Pub Date : 2024-10-30DOI: 10.1016/j.ejphar.2024.177076
Giorgio Guglielmi , Claudio Zamagni , Marzia Del Re , Romano Danesi , Stefano Fogli
Understanding the capability of a drug to penetrate the blood-brain barrier (BBB) is an unmet medical need in patients with positive human epidermal growth factor receptor 2 (HER2 positive) and brain metastases. The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib in co-administration with monoclonal antibodies or chemotherapy drugs and the antibody-drug conjugates (ADCs) trastuzumab-deruxtecan and trastuzumab-emtansine. Predicting the BBB permeability of these therapeutic agents is a pharmacological challenge due to the various factors involved in the barrier functions. In this review article, we discuss about the molecular and cellular features of the barriers located in the central nervous system and the pharmacological parameters found to be important in predicting BBB permeability in human normal brain, and in the presence of brain metastases. Finally, we reported the clinical outcomes and intracranial response of patients with HER2-positive breast cancer with brain metastases treated with targeted TKIs and ADCs.
{"title":"Targeting HER2 in breast cancer with brain metastases: A pharmacological point of view with special focus on the permeability of blood-brain barrier to targeted treatments","authors":"Giorgio Guglielmi , Claudio Zamagni , Marzia Del Re , Romano Danesi , Stefano Fogli","doi":"10.1016/j.ejphar.2024.177076","DOIUrl":"10.1016/j.ejphar.2024.177076","url":null,"abstract":"<div><div>Understanding the capability of a drug to penetrate the blood-brain barrier (BBB) is an unmet medical need in patients with positive human epidermal growth factor receptor 2 (HER2 positive) and brain metastases. The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib in co-administration with monoclonal antibodies or chemotherapy drugs and the antibody-drug conjugates (ADCs) trastuzumab-deruxtecan and trastuzumab-emtansine. Predicting the BBB permeability of these therapeutic agents is a pharmacological challenge due to the various factors involved in the barrier functions. In this review article, we discuss about the molecular and cellular features of the barriers located in the central nervous system and the pharmacological parameters found to be important in predicting BBB permeability in human normal brain, and in the presence of brain metastases. Finally, we reported the clinical outcomes and intracranial response of patients with HER2-positive breast cancer with brain metastases treated with targeted TKIs and ADCs.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177076"},"PeriodicalIF":4.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1016/j.ejphar.2024.177074
Sijia Jiang , Xiaoxu Fan , Jian Hua , Shuangqiao Liu , Yingtong Feng , Danyue Shao , Yiwei Shen , Zhen Wang , Xuehua Yan , Jingxia Wang
Introduction
The rising prevalence and severe consequences of nonalcoholic fatty liver disease (NAFLD) have driven the quest for preventive medications. Complanatoside A (CA) is the marked flavonoid of Astragali complanati semen, a traditional Chinese herb that acts on the liver meridian and is widely used to treat liver problems. CA has been proven to have considerable lipid-lowering and liver-protective effects in vitro. However, the efficacy of CA in preventing NAFLD has yet to be shown in vivo.
Methods
First, the effectiveness of CA against NAFLD was assessed using a high-fat diet (HFD) mouse model. Second, the CA protective mechanism against NAFLD was investigated using a combined metabolomics and network pharmacology strategy. Differential metabolites were identified by metabolomics-based analyses, and metabolic pathway analysis was accomplished by MetaboAnalyst. Potential therapeutic targets were obtained through network pharmacology. Finally, key targets were identified via compound–target networks and validated by molecular docking and western blotting.
Results
CA prevented NAFLD mainly by reducing liver lipid accumulation in HFD mice. Metabolomics identified 22 potential biomarkers for CA treatment of NAFLD, primarily involving glycerophospholipid and arachidonic acid metabolism. Fifty-one potential targets were determined by network pharmacology. Co-analysis revealed that albumin, peroxisome proliferator-activated receptor-alpha, retinoid X receptor alpha, interleukin-6, and tumor necrosis factor alpha were key targets.
Conclusion
This experiment revealed that CA has a preventive effect on NAFLD, primarily by regulating the peroxisome proliferator-activated receptor-alpha/retinoid X receptor alpha pathway. Furthermore, it provides evidence supporting the potential use of CA in the long-term prevention of NAFLD.
