首页 > 最新文献

Naunyn-Schmiedeberg's archives of pharmacology最新文献

英文 中文
Retraction Note: Anti-inflammatory activity of novel derivatives of pyrazolo [3,4d] pyridazine against digestive system inflammation. 注:新型吡唑啉[3,4d]吡嗪衍生物对消化系统炎症的抗炎活性。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-02-03 DOI: 10.1007/s00210-026-05069-3
Abdulrahman A Almehizia, Abd El-Nasser A Khattab, Ahmed Mohamed Darwish, Mohamed A Al-Omar, Ahmed M Naglah, Mashooq A Bhat, Atef Kalmouch
{"title":"Retraction Note: Anti-inflammatory activity of novel derivatives of pyrazolo [3,4d] pyridazine against digestive system inflammation.","authors":"Abdulrahman A Almehizia, Abd El-Nasser A Khattab, Ahmed Mohamed Darwish, Mohamed A Al-Omar, Ahmed M Naglah, Mashooq A Bhat, Atef Kalmouch","doi":"10.1007/s00210-026-05069-3","DOIUrl":"https://doi.org/10.1007/s00210-026-05069-3","url":null,"abstract":"","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Ruminococcaceae promotes the NLRP3/ASC/Caspase-1 axis-mediated pyroptotic signaling in papillary thyroid carcinoma by upregulating RBM15 to increase the N6-methyladenosine methylation modulation of NLRP3. Ruminococcaceae通过上调RBM15,增加NLRP3的n6 -甲基腺苷甲基化调节,促进NLRP3/ASC/Caspase-1轴介导的甲状腺乳头状癌热凋亡信号。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-02-02 DOI: 10.1007/s00210-026-05025-1
Kai Sang, Jingchao Xu, Junzhu Chen, Ning Zhang, Yuze Wang, Guangzhi Wang, Yongfu Zhao

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. The "mild" clinical behavior of PTC often leads to underestimation of the complexity of its treatment. Ruminococcus (Rum) is a cancer-related intestinal flora. Further study on its functional mechanism is expected to provide a new direction for microbial targeted therapy of cancer. Therefore, the aim of this study was to investigate the therapeutic effect of Rum on PTC and its related mechanism. Rum upregulated the mRNA expression level of RBM15 in BCPAP and KTC-1 cells, decreased their cell viability, promoted pyroptotic signaling, and inhibited their invasion and migration, as well as reduced the volume and weight of tumor tissue and aggravated their pathological injuries. Moreover, Rum downregulated MMP2 and MMP9 mRNA and protein expression levels and upregulated IFN-γ, IL-1β, and IL-18 expression levels, as well as NLRP3, ASC, Caspase-1 mRNA and protein expression levels, the m6A methylation content, and the m6A methylation of NLRP3 in vivo and in vitro. In addition, knocking down RBM15 effectively reversed the effects of Rum mentioned above in vivo and in vitro. Mechanistically, Rum activates the NLRP3/ASC/Caspase-1 axis-mediated pyroptotic signaling in PTC by upregulating RBM15 to increase the N6-methyladenosine methylation modulation of NLRP3, thereby providing a novel strategy and target for the clinical treatment of PTC.

甲状腺乳头状癌(PTC)是最常见的甲状腺癌类型。PTC的“轻微”临床表现往往导致低估其治疗的复杂性。Ruminococcus (Rum)是一种与癌症相关的肠道菌群。对其作用机制的进一步研究有望为肿瘤的微生物靶向治疗提供新的方向。因此,本研究旨在探讨朗姆酒对PTC的治疗作用及其机制。朗姆酒上调BCPAP和KTC-1细胞中RBM15 mRNA的表达水平,降低细胞活力,促进凋亡信号传导,抑制其侵袭和迁移,减少肿瘤组织的体积和重量,加重其病理损伤。朗姆酒下调MMP2和MMP9 mRNA和蛋白表达水平,上调IFN-γ、IL-1β和IL-18表达水平,上调NLRP3、ASC、Caspase-1 mRNA和蛋白表达水平,上调m6A甲基化含量,上调NLRP3的m6A甲基化水平。此外,在体内和体外,敲除RBM15可有效逆转朗姆酒的上述作用。在机制上,Rum通过上调RBM15激活PTC中NLRP3/ASC/Caspase-1轴介导的热凋亡信号,增加NLRP3的n6 -甲基腺苷甲基化调节,从而为PTC的临床治疗提供了新的策略和靶点。
{"title":"Ruminococcaceae promotes the NLRP3/ASC/Caspase-1 axis-mediated pyroptotic signaling in papillary thyroid carcinoma by upregulating RBM15 to increase the N6-methyladenosine methylation modulation of NLRP3.","authors":"Kai Sang, Jingchao Xu, Junzhu Chen, Ning Zhang, Yuze Wang, Guangzhi Wang, Yongfu Zhao","doi":"10.1007/s00210-026-05025-1","DOIUrl":"https://doi.org/10.1007/s00210-026-05025-1","url":null,"abstract":"<p><p>Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. The \"mild\" clinical behavior of PTC often leads to underestimation of the complexity of its treatment. Ruminococcus (Rum) is a cancer-related intestinal flora. Further study on its functional mechanism is expected to provide a new direction for microbial targeted therapy of cancer. Therefore, the aim of this study was to investigate the therapeutic effect of Rum on PTC and its related mechanism. Rum upregulated the mRNA expression level of RBM15 in BCPAP and KTC-1 cells, decreased their cell viability, promoted pyroptotic signaling, and inhibited their invasion and migration, as well as reduced the volume and weight of tumor tissue and aggravated their pathological injuries. Moreover, Rum downregulated MMP2 and MMP9 mRNA and protein expression levels and upregulated IFN-γ, IL-1β, and IL-18 expression levels, as well as NLRP3, ASC, Caspase-1 mRNA and protein expression levels, the m6A methylation content, and the m6A methylation of NLRP3 in vivo and in vitro. In addition, knocking down RBM15 effectively reversed the effects of Rum mentioned above in vivo and in vitro. Mechanistically, Rum activates the NLRP3/ASC/Caspase-1 axis-mediated pyroptotic signaling in PTC by upregulating RBM15 to increase the N6-methyladenosine methylation modulation of NLRP3, thereby providing a novel strategy and target for the clinical treatment of PTC.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Lacosamide prevents cyclophosphamide-induced testicular dysfunction via inhibition of NF-κB/IL-6/STAT-3 and JNK1/Caspase-3 axes with AR and HO-1 preservation: in vivo and in silico evidence. 拉科沙胺通过抑制NF-κB/IL-6/STAT-3和JNK1/Caspase-3轴并保留AR和HO-1来预防环磷酰胺诱导的睾丸功能障碍:体内和体外证据。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-02-02 DOI: 10.1007/s00210-026-04994-7
Mohammed R A Ali, Basim A S Messiha, Ahmed S Abdel-Samea, Mina Ezzat Attya, Reham H Mohyeldin

