Pub Date : 2025-01-01Epub Date: 2025-07-01DOI: 10.37349/eds.2025.1008116
Hassan Aliashrafzadeh, Dewey Liu, Samantha De Alba, Imad Akbar, Austin Lui, Jordan Vanleuven, Ryan Martin, Zhang Wang, Da Zhi Liu
Since our previous summary of the 74 FDA-approved kinase inhibitors in clinical and preclinical trials for non-cancerous neurological treatment, the US FDA has approved 13 additional kinase inhibitors since early 2022. This update incorporates new evidence for the now 87 FDA-approved kinase inhibitors in clinical and preclinical trials for the treatment of non-cancerous neurological disorders. By the end of October 2024, nearly all 87 FDA-approved kinase inhibitors have been tested in various animal models of non-cancerous neurological disorders, with twenty entered into clinical trials and six used for off-label treatments of neurological conditions in humans. Considering the challenges posed by intellectual property (IP), legal considerations, and limited blood-brain barrier (BBB) permeability, which may restrict some FDA-approved kinase inhibitors from effectively targeting the central nervous system (CNS), we further discuss the feasibility of designing novel proprietary analogs with enhanced BBB penetration to improve their therapeutic potential in neurological disorders. The new drugs typically retain full IP rights and remain costly; while repurposing kinase inhibitors may provide effective and affordable treatments for non-cancerous neurological disorders.
{"title":"Experimental and clinical tests of FDA-approved kinase inhibitors for the treatment of neurological disorders (update 2024).","authors":"Hassan Aliashrafzadeh, Dewey Liu, Samantha De Alba, Imad Akbar, Austin Lui, Jordan Vanleuven, Ryan Martin, Zhang Wang, Da Zhi Liu","doi":"10.37349/eds.2025.1008116","DOIUrl":"10.37349/eds.2025.1008116","url":null,"abstract":"<p><p>Since our previous summary of the 74 FDA-approved kinase inhibitors in clinical and preclinical trials for non-cancerous neurological treatment, the US FDA has approved 13 additional kinase inhibitors since early 2022. This update incorporates new evidence for the now 87 FDA-approved kinase inhibitors in clinical and preclinical trials for the treatment of non-cancerous neurological disorders. By the end of October 2024, nearly all 87 FDA-approved kinase inhibitors have been tested in various animal models of non-cancerous neurological disorders, with twenty entered into clinical trials and six used for off-label treatments of neurological conditions in humans. Considering the challenges posed by intellectual property (IP), legal considerations, and limited blood-brain barrier (BBB) permeability, which may restrict some FDA-approved kinase inhibitors from effectively targeting the central nervous system (CNS), we further discuss the feasibility of designing novel proprietary analogs with enhanced BBB penetration to improve their therapeutic potential in neurological disorders. The new drugs typically retain full IP rights and remain costly; while repurposing kinase inhibitors may provide effective and affordable treatments for non-cancerous neurological disorders.</p>","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"3 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-01-14DOI: 10.37349/eds.2025.100883
Anita Thyagarajan, Zaid Sirhan, Ravi P Sahu
The integration between the tumor-suppressive and oncogenic signaling pathways controls various cellular activities of cancer cells, including cell growth and apoptosis. While the activation of oncogenes fuels cancer progression and escape mechanisms, tumor suppressors regulate and counterbalance the negative effects of oncogenic signaling. Notably, phosphatase and tensin homolog (PTEN) constitute one of the important family members of tumor suppressor genes, which play critical roles in regulating the activities of tumor cells. Thus, an impaired, mutated, or loss of PTEN is associated with low survival or high tumor recurrence rates in cancer patients. Importantly, high tumor expression of a G-protein coupled platelet-activating factor-receptor (PAFR) is associated with increased tumor progression as well as decreased overall survival and poor prognosis in malignancies such as non-small cell lung cancer (NSCLC). Along similar lines, overactivation or mutations in epidermal growth factor receptor (EGFR) signaling are detected in various human malignancies and associated with poor prognosis. The goal of the current minireview was to highlight the significance of the mechanistic insights between the PTEN and PAFR as well as the PAFR and EGFR pathways in impacting cancer growth and/or efficacy of therapeutic agents in experimental model systems.