导言：非酒精性脂肪肝（NAFLD）发病率的上升和严重后果促使人们寻求预防性药物。蟾酥苷 A（CA）是黄芪精液中的显著黄酮类化合物，是一种作用于肝经的传统中草药，被广泛用于治疗肝脏疾病。CA 在体外已被证明具有相当的降脂和保肝作用。然而，CA在预防非酒精性脂肪肝方面的功效尚未在体内得到证实：方法：首先，使用高脂饮食（HFD）小鼠模型评估CA对非酒精性脂肪肝的疗效。方法：首先，利用高脂饮食（HFD）小鼠模型评估CA对非酒精性脂肪肝的有效性；其次，采用代谢组学和网络药理学相结合的策略研究CA对非酒精性脂肪肝的保护机制。代谢组学分析确定了差异代谢物，代谢通路分析由 MetaboAnalyst 完成。通过网络药理学获得了潜在的治疗靶点。最后，通过化合物-靶点网络确定了关键靶点，并通过分子对接和免疫印迹进行了验证：结果：CA主要通过减少高脂血症小鼠的肝脏脂质积累来预防非酒精性脂肪肝。代谢组学确定了 22 个 CA 治疗非酒精性脂肪肝的潜在生物标志物，主要涉及甘油磷脂和花生四烯酸代谢。网络药理学确定了51个潜在靶点。共同分析显示，白蛋白、过氧化物酶体增殖激活受体α、视黄醇X受体α、白细胞介素-6和肿瘤坏死因子α是关键靶点：本实验揭示了 CA 主要通过调节过氧化物酶体增殖激活受体-α/视黄醇 X 受体α途径对非酒精性脂肪肝具有预防作用。此外，该实验还为 CA 在长期预防非酒精性脂肪肝方面的潜在应用提供了证据支持。
{"title":"Integrated metabolomics and network pharmacology analysis to reveal the protective effect of Complanatoside A on nonalcoholic fatty liver disease","authors":"Sijia Jiang , Xiaoxu Fan , Jian Hua , Shuangqiao Liu , Yingtong Feng , Danyue Shao , Yiwei Shen , Zhen Wang , Xuehua Yan , Jingxia Wang","doi":"10.1016/j.ejphar.2024.177074","DOIUrl":"10.1016/j.ejphar.2024.177074","url":null,"abstract":"<div><h3>Introduction</h3><div>The rising prevalence and severe consequences of nonalcoholic fatty liver disease (NAFLD) have driven the quest for preventive medications. Complanatoside A (CA) is the marked flavonoid of Astragali complanati semen, a traditional Chinese herb that acts on the liver meridian and is widely used to treat liver problems. CA has been proven to have considerable lipid-lowering and liver-protective effects in vitro. However, the efficacy of CA in preventing NAFLD has yet to be shown in vivo.</div></div><div><h3>Methods</h3><div>First, the effectiveness of CA against NAFLD was assessed using a high-fat diet (HFD) mouse model. Second, the CA protective mechanism against NAFLD was investigated using a combined metabolomics and network pharmacology strategy. Differential metabolites were identified by metabolomics-based analyses, and metabolic pathway analysis was accomplished by MetaboAnalyst. Potential therapeutic targets were obtained through network pharmacology. Finally, key targets were identified via compound–target networks and validated by molecular docking and western blotting.</div></div><div><h3>Results</h3><div>CA prevented NAFLD mainly by reducing liver lipid accumulation in HFD mice. Metabolomics identified 22 potential biomarkers for CA treatment of NAFLD, primarily involving glycerophospholipid and arachidonic acid metabolism. Fifty-one potential targets were determined by network pharmacology. Co-analysis revealed that albumin, peroxisome proliferator-activated receptor-alpha, retinoid X receptor alpha, interleukin-6, and tumor necrosis factor alpha were key targets.</div></div><div><h3>Conclusion</h3><div>This experiment revealed that CA has a preventive effect on NAFLD, primarily by regulating the peroxisome proliferator-activated receptor-alpha/retinoid X receptor alpha pathway. <span>Furthermore</span>, it provides evidence supporting the potential use of <span>CA</span> in the long-term prevention of NAFLD.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177074"},"PeriodicalIF":4.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1016/j.ejphar.2024.177083
Japneet Singh Purewal, Gaurav Mahesh Doshi
Psoriasis (Pso) is an autoimmune inflammatory skin disease characterised by well-demarcated, red plaques covered in silver scales. It affects people of all ages and can be passed down through generations. Genetics play an important role in determining vulnerability to develop Pso. Several large-scale genome-wide association studies have identified over 80 genetic loci associated with Pso susceptibility. Gene expression can be regulated via RNA interference (RNAi). RNAi suppresses gene expression by degrading mRNA molecules. Since its discovery, RNAi has generated considerable excitement over its potential therapeutic benefits. RNAi is mediated by endogenous small RNA molecules like microRNA (miRNA) or exogenous small RNA molecules like small interfering RNA (siRNA), short hairpin RNA (shRNA), and artificial micro RNA (amiRNA). These small RNA molecules can silence a disease-related gene in a sequence-specific manner. Targeting RNAi pathways can help modify disease-related biological processes in various medical conditions, including autoimmune disorders. In Pso, RNAi can downregulate the expression of molecules involved in the pathophysiology of the disease. Significant progress has been made in the field of RNAi therapeutics. However, further research is needed to fine-tune the design and delivery of RNAi therapeutics in humans. In this review, we discuss various effectors of RNAi, some challenges related to RNAi therapeutics (emphasizing siRNA) and strategies to overcome these challenges. Furthermore, we have discussed some studies that employ RNAi therapeutics for Pso.