This study investigated lacosamide (LCM), a third-generation antiepileptic drug, as a potential gonadoprotective agent against cyclophosphamide (CP)-induced testicular injury. The research addressed the critical need for safer antiepileptic alternatives in cancer patients requiring concurrent chemotherapy and seizure control. Male Wistar rats underwent comprehensive biochemical and histopathological analyses including Western blot, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, steroidogenic enzyme activity assessments, sexual hormone measurements, sperm quality evaluations, and molecular docking studies to evaluate LCM's protective mechanisms against CP-induced testicular damage. CP administration significantly elevated oxidative stress markers, pro-inflammatory mediators (Nuclear factor kappa B [NF-κB], Tumor necrosis factor-α [TNF-α], Interleukin-6 [IL-6], Interleukin-1β [IL-1β]), and apoptotic signaling (Bcl-2-associated x protein [Bax], caspase-3), while activating regulatory proteins c-jun N-terminal kinase 1 (JNK1) and Signal transducer and activator of transcription 3 (STAT-3) (identified as novel markers in CP-induced testicular injury). CP suppressed antioxidant defenses, steroidogenic factors (steroidogenic acute regulatory protein [StAR], 3β-hydroxysteroid dehydrogenase [3β-HSD], 17β-hydroxysteroid dehydrogenase [17β-HSD]), Heme oxygenase 1 (HO-1) expression, and androgen receptor (AR) functionality, resulting in decreased testosterone, gonadotropin levels, and compromised spermatogenesis. LCM treatment effectively mitigated these deleterious effects through multi-target protective mechanisms including c-jun N-terminal kinase 1(JNK1)-mediated apoptosis inhibition, HO-1 upregulation, IL-6/ signal transducer and activator of transcription 3 (STAT-3) signaling suppression, prevention of p-JNK1/STAT-3 crosstalk, and AR preservation. This study establishes LCM's multi-target protective efficacy, supporting its potential as a safer antiepileptic alternative providing dual benefits of seizure control and reproductive preservation during chemotherapy.

本研究探讨了第三代抗癫痫药物拉科沙胺(lacosamide, LCM)作为一种潜在的促性腺保护剂对环磷酰胺(cyclophosphamide, CP)致睾丸损伤的作用。该研究解决了需要同时进行化疗和癫痫控制的癌症患者对更安全的抗癫痫替代药物的迫切需求。对雄性Wistar大鼠进行了全面的生化和组织病理学分析,包括Western blot、定量逆转录聚合酶链反应(qRT-PCR)、免疫组织化学、甾体酶活性评估、性激素测量、精子质量评估和分子对接研究,以评估LCM对cp诱导的睾丸损伤的保护机制。CP处理显著提高氧化应激标志物、促炎介质(核因子κB [NF-κB]、肿瘤坏死因子-α [TNF-α]、白细胞介素-6 [IL-6]、白细胞介素-1β [IL-1β])和凋亡信号(bcl -2相关x蛋白[Bax]、caspase-3),同时激活调节蛋白c-jun n-末端激酶1 (JNK1)和转录信号转导激活因子3 (STAT-3)(被认为是CP诱导睾丸损伤的新标志物)。CP抑制抗氧化防御、类固醇生成因子(类固醇急性调节蛋白[StAR]、3β-羟基类固醇脱氢酶[3β-HSD]、17β-羟基类固醇脱氢酶[17β-HSD])、血红素加氧酶1 (HO-1)表达和雄激素受体(AR)功能,导致睾酮、促性腺激素水平降低,精子发生受损。LCM处理通过多靶点保护机制有效减轻了这些有害影响,包括c-jun n -末端激酶1(JNK1)介导的凋亡抑制、HO-1上调、IL-6/信号转导和转录激活因子3 (STAT-3)信号抑制、防止p-JNK1/STAT-3串扰和AR保存。本研究确立了LCM的多靶点保护功效,支持其作为一种更安全的抗癫痫替代药物的潜力,在化疗期间提供癫痫控制和生殖保护的双重益处。
{"title":"Lacosamide prevents cyclophosphamide-induced testicular dysfunction via inhibition of NF-κB/IL-6/STAT-3 and JNK1/Caspase-3 axes with AR and HO-1 preservation: in vivo and in silico evidence.","authors":"Mohammed R A Ali, Basim A S Messiha, Ahmed S Abdel-Samea, Mina Ezzat Attya, Reham H Mohyeldin","doi":"10.1007/s00210-026-04994-7","DOIUrl":"https://doi.org/10.1007/s00210-026-04994-7","url":null,"abstract":"<p><p>This study investigated lacosamide (LCM), a third-generation antiepileptic drug, as a potential gonadoprotective agent against cyclophosphamide (CP)-induced testicular injury. The research addressed the critical need for safer antiepileptic alternatives in cancer patients requiring concurrent chemotherapy and seizure control. Male Wistar rats underwent comprehensive biochemical and histopathological analyses including Western blot, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, steroidogenic enzyme activity assessments, sexual hormone measurements, sperm quality evaluations, and molecular docking studies to evaluate LCM's protective mechanisms against CP-induced testicular damage. CP administration significantly elevated oxidative stress markers, pro-inflammatory mediators (Nuclear factor kappa B [NF-κB], Tumor necrosis factor-α [TNF-α], Interleukin-6 [IL-6], Interleukin-1β [IL-1β]), and apoptotic signaling (Bcl-2-associated x protein [Bax], caspase-3), while activating regulatory proteins c-jun N-terminal kinase 1 (JNK1) and Signal transducer and activator of transcription 3 (STAT-3) (identified as novel markers in CP-induced testicular injury). CP suppressed antioxidant defenses, steroidogenic factors (steroidogenic acute regulatory protein [StAR], 3β-hydroxysteroid dehydrogenase [3β-HSD], 17β-hydroxysteroid dehydrogenase [17β-HSD]), Heme oxygenase 1 (HO-1) expression, and androgen receptor (AR) functionality, resulting in decreased testosterone, gonadotropin levels, and compromised spermatogenesis. LCM treatment effectively mitigated these deleterious effects through multi-target protective mechanisms including c-jun N-terminal kinase 1(JNK1)-mediated apoptosis inhibition, HO-1 upregulation, IL-6/ signal transducer and activator of transcription 3 (STAT-3) signaling suppression, prevention of p-JNK1/STAT-3 crosstalk, and AR preservation. This study establishes LCM's multi-target protective efficacy, supporting its potential as a safer antiepileptic alternative providing dual benefits of seizure control and reproductive preservation during chemotherapy.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Methanimine derivative (BN3) alleviates obesity-associated neurobehavior alteration by influencing metabolic and neuroinflammatory gene pathways in in-vivo zebrafish model. 甲基亚胺衍生物(BN3)通过影响斑马鱼体内模型的代谢和神经炎症基因通路,减轻肥胖相关的神经行为改变。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-02-02 DOI: 10.1007/s00210-026-05014-4
Karthikeyan Ramamurthy, Magesh Santhanakrishnan, Jagan Kannan, Naveen Kumar, Ilavenil Soundharrajan, Bader O Almutairi, Senthilkumar Palaniappan, Kathiravan Muthu Kumaradoss, Jesu Arockiaraj

