppresses hepatocyte ferroptosis in MASH by regulating the Pten/Akt/β catenin axis 通过调节 Pten/Akt/β catenin 轴，靶向 AhR 可抑制 MASH 中肝细胞的铁突变。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116711

Chenhui Ma , Li Han , Wenxuan Zhao , Feihong Chen , Ruimin Huang , Cheng Heng Pang , Zheying Zhu , Guoyu Pan

Aryl hydrocarbon Receptor (AhR), an essential host regulator, has been observed to be significantly upregulated in patients with Metabolic dysfunction-associated steatohepatitis (MASH). However, the underlying mechanism remains unclear. The specific AhR antagonist CH223191 and siRNAs were employed to investigated the role of AhR and its potential as a therapeutic target for MASH in mice and hepatocytes model. Significant upregulation of hepatic AhR was found in our MASH model and across three public datasets. CH223191 (5 mg/kg) treatment effectively ameliorated lipid deposition, serum ALT/AST level, inflammatory cytokines and hepatocyte senescence. Moreover, inhibiting AhR reduced aberrant iron overload, MDA and ROS levels, and suppressed iron transporter DMT1 and iron storage protein ferritin. Furthermore, CH223191 treatment resulted in the restoration of β-catenin and Pten while reducing the phosphorylation of Akt. Suppression of Pten or β-catenin by specific antagonists significantly abolished the hepatoprotective effects of CH223191, leading to increased DMT1 and ferritin and subsequent hepatic ferroptosis in mice. In conclusions, these findings suggested a novel regulatory role of AhR plays in ferroptosis and iron overload through the Pten/Akt/βcatenin pathway, which makes AhR a promising therapeutic target for the treatment of MASH.

芳烃受体（AhR）是一种重要的宿主调节因子，在代谢功能障碍相关脂肪性肝炎（MASH）患者中被观察到显著上调。然而，其潜在机制尚不清楚。利用特异性AhR拮抗剂CH223191和sirna在小鼠和肝细胞模型中研究AhR的作用及其作为MASH治疗靶点的潜力。在我们的MASH模型和三个公共数据集中发现了肝脏AhR的显著上调。CH223191（5 mg/kg）有效改善脂质沉积、血清ALT/AST水平、炎症因子和肝细胞衰老。此外，抑制AhR可降低异常铁超载、MDA和ROS水平，抑制铁转运蛋白DMT1和铁蛋白储存。此外，CH223191处理导致β-catenin和Pten的恢复，同时降低Akt的磷酸化。特异性拮抗剂抑制Pten或β-catenin可显著破坏CH223191的肝保护作用，导致DMT1和铁蛋白增加，导致小鼠肝铁凋亡。综上所述，这些发现提示AhR通过Pten/Akt/βcatenin通路在铁下垂和铁过载中发挥新的调节作用，这使得AhR成为治疗MASH的有希望的治疗靶点。

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引用次数: 0

The NLRP3 inflammasome: A central player in multiple sclerosis NLRP3炎性小体：多发性硬化症的核心参与者。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116667

Almudena Otálora-Alcaraz , Thomas Reilly , Martí Oró-Nolla , Melody Cui Sun , Lisa Costelloe , Hugh Kearney , Pabitra H. Patra , Eric J. Downer

Multiple sclerosis (MS) is a neurological autoimmune condition associated with many symptoms including spasticity, pain, limb numbness and weakness. It is characterised by inflammatory demyelination and axonal degeneration of the brain and spinal cord. A range of disease-modifying therapies (DMTs) are available to suppress inflammatory disease activity in MS, however, there is a pressing need for new therapeutic avenues as DMTs have a limited ability to suppress confirmed disability progression. A body of literature indicates that innate immune inflammation is linked to MS progression. The nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing protein 3 (NLRP3) inflammasome has a well-established function in innate immunity which is closely associated with the pathogenesis of neuroinflammatory conditions. Evidence suggests that the inflammasome may be a therapeutic target in disorders such as MS and at present, inhibitors of the NLRP3 inflammasome are in pre-clinical development. Therefore, this review systematically highlights the pathogenic role of inflammasomes in MS, presenting an overview of research evidence linking inflammasome-related polymorphisms to MS susceptibility, and gathering evidence investigating NLRP3 biomarkers in MS. The role of the NLRP3 inflammasome in murine models of MS is furthermore discussed. Finally, a significant component of this review focuses on evidence that NLRP3 signalling components are novel drug targets in MS. Overall this review defines the role of the inflammasome in MS pathogenesis and identifies inflammasome inhibitor targets that warrant full investigation in MS and related disorders.