{"title":"RNAi in psoriasis: A melodic exploration of miRNA, shRNA, and amiRNA with a spotlight on siRNA","authors":"Japneet Singh Purewal, Gaurav Mahesh Doshi","doi":"10.1016/j.ejphar.2024.177083","DOIUrl":"10.1016/j.ejphar.2024.177083","url":null,"abstract":"<div><div>Psoriasis (Pso) is an autoimmune inflammatory skin disease characterised by well-demarcated, red plaques covered in silver scales. It affects people of all ages and can be passed down through generations. Genetics play an important role in determining vulnerability to develop Pso. Several large-scale genome-wide association studies have identified over 80 genetic loci associated with Pso susceptibility. Gene expression can be regulated via RNA interference (RNAi). RNAi suppresses gene expression by degrading mRNA molecules. Since its discovery, RNAi has generated considerable excitement over its potential therapeutic benefits. RNAi is mediated by endogenous small RNA molecules like microRNA (miRNA) or exogenous small RNA molecules like small interfering RNA (siRNA), short hairpin RNA (shRNA), and artificial micro RNA (amiRNA). These small RNA molecules can silence a disease-related gene in a sequence-specific manner. Targeting RNAi pathways can help modify disease-related biological processes in various medical conditions, including autoimmune disorders. In Pso, RNAi can downregulate the expression of molecules involved in the pathophysiology of the disease. Significant progress has been made in the field of RNAi therapeutics. However, further research is needed to fine-tune the design and delivery of RNAi therapeutics in humans. In this review, we discuss various effectors of RNAi, some challenges related to RNAi therapeutics (emphasizing siRNA) and strategies to overcome these challenges. Furthermore, we have discussed some studies that employ RNAi therapeutics for Pso.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177083"},"PeriodicalIF":4.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1016/j.ejphar.2024.177082
Shao-hua Ren , Bo Shao , Hong-da Wang , Jing-yi Zhang , Hong Qin , Cheng-lu Sun , Yang-lin Zhu , Zhao-bo Wang , Xu Lan , Yong-chang Gao , Hao Wang
Background
Chronic rejection (CR) is a significant obstacle to long-term allograft survival. Oxymatrine (OMT) is a prominent bioactive compound widely utilized in traditional Chinese medicine for the management of inflammatory disorders and it has considerable potential as a therapeutic candidate for the treatment of CR.
Methods
Well-established major histocompatibility complex (MHC) class II mismatched B6 mice. C-H-2bm12-to-C57BL/6 mouse transplantation was used as a CR model. Hematoxylin and eosin (H&E) staining, immunohistochemistry, and Masson's trichrome staining were used to assess pathological changes in the grafts, and the percentages of immune cells were determined by flow cytometry. The effects of OMT on the regulation of CD4+ T cell differentiation and cytokine secretion were verified in vitro.
Results
OMT effectively alleviated pathological graft damage, characterized by chronic changes in intimal lesions, vasculopathy, and fibrosis and significantly prolonged cardiac allograft survival. OMT exerted its immunomodulatory effects by inhibiting T helper 1 (Th1) and T helper 17 (Th17) cell differentiation while promoting Treg differentiation both in vivo and in vitro. Further studies revealed that OMT inhibited the phosphorylation of mammalian target of rapamycin (mTOR), which is a potential mechanism underlying its immunosuppressive effects. OMT also inhibited the activation of B cells and the production of donor-specific antibody (DSA). In addition, OMT effectively alleviated chronic changes in fibrosis in cardiac allografts, and these changes may be related to the inhibition of the transforming growth factor-β (TGF-β)-Smad 2/3 pathway.
Conclusions
OMT attenuated CR by modulating the immune response and inhibiting graft fibrosis. Further in-depth investigations of OMT may provide valuable insights into the development of novel therapeutic strategies for CR inhibition.
背景：慢性排斥反应（CR）是异体移植长期存活的一大障碍。氧化苦参碱（OMT）是一种突出的生物活性化合物，在传统中药中被广泛用于治疗炎症性疾病，作为治疗慢性排斥反应的候选药物具有相当大的潜力：方法：采用成熟的主要组织相容性复合体（MHC）II类错配B6小鼠。C-H-2bm12到C57BL/6小鼠移植被用作CR模型。采用苏木精和伊红（H&E）染色、免疫组化和马森三色染色评估移植物的病理变化，并通过流式细胞术测定免疫细胞的百分比。在体外验证了 OMT 对 CD4+ T 细胞分化和细胞因子分泌的调节作用：结果：OMT有效缓解了以内膜病变、血管病变和纤维化的慢性变化为特征的病理移植物损伤，并显著延长了心脏异体移植的存活时间。OMT通过抑制T辅助细胞1（Th1）和T辅助细胞17（Th17）的分化，同时促进体内和体外Treg的分化来发挥其免疫调节作用。进一步的研究发现，OMT 可抑制哺乳动物雷帕霉素靶标（mTOR）的磷酸化，这是其免疫抑制作用的潜在机制。OMT 还能抑制 B 细胞的活化和供体特异性抗体（DSA）的产生。此外，OMT还有效缓解了心脏异体移植物纤维化的慢性变化，这些变化可能与抑制转化生长因子-β（TGF-β）-Smad 2/3通路有关：结论：OMT通过调节免疫反应和抑制移植物纤维化来减轻CR。进一步深入研究 OMT 可为开发抑制 CR 的新型治疗策略提供有价值的见解。
{"title":"Oxymatrine attenuates chronic allograft rejection by modulating immune responses and inhibiting fibrosis","authors":"Shao-hua Ren , Bo Shao , Hong-da Wang , Jing-yi Zhang , Hong Qin , Cheng-lu Sun , Yang-lin Zhu , Zhao-bo Wang , Xu Lan , Yong-chang Gao , Hao Wang","doi":"10.1016/j.ejphar.2024.177082","DOIUrl":"10.1016/j.ejphar.2024.177082","url":null,"abstract":"<div><h3>Background</h3><div>Chronic rejection (CR) is a significant obstacle to long-term allograft survival. Oxymatrine (OMT) is a prominent bioactive compound widely utilized in traditional Chinese medicine for the management of inflammatory disorders and it has considerable potential as a therapeutic candidate for the treatment of CR.</div></div><div><h3>Methods</h3><div>Well-established major histocompatibility complex (MHC) class II mismatched B6 mice. C-H-2<sup>bm12</sup>-to-C57BL/6 mouse transplantation was used as a CR model. Hematoxylin and eosin (H&E) staining, immunohistochemistry, and Masson's trichrome staining were used to assess pathological changes in the grafts, and the percentages of immune cells were determined by flow cytometry. The effects of OMT on the regulation of CD4<sup>+</sup> T cell differentiation and cytokine secretion were verified <em>in vitro</em>.