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Hexahydrocurcumin inhibits osteoclastogenesis and bone destruction in osteoporosis by targeting c-Src 六氢姜黄素通过靶向c-Src抑制骨质疏松症的破骨细胞生成和骨破坏。
IF 7.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-04 DOI: 10.1016/j.biopha.2026.119021
Lihong Li , Wenqi Dai , Zhuwei Zhong , Qin Yang , Jiehuang Zheng , Yan Chen , Ziye Chen , Qinghe Liang , Chujiang Xu , Xiaojuan Li , Gang Huang
Osteoporosis is a chronic disorder marked by bone wasting and increased bone fragility. Targeted inhibition of osteoclastogensis is currently the core therapeutic strategy. Hexahydrocurcumin (HHC), derived from Zingiberis Rhizoma, has been shown to exhibit anti-inflammatory and antioxidant properties; however, its effects on osteoclasts regulation and osteoporosis pathogenesis remain unexplored. We conducted this study to observe the influence of HHC on RANKL-mediated osteoclast precursor differentiation and OVX-dependent osteoporotic mice. In this study, we revealed that HHC significantly attenuated the generation and bone resorptive function of osteoclasts induced by RANKL in vitro, which was achieved by targeting and inhibiting the phosphorylation of c-Src, a critical molecule in osteoclast differentiation. Next, HHC inhibited the subsequent Ca2+ influx and NFATc1 nuclear translocation, thereby suppressing the expression of osteoclastogenic regulators such as Acp5 and Mmp9. Furthermore, we validated that HHC inhibits osteoclastogenesis by targeting c-Src through siRNA-mediated silencing of c-Src. In the in vivo study, HHC notably alleviated bone loss in OVX-dependent osteoporotic mice. These findings suggest that HHC alleviates osteoporosis by inhibiting osteoclastogenesis via targeting c-Src, which provide preliminary evidence for the potential of HHC for the treatment of osteoporosis.
骨质疏松症是一种慢性疾病,其特征是骨质流失和骨质脆性增加。靶向抑制破骨细胞生成是目前的核心治疗策略。从姜黄中提取的六氢姜黄素(HHC)已被证明具有抗炎和抗氧化的特性;然而,其在破骨细胞调控和骨质疏松发病机制中的作用仍未被研究。本研究旨在观察HHC对rankl介导的破骨细胞前体分化及ovx依赖性骨质疏松小鼠的影响。在本研究中,我们发现HHC通过靶向和抑制c-Src(破骨细胞分化的关键分子)的磷酸化,显著减弱了RANKL诱导的体外破骨细胞的生成和骨吸收功能。接下来,HHC抑制了随后的Ca2+内流和NFATc1核易位,从而抑制了破骨细胞生成调节因子如Acp5和Mmp9的表达。此外,我们验证了HHC通过sirna介导的c-Src沉默来靶向c-Src,从而抑制破骨细胞的发生。在体内研究中,HHC显著减轻了ovx依赖性骨质疏松小鼠的骨质流失。这些研究结果表明,HHC通过靶向c-Src抑制破骨细胞生成来缓解骨质疏松症,这为HHC治疗骨质疏松症的潜力提供了初步证据。
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引用次数: 0
Identification of 3-cyanoquinolines as broad-spectrum inhibitors of Monkeypox virus and other sexually transmitted pathogens 3-氰喹啉类化合物作为猴痘病毒和其他性传播病原体广谱抑制剂的鉴定。
IF 7.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-04 DOI: 10.1016/j.biopha.2026.119080
Maria Grazia Martina , Gregory Mathez , Daniele Rubini , Martina Eleonora Valenti , Paul Lachat , Sara Cristinelli , Carole Kebbi Beghdadi , Vincent Carlen , Emmanuele Crespan , Elena Bianchi , Onya Opota , Gilbert Greub , Angela Ciuffi , Jérôme Gouttenoire , Marco Radi , Valeria Cagno
Sexually transmitted infections (STIs) remain a major global health concern, contributing significantly to morbidity and facilitating the co-transmission of other pathogens. Recent outbreaks of Monkeypox virus (MPXV) have further underscored the urgent need for broad-spectrum antiviral agents effective against emerging and re-emerging sexually transmissible viruses. We report here the design and synthesis of a series of 3-cyanoquinoline-based Src inhibitors to evaluate their antimicrobial efficacy against sexually transmitted pathogens. Among them, compound 7d demonstrated potent inhibitory activity against MPXV, Herpes simplex virus types 1 and 2, Hepatitis C virus, Human immunodeficiency virus, and Chlamydia trachomatis at non-toxic concentrations. Owing to its broad-spectrum profile and favorable cytotoxicity profile, compound 7d represents a promising candidate for development as a topical microbicide for the prevention and treatment of STIs. Interestingly, the screening also identified compound 7g, which, despite lacking Src inhibitory activity, exhibited selective antiviral activity against members of the Poxviridae family, suggesting the involvement of alternative host-dependent mechanisms that can be further exploited. Both compounds were non-toxic in relevant epithelial and mucosal tissue models. Collectively, these findings highlight the therapeutic potential of 3-cyanoquinoline derivatives as scaffolds for the development of novel broad-spectrum microbicides targeting a range of sexually transmitted pathogens.