多发性硬化症（MS）是一种神经自身免疫性疾病，与痉挛、疼痛、肢体麻木和虚弱等许多症状相关。它的特征是炎症性脱髓鞘和脑和脊髓轴突变性。一系列疾病修饰疗法（DMTs）可用于抑制多发性硬化症的炎症性疾病活动，然而，迫切需要新的治疗途径，因为DMTs抑制已证实的残疾进展的能力有限。大量文献表明，先天免疫炎症与多发性硬化症进展有关。核苷酸结合寡聚化结构域（NOD）样受体pyrin结构域含蛋白3 （NLRP3）炎性小体在先天免疫中具有明确的功能，与神经炎症的发病机制密切相关。有证据表明，炎症小体可能是MS等疾病的治疗靶点，目前，NLRP3炎症小体的抑制剂正处于临床前开发阶段。因此，本文系统地强调了炎症小体在MS中的致病作用，综述了炎症小体相关多态性与MS易感性的研究证据，并收集了NLRP3生物标志物在MS中的研究证据，并进一步讨论了NLRP3炎症小体在MS小鼠模型中的作用。最后，本综述的一个重要组成部分集中在NLRP3信号传导成分是MS中新的药物靶点的证据上。总体而言，本综述定义了炎性小体在MS发病机制中的作用，并确定了炎性小体抑制剂靶点，这些靶点在MS和相关疾病中值得充分研究。

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引用次数: 0

β-Elemene inhibits epithelial-mesenchymal transformation in non-small cell lung cancer by targeting ALDH3B2/RPSA axis β-榄香烯通过靶向ALDH3B2/RPSA轴抑制非小细胞肺癌上皮间质转化。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116709

Jiawei Zhou , Yanhua Kang , Yuan Gao , Xiang-Yang Ye , Hang Zhang , Tian Xie

The pharmacological mechanism of β-elemene in non-small cell lung cancer (NSCLC) remains poorly understood. In this study, we identified aldehyde dehydrogenase 3B2 (ALDH3B2) as a pivotal target for β-elemene’s anti-tumor effects in NSCLC by bioinformatic analysis. The overexpression of ALDH3B2 is specifically associated with the malignancy of NSCLC and the poor prognosis in patients with lung adenocarcinoma. Furthermore, we observed a positive correlation between ALDH3B2 levels and the sensitivity of cells to β-elemene. Additionally, we confirmed that β-elemene suppresses ALDH3B2 expression in PC-9 and NCI-H1373 cell lines. Notably, ALDH3B2 overexpression in NCI-H1373 cells resulted in enhanced migration, invasion, and a prominent epithelial-mesenchymal transition (EMT), which could be attenuated by β-elemene via inhibition of ALDH3B2 expression. Subsequent investigations demonstrated that ALDH3B2 overexpression upregulated ribosomal protein SA (RPSA) expression. β-elemene counteracted the upregulation of RPSA by suppressing ALDH3B2. Furthermore, knocking down of ALDH3B2 and β-elemene treatment significantly reduced the activation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) signaling pathways via suppression of RPSA. In summary, our research uncovers that in NSCLC, ALDH3B2 functions as an oncogenic protein, promoting tumor progression. Meanwhile, β-elemene inhibits EMT of NSCLC by inhibition of ALDH3B2/RPSA axis and subsequently downregulating AKT and ERK signaling pathways. Our study highlights the significant role of ALDH3B2 in the progression of NSCLC, signifying it as a potential pharmacodynamic biomarker for β-elemene. These findings enrich the understanding of anti-tumor pharmacological mechanism of β-elemene, and provides new theoretical and experimental foundations for its potential application in the treatment of NSCLC.

β-榄香烯在非小细胞肺癌（NSCLC）中的药理机制尚不清楚。本研究通过生物信息学分析发现，醛脱氢酶3B2 （ALDH3B2）是β-榄香烯抗NSCLC肿瘤作用的关键靶点。ALDH3B2过表达与非小细胞肺癌的恶性和肺腺癌患者的不良预后特异性相关。此外，我们观察到ALDH3B2水平与细胞对β-榄香烯的敏感性呈正相关。此外，我们证实β-榄香烯可抑制PC-9和NCI-H1373细胞系中ALDH3B2的表达。值得注意的是，ALDH3B2在NCI-H1373细胞中的过表达导致迁移、侵袭增强，上皮-间质转化（EMT）显著，而β-榄香烯可以通过抑制ALDH3B2的表达来减弱这种转变。随后的研究表明，ALDH3B2过表达上调核糖体蛋白SA （RPSA）的表达。β-榄香烯通过抑制ALDH3B2来抵消RPSA的上调。此外，敲除ALDH3B2和β-榄香烯处理可通过抑制RPSA显著降低蛋白激酶B （AKT）和细胞外信号调节激酶（ERK）信号通路的激活。综上所述，我们的研究发现，在NSCLC中，ALDH3B2作为一种致癌蛋白，促进肿瘤进展。同时，β-榄香烯通过抑制ALDH3B2/RPSA轴，进而下调AKT和ERK信号通路抑制NSCLC的EMT。我们的研究强调了ALDH3B2在NSCLC进展中的重要作用，表明它是β-榄香烯的潜在药效学生物标志物。这些发现丰富了对β-榄香烯抗肿瘤药理机制的认识，为其在非小细胞肺癌治疗中的潜在应用提供了新的理论和实验基础。

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