</div></div><div><h3>Results</h3><div>OMT effectively alleviated pathological graft damage, characterized by chronic changes in intimal lesions, vasculopathy, and fibrosis and significantly prolonged cardiac allograft survival. OMT exerted its immunomodulatory effects by inhibiting T helper 1 (Th1) and T helper 17 (Th17) cell differentiation while promoting Treg differentiation both <em>in vivo</em> and <em>in vitro.</em> Further studies revealed that OMT inhibited the phosphorylation of mammalian target of rapamycin (mTOR), which is a potential mechanism underlying its immunosuppressive effects. OMT also inhibited the activation of B cells and the production of donor-specific antibody (DSA). In addition, OMT effectively alleviated chronic changes in fibrosis in cardiac allografts, and these changes may be related to the inhibition of the transforming growth factor-β (TGF-β)-Smad 2/3 pathway.</div></div><div><h3>Conclusions</h3><div>OMT attenuated CR by modulating the immune response and inhibiting graft fibrosis. Further in-depth investigations of OMT may provide valuable insights into the development of novel therapeutic strategies for CR inhibition.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177082"},"PeriodicalIF":4.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1016/j.ejphar.2024.177086
Minghua Hong , Juan Guo , Youshan Zhao, Luxi Song, Sida Zhao, Roujia Wang, Lei Shi, Zheng Zhang, Dong Wu, Qi He, Chunkang Chang
In low-risk myelodysplastic syndromes (MDS), the proinflammatory signaling is excessive, and the proliferation and differentiation potentials of mesenchymal stromal cells (MSCs) are strongly impaired. Eltrombopag (ELT) has been demonstrated recently effective and relatively safe in low-risk MDS with severe thrombocytopenia. However, its impact on the MDS-MSCs has not been investigated in any detail. Here, for the first time, we investigated the changes induced by ELT in MSCs’ viability, proliferation, apoptosis, senescence, multilineage differentiation properties, and stem cell support capacity in low-risk MDS patients. We demonstrated that ELT may act on improving the impaired inflammatory profile and reactivating the downregulated canonical WNT signaling pathway in low-risk MDS, and also restoring the self-renewal capacity and the balance in adipose-osteogenic differentiation of MDS-MSCs.
{"title":"Eltrombopag restores proliferative capacity and adipose-osteogenic balance of mesenchymal stromal cells in low-risk myelodysplastic syndromes","authors":"Minghua Hong , Juan Guo , Youshan Zhao, Luxi Song, Sida Zhao, Roujia Wang, Lei Shi, Zheng Zhang, Dong Wu, Qi He, Chunkang Chang","doi":"10.1016/j.ejphar.2024.177086","DOIUrl":"10.1016/j.ejphar.2024.177086","url":null,"abstract":"<div><div>In low-risk myelodysplastic syndromes (MDS), the proinflammatory signaling is excessive, and the proliferation and differentiation potentials of mesenchymal stromal cells (MSCs) are strongly impaired. Eltrombopag (ELT) has been demonstrated recently effective and relatively safe in low-risk MDS with severe thrombocytopenia. However, its impact on the MDS-MSCs has not been investigated in any detail. Here, for the first time, we investigated the changes induced by ELT in MSCs’ viability, proliferation, apoptosis, senescence, multilineage differentiation properties, and stem cell support capacity in low-risk MDS patients. We demonstrated that ELT may act on improving the impaired inflammatory profile and reactivating the downregulated canonical WNT signaling pathway in low-risk MDS, and also restoring the self-renewal capacity and the balance in adipose-osteogenic differentiation of MDS-MSCs.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177086"},"PeriodicalIF":4.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.ejphar.2024.177073
Luis García-García , Francisca Gómez-Oliver , Rubén Fernández de la Rosa , Miguel Ángel Pozo
Status epilepticus (SE) is a neurologic emergency characterized by prolonged or rapidly recurring seizures. Increased intracellular calcium concentration ([Ca2+]i) occurring after SE is a key mediator of excitotoxicity that contributes to the brain damage associated with the development of epilepsy. Accumulated evidence indicates that dantrolene, a ryanodine receptor (RyR) blocker may have protective effects against the SE-induced damage. We evaluated whether dantrolene (10 mg/kg, i.p.) administered twice, 5 min and 24 h after the lithium-pilocarpine-induced SE in rats, had neuroprotective effects. Dantrolene by itself had no effects on control rats. However, it exacerbated the signs of damage in rats that underwent SE, increasing brain glucose hypometabolism as measured by PET neuroimaging 3 days after SE. Likewise, the neurohistochemical studies revealed that dantrolene aggravated signs of hippocampal neurodegeneration, neuronal death and microglia-induced neuroinflammation. Besides, the damaging effects were reflected by severe body weight loss. Overall, our results point towards a deleterious effect of dantrolene in the lithium-pilocarpine-induced SE model. Nonetheless, our results are in opposition to the reported neuroprotective effects of dantrolene. Whether the mechanisms underlying [Ca2+]i increase might significantly differ depending on the particularities of the model of epilepsy used and general experimental conditions need further studies. Besides, it is yet to be determined which isoform of RyRs significantly contributes to Ca2+-induced excitotoxicity in the lithium-pilocarpine SE rat model.
癫痫状态（SE）是一种神经系统急症，其特点是癫痫发作持续时间长或快速复发。癫痫状态发作后细胞内钙浓度（[Ca2+]i）升高，是兴奋性毒性的一个关键介质，导致与癫痫发展相关的脑损伤。累积的证据表明，雷诺丁受体（RyR）阻断剂丹曲林可能对 SE 诱导的损伤具有保护作用。我们评估了在锂-匹洛卡品诱导的大鼠 SE 后 5 分钟和 24 小时两次注射丹曲林（10 毫克/千克，静脉注射）是否具有神经保护作用。丹曲林本身对对照组大鼠没有影响。然而，丹曲林会加重 SE 大鼠的损伤症状，SE 大鼠 3 天后的 PET 神经影像学测量显示，丹曲林会增加脑葡萄糖低代谢。同样，神经组织化学研究显示，丹曲林加重了海马神经变性、神经元死亡和小胶质细胞诱导的神经炎症。此外，体重严重下降也反映了这种破坏性影响。总之，我们的研究结果表明，丹曲林在锂-匹罗卡品诱导的 SE 模型中具有有害作用。然而，我们的结果与所报道的丹曲林的神经保护作用相反。至于[Ca2+]i增加的机制是否会因所用癫痫模型的特殊性和一般实验条件的不同而有显著差异，还需要进一步研究。此外，在锂-匹洛卡品 SE 大鼠模型中，RyRs 的哪种同工酶形式对 Ca2+ 诱导的兴奋毒性有重要作用还有待确定。
{"title":"Dantrolene paradoxically exacerbates short-term brain glucose hypometabolism, hippocampal damage and neuroinflammation induced by status epilepticus in the rat lithium-pilocarpine model","authors":"Luis García-García , Francisca Gómez-Oliver , Rubén Fernández de la Rosa , Miguel Ángel Pozo","doi":"10.1016/j.ejphar.2024.177073","DOIUrl":"10.1016/j.ejphar.2024.177073","url":null,"abstract":"<div><div>Status epilepticus (SE) is a neurologic emergency characterized by prolonged or rapidly recurring seizures. Increased intracellular calcium concentration ([Ca<sup>2+</sup>]<sub>i</sub>) occurring after SE is a key mediator of excitotoxicity that contributes to the brain damage associated with the development of epilepsy. Accumulated evidence indicates that dantrolene, a ryanodine receptor (RyR) blocker may have protective effects against the SE-induced damage. We evaluated whether dantrolene (10 mg/kg, i.p.) administered twice, 5 min and 24 h after the lithium-pilocarpine-induced SE in rats, had neuroprotective effects. Dantrolene by itself had no effects on control rats. However, it exacerbated the signs of damage in rats that underwent SE, increasing brain glucose hypometabolism as measured by PET neuroimaging 3 days after SE. Likewise, the neurohistochemical studies revealed that dantrolene aggravated signs of hippocampal neurodegeneration, neuronal death and microglia-induced neuroinflammation. Besides, the damaging effects were reflected by severe body weight loss. Overall, our results point towards a deleterious effect of dantrolene in the lithium-pilocarpine-induced SE model. Nonetheless, our results are in opposition to the reported neuroprotective effects of dantrolene. Whether the mechanisms underlying [Ca<sup>2+</sup>]<sub>i</sub> increase might significantly differ depending on the particularities of the model of epilepsy used and general experimental conditions need further studies. Besides, it is yet to be determined which isoform of RyRs significantly contributes to Ca<sup>2+</sup>-induced excitotoxicity in the lithium-pilocarpine SE rat model.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177073"},"PeriodicalIF":4.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.ejphar.2024.177081
Chenlin Feng , Rongfang Liu , Reno Brooks , Xuesong Wang , Willem Jespers , Marina Gorostiola González , Gerard J.P. van Westen , Erik H.J. Danen , Laura H. Heitman
The serotonin 5-HT2C receptor is a G protein-coupled receptor (GPCR) mainly expressed in the central nervous system. Besides regulating mood, appetite, and reproductive behavior, it has been identified as a potential target for cancer treatment. In this study, we aimed to investigate the effects of cancer patient-derived 5-HT2C receptor mutations on ligand binding and receptor functionality. By filtering the sequencing data from the Genomic Data Commons data portal (GDC), we selected 12 mutations from multiple cancer types. We found that the affinity of the endogenous agonist serotonin (5-HT) and inverse agonist mesulergine were both drastically decreased by mutations L209HECL2 and F328S6.52, which are located in the orthosteric binding pocket. In the calcium-flux assay, the potency of 5-HT was decreased at F328S6.52, while a trend of increased efficacy was observed. In contrast, 5-HT displayed higher affinity at E306K6.30 and E306A6.30, while a trend of decreased efficacy was observed. These two mutations may disrupt the conserved ionic interaction between E6.30 and R3.50, and thus increase the constitutive activity of the receptor. The inhibitory potency of mesulergine was increased at E306A6.30 but not E306K6.30. Lastly, P365H7.50 decreased the expression level of the receptor by more than ten-fold, which prevented further functional analyses. This study shows that cancer-associated mutations of 5-HT2C receptor have diverse effects on ligand binding and function. Such mutations may affect serotonin-mediated signaling in tumor cells as well as treatment strategies targeting this receptor.
{"title":"The effect of cancer-associated mutations on ligand binding and receptor function – A case for the 5-HT2C receptor","authors":"Chenlin Feng , Rongfang Liu , Reno Brooks , Xuesong Wang , Willem Jespers , Marina Gorostiola González , Gerard J.P. van Westen , Erik H.J. Danen , Laura H. Heitman","doi":"10.1016/j.ejphar.2024.177081","DOIUrl":"10.1016/j.ejphar.2024.177081","url":null,"abstract":"<div><div>The serotonin 5-HT<sub>2C</sub> receptor is a G protein-coupled receptor (GPCR) mainly expressed in the central nervous system. Besides regulating mood, appetite, and reproductive behavior, it has been identified as a potential target for cancer treatment. In this study, we aimed to investigate the effects of cancer patient-derived 5-HT<sub>2C</sub> receptor mutations on ligand binding and receptor functionality. By filtering the sequencing data from the Genomic Data Commons data portal (GDC), we selected 12 mutations from multiple cancer types. We found that the affinity of the endogenous agonist serotonin (5-HT) and inverse agonist mesulergine were both drastically decreased by mutations L209H<sup>ECL2</sup> and F328S<sup>6.52</sup>, which are located in the orthosteric binding pocket. In the calcium-flux assay, the potency of 5-HT was decreased at F328S<sup>6.52</sup>, while a trend of increased efficacy was observed. In contrast, 5-HT displayed higher affinity at E306K<sup>6.30</sup> and E306A<sup>6.30</sup>, while a trend of decreased efficacy was observed. These two mutations may disrupt the conserved ionic interaction between E<sup>6.30</sup> and R<sup>3.50</sup>, and thus increase the constitutive activity of the receptor. The inhibitory potency of mesulergine was increased at E306A<sup>6.30</sup> but not E306K<sup>6.30</sup>. Lastly, P365H<sup>7.50</sup> decreased the expression level of the receptor by more than ten-fold, which prevented further functional analyses. This study shows that cancer-associated mutations of 5-HT<sub>2C</sub> receptor have diverse effects on ligand binding and function. Such mutations may affect serotonin-mediated signaling in tumor cells as well as treatment strategies targeting this receptor.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177081"},"PeriodicalIF":4.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1016/j.ejphar.2024.177067
Pedram Asadi Sarabi , Mahshid Shabanpouremam , Amir Reza Eghtedari , Mahsa Barat , Behzad Moshiri , Ali Zarrabi , Massoud Vosough
The emergence of Artificial Intelligence (AI) and its usage in regenerative medicine represents a significant opportunity that holds the promise of tackling critical challenges and improving therapeutic outcomes. This article examines the ways in which AI, including machine learning and data fusion techniques, can contribute to regenerative medicine, particularly in gene therapy, stem cell therapy, and tissue engineering. In gene therapy, AI tools can boost the accuracy and safety of treatments by analyzing extensive genomic datasets to target and modify genetic material in a precise manner. In cell therapy, AI improves the characterization and optimization of cell products like mesenchymal stem cells (MSCs) by predicting their function and potency. Additionally, AI enhances advanced microscopy techniques, enabling accurate, non-invasive and quantitative analyses of live cell cultures. AI enhances tissue engineering by optimizing biomaterial and scaffold designs, predicting interactions with tissues, and streamlining development. This leads to faster and more cost-effective innovations by decreasing trial and error. The convergence of AI and regenerative medicine holds great transformative potential, promising effective treatments and innovative therapeutic strategies. This review highlights the importance of interdisciplinary collaboration and the continued integration of AI-based technologies, such as data fusion methods, to overcome current challenges and advance regenerative medicine.
{"title":"AI-Based solutions for current challenges in regenerative medicine","authors":"Pedram Asadi Sarabi , Mahshid Shabanpouremam , Amir Reza Eghtedari , Mahsa Barat , Behzad Moshiri , Ali Zarrabi , Massoud Vosough","doi":"10.1016/j.ejphar.2024.177067","DOIUrl":"10.1016/j.ejphar.2024.177067","url":null,"abstract":"<div><div>The emergence of Artificial Intelligence (AI) and its usage in regenerative medicine represents a significant opportunity that holds the promise of tackling critical challenges and improving therapeutic outcomes. This article examines the ways in which AI, including machine learning and data fusion techniques, can contribute to regenerative medicine, particularly in gene therapy, stem cell therapy, and tissue engineering. In gene therapy, AI tools can boost the accuracy and safety of treatments by analyzing extensive genomic datasets to target and modify genetic material in a precise manner. In cell therapy, AI improves the characterization and optimization of cell products like mesenchymal stem cells (MSCs) by predicting their function and potency. Additionally, AI enhances advanced microscopy techniques, enabling accurate, non-invasive and quantitative analyses of live cell cultures. AI enhances tissue engineering by optimizing biomaterial and scaffold designs, predicting interactions with tissues, and streamlining development. This leads to faster and more cost-effective innovations by decreasing trial and error. The convergence of AI and regenerative medicine holds great transformative potential, promising effective treatments and innovative therapeutic strategies. This review highlights the importance of interdisciplinary collaboration and the continued integration of AI-based technologies, such as data fusion methods, to overcome current challenges and advance regenerative medicine.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177067"},"PeriodicalIF":4.2,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-22DOI: 10.1016/j.ejphar.2024.177071
Iury A. Paz , Pedro M. Silva Filho , Alexandre S. Leitão Junior , Tatiana Oliveira Pessoa , Renata O. Santiago , Nádia Osório de Oliveira , Elisane Longhinotti , Eduardo H.S. Sousa , Luiz G.F. Lopes , Claudia F. Santos , Manassés C. Fonteles , Nilberto R.F. Nascimento
The failure of achieving a penile erection for satisfactory sexual intercourse is known as erectile dysfunction (ED). The primary mediator for penile erection is nitric oxide (NO). ED is often associated with endothelial/nitrergic dysfunction characterized by a reduction of the bioavailability of NO. Phosphodiesterase-5 inhibitors (PDE-5Is) clinical efficacy in the treatment of ED depends on the integrity of the NO-sGC-PKG pathway. In the present study, we probed the effect of sodium nitroprusside incorporated into mesoporous silica nanoparticles (MPSi-NP), which traps cyanide and slowly releases NO. MPSi-NP induced a maximal relaxation of 92.8 ± 5.2% in rabbit corpora cavernosa (RbCC), blunted by a soluble guanylate cyclase (sGC) inhibitor and blockers of calcium-dependent potassium channels. MPSi-NP abolished spontaneous contractions of human corpora cavernosa (HCC) strips. In addition, MPSi-NP induced maximal relaxation of phenylephrine precontracted HCC by 118.6 ± 3.6%, and in comparison, tadalafil induced a maximal relaxation of HCC by 98.3 ± 1.2%. Similarly, the sGC inhibitor blocked the MPSi-NP relaxation. MPSi-NP potentiated the relaxation induced by tadalafil. MPSi-NP increased cGMP levels in HCC strips by 2.6-fold and increased by 3.5-fold the phosphorylation level of the VASP protein, which is a downstream target to PKG. MPSi-NP effectively relaxes RbCC and HCC by activating the sGC-PKG pathway and potentiates the tadalafil response. MPSi-NP could be helpful in conditions where nitric oxide availability is decreased. A topical gel formulation of MPSi-NP could be used as a rescue therapy to treat true non-responders of PDE5Is drugs.