性传播感染仍然是一个主要的全球健康问题,大大增加了发病率并促进了其他病原体的共同传播。最近猴痘病毒(MPXV)的暴发进一步强调迫切需要对新出现和再出现的性传播病毒有效的广谱抗病毒药物。我们在这里报道了一系列基于3-氰喹啉的Src抑制剂的设计和合成,以评估它们对性传播病原体的抗菌效果。其中,化合物7d在无毒浓度下对MPXV、单纯疱疹病毒1型和2型、丙型肝炎病毒、人类免疫缺陷病毒和沙眼衣原体具有较强的抑制活性。由于其广谱特征和良好的细胞毒性特征,化合物7d有望成为预防和治疗性传播感染的局部杀微生物剂。有趣的是,筛选还发现了化合物7g,尽管缺乏Src抑制活性,但对痘病毒科成员表现出选择性抗病毒活性,这表明可以进一步利用其他宿主依赖机制。两种化合物在相关上皮和粘膜组织模型中均无毒。总之,这些发现突出了3-氰喹啉衍生物作为开发针对一系列性传播病原体的新型广谱杀微生物剂的支架的治疗潜力。
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引用次数: 0
Shifting the paradigm of PSMA delivery in prostate cancer for internal radiotherapy: An innovative ultrasound-mediated approach 转移PSMA在前列腺癌内放疗中的传递范式:一种创新的超声介导方法。
IF 7.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-03 DOI: 10.1016/j.biopha.2026.119075
Sophie Tran, Anne-Laure Grindel, Dimitri Kereselidze, Laurène Jourdain, Caroline Denis, Benoit Jego, Soizic Martin-Aubert, Jean-Luc Gennisson, Jean-Michel Daugas, Anthony Novell , Charles Truillet
Radioligand therapy targeting prostate-specific membrane antigen (PSMA) has demonstrated promising clinical outcomes for patients with metastatic castration-resistant prostate cancer. However, accumulation in non-target organs can lead to significant radiotoxicity, affecting patient well-being and potentially requiring treatment discontinuation. Ultrasound combined with microbubbles (USMB) has been shown to transiently permeabilize biological barriers, enabling efficient and safe drug delivery to tumor tissues while minimizing dose-limiting toxicities. This study explores the impact of different conditions of USMB on the distribution of the diagnostic radiopharmaceutical [18F]F-PSMA-1007 as a preliminary step before applying therapeutic radiopharmaceuticals (RPs) in a preclinical subcutaneous model. Immunodeficient mice bearing human LNCaP tumors were treated with different ultrasound parameters (i.e., pulse length and pressure). Each mouse received an intravenous injection of [18F]F-PSMA-1007 (5.1 ± 1.7 MBq) and was imaged by PET/CT 2 h post-injection (p.i.). Additionally, an intravenous injection of TRITC Dextran (100 µL, 70 kDa, 5 mg/mL) was administered to quantify its extravasation into the tumor, correlated with PSMA and CD31 expression via immunofluorescence. Contrast-enhanced ultrasound imaging was also performed to assess tumor perfusion. Results showed a mild, though non-significant, trend toward increased [18 F]F-PSMA-1007 in most groups compared to the control, except for those exposed to short pulses associated with high-pressure. These findings highlight the potential of USMB to enhance drug delivery for PSMA uptake but also underscore the necessity for careful consideration of ultrasound parameters to prevent tissue damage.
针对前列腺特异性膜抗原(PSMA)的放射配体治疗对于转移性去势抵抗性前列腺癌患者已显示出良好的临床结果。然而,在非靶器官的积累可导致显著的放射毒性,影响患者的健康,并可能需要停止治疗。超声结合微泡(USMB)已被证明可以瞬间穿透生物屏障,使药物能够有效和安全地输送到肿瘤组织,同时最大限度地减少剂量限制性毒性。本研究在临床前皮下模型中应用治疗性放射性药物(RPs)之前,探讨了不同条件下USMB对诊断性放射性药物[18F]F-PSMA-1007分布的影响。用不同的超声参数(即脉冲长度和压力)治疗携带人类LNCaP肿瘤的免疫缺陷小鼠。每只小鼠静脉注射[18F]F-PSMA-1007(5.1 ± 1.7 MBq),并于注射后 小时(p.i)行PET/CT 2成像。此外,静脉注射TRITC葡聚糖(100 µL, 70 kDa, 5 mg/mL),通过免疫荧光定量其向肿瘤外渗,与PSMA和CD31表达相关。超声造影评估肿瘤灌注。结果显示,与对照组相比,大多数组的F- psma -1007有轻微但不显著的升高趋势[18 F],但高压短脉冲暴露组除外。这些发现强调了USMB增强PSMA摄取药物传递的潜力,但也强调了仔细考虑超声参数以防止组织损伤的必要性。
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引用次数: 0
Calycosin extracted from Astragalus membranaceus root inhibits platelet activation and thrombus formation: Insights from in vivo and in vitro experiments 黄芪根毛蕊花素抑制血小板活化和血栓形成:体内和体外实验的启示。
IF 7.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-02 DOI: 10.1016/j.biopha.2026.119084
Jiun-Yi Li , Kuan-Hung Lin , Ting-Yu Chen , Ray-Jade Chen , Hsueh-Hsiao Wang , Hsien-Yu Peng , Wan-Jung Lu
Platelets, which mediate hemostasis, have been implicated in cardiovascular diseases such as myocardial infarction and stroke. Calycosin, a flavonoid extracted from the root of Astragalus membranaceus, has diverse biological effects, including anticancer, anti-inflammatory, and antidiabetic effects. Whether calycosin inhibits platelet activation and thrombus formation is unclear. The present study explored the mechanisms underlying the potential antiplatelet and antithrombotic effects of calycosin. Platelet aggregation assays, flow cytometry, and Western blotting were performed to analyze the antiplatelet effects of calycosin. Thrombus formation in mouse mesenteric vessels was investigated to analyze the antithrombotic effects of calycosin. Calycosin selectively inhibited collagen-induced platelet aggregation and glycoprotein VI-mediated downstream signaling, including pathways involving phospholipase Cγ2 and protein kinase C. Additionally, calycosin attenuated the activation of protein kinase B and mitogen-activated protein kinase and further suppressed collagen-induced granule release, calcium mobilization, and glycoprotein IIb/IIIa activation. In vivo experiments revealed that calycosin prevented pulmonary thromboembolism and delayed thrombus formation in mouse mesenteric vessels, without affecting hemostasis. This study is the first to demonstrate that calycosin effectively prevents platelet activation and thrombus formation, partly by targeting glycoprotein VI-mediated signaling, without affecting hemostasis. These findings highlight the therapeutic potential of calycosin for cardiovascular diseases.
血小板介导止血,与心血管疾病如心肌梗死和中风有关。毛蕊花素是一种从黄芪根中提取的类黄酮,具有多种生物作用,包括抗癌、抗炎和降糖作用。毛蕊异黄酮是否抑制血小板活化和血栓形成尚不清楚。本研究探讨了毛蕊异黄酮潜在的抗血小板和抗血栓作用的机制。采用血小板聚集试验、流式细胞术和Western blotting分析毛蕊异黄酮的抗血小板作用。观察小鼠肠系膜血管血栓形成情况,分析毛蕊异黄酮的抗血栓作用。Calycosin选择性地抑制胶原诱导的血小板聚集和糖蛋白vi介导的下游信号通路,包括磷脂酶Cγ2和蛋白激酶c。此外,Calycosin减弱蛋白激酶B和丝裂原激活的蛋白激酶的激活,并进一步抑制胶原诱导的颗粒释放、钙动员和糖蛋白IIb/IIIa的激活。体内实验表明,毛蕊异黄酮可预防肺血栓栓塞和延迟小鼠肠系膜血管血栓形成,而不影响止血。本研究首次证明毛蕊异黄酮有效地阻止血小板活化和血栓形成,部分是通过靶向糖蛋白vi介导的信号传导,而不影响止血。这些发现突出了毛蕊异黄酮治疗心血管疾病的潜力。
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引用次数: 0
MG-101, a cysteine protease inhibitor identified through high-throughput screening, exhibits in vivo efficacy and synergy with remdesivir against SARS-CoV-2 MG-101是一种通过高通量筛选鉴定的半胱氨酸蛋白酶抑制剂,它与瑞德西韦在体内具有抗SARS-CoV-2的有效性和协同作用。
IF 7.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-02 DOI: 10.1016/j.biopha.2026.119076
Jinyeong Heo , Soonju Park , Honggun Lee , Yeonguk Jeon , Sangeun Jeon , Dawoon Lee , Inhee Choi , Young Mi Kim , Ju Hwan Jeong , Seong Cheol Min , Min-Suk Song , Seungtaek Kim , David Shum , Jiho Kim
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need for broad and potent antiviral agents. Although overall disease severity has diminished, the persistent risk of reinfection highlights the continued demand for novel therapeutic options.
In this study, we performed an image-based high-throughput screening campaign of 11,030 small molecules—including nucleoside analogs, known antivirals, and diverse bioactives—to identify inhibitors of SARS-CoV-2 infection. Using an immunofluorescence assay that quantified viral proteins and assessed cell viability by Hoechst nuclear staining, we identified 97 primary hits in infected Vero cells. Dose–response evaluation confirmed 18 compounds active against both ancestral and Omicron variants, and subsequent validation in human lung cell lines (A549-hACE2-TMPRSS2 and Calu-3) highlighted multiple cysteine protease inhibitors as strong antiviral candidates.
Among these, MG-101 emerged as a potent cysteine protease inhibitor with favorable pharmacokinetics, metabolic stability, and robust in vivo antiviral efficacy. Docking analysis and enzymatic assays demonstrated that MG-101 inhibits the SARS-CoV-2 3CL protease, and combination studies revealed in vitro synergistic antiviral activity with remdesivir.
Together, these findings establish MG-101 as a potential therapeutic lead for COVID-19 and illustrate the value of image-based high-throughput screening for accelerating antiviral drug discovery.