Obesity is a chronic disease caused by the accumulation of cholesterol, which often requires long-term management strategies, such as dietary changes, increased physical activity, and psychological support. Obesity associated neurobehavioral disorders are a growing global health concern, emphasizing the need for innovative therapeutic strategies. Our study evaluates the therapeutic efficacy of (Z)-1-(furan-2-yl)-N-(4-(2-nitrophenyl)-6-(p-tolyl)pyrimidin-2-yl)methanimine referred as BN3 derivative, in treating high-fat diet-induced metabolic and behavioral dysfunctions in a zebrafish model. The research focused on reducing oxidative stress, lipid accumulation, and neurobehavioral deficits, which are closely linked to obesity-related metabolic stress. In this study, zebrafish were divided into five separate experimental groups: control group, model of obesity caused by high-fat diets, BN3 (50 µM and 100 µM), and Positive Control (PC) Group treated with Lovastatin 100 µM. Initially, fish were fed a high-fat diet for 14 days and followed by 30 days of exercise and simultaneously administering BN3 treatments via oral gavage. Assessment of biochemical, histopathology, gene expression, and behavioral were carried out. The results indicated that BN3 treatment significantly decreased oxidative stress levels by enhancing the activity of four antioxidant enzymes (Superoxide Dismutase, Catalase, Glutathione Transferase and Glutathione Peroxidase). BN3 also decreased lipid accumulation as evidenced through histological staining analysis, and total cholesterol estimation. BN3 enhanced locomotion, social interaction, and exploratory behaviors, and reduced anxiety, with the 100 µM treatment group exhibiting the same results as the PC. Gene expression analysis indicates that BN3 is modulating pparγ, fas, pik3cd, src-3, and bdnf pathways (metabolic and neuroinflammation pathways). BN3 impacted these multiple metabolic and neurobehavioral impairments associated with obesity through a multisite treatment approach. BN3 demonstrates significant therapeutic potential, assuring further studies to explore its long-term safety, pharmacokinetics, and translational application in managing obesity and related disorders.

肥胖是一种由胆固醇积累引起的慢性疾病,通常需要长期的管理策略,如改变饮食、增加身体活动和心理支持。肥胖相关的神经行为障碍是一个日益增长的全球健康问题,强调需要创新的治疗策略。我们的研究评估了(Z)-1-(呋喃-2-基)- n-(4-(2-硝基)-6-(对甲苯基)嘧啶-2-基)甲亚胺(BN3衍生物)治疗高脂肪饮食诱导的斑马鱼模型代谢和行为功能障碍的疗效。这项研究的重点是减少氧化应激、脂质积累和神经行为缺陷,这些与肥胖相关的代谢应激密切相关。本研究将斑马鱼分为5个单独的实验组:对照组、高脂饮食引起的肥胖模型、BN3(50µM和100µM)和阳性对照(PC)组(Lovastatin 100µM)。最初,鱼被喂食高脂肪饲料14天,随后进行30天的运动,同时通过灌胃给予BN3治疗。进行生化、组织病理学、基因表达和行为学评估。结果表明,BN3处理通过提高4种抗氧化酶(超氧化物歧化酶、过氧化氢酶、谷胱甘肽转移酶和谷胱甘肽过氧化物酶)的活性,显著降低了氧化应激水平。通过组织学染色分析和总胆固醇估算,BN3也能降低脂质积累。BN3增强了运动、社会互动和探索行为,并减少了焦虑,100µM治疗组与PC组表现出相同的结果。基因表达分析表明,BN3调节pparγ、fas、pik3cd、src-3和bdnf通路(代谢和神经炎症通路)。BN3通过多位点治疗方法影响与肥胖相关的多种代谢和神经行为障碍。BN3显示出显著的治疗潜力,确保进一步研究其长期安全性、药代动力学和在肥胖及相关疾病治疗中的转化应用。
{"title":"Methanimine derivative (BN3) alleviates obesity-associated neurobehavior alteration by influencing metabolic and neuroinflammatory gene pathways in in-vivo zebrafish model.","authors":"Karthikeyan Ramamurthy, Magesh Santhanakrishnan, Jagan Kannan, Naveen Kumar, Ilavenil Soundharrajan, Bader O Almutairi, Senthilkumar Palaniappan, Kathiravan Muthu Kumaradoss, Jesu Arockiaraj","doi":"10.1007/s00210-026-05014-4","DOIUrl":"https://doi.org/10.1007/s00210-026-05014-4","url":null,"abstract":"<p><p>Obesity is a chronic disease caused by the accumulation of cholesterol, which often requires long-term management strategies, such as dietary changes, increased physical activity, and psychological support. Obesity associated neurobehavioral disorders are a growing global health concern, emphasizing the need for innovative therapeutic strategies. Our study evaluates the therapeutic efficacy of (Z)-1-(furan-2-yl)-N-(4-(2-nitrophenyl)-6-(p-tolyl)pyrimidin-2-yl)methanimine referred as BN3 derivative, in treating high-fat diet-induced metabolic and behavioral dysfunctions in a zebrafish model. The research focused on reducing oxidative stress, lipid accumulation, and neurobehavioral deficits, which are closely linked to obesity-related metabolic stress. In this study, zebrafish were divided into five separate experimental groups: control group, model of obesity caused by high-fat diets, BN3 (50 µM and 100 µM), and Positive Control (PC) Group treated with Lovastatin 100 µM. Initially, fish were fed a high-fat diet for 14 days and followed by 30 days of exercise and simultaneously administering BN3 treatments via oral gavage. Assessment of biochemical, histopathology, gene expression, and behavioral were carried out. The results indicated that BN3 treatment significantly decreased oxidative stress levels by enhancing the activity of four antioxidant enzymes (Superoxide Dismutase, Catalase, Glutathione Transferase and Glutathione Peroxidase). BN3 also decreased lipid accumulation as evidenced through histological staining analysis, and total cholesterol estimation. BN3 enhanced locomotion, social interaction, and exploratory behaviors, and reduced anxiety, with the 100 µM treatment group exhibiting the same results as the PC. Gene expression analysis indicates that BN3 is modulating pparγ, fas, pik3cd, src-3, and bdnf pathways (metabolic and neuroinflammation pathways). BN3 impacted these multiple metabolic and neurobehavioral impairments associated with obesity through a multisite treatment approach. BN3 demonstrates significant therapeutic potential, assuring further studies to explore its long-term safety, pharmacokinetics, and translational application in managing obesity and related disorders.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Przewaquinone A regulates cell cycle and autophagy through the SrC/STAT3 signaling pathway to inhibit colorectal cancer progression. przewa醌A通过SrC/STAT3信号通路调控细胞周期和自噬,抑制结直肠癌的进展。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-31 DOI: 10.1007/s00210-026-05042-0
Jinsong Su, Tianqi Wan, Shengnan Tian

Przewaquinone A (PrA), a natural active substance extracted from Salvia przewalskii Maxim, has been shown to have antitumor activity and can act as a STAT3 inhibitor to modulate the Src/STAT3 pathway. However, its role in colorectal cancer (CRC), along with its related mechanisms, has not yet been clarified. This study aims to explore whether PrA inhibits the malignant advancement of CRC via the Src/STAT3 pathway, and to provide new drug candidates and molecular targets for CRC clinical treatment. The toxic effects of PrA on normal cells NCM460 and on CRC cells (SW480, HCT116, etc.) were explored by Cell Counting Kit-8 (CCK-8) assay. The malignant phenotype, cell cycle distribution, and apoptosis rate were analyzed with the help of Transwell assay, clone formation assay, and flow cytometry. The impact of PrA on autophagic flow in CRC cells was analyzed by GFP-RFP-LC3 dual fluorescent labeling. Plasmid transfection was used to modulate Src expression to verify whether PrA acts through the Src/STAT3 pathway. Finally, subcutaneous graft tumor and carcinoma in situ models were constructed in nude mice, and cell proliferation and apoptosis were detected by pathological staining, and the expression of indicator proteins and Src/STAT3 pathway-related proteins were evaluated via western blot. PrA at 1 ~ 4 µM did not markedly impact NCM460 cell viability, but it dose-dependently reduced CRC cell viability. PrA also diminished the migration and invasion ability of CRC cells, induced G0/G1 phase cycle block, apoptosis, and autophagy, and inhibited Src/STAT3 pathway activation and nuclear translocation of STAT3. Furthermore, overexpression of Src reversed the regulatory impacts of PrA described above. In vivo, PrA treatment hindered tumor growth in nude mice, inhibited cell proliferation, and promoted apoptosis, whereas Src overexpression attenuated the tumor-suppressive effects of PrA. By suppressing the Src/STAT3 pathway, PrA regulates cell cycle and autophagy in CRC cells, thereby inhibiting CRC malignant progression.