{"title":"Pharmacological evaluation of a new nanoformulation in the erectile tissue of rabbits and humans","authors":"Iury A. Paz , Pedro M. Silva Filho , Alexandre S. Leitão Junior , Tatiana Oliveira Pessoa , Renata O. Santiago , Nádia Osório de Oliveira , Elisane Longhinotti , Eduardo H.S. Sousa , Luiz G.F. Lopes , Claudia F. Santos , Manassés C. Fonteles , Nilberto R.F. Nascimento","doi":"10.1016/j.ejphar.2024.177071","DOIUrl":"10.1016/j.ejphar.2024.177071","url":null,"abstract":"<div><div>The failure of achieving a penile erection for satisfactory sexual intercourse is known as erectile dysfunction (ED). The primary mediator for penile erection is nitric oxide (NO). ED is often associated with endothelial/nitrergic dysfunction characterized by a reduction of the bioavailability of NO. Phosphodiesterase-5 inhibitors (PDE-5Is) clinical efficacy in the treatment of ED depends on the integrity of the NO-sGC-PKG pathway. In the present study, we probed the effect of sodium nitroprusside incorporated into mesoporous silica nanoparticles (MPSi-NP), which traps cyanide and slowly releases NO. MPSi-NP induced a maximal relaxation of 92.8 ± 5.2% in rabbit corpora cavernosa (RbCC), blunted by a soluble guanylate cyclase (sGC) inhibitor and blockers of calcium-dependent potassium channels. MPSi-NP abolished spontaneous contractions of human corpora cavernosa (HCC) strips. In addition, MPSi-NP induced maximal relaxation of phenylephrine precontracted HCC by 118.6 ± 3.6%, and in comparison, tadalafil induced a maximal relaxation of HCC by 98.3 ± 1.2%. Similarly, the sGC inhibitor blocked the MPSi-NP relaxation. MPSi-NP potentiated the relaxation induced by tadalafil. MPSi-NP increased cGMP levels in HCC strips by 2.6-fold and increased by 3.5-fold the phosphorylation level of the VASP protein, which is a downstream target to PKG. MPSi-NP effectively relaxes RbCC and HCC by activating the sGC-PKG pathway and potentiates the tadalafil response. MPSi-NP could be helpful in conditions where nitric oxide availability is decreased. A topical gel formulation of MPSi-NP could be used as a rescue therapy to treat true non-responders of PDE5Is drugs.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177071"},"PeriodicalIF":4.2,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-22DOI: 10.1016/j.ejphar.2024.177072
Zengbing Lu , Sze Wa Chan , Bin Jiang , Dexuan Cui , Ichiro Sakata , Takafumi Sakai , Xiaofei Huang , Julia Yuen Hang Liu , Tak Wah Dominic Chan , John A. Rudd
Cocaine- and amphetamine-regulated transcript (CART) peptide is a brain-gut neuropeptide that has been implicated in a range of physiological functions including appetite, which is disturbed during chemotherapy. The aims of the present study were to identify the distribution and expression of CART mRNA and CART peptide, and to examine the potential of CART (55–102) to attenuate cisplatin-induced emesis in Suncus murinus. CART mRNA and peptide were detected throughout the entire brain, including the forebrain, hypothalamus, and brainstem, and also in the gut wall and stomach. In conscious, freely moving animals, intracerebroventricular administration of CART (55–102) did not modulate food and water intake or alter locomotor activity when administered alone. Cisplatin induced emesis and upregulated the expression of CART mRNA in the brainstem. However, CART (55–102) reduced the number of cisplatin-induced retches. Both CART (55–102) and cisplatin increased the number of c-Fos positive cells in the nucleus tractus solitarius, lateral hypothalamus, paraventricular hypothalamus, and bed nucleus of the stria terminalis (BNST), compared to saline-treated animals, whereas cisplatin also induced c-Fos expression in the area postrema (AP), arcuate nucleus, and central nucleus of the amygdala. Pre-treatment with CART (55–102) significantly attenuated the increased c-Fos positive cells in the BNST and AP. These data indicate that CART mRNA and peptide were localized to regions involved in reward/enforcement, emotion, feeding and emesis. The anti-emetic effect of CART (55–102) against cisplatin-induced emesis may involve both the forebrain limbic system and the brainstem.
{"title":"Action of cocaine- and amphetamine-regulated transcript (CART) peptide to attenuate cisplatin-induced emesis in Suncus murinus (house musk shrew)","authors":"Zengbing Lu , Sze Wa Chan , Bin Jiang , Dexuan Cui , Ichiro Sakata , Takafumi Sakai , Xiaofei Huang , Julia Yuen Hang Liu , Tak Wah Dominic Chan , John A. Rudd","doi":"10.1016/j.ejphar.2024.177072","DOIUrl":"10.1016/j.ejphar.2024.177072","url":null,"abstract":"<div><div>Cocaine- and amphetamine-regulated transcript (CART) peptide is a brain-gut neuropeptide that has been implicated in a range of physiological functions including appetite, which is disturbed during chemotherapy. The aims of the present study were to identify the distribution and expression of CART mRNA and CART peptide, and to examine the potential of CART (55–102) to attenuate cisplatin-induced emesis in <em>Suncus murinus</em>. CART mRNA and peptide were detected throughout the entire brain, including the forebrain, hypothalamus, and brainstem, and also in the gut wall and stomach. In conscious, freely moving animals, intracerebroventricular administration of CART (55–102) did not modulate food and water intake or alter locomotor activity when administered alone. Cisplatin induced emesis and upregulated the expression of CART mRNA in the brainstem. However, CART (55–102) reduced the number of cisplatin-induced retches. Both CART (55–102) and cisplatin increased the number of c-Fos positive cells in the nucleus tractus solitarius, lateral hypothalamus, paraventricular hypothalamus, and bed nucleus of the stria terminalis (BNST), compared to saline-treated animals, whereas cisplatin also induced c-Fos expression in the area postrema (AP), arcuate nucleus, and central nucleus of the amygdala. Pre-treatment with CART (55–102) significantly attenuated the increased c-Fos positive cells in the BNST and AP. These data indicate that CART mRNA and peptide were localized to regions involved in reward/enforcement, emotion, feeding and emesis. The anti-emetic effect of CART (55–102) against cisplatin-induced emesis may involve both the forebrain limbic system and the brainstem.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177072"},"PeriodicalIF":4.2,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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