{"title":"Impact of the crosstalk between the PTEN and PAFR as well as PAFR and EGFR pathways in cancer.","authors":"Anita Thyagarajan, Zaid Sirhan, Ravi P Sahu","doi":"10.37349/eds.2025.100883","DOIUrl":"10.37349/eds.2025.100883","url":null,"abstract":"<p><p>The integration between the tumor-suppressive and oncogenic signaling pathways controls various cellular activities of cancer cells, including cell growth and apoptosis. While the activation of oncogenes fuels cancer progression and escape mechanisms, tumor suppressors regulate and counterbalance the negative effects of oncogenic signaling. Notably, phosphatase and tensin homolog (PTEN) constitute one of the important family members of tumor suppressor genes, which play critical roles in regulating the activities of tumor cells. Thus, an impaired, mutated, or loss of PTEN is associated with low survival or high tumor recurrence rates in cancer patients. Importantly, high tumor expression of a G-protein coupled platelet-activating factor-receptor (PAFR) is associated with increased tumor progression as well as decreased overall survival and poor prognosis in malignancies such as non-small cell lung cancer (NSCLC). Along similar lines, overactivation or mutations in epidermal growth factor receptor (EGFR) signaling are detected in various human malignancies and associated with poor prognosis. The goal of the current minireview was to highlight the significance of the mechanistic insights between the PTEN and PAFR as well as the PAFR and EGFR pathways in impacting cancer growth and/or efficacy of therapeutic agents in experimental model systems.</p>","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"3 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Barragán-Cárdenas, Daniel Castellar-Almonacid, Yerly Vargas-Casanova, C. Parra-Giraldo, Adriana Umaña-Pérez, J. López-Meza, Z. Rivera-Monroy, J. García-Castañeda
Aim: Evaluate the selective cytotoxic effect of the palindromic sequence RWQWRWQWR and its analogues obtained by replacement of L-amino acids by D-amino acids or the functionalization by adding the RGD (integrin ligand motif) to the peptide. Methods: Peptides were obtained by SPPS, characterized by RP-HPLC and ESI-QTOF and its biological activity was evaluated using MTT assays. Evaluation of mechanism associated to the cytotoxic effect were carried out by flow cytometry, RT-qPCR, wound healing, transwell and zymography. Results: The peptides with replacements of D-amino acid showed a lesser cytotoxic effect against breast cancer cell lines, regardless it was one or several residues modified which suggested a possible specific interaction between the peptide and the cancer cell membrane besides its initial electrostatically contact. On the other hand, addition of the RGD sequence to the palindromic peptide in the N-terminal end resulted in a greater cytotoxic effect against cell lines derived from the three mainly diagnosed breast cancer molecular subtypes. An approximation on mechanisms associated to this effect was evaluated on MCF-7 cells, it shows that the peptide induced apoptosis by activating intrinsic and extrinsic pathway, which correlates with the possibility of a specific interaction, and induces mitochondrial depolarization with release of oxygen reactive species. Also, this peptide induces a reduction in migration and invasion associated with a diminish in metalloprotease 9 activity and a lesser release of IL-6, IL-10 and arginase cytokines. Conclusions: Our results suggest that this promising peptide can be considered for preclinical evaluation in the development of drugs to treat breast cancer and thus mitigate the impact of this disease.