Przewaquinone A (PrA)是一种从丹参中提取的天然活性物质,具有抗肿瘤活性,可以作为STAT3抑制剂调节Src/STAT3通路。然而,其在结直肠癌(CRC)中的作用及其相关机制尚未明确。本研究旨在探讨PrA是否通过Src/STAT3通路抑制结直肠癌恶性进展,为结直肠癌临床治疗提供新的候选药物和分子靶点。通过细胞计数试剂盒-8 (Cell Counting Kit-8, CCK-8)检测,探讨PrA对正常细胞NCM460和CRC细胞SW480、HCT116等的毒性作用。采用Transwell实验、克隆形成实验和流式细胞术分析恶性表型、细胞周期分布和凋亡率。采用GFP-RFP-LC3双荧光标记法分析PrA对结直肠癌细胞自噬流的影响。通过质粒转染调节Src表达,验证PrA是否通过Src/STAT3通路起作用。最后建立裸鼠皮下移植瘤和原位癌模型,病理染色检测细胞增殖和凋亡,western blot检测指示蛋白和Src/STAT3通路相关蛋白的表达。1 ~ 4µM的PrA对NCM460细胞活力无显著影响,但剂量依赖性地降低了CRC细胞活力。PrA还降低CRC细胞的迁移和侵袭能力,诱导G0/G1期周期阻滞、细胞凋亡和自噬,抑制Src/STAT3通路激活和STAT3核转运。此外,Src的过表达逆转了上述PrA的调节作用。在体内,PrA处理阻碍了裸鼠的肿瘤生长,抑制了细胞增殖,促进了细胞凋亡,而Src过表达则减弱了PrA的抑瘤作用。PrA通过抑制Src/STAT3通路,调节CRC细胞的细胞周期和自噬,从而抑制CRC恶性进展。
{"title":"Przewaquinone A regulates cell cycle and autophagy through the SrC/STAT3 signaling pathway to inhibit colorectal cancer progression.","authors":"Jinsong Su, Tianqi Wan, Shengnan Tian","doi":"10.1007/s00210-026-05042-0","DOIUrl":"https://doi.org/10.1007/s00210-026-05042-0","url":null,"abstract":"<p><p>Przewaquinone A (PrA), a natural active substance extracted from Salvia przewalskii Maxim, has been shown to have antitumor activity and can act as a STAT3 inhibitor to modulate the Src/STAT3 pathway. However, its role in colorectal cancer (CRC), along with its related mechanisms, has not yet been clarified. This study aims to explore whether PrA inhibits the malignant advancement of CRC via the Src/STAT3 pathway, and to provide new drug candidates and molecular targets for CRC clinical treatment. The toxic effects of PrA on normal cells NCM460 and on CRC cells (SW480, HCT116, etc.) were explored by Cell Counting Kit-8 (CCK-8) assay. The malignant phenotype, cell cycle distribution, and apoptosis rate were analyzed with the help of Transwell assay, clone formation assay, and flow cytometry. The impact of PrA on autophagic flow in CRC cells was analyzed by GFP-RFP-LC3 dual fluorescent labeling. Plasmid transfection was used to modulate Src expression to verify whether PrA acts through the Src/STAT3 pathway. Finally, subcutaneous graft tumor and carcinoma in situ models were constructed in nude mice, and cell proliferation and apoptosis were detected by pathological staining, and the expression of indicator proteins and Src/STAT3 pathway-related proteins were evaluated via western blot. PrA at 1 ~ 4 µM did not markedly impact NCM460 cell viability, but it dose-dependently reduced CRC cell viability. PrA also diminished the migration and invasion ability of CRC cells, induced G0/G1 phase cycle block, apoptosis, and autophagy, and inhibited Src/STAT3 pathway activation and nuclear translocation of STAT3. Furthermore, overexpression of Src reversed the regulatory impacts of PrA described above. In vivo, PrA treatment hindered tumor growth in nude mice, inhibited cell proliferation, and promoted apoptosis, whereas Src overexpression attenuated the tumor-suppressive effects of PrA. By suppressing the Src/STAT3 pathway, PrA regulates cell cycle and autophagy in CRC cells, thereby inhibiting CRC malignant progression.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
A network pharmacology-based study on the mechanism of hirudin attenuates renal interstitial fibrosis through Nrf2 and NF-κB signalling pathways. 水蛭素通过Nrf2和NF-κB信号通路减轻肾间质纤维化机制的网络药理学研究
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-31 DOI: 10.1007/s00210-026-05036-y
Kang Yang, Yijiao Wang, Xiaoxia Xun, Hao Zhao, Guanting Chen, Tao Li, Jinhua Ge, Siyu Guo, Shengtao Ye, Zhenzhen Wang, Yaoxian Wang

This study was aimed at elucidating the therapeutic effects of hirudin on renal interstitial fibrosis (RIF) and at delineating the molecular mechanisms underlying its antifibrotic actions. A comprehensive research approach was adopted, integrating network pharmacology, molecular docking, molecular dynamics simulations, and in vitro experimental validation, to explore the mechanisms through which hirudin alleviates RIF. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified 185 enriched signalling pathways, with the primary ones being the VEGF signalling pathway, TNFA signalling pathway and NF-κB signalling pathway. Gene Ontology (GO) analysis revealed that hirudin's antifibrotic effects were associated with inflammatory responses, canonical NF-κB signal transduction, and cellular responses to oxidative stress. Protein-protein interaction (PPI) network analysis identified TNF, HIF1A, HO-1, CASP3, IKBA, KEAP1, and RELA as key hub proteins. Experimental validation demonstrated that hirudin significantly reduced the protein levels of fibronectin (FN) and collagen I (Col I) in TGF-β1-stimulated HK-2 cells. Additionally, hirudin downregulated pro-inflammatory markers (TNF-α, MCP-1, p-P65, and p-IκBα) while upregulating antioxidant proteins (Nrf2, HO-1, and SOD-1). These findings suggest that hirudin mitigates TGF-β1-induced inflammation and oxidative stress in HK-2 cells by modulating the Nrf2 and NF-κB signalling pathways, thereby impeding the progression of RIF.

本研究旨在阐明水蛭素对肾间质纤维化(RIF)的治疗作用,并描述其抗纤维化作用的分子机制。采用网络药理学、分子对接、分子动力学模拟、体外实验验证等综合研究方法,探讨水蛭素缓解RIF的机制。京都基因与基因组百科全书(KEGG)分析鉴定出185条富集的信号通路,主要是VEGF信号通路、TNFA信号通路和NF-κB信号通路。基因本体(Gene Ontology, GO)分析显示水蛭素的抗纤维化作用与炎症反应、典型NF-κB信号转导和细胞对氧化应激的反应有关。蛋白-蛋白相互作用(PPI)网络分析发现TNF、HIF1A、HO-1、CASP3、IKBA、KEAP1和RELA是关键枢纽蛋白。实验证实水蛭素显著降低TGF-β1刺激的HK-2细胞中纤维连接蛋白(FN)和胶原蛋白(Col I)的蛋白水平。此外,水貂素下调促炎标志物(TNF-α、MCP-1、p-P65和p- κ b α),上调抗氧化蛋白(Nrf2、HO-1和SOD-1)。这些发现表明水蛭素通过调节Nrf2和NF-κB信号通路减轻TGF-β1诱导的HK-2细胞炎症和氧化应激,从而阻碍RIF的进展。
{"title":"A network pharmacology-based study on the mechanism of hirudin attenuates renal interstitial fibrosis through Nrf2 and NF-κB signalling pathways.","authors":"Kang Yang, Yijiao Wang, Xiaoxia Xun, Hao Zhao, Guanting Chen, Tao Li, Jinhua Ge, Siyu Guo, Shengtao Ye, Zhenzhen Wang, Yaoxian Wang","doi":"10.1007/s00210-026-05036-y","DOIUrl":"https://doi.org/10.1007/s00210-026-05036-y","url":null,"abstract":"<p><p>This study was aimed at elucidating the therapeutic effects of hirudin on renal interstitial fibrosis (RIF) and at delineating the molecular mechanisms underlying its antifibrotic actions. A comprehensive research approach was adopted, integrating network pharmacology, molecular docking, molecular dynamics simulations, and in vitro experimental validation, to explore the mechanisms through which hirudin alleviates RIF. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified 185 enriched signalling pathways, with the primary ones being the VEGF signalling pathway, TNFA signalling pathway and NF-κB signalling pathway. Gene Ontology (GO) analysis revealed that hirudin's antifibrotic effects were associated with inflammatory responses, canonical NF-κB signal transduction, and cellular responses to oxidative stress. Protein-protein interaction (PPI) network analysis identified TNF, HIF1A, HO-1, CASP3, IKBA, KEAP1, and RELA as key hub proteins. Experimental validation demonstrated that hirudin significantly reduced the protein levels of fibronectin (FN) and collagen I (Col I) in TGF-β1-stimulated HK-2 cells. Additionally, hirudin downregulated pro-inflammatory markers (TNF-α, MCP-1, p-P65, and p-IκBα) while upregulating antioxidant proteins (Nrf2, HO-1, and SOD-1). These findings suggest that hirudin mitigates TGF-β1-induced inflammation and oxidative stress in HK-2 cells by modulating the Nrf2 and NF-κB signalling pathways, thereby impeding the progression of RIF.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Paying peer reviewers: benefits, risks, and challenges. 支付同行评审:利益、风险和挑战。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-31 DOI: 10.1007/s00210-025-04969-0
Jaime A Teixeira da Silva

The vast majority of peer-reviewed journals rely on specialists' voluntary services in order to ensure that work they publish is as advertised, i.e., peer reviewed. In the real, commercial world, work that relies on expert opinions, i.e., in the form of consultancy, carries a financial cost and is usually very well remunerated. However, exceptionally, in the world of academic publishing, this reliance on experts has been reduced to an art of exploitation, although it has been marketed as a necessary community service, duty or professional obligation. Ultimately, a journal that claims to conduct peer review must do so, or risk the label of engaging in fake peer review or worse-predatory publishing behavior-by claiming peer review when none has been conducted, so there is constant pressure on editors (and to a lesser extent, publishers) to secure a constant stream of peer reviewers to match or exceed the influx of submissions. Although relying on free labor has its benefits, the most obvious being the absence of costs, the risks are incalculable and can include the use of individuals who are tardy, unprofessional, abusive, frustrated, only provide superficial feedback, or may engage in this task exclusively for rewards even if they do not deliver quality reports. Editors may even have to contend with those that agree to complete the task but then fail to deliver on time, or at all. Although the issue of paying reviewers is a well-debated topic and one with seemingly no sustainable solution, it may have become a rather miniscule issue now that large language models and generative AI are reaching prominence in academic publishing, with the risk that free human peer reviewers will be substituted by free AI-driven "reviewers".

绝大多数同行评议期刊依靠专家的自愿服务,以确保他们发表的作品如广告所说,即同行评议。在真实的商业世界中,依赖于专家意见的工作,即以咨询形式进行的工作,会产生财务成本,而且通常报酬很高。然而,例外的是,在学术出版界,这种对专家的依赖已沦为一种剥削的艺术,尽管它已被推销为一种必要的社区服务、责任或专业义务。最终,声称进行同行评议的期刊必须这样做,否则就有可能被贴上虚假同行评议或更糟糕的掠夺性出版行为的标签——在没有进行同行评议的情况下声称进行了同行评议。因此,编辑(以及较小程度上的出版商)面临着持续的压力,需要确保不断有同行评议者来匹配或超过投稿量。尽管依靠免费劳动力有其好处,最明显的是没有成本,但风险是无法估量的,并且可能包括使用那些迟到的、不专业的、滥用的、沮丧的、只提供表面反馈的人,或者即使他们没有提供高质量的报告,也可能只为了奖励而从事这项任务。编辑们甚至可能不得不与那些同意完成任务,但却没有按时交付,或者根本没有交付的人抗争。尽管付费审稿人的问题是一个备受争议的话题,而且似乎没有可持续的解决方案,但随着大型语言模型和生成式人工智能在学术出版领域的突出地位,它可能已经成为一个相当微不足道的问题,免费的人类同行审稿人将被免费的人工智能驱动的“审稿人”所取代。
{"title":"Paying peer reviewers: benefits, risks, and challenges.","authors":"Jaime A Teixeira da Silva","doi":"10.1007/s00210-025-04969-0","DOIUrl":"https://doi.org/10.1007/s00210-025-04969-0","url":null,"abstract":"<p><p>The vast majority of peer-reviewed journals rely on specialists' voluntary services in order to ensure that work they publish is as advertised, i.e., peer reviewed. In the real, commercial world, work that relies on expert opinions, i.e., in the form of consultancy, carries a financial cost and is usually very well remunerated. However, exceptionally, in the world of academic publishing, this reliance on experts has been reduced to an art of exploitation, although it has been marketed as a necessary community service, duty or professional obligation. Ultimately, a journal that claims to conduct peer review must do so, or risk the label of engaging in fake peer review or worse-predatory publishing behavior-by claiming peer review when none has been conducted, so there is constant pressure on editors (and to a lesser extent, publishers) to secure a constant stream of peer reviewers to match or exceed the influx of submissions. Although relying on free labor has its benefits, the most obvious being the absence of costs, the risks are incalculable and can include the use of individuals who are tardy, unprofessional, abusive, frustrated, only provide superficial feedback, or may engage in this task exclusively for rewards even if they do not deliver quality reports. Editors may even have to contend with those that agree to complete the task but then fail to deliver on time, or at all. Although the issue of paying reviewers is a well-debated topic and one with seemingly no sustainable solution, it may have become a rather miniscule issue now that large language models and generative AI are reaching prominence in academic publishing, with the risk that free human peer reviewers will be substituted by free AI-driven \"reviewers\".</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Integrative bulk and single-cell transcriptomic analyses reveal nucleus pulposus cell fibrosis as a therapeutic target in intervertebral disc degeneration and identify quercetin as a potential antifibrotic agent. 整体和单细胞转录组学分析显示髓核细胞纤维化是椎间盘退变的治疗靶点,槲皮素是一种潜在的抗纤维化药物。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-31 DOI: 10.1007/s00210-026-05035-z
Peilin He, Jun Tao, Guo Li, Ye Mu, Rong Hu, Junming Chen, Wenqi Feng

Intervertebral disc degeneration (IVDD) is a leading cause of chronic low back pain, in which fibrotic transformation of nucleus pulposus cells (NPCs) plays a critical pathological role. However, the regulatory mechanisms underlying NP cell fibrosis remain poorly understood. This study aimed to explore the role of NP cell fibrosis in IVDD and identify natural compounds capable of targeting this process. Bulk and single-cell transcriptomic data were integrated to explore the role of NP cell fibrosis in IVDD and to identify natural compounds capable of targeting this pathological process. Cellular and animal experiments were conducted for validation. Transcriptomic analysis revealed that the intersection of differentially expressed genes (DEGs), WGCNA-identified module genes, and fibrosis-related genes-termed fibrosis-related differentially expressed genes (FRDEGs)-was significantly enriched in the TGF-β signaling pathway. Based on FRDEGs, quercetin (QUE), a natural flavonoid, was identified as a candidate compound. TGF-β and TGF-βR2 were identified as hub genes. Single-cell analysis confirmed high expression of these genes in NP cells, especially within fibrotic subpopulations (Fibro-NPCs), where TGF-β pathway activity was notably elevated. Molecular docking indicated strong binding affinity between QUE and TGF-β. In vitro, QUE treatment suppressed IL-1β-induced expression of TGF-β/TGF-βR2 in degenerative NP cells. In vivo, QUE administration attenuated NP fibrosis and mitigated IVDD progression in a rat puncture model. This study uncovers the critical role of NP cell fibrosis in IVDD and demonstrates that QUE mitigates disc degeneration by targeting the TGF-β signaling pathway. These findings suggest a novel anti-fibrotic therapeutic strategy for IVDD based on natural compound intervention.

椎间盘退变(IVDD)是慢性腰痛的主要原因,其中髓核细胞(NPCs)的纤维化转化起着关键的病理作用。然而,NP细胞纤维化的调控机制仍然知之甚少。本研究旨在探讨NP细胞纤维化在IVDD中的作用,并鉴定能够靶向这一过程的天然化合物。整合了大量和单细胞转录组数据,以探索NP细胞纤维化在IVDD中的作用,并鉴定能够靶向这一病理过程的天然化合物。进行了细胞和动物实验以进行验证。转录组学分析显示,在TGF-β信号通路中,差异表达基因(DEGs)、wgna鉴定的模块基因和纤维化相关基因(称为纤维化相关差异表达基因(FRDEGs))的交集显著富集。基于FRDEGs,槲皮素(quercetin, QUE)是一种天然类黄酮,被确定为候选化合物。TGF-β和TGF-β r2被鉴定为枢纽基因。单细胞分析证实这些基因在NP细胞中高表达,特别是在纤维化亚群(纤维- npc)中,TGF-β通路活性显著升高。分子对接表明QUE与TGF-β具有较强的结合亲和力。在体外,QUE处理可抑制il -1β诱导的变性NP细胞中TGF-β/TGF-β r2的表达。在体内,在大鼠穿刺模型中,QUE给药可减轻NP纤维化并减轻IVDD进展。本研究揭示了NP细胞纤维化在IVDD中的关键作用,并证明QUE通过靶向TGF-β信号通路减轻椎间盘退变。这些发现为IVDD提供了一种基于天然化合物干预的新型抗纤维化治疗策略。
{"title":"Integrative bulk and single-cell transcriptomic analyses reveal nucleus pulposus cell fibrosis as a therapeutic target in intervertebral disc degeneration and identify quercetin as a potential antifibrotic agent.","authors":"Peilin He, Jun Tao, Guo Li, Ye Mu, Rong Hu, Junming Chen, Wenqi Feng","doi":"10.1007/s00210-026-05035-z","DOIUrl":"https://doi.org/10.1007/s00210-026-05035-z","url":null,"abstract":"<p><p>Intervertebral disc degeneration (IVDD) is a leading cause of chronic low back pain, in which fibrotic transformation of nucleus pulposus cells (NPCs) plays a critical pathological role. However, the regulatory mechanisms underlying NP cell fibrosis remain poorly understood. This study aimed to explore the role of NP cell fibrosis in IVDD and identify natural compounds capable of targeting this process. Bulk and single-cell transcriptomic data were integrated to explore the role of NP cell fibrosis in IVDD and to identify natural compounds capable of targeting this pathological process. Cellular and animal experiments were conducted for validation. Transcriptomic analysis revealed that the intersection of differentially expressed genes (DEGs), WGCNA-identified module genes, and fibrosis-related genes-termed fibrosis-related differentially expressed genes (FRDEGs)-was significantly enriched in the TGF-β signaling pathway. Based on FRDEGs, quercetin (QUE), a natural flavonoid, was identified as a candidate compound. TGF-β and TGF-βR2 were identified as hub genes. Single-cell analysis confirmed high expression of these genes in NP cells, especially within fibrotic subpopulations (Fibro-NPCs), where TGF-β pathway activity was notably elevated. Molecular docking indicated strong binding affinity between QUE and TGF-β. In vitro, QUE treatment suppressed IL-1β-induced expression of TGF-β/TGF-βR2 in degenerative NP cells. In vivo, QUE administration attenuated NP fibrosis and mitigated IVDD progression in a rat puncture model. This study uncovers the critical role of NP cell fibrosis in IVDD and demonstrates that QUE mitigates disc degeneration by targeting the TGF-β signaling pathway. These findings suggest a novel anti-fibrotic therapeutic strategy for IVDD based on natural compound intervention.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Preclinical evaluation of gefitinib and betulin-loaded surface functionalized liposomes for the treatment of hepatocellular carcinoma via asialoglycoprotein receptor targeting. 吉非替尼和白桦脂素负载的表面功能化脂质体通过asialglyprotein receptor靶向治疗肝癌的临床前评价。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-30 DOI: 10.1007/s00210-026-04999-2
Amita Singh, Vipin Kumar, Km Prachi, Nitin Rajan, Sanjay Singh, Vijayakumar Mahalingam Rajamanickam

Hepatocellular carcinoma (HCC) is difficult to treat, and gefitinib (GEF) monotherapy may offer limited therapeutic benefits. Combination or multimodal approaches are often required to achieve therapeutic efficacy in such cases. Betulin (BET), a naturally occurring triterpene, is used in combination with GEF to enhance therapeutic efficacy against HCC, but its clinical translation is not possible due to poor bioavailability and lack of targeted delivery. Therefore, we developed non-targeted and lactoferrin (Lf) grafted targeted liposomes of GEF (GEF-Lipo and GEF-Lf-Lipo) and BET (BET-Lipo and BET-Lf-Lipo) by the ethanol injection method and subsequently characterized them. The vesicular size of GEF-Lipo, GEF-Lf-Lipo, BET-Lipo, and BET-Lf-Lipo was found to be 119.5 ± 6.5, 159.1 ± 16.4, 140.7 ± 16.4, and 181.6 ± 4.8 nm, respectively. Polydispersity index (PDI) of GEF-Lipo, GEF-Lf-Lipo, BET-Lipo, and BET-Lf-Lipo was found to be 0.329 ± 0.1, 0.371 ± 0.05, 0.33 ± 0.14, and 0.399 ± 0.030, respectively. Encapsulation efficiencies (EE%) of GEF-Lipo, GEF-Lf-Lipo, BET-Lipo, and BET-Lf-Lipo were found to be 84.7 ± 1.22%, 90.08 ± 1.73%, 91.4 ± 2.63%, and 93.21 ± 1.88%, respectively. Furthermore, the in vivo study has been performed to assess the effectiveness of mixtures of GEF-BET, GEF-BET-Lipo, and asialoglycoprotein receptor (ASGPR) targeted GEF-BET-Lf-Lipo. Physiological parameters and HCC biomarker AFP were quantified. AFP levels were significantly increased in the cancer control versus normal control (p < 0.0001) and were significantly reduced by treatment with pristine drugs, non-targeted liposomes, and targeted liposomes (p < 0.0001), supporting the therapeutic effects of the formulations. Morphological changes in liver tissue were evaluated through histopathological examination and scanning electron microscopy (SEM). Western blotting and immunohistochemistry (IHC) showed that both GEF-BET-Lipo and GEF-BET-Lf-Lipo treatments significantly reduced pSTAT3 expression and increased the levels of the apoptotic marker caspase-3. Overall, the findings support the enhanced antitumor potential of GEF-BET-Lf-Lipo against HCC in animals.

肝细胞癌(HCC)很难治疗,吉非替尼(GEF)单药治疗可能提供有限的治疗效果。在这种情况下,通常需要联合或多模式方法来达到治疗效果。桦木素(Betulin, BET)是一种天然存在的三萜,与GEF联合使用可提高对HCC的治疗效果,但由于生物利用度差且缺乏靶向递送,其临床转化无法实现。因此,我们通过乙醇注射法制备了GEF (GEF- lipo和GEF-Lf- lipo)和BET (BET- lipo和BET-Lf- lipo)的非靶向和乳铁蛋白(Lf)靶向脂质体,并对其进行了表征。GEF-Lipo、GEF-Lf-Lipo、BET-Lipo和BET-Lf-Lipo的囊泡大小分别为119.5±6.5 nm、159.1±16.4 nm、140.7±16.4 nm和181.6±4.8 nm。GEF-Lipo、GEF-Lf-Lipo、BET-Lipo和BET-Lf-Lipo的多分散指数(PDI)分别为0.329±0.1、0.371±0.05、0.33±0.14和0.399±0.030。GEF-Lipo、GEF-Lf-Lipo、BET-Lipo和BET-Lf-Lipo的包封效率(EE%)分别为84.7±1.22%、90.08±1.73%、91.4±2.63%和93.21±1.88%。此外,还进行了体内研究,以评估GEF-BET、GEF-BET- lipo和asialglycoprotein receptor (ASGPR)靶向GEF-BET- lf - lipo的混合物的有效性。定量测定肝细胞癌生理参数及生物标志物AFP。癌症对照组的甲胎蛋白水平明显高于正常对照组(p
{"title":"Preclinical evaluation of gefitinib and betulin-loaded surface functionalized liposomes for the treatment of hepatocellular carcinoma via asialoglycoprotein receptor targeting.","authors":"Amita Singh, Vipin Kumar, Km Prachi, Nitin Rajan, Sanjay Singh, Vijayakumar Mahalingam Rajamanickam","doi":"10.1007/s00210-026-04999-2","DOIUrl":"https://doi.org/10.1007/s00210-026-04999-2","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is difficult to treat, and gefitinib (GEF) monotherapy may offer limited therapeutic benefits. Combination or multimodal approaches are often required to achieve therapeutic efficacy in such cases. Betulin (BET), a naturally occurring triterpene, is used in combination with GEF to enhance therapeutic efficacy against HCC, but its clinical translation is not possible due to poor bioavailability and lack of targeted delivery. Therefore, we developed non-targeted and lactoferrin (Lf) grafted targeted liposomes of GEF (GEF-Lipo and GEF-Lf-Lipo) and BET (BET-Lipo and BET-Lf-Lipo) by the ethanol injection method and subsequently characterized them. The vesicular size of GEF-Lipo, GEF-Lf-Lipo, BET-Lipo, and BET-Lf-Lipo was found to be 119.5 ± 6.5, 159.1 ± 16.4, 140.7 ± 16.4, and 181.6 ± 4.8 nm, respectively. Polydispersity index (PDI) of GEF-Lipo, GEF-Lf-Lipo, BET-Lipo, and BET-Lf-Lipo was found to be 0.329 ± 0.1, 0.371 ± 0.05, 0.33 ± 0.14, and 0.399 ± 0.030, respectively. Encapsulation efficiencies (EE%) of GEF-Lipo, GEF-Lf-Lipo, BET-Lipo, and BET-Lf-Lipo were found to be 84.7 ± 1.22%, 90.08 ± 1.73%, 91.4 ± 2.63%, and 93.21 ± 1.88%, respectively. Furthermore, the in vivo study has been performed to assess the effectiveness of mixtures of GEF-BET, GEF-BET-Lipo, and asialoglycoprotein receptor (ASGPR) targeted GEF-BET-Lf-Lipo. Physiological parameters and HCC biomarker AFP were quantified. AFP levels were significantly increased in the cancer control versus normal control (p < 0.0001) and were significantly reduced by treatment with pristine drugs, non-targeted liposomes, and targeted liposomes (p < 0.0001), supporting the therapeutic effects of the formulations. Morphological changes in liver tissue were evaluated through histopathological examination and scanning electron microscopy (SEM). Western blotting and immunohistochemistry (IHC) showed that both GEF-BET-Lipo and GEF-BET-Lf-Lipo treatments significantly reduced pSTAT3 expression and increased the levels of the apoptotic marker caspase-3. Overall, the findings support the enhanced antitumor potential of GEF-BET-Lf-Lipo against HCC in animals.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Synthesis and integrative multimodal evaluation of cholic acid-based hydrazone conjugates: in vitro, in silico, and in vivo studies. 胆酸基腙缀合物的合成和综合多模态评价:体外、硅和体内研究。
IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2026-01-30 DOI: 10.1007/s00210-026-04991-w
Muhammad Hassan Butt, Kanwal Rehman, Shagufta Kamal, Muhammad Sajid Hamid Akash

Cholic acid-derived hydrazones represent a promising scaffold for multifunctional drug discovery. We synthesized and characterized two novel cholic acid-based hydrazone derivatives: DFBCH (2,4-difluorobenzylidene conjugate) and MEBCH (3-methoxybenzylidene conjugate) through various spectroscopic techniques, confirming the structural integrity of the synthesized compounds, followed by their comprehensive biological evaluation. In vitro screening showed a greater antibacterial zone of inhibition of MEBCH compound as compared to DFBCH against the tested strains. MEBCH demonstrated potent antioxidant activity (IC50 1.87 ± 0.20 mg/mL) relative to ascorbic acid (IC50 7.3 ± 1.40 mg/mL) by DPPH assay illustrating superior antioxidant activity. Both the compounds exhibited greater % inhibition against Hela cell line as compared to doxorubicin, suggesting greater inhibitory activity. MEBCH was the superior inhibitor of acetylcholinesterase (IC50 1.67 ± 0.61 µM), surpassing the standard donepezil (IC50 3.13 ± 0.1 µM), and demonstrated effective tyrosinase inhibition (IC50 1.87 ± 0.88 µM), comparable to kojic acid (IC50 2.38 ± 0.75 µM). Both of these compounds demonstrated effective β-glucosidase inhibition with an IC50 ≈ 2.23 µM, comparable to standard miglustat (IC50 2.02 ± 1.05 µM). Molecular docking (Glide) revealed MEBCH producing a favorable docking score with AChE (- 6.711; E-model - 57.480), indicating a stable predicted binding pose relative to DFBCH. BioTransformer 3.0 predicted CYP 450-mediated pathways for both analogues; docking of predicted metabolites showed retained or improved affinity (MEBCH metabolite to AChE - 6.3 kcal/mol) and lower RMSD bounds (AChE; lb/ub ≈ 5.8/6.2 Å; β-glucosidase lb/ub ≈ 5.25/5.73 Å). DFT calculations revealed small HOMO-LUMO gaps and solvent-sensitive dipole moments consistent with moderate chemical reactivity and solvent stabilization. Single-dose oral pharmacokinetics (10 mg/kg) in rats revealed MEBCH with higher Cmax, AUC, longer t1/2, and greater oral bioavailability than DFBCH. Collectively, these data nominate MEBCH as a lead cholic-hydrazone for further preclinical development against enzyme targets relevant to neurological and oxidative-stress pathways.

胆酸衍生的腙是一种很有前途的多功能药物开发支架。我们合成并表征了两个新的胆酸基腙衍生物:DFBCH(2,4-二氟苄基偶联物)和MEBCH(3-甲氧基苄基偶联物),通过各种光谱技术确认了合成化合物的结构完整性,并对其进行了综合生物学评价。体外筛选表明,MEBCH化合物对实验菌株的抑菌区比DFBCH大。DPPH实验显示,MEBCH对抗坏血酸(IC50为7.3±1.40 mg/mL)具有较强的抗氧化活性(IC50为1.87±0.20 mg/mL)。与阿霉素相比,这两种化合物对海拉细胞系的抑制作用更大,表明其抑制活性更强。MEBCH是较好的乙酰胆碱酯酶抑制剂(IC50为1.67±0.61µM),超过标准的多奈哌齐(IC50为3.13±0.1µM),对酪氨酸酶的抑制效果为1.87±0.88µM,与曲酸(IC50为2.38±0.75µM)相当。这两种化合物均表现出有效的β-葡萄糖苷酶抑制作用,IC50≈2.23µM,与标准的米卢司他(IC50为2.02±1.05µM)相当。分子对接(Glide)显示MEBCH与AChE的对接得分较好(- 6.711;E-model - 57.480),表明MEBCH相对于DFBCH具有稳定的预测结合姿态。BioTransformer 3.0预测了两种类似物的CYP 450介导通路;对接预测代谢物显示保留或改善的亲和力(MEBCH代谢物对AChE - 6.3 kcal/mol)和较低的RMSD边界(AChE; lb/ub≈5.8/6.2 Å; β-葡萄糖苷酶lb/ub≈5.25/5.73 Å)。DFT计算显示,HOMO-LUMO间隙小,偶极矩对溶剂敏感,具有中等的化学反应性和溶剂稳定性。大鼠单剂量口服药代动力学(10 mg/kg)表明,MEBCH比DFBCH具有更高的Cmax、AUC、更长的t1/2和更高的口服生物利用度。总的来说,这些数据表明MEBCH是一种先导的胆酰腙,可用于进一步的临床前开发,以对抗与神经和氧化应激途径相关的酶靶点。
{"title":"Synthesis and integrative multimodal evaluation of cholic acid-based hydrazone conjugates: in vitro, in silico, and in vivo studies.","authors":"Muhammad Hassan Butt, Kanwal Rehman, Shagufta Kamal, Muhammad Sajid Hamid Akash","doi":"10.1007/s00210-026-04991-w","DOIUrl":"https://doi.org/10.1007/s00210-026-04991-w","url":null,"abstract":"<p><p>Cholic acid-derived hydrazones represent a promising scaffold for multifunctional drug discovery. We synthesized and characterized two novel cholic acid-based hydrazone derivatives: DFBCH (2,4-difluorobenzylidene conjugate) and MEBCH (3-methoxybenzylidene conjugate) through various spectroscopic techniques, confirming the structural integrity of the synthesized compounds, followed by their comprehensive biological evaluation. In vitro screening showed a greater antibacterial zone of inhibition of MEBCH compound as compared to DFBCH against the tested strains. MEBCH demonstrated potent antioxidant activity (IC<sub>50</sub> 1.87 ± 0.20 mg/mL) relative to ascorbic acid (IC<sub>50</sub> 7.3 ± 1.40 mg/mL) by DPPH assay illustrating superior antioxidant activity. Both the compounds exhibited greater % inhibition against Hela cell line as compared to doxorubicin, suggesting greater inhibitory activity. MEBCH was the superior inhibitor of acetylcholinesterase (IC<sub>50</sub> 1.67 ± 0.61 µM), surpassing the standard donepezil (IC<sub>50</sub> 3.13 ± 0.1 µM), and demonstrated effective tyrosinase inhibition (IC<sub>50</sub> 1.87 ± 0.88 µM), comparable to kojic acid (IC<sub>50</sub> 2.38 ± 0.75 µM). Both of these compounds demonstrated effective β-glucosidase inhibition with an IC<sub>50</sub> ≈ 2.23 µM, comparable to standard miglustat (IC<sub>50</sub> 2.02 ± 1.05 µM). Molecular docking (Glide) revealed MEBCH producing a favorable docking score with AChE (- 6.711; E-model - 57.480), indicating a stable predicted binding pose relative to DFBCH. BioTransformer 3.0 predicted CYP 450-mediated pathways for both analogues; docking of predicted metabolites showed retained or improved affinity (MEBCH metabolite to AChE - 6.3 kcal/mol) and lower RMSD bounds (AChE; lb/ub ≈ 5.8/6.2 Å; β-glucosidase lb/ub ≈ 5.25/5.73 Å). DFT calculations revealed small HOMO-LUMO gaps and solvent-sensitive dipole moments consistent with moderate chemical reactivity and solvent stabilization. Single-dose oral pharmacokinetics (10 mg/kg) in rats revealed MEBCH with higher C<sub>max</sub>, AUC, longer t<sub>1/2</sub>, and greater oral bioavailability than DFBCH. Collectively, these data nominate MEBCH as a lead cholic-hydrazone for further preclinical development against enzyme targets relevant to neurological and oxidative-stress pathways.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
期刊
Naunyn-Schmiedeberg's archives of pharmacology
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1