由严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)引起的COVID-19大流行强调了需要广泛和有效的抗病毒药物。尽管总体疾病严重程度已经降低,但再次感染的持续风险突出了对新治疗方案的持续需求。在这项研究中,我们对11030种小分子(包括核苷类似物、已知抗病毒药物和多种生物活性物质)进行了基于图像的高通量筛选,以确定SARS-CoV-2感染的抑制剂。使用免疫荧光法定量病毒蛋白并通过Hoechst核染色评估细胞活力,我们在感染的Vero细胞中鉴定了97个原发命中。剂量反应评估证实了18种化合物对祖先和Omicron变体都有活性,随后在人肺细胞系(A549-hACE2-TMPRSS2和Calu-3)的验证强调了多种半胱氨酸蛋白酶抑制剂是强抗病毒候选药物。其中,MG-101是一种有效的半胱氨酸蛋白酶抑制剂,具有良好的药代动力学、代谢稳定性和强大的体内抗病毒功效。对接分析和酶促实验显示MG-101抑制SARS-CoV-2 3CL蛋白酶,联合研究显示MG-101与瑞德西韦体外协同抗病毒活性。总之,这些发现确定了MG-101作为COVID-19的潜在治疗先导,并说明了基于图像的高通量筛选在加速抗病毒药物发现方面的价值。
{"title":"MG-101, a cysteine protease inhibitor identified through high-throughput screening, exhibits in vivo efficacy and synergy with remdesivir against SARS-CoV-2","authors":"Jinyeong Heo ,&nbsp;Soonju Park ,&nbsp;Honggun Lee ,&nbsp;Yeonguk Jeon ,&nbsp;Sangeun Jeon ,&nbsp;Dawoon Lee ,&nbsp;Inhee Choi ,&nbsp;Young Mi Kim ,&nbsp;Ju Hwan Jeong ,&nbsp;Seong Cheol Min ,&nbsp;Min-Suk Song ,&nbsp;Seungtaek Kim ,&nbsp;David Shum ,&nbsp;Jiho Kim","doi":"10.1016/j.biopha.2026.119076","DOIUrl":"10.1016/j.biopha.2026.119076","url":null,"abstract":"<div><div>The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need for broad and potent antiviral agents. Although overall disease severity has diminished, the persistent risk of reinfection highlights the continued demand for novel therapeutic options.</div><div>In this study, we performed an image-based high-throughput screening campaign of 11,030 small molecules—including nucleoside analogs, known antivirals, and diverse bioactives—to identify inhibitors of SARS-CoV-2 infection. Using an immunofluorescence assay that quantified viral proteins and assessed cell viability by Hoechst nuclear staining, we identified 97 primary hits in infected Vero cells. Dose–response evaluation confirmed 18 compounds active against both ancestral and Omicron variants, and subsequent validation in human lung cell lines (A549-hACE2-TMPRSS2 and Calu-3) highlighted multiple cysteine protease inhibitors as strong antiviral candidates.</div><div>Among these, MG-101 emerged as a potent cysteine protease inhibitor with favorable pharmacokinetics, metabolic stability, and robust <em>in vivo</em> antiviral efficacy. Docking analysis and enzymatic assays demonstrated that MG-101 inhibits the SARS-CoV-2 3CL protease, and combination studies revealed <em>in vitro</em> synergistic antiviral activity with remdesivir.</div><div>Together, these findings establish MG-101 as a potential therapeutic lead for COVID-19 and illustrate the value of image-based high-throughput screening for accelerating antiviral drug discovery.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"196 ","pages":"Article 119076"},"PeriodicalIF":7.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibition of TRAP1 in the C-terminal domain influences mitochondria properties and breast cancer cell metabolism c端结构域TRAP1的抑制影响线粒体特性和乳腺癌细胞代谢。
IF 7.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-02 DOI: 10.1016/j.biopha.2026.119060
Clélia Mathieu , Jessica Ristow Branco , Patricia Zancan , Catherine Brenner , Samir Messaoudi , Elias Fattal , Juliette Vergnaud
Breast cancers are characterized by complex energy metabolisms involving the Warburg effect but also mitochondria, although this area is not yet well understood. Tumor cells are particularly flexible by choosing oxidative phosphorylation (OXPHOS) or glycolysis depending on the needs and aggressiveness. Within the mitochondria, a HSP90-chaperone protein, TRAP1, exerts regulatory effects on several vital functions such as OXPHOS, production of reactive oxygen species and apoptosis by interacting with members of the respiratory chain or the mPTP. However, not all of its roles have yet been elucidated. Here, we propose to modulate TRAP1 functions using a mitochondriotropic molecule (containing triphenylphosphonium) targeting its C-terminal domain, 6BrCaQ-C10-TPP, in breast tumor cells. Its blocks proliferation with no massive apoptosis, after 24 h of treatment, and induces dissipation of the mitochondrial membrane potential. 6BrCaQ-C10-TPP also appears to modulate regulators of epithelial-mesenchymal transition (Snail and ZEB1) without a common response in all cell lines. Furthermore, the chaperone machinery is affected with a decrease of HSF1 and HSP70, but without degradation of HSP90 or TRAP1, while decreasing the levels of SDH-A and/or SDH-B, partner of TRAP1. Finally, short-term treatments (1 and 3 h) with 6BrCaQ-C10-TPP modify energy metabolism by promoting glycolysis. In conclusion, modulation of TRAP1 on the C-terminal domain by 6BrCaQ-C10-TPP exerts a cell-line dependent anti-tumor effect by modulating major mitochondrial functions in vitro. The differences between cell types need to be clarified. This study confirms that TRAP1 is a target of interest in breast cancer cells, but some of its functions still need to be elucidated.
乳腺癌的特点是复杂的能量代谢,包括Warburg效应和线粒体,尽管这方面还没有得到很好的理解。肿瘤细胞特别灵活,可以根据需要和侵袭性选择氧化磷酸化(OXPHOS)或糖酵解。在线粒体内,hsp90伴侣蛋白TRAP1通过与呼吸链成员或mPTP相互作用,对OXPHOS、活性氧的产生和细胞凋亡等几个重要功能发挥调节作用。然而,并不是所有的作用都被阐明了。在此,我们提出在乳腺肿瘤细胞中,利用线粒体性分子(含三苯基磷)靶向其c -末端结构域6BrCaQ-C10-TPP来调节TRAP1的功能。处理24 h后,可阻断细胞增殖,无大量细胞凋亡,诱导线粒体膜电位耗散。6BrCaQ-C10-TPP似乎也能调节上皮-间质转化的调节因子(Snail和ZEB1),但在所有细胞系中没有共同的反应。此外,伴侣机制受到HSF1和HSP70降低的影响,但HSP90或TRAP1没有降解,而TRAP1的伴侣SDH-A和/或SDH-B的水平降低。最后,6BrCaQ-C10-TPP短期治疗(1和3 h)通过促进糖酵解来改变能量代谢。综上所述,6BrCaQ-C10-TPP对TRAP1在c -末端结构域的调节通过调节线粒体主要功能在体外发挥细胞系依赖性抗肿瘤作用。细胞类型之间的差异需要澄清。本研究证实,TRAP1是乳腺癌细胞的靶标,但其部分功能仍有待阐明。
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引用次数: 0
Liraglutide alters gut microbiota and improves endothelium-dependent relaxation in db/db mice 利拉鲁肽改变db/db小鼠的肠道微生物群并改善内皮依赖性松弛。
IF 7.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-02 DOI: 10.1016/j.biopha.2026.119042
Eun Yi Oh , Soo Hwan Suh , Seonhee Byeon , Jooyong Lee , Young-Ho Lee , Soo-Kyoung Choi
Endothelial dysfunction is a hallmark of type 2 diabetes mellitus (T2DM) and a major contributor to cardiovascular complications. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycemic control and cardiovascular outcomes, the mechanisms linking GLP-1RA therapy, gut microbiome modulation, and endothelial function remain incompletely understood. In this study, we investigated whether the GLP-1RA liraglutide improves endothelial dysfunction in T2DM through microbiome-associated mechanisms that support vascular homeostasis. Male db/db mice and non-diabetic controls were treated with liraglutide (300 μg/kg/day, intraperitoneally) or saline for two weeks. Vascular function was assessed in mesenteric resistance arteries using wire myography. Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose with or without liraglutide or the short chain fatty acid (SCFA), butyrate. Endothelial nitric oxide (NO) signaling was evaluated by eNOS (at Ser1177) phosphorylation and nitrite production. Gut microbiota composition was analyzed by 16S rRNA gene sequencing. Liraglutide significantly improved endothelium-dependent relaxation in db/db mice and restored high glucose-induced impairment of eNOS phosphorylation and NO production in HUVECs. In vivo, diabetes was associated with marked gut dysbiosis characterized by reduced alpha diversity and depletion of SCFA-producing taxa. Liraglutide treatment substantially restored microbial diversity and enriched beneficial genera, including Lachnospiraceae and Lactobacillus. Consistently, low-dose butyrate modestly enhanced NO production in endothelial cells. These findings support the concept of a GLP-1RA–microbiome–vascular axis, in which liraglutide-associated remodeling of the gut microbiota may contribute to improved endothelial NO signaling and vascular function in diabetes.
内皮功能障碍是2型糖尿病(T2DM)的标志,也是心血管并发症的主要因素。尽管胰高血糖素样肽-1受体激动剂(GLP-1RAs)可以改善血糖控制和心血管结局,但GLP-1RA治疗、肠道微生物组调节和内皮功能之间的联系机制仍不完全清楚。在这项研究中,我们研究了GLP-1RA利拉鲁肽是否通过支持血管稳态的微生物相关机制改善T2DM的内皮功能障碍。雄性db/db小鼠和非糖尿病对照组分别给予利拉鲁肽(300 μg/kg/天,腹腔注射)或生理盐水治疗2周。采用钢丝肌造影评估肠系膜阻力动脉的血管功能。人脐静脉内皮细胞(HUVECs)暴露于高糖环境中,有或没有利拉鲁肽或短链脂肪酸(SCFA)丁酸盐。内皮一氧化氮(NO)信号通过eNOS (Ser1177)磷酸化和亚硝酸盐生成来评估。采用16S rRNA基因测序分析肠道菌群组成。利拉鲁肽显著改善db/db小鼠内皮依赖性松弛,恢复高糖诱导的HUVECs eNOS磷酸化和NO生成损伤。在体内,糖尿病与显著的肠道生态失调有关,其特征是α多样性减少和产生scfa的分类群的消耗。利拉鲁肽处理大大恢复了微生物多样性,并丰富了有益的属,包括毛螺杆菌科和乳杆菌。一致地,低剂量丁酸盐适度增强内皮细胞NO的产生。这些发现支持glp - 1ra -微生物-血管轴的概念,其中利拉鲁肽相关的肠道微生物群重塑可能有助于改善糖尿病内皮NO信号和血管功能。
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引用次数: 0
Targeting c-Met and EMT, PI3K/Akt/mTOR/MEK signaling with Dihydropyrimidinone-Piperazine-based scaffold that triggers apoptosis, autophagy, and paraptosis in breast carcinomas 以二氢嘧啶-哌嗪为基础的支架靶向c-Met和EMT、PI3K/Akt/mTOR/MEK信号通路,触发乳腺癌细胞凋亡、自噬和旁凋亡
IF 7.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-01 DOI: 10.1016/j.biopha.2026.119059
Monisha Yadav H S , Young Yun Jung , Narasimha M. Beeraka , Bhoomika B R , Doddahosuru M. Gurudatt , Keshav Kumar Harish , Mahendra Madegowda , Santosh L. Gaonkar , Shreeja Basappa , Vladimir N. Nikolenko , Riyaz Ali M. Osmani , Kanchugarakoppal S. Rangappa , Basappa Basappa , Kwang Seok Ahn

Background

The development of targeted anticancer agents capable of selectively eliminating breast cancer cells while sparing normal tissues remains a critical therapeutic challenge. MCB-04, a novel dihydropyrimidinone (DHPM)-tethered piperazine derivative synthesized via a TiO₂ nanoparticle-mediated catalytic strategy, demonstrates promising anticancer potential.

Objectives

This study aimed to synthesize DHPM-tethered piperazine derivatives using a TiO₂-catalyzed approach and to comprehensively evaluate the cytotoxic efficacy of the lead compound MCB-04 against human breast cancer cells, with particular emphasis on elucidating its underlying molecular mechanisms of cell death.

Methods

A library of DHPM-tethered piperazine derivatives was synthesized and characterized, and MCB-04 was identified as the lead compound. Cytotoxicity was assessed using the MTT assay in MDA-MB-231, MCF-7, BT-474, and SK-BR-3 breast cancer cell lines, as well as normal MCF-10A cells. Apoptosis and autophagy were analyzed by live/dead assays, Annexin V/PI staining, immunocytochemistry, and Western blotting. Mitochondrial dysfunction and oxidative stress were evaluated by measuring mitochondrial membrane potential (Δψm) and intracellular ROS levels using flow cytometry. The involvement of paraptosis and c-Met–mediated signaling pathways was further investigated.

Results

MCB-04 exhibited potent and selective cytotoxicity toward breast cancer cells, with the highest sensitivity observed in MDA-MB-231 cells (IC50 = 20 µM), while exerting minimal toxicity in normal MCF-10A cells. MCB-04 treatment significantly increased intracellular ROS levels and disrupted Δψm, indicating mitochondrial dysfunction. Mechanistically, MCB-04 induced apoptosis through activation of cleaved PARP and cleaved caspase-3, an increased Bax/Bcl-2 ratio, and upregulation of p53 and phosphorylated p53. Concurrently, autophagy was evidenced by LC3-II accumulation and increased Atg5 and Beclin-1 expression. Markers of ER stress-mediated paraptosis, including ATF4 and CHOP, were also elevated with concomintant decline in Alix. Furthermore, MCB-04 markedly suppressed phosphorylated c-Met, EMT-related VEGF, MMP-9 expression and downstream PI3K/Akt/mTOR/MEK signaling pathways.

Conclusion

MCB-04 exerts robust anti-breast cancer activity by triggering multiple programmed cell death pathways include apoptosis, autophagy, and paraptosis primarily through ROS-mediated mitochondrial dysfunction and inhibition of c-Met-dependent oncogenic signaling. These findings position MCB-04 as a promising multi-targeted therapeutic candidate, warranting further in vivo validation and preclinical development for breast cancer treatment.
开发能够选择性地消除乳腺癌细胞同时保留正常组织的靶向抗癌药物仍然是一个关键的治疗挑战。MCB-04是一种新型的二氢嘧啶(DHPM)系哌嗪衍生物,通过tio2纳米颗粒介导的催化策略合成,具有良好的抗癌潜力。目的采用tio2催化方法合成dhpm系链哌嗪衍生物,并综合评价其先导化合物MCB-04对人乳腺癌细胞的细胞毒作用,重点阐明其细胞死亡的潜在分子机制。方法合成并表征了dhpm系链哌嗪衍生物文库,以MCB-04为先导化合物。采用MTT法对MDA-MB-231、MCF-7、BT-474和SK-BR-3乳腺癌细胞系以及正常的MCF-10A细胞进行细胞毒性评估。通过活/死实验、Annexin V/PI染色、免疫细胞化学和Western blotting分析细胞凋亡和自噬。通过测定线粒体膜电位(Δψm)和流式细胞术测定细胞内ROS水平来评估线粒体功能障碍和氧化应激。我们进一步研究了细胞凋亡和c- met介导的信号通路的参与。结果smcb -04对乳腺癌细胞具有强选择性的细胞毒性,对MDA-MB-231细胞的敏感性最高(IC50 = 20 µM),对正常MCF-10A细胞的毒性最小。MCB-04治疗显著增加细胞内ROS水平并扰乱Δψm,表明线粒体功能障碍。机制上,MCB-04通过激活裂解的PARP和裂解的caspase-3,增加Bax/Bcl-2比率,上调p53和磷酸化p53诱导细胞凋亡。同时,LC3-II的积累和Atg5和Beclin-1表达的增加证明了自噬。内质网应激介导的凋亡标志物,包括ATF4和CHOP,也随着Alix的下降而升高。此外,MCB-04显著抑制磷酸化的c-Met、emt相关的VEGF、MMP-9表达和下游PI3K/Akt/mTOR/MEK信号通路。结论mcb -04主要通过ros介导的线粒体功能障碍和c- met依赖性致癌信号的抑制,触发包括凋亡、自噬和凋亡在内的多种程序性细胞死亡途径,具有较强的抗乳腺癌活性。这些发现使MCB-04成为一种有前途的多靶点治疗候选药物,需要进一步的体内验证和乳腺癌治疗的临床前开发。
{"title":"Targeting c-Met and EMT, PI3K/Akt/mTOR/MEK signaling with Dihydropyrimidinone-Piperazine-based scaffold that triggers apoptosis, autophagy, and paraptosis in breast carcinomas","authors":"Monisha Yadav H S ,&nbsp;Young Yun Jung ,&nbsp;Narasimha M. Beeraka ,&nbsp;Bhoomika B R ,&nbsp;Doddahosuru M. Gurudatt ,&nbsp;Keshav Kumar Harish ,&nbsp;Mahendra Madegowda ,&nbsp;Santosh L. Gaonkar ,&nbsp;Shreeja Basappa ,&nbsp;Vladimir N. Nikolenko ,&nbsp;Riyaz Ali M. Osmani ,&nbsp;Kanchugarakoppal S. Rangappa ,&nbsp;Basappa Basappa ,&nbsp;Kwang Seok Ahn","doi":"10.1016/j.biopha.2026.119059","DOIUrl":"10.1016/j.biopha.2026.119059","url":null,"abstract":"<div><h3>Background</h3><div>The development of targeted anticancer agents capable of selectively eliminating breast cancer cells while sparing normal tissues remains a critical therapeutic challenge. MCB-04, a novel dihydropyrimidinone (DHPM)-tethered piperazine derivative synthesized via a TiO₂ nanoparticle-mediated catalytic strategy, demonstrates promising anticancer potential.</div></div><div><h3>Objectives</h3><div>This study aimed to synthesize DHPM-tethered piperazine derivatives using a TiO₂-catalyzed approach and to comprehensively evaluate the cytotoxic efficacy of the lead compound MCB-04 against human breast cancer cells, with particular emphasis on elucidating its underlying molecular mechanisms of cell death.</div></div><div><h3>Methods</h3><div>A library of DHPM-tethered piperazine derivatives was synthesized and characterized, and MCB-04 was identified as the lead compound. Cytotoxicity was assessed using the MTT assay in MDA-MB-231, MCF-7, BT-474, and SK-BR-3 breast cancer cell lines, as well as normal MCF-10A cells. Apoptosis and autophagy were analyzed by live/dead assays, Annexin V/PI staining, immunocytochemistry, and Western blotting. Mitochondrial dysfunction and oxidative stress were evaluated by measuring mitochondrial membrane potential (Δψm) and intracellular ROS levels using flow cytometry. The involvement of paraptosis and c-Met–mediated signaling pathways was further investigated.</div></div><div><h3>Results</h3><div>MCB-04 exhibited potent and selective cytotoxicity toward breast cancer cells, with the highest sensitivity observed in MDA-MB-231 cells (IC50 = 20 µM), while exerting minimal toxicity in normal MCF-10A cells. MCB-04 treatment significantly increased intracellular ROS levels and disrupted Δψm, indicating mitochondrial dysfunction. Mechanistically, MCB-04 induced apoptosis through activation of cleaved PARP and cleaved caspase-3, an increased Bax/Bcl-2 ratio, and upregulation of p53 and phosphorylated p53. Concurrently, autophagy was evidenced by LC3-II accumulation and increased Atg5 and Beclin-1 expression. Markers of ER stress-mediated paraptosis, including ATF4 and CHOP, were also elevated with concomintant decline in Alix. Furthermore, MCB-04 markedly suppressed phosphorylated c-Met, EMT-related VEGF, MMP-9 expression and downstream PI3K/Akt/mTOR/MEK signaling pathways.</div></div><div><h3>Conclusion</h3><div>MCB-04 exerts robust anti-breast cancer activity by triggering multiple programmed cell death pathways include apoptosis, autophagy, and paraptosis primarily through ROS-mediated mitochondrial dysfunction and inhibition of c-Met-dependent oncogenic signaling. These findings position MCB-04 as a promising multi-targeted therapeutic candidate, warranting further in vivo validation and preclinical development for breast cancer treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119059"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The multifaceted antineoplastic effects of arenobufagin against human cancers 槟榔素对人类癌症的多方面抗肿瘤作用。
IF 7.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-01 DOI: 10.1016/j.biopha.2026.119062
Gulafsha Siddiqui , Aditya Bhushan Pant , Chakrabhavi Dhananjaya Mohan
Toad-based therapies (Chansu) are a part of traditional Chinese medicine (TCM) in which toad venom is used for the treatment of cancers. Toad venom is a complex mixture of steroid-based compounds called bufadienolides, which have good anticancer potential. Arenobufagin is a toad venom-derived bufadienolide that has been endowed with strong antitumor activity. Most of the studies have demonstrated that arenobufagin shows potent cytotoxicity in cell-based assay systems (IC50 value: <100 nM) and significant antitumor efficacy in preclinical cancer models at lower doses (between 3 and 5 mg/kg). Arenobufagin has been reported to target signaling axes such as the PI3K/Akt/mTOR, Nrf2, ATM/ATR, NF-κB, MAPKs, and Jagged1/Notch in various types of cancer cells. Pharmacokinetic studies have shown that arenobufagin has rapid absorption and gradual elimination from the system compared to many other bufadienolides. In the present article, we have comprehensively reviewed the literature related to the in vitro and in vivo anticancer properties of the arenobufagin. We have discussed the mechanism of the arenobufagin-induced cytotoxicity in different types of cancer cells and xenograft models, pharmacokinetics, and toxicity associated with its administration. Overall, the present article provides up-to-date information about arenobufagin in connection with its anticancer potential.
蟾蜍疗法(Chansu)是传统中医(TCM)的一部分,其中蟾蜍毒液用于治疗癌症。蟾蜍毒液是一种名为蟾二烯内酯的类固醇化合物的复杂混合物,具有良好的抗癌潜力。蟾毒素是蟾蜍毒液衍生的蟾毒二烯内酯,具有很强的抗肿瘤活性。大多数研究表明,在基于细胞的检测系统中,槟榔素显示出强大的细胞毒性(IC50值:
{"title":"The multifaceted antineoplastic effects of arenobufagin against human cancers","authors":"Gulafsha Siddiqui ,&nbsp;Aditya Bhushan Pant ,&nbsp;Chakrabhavi Dhananjaya Mohan","doi":"10.1016/j.biopha.2026.119062","DOIUrl":"10.1016/j.biopha.2026.119062","url":null,"abstract":"<div><div>Toad-based therapies (Chansu) are a part of traditional Chinese medicine (TCM) in which toad venom is used for the treatment of cancers. Toad venom is a complex mixture of steroid-based compounds called bufadienolides, which have good anticancer potential. Arenobufagin is a toad venom-derived bufadienolide that has been endowed with strong antitumor activity. Most of the studies have demonstrated that arenobufagin shows potent cytotoxicity in cell-based assay systems (IC<sub>50</sub> value: &lt;100 nM) and significant antitumor efficacy in preclinical cancer models at lower doses (between 3 and 5 mg/kg). Arenobufagin has been reported to target signaling axes such as the PI3K/Akt/mTOR, Nrf2, ATM/ATR, NF-κB, MAPKs, and Jagged1/Notch in various types of cancer cells. Pharmacokinetic studies have shown that arenobufagin has rapid absorption and gradual elimination from the system compared to many other bufadienolides. In the present article, we have comprehensively reviewed the literature related to the <em>in vitro</em> and <em>in vivo</em> anticancer properties of the arenobufagin. We have discussed the mechanism of the arenobufagin-induced cytotoxicity in different types of cancer cells and xenograft models, pharmacokinetics, and toxicity associated with its administration. Overall, the present article provides up-to-date information about arenobufagin in connection with its anticancer potential.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119062"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Corrigendum to “A phenotype-driven data and drug repurposing strategy used to identify potential treatments targeting chondrocyte hypertrophy in osteoarthritis” [Biomed. Pharmacother. 193 (December) (2025) 118773] “表型驱动数据和药物再利用策略用于确定骨关节炎软骨细胞肥大的潜在治疗方法”的更正[Biomed]。药学。193(十二月)(2025)118773]。
IF 7.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-02-01 DOI: 10.1016/j.biopha.2026.119004
Judith Veldman , Mauricio N. Ferrao Blanco , Nicole Kops , Wendy J.L.M. Koevoet , Eric M.J. Bindels , Gregory van Beek , Remco M. Hoogenboezem , Kavitha Sivasubramaniyan , Jeroen van Rooij , Andrea Lolli , Eric Farrell , Gerjo J.V.M. van Osch
{"title":"Corrigendum to “A phenotype-driven data and drug repurposing strategy used to identify potential treatments targeting chondrocyte hypertrophy in osteoarthritis” [Biomed. Pharmacother. 193 (December) (2025) 118773]","authors":"Judith Veldman ,&nbsp;Mauricio N. Ferrao Blanco ,&nbsp;Nicole Kops ,&nbsp;Wendy J.L.M. Koevoet ,&nbsp;Eric M.J. Bindels ,&nbsp;Gregory van Beek ,&nbsp;Remco M. Hoogenboezem ,&nbsp;Kavitha Sivasubramaniyan ,&nbsp;Jeroen van Rooij ,&nbsp;Andrea Lolli ,&nbsp;Eric Farrell ,&nbsp;Gerjo J.V.M. van Osch","doi":"10.1016/j.biopha.2026.119004","DOIUrl":"10.1016/j.biopha.2026.119004","url":null,"abstract":"","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119004"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Biomedicine & Pharmacotherapy
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