{"title":"Enhanced breast cancer cell targeting: RGD integrin ligand potentiates RWQWRWQWR’s cytotoxicity and inhibits migration","authors":"A. Barragán-Cárdenas, Daniel Castellar-Almonacid, Yerly Vargas-Casanova, C. Parra-Giraldo, Adriana Umaña-Pérez, J. López-Meza, Z. Rivera-Monroy, J. García-Castañeda","doi":"10.37349/eds.2024.00052","DOIUrl":"https://doi.org/10.37349/eds.2024.00052","url":null,"abstract":"Aim: Evaluate the selective cytotoxic effect of the palindromic sequence RWQWRWQWR and its analogues obtained by replacement of L-amino acids by D-amino acids or the functionalization by adding the RGD (integrin ligand motif) to the peptide. Methods: Peptides were obtained by SPPS, characterized by RP-HPLC and ESI-QTOF and its biological activity was evaluated using MTT assays. Evaluation of mechanism associated to the cytotoxic effect were carried out by flow cytometry, RT-qPCR, wound healing, transwell and zymography. Results: The peptides with replacements of D-amino acid showed a lesser cytotoxic effect against breast cancer cell lines, regardless it was one or several residues modified which suggested a possible specific interaction between the peptide and the cancer cell membrane besides its initial electrostatically contact. On the other hand, addition of the RGD sequence to the palindromic peptide in the N-terminal end resulted in a greater cytotoxic effect against cell lines derived from the three mainly diagnosed breast cancer molecular subtypes. An approximation on mechanisms associated to this effect was evaluated on MCF-7 cells, it shows that the peptide induced apoptosis by activating intrinsic and extrinsic pathway, which correlates with the possibility of a specific interaction, and induces mitochondrial depolarization with release of oxygen reactive species. Also, this peptide induces a reduction in migration and invasion associated with a diminish in metalloprotease 9 activity and a lesser release of IL-6, IL-10 and arginase cytokines. Conclusions: Our results suggest that this promising peptide can be considered for preclinical evaluation in the development of drugs to treat breast cancer and thus mitigate the impact of this disease.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":" 365","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141823599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Premature aging can be partially explained by inefficient autophagy (the process of cellular self-digestion that recycles intracellular components) and premature senescence (cease of cellular division without cell death activation). Autophagy and senescence are among the basic biochemical pathways in plants and fungi suggesting that some of their metabolites have the potential to act as autophagy inducers (AI) and senescence inhibitors (SI) and to inhibit inflammation and human aging. Several compounds have already been identified: trehalose and resveratrol are natural compounds that act as AI; flavonoids found in fruit and vegetables (curcumin, quercetin, and fisetin) are among the first SI discovered so far. New AI/SI can be identified using various approaches like hypothesis-driven approach for screening receptor agonists using an in-silico library of thousands of natural compounds; cheminformatics studies of phytochemicals using docking and molecular dynamics simulation, structure similarities/mimicry in vitro, “blind” high throughput screening (HTS) of libraries of natural metabolites against relevant models, and more. This article aims to promote the use of plant and fungi novel resources to identify bioactive molecules relevant for healthy aging based on the knowledge that plants and fungi use autophagy and senescence mechanisms for their own survival and homeostasis. As autophagy and senescence are interconnected, how drugs targeting autophagy, senescence, or both could contribute to healthy aging in humans will be speculated.
{"title":"Plants and fungi metabolites as novel autophagy inducers and senescence inhibitors","authors":"Rivka Ofir","doi":"10.37349/eds.2024.00051","DOIUrl":"https://doi.org/10.37349/eds.2024.00051","url":null,"abstract":"Premature aging can be partially explained by inefficient autophagy (the process of cellular self-digestion that recycles intracellular components) and premature senescence (cease of cellular division without cell death activation). Autophagy and senescence are among the basic biochemical pathways in plants and fungi suggesting that some of their metabolites have the potential to act as autophagy inducers (AI) and senescence inhibitors (SI) and to inhibit inflammation and human aging. Several compounds have already been identified: trehalose and resveratrol are natural compounds that act as AI; flavonoids found in fruit and vegetables (curcumin, quercetin, and fisetin) are among the first SI discovered so far. New AI/SI can be identified using various approaches like hypothesis-driven approach for screening receptor agonists using an in-silico library of thousands of natural compounds; cheminformatics studies of phytochemicals using docking and molecular dynamics simulation, structure similarities/mimicry in vitro, “blind” high throughput screening (HTS) of libraries of natural metabolites against relevant models, and more. This article aims to promote the use of plant and fungi novel resources to identify bioactive molecules relevant for healthy aging based on the knowledge that plants and fungi use autophagy and senescence mechanisms for their own survival and homeostasis. As autophagy and senescence are interconnected, how drugs targeting autophagy, senescence, or both could contribute to healthy aging in humans will be speculated.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"10 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141703566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aim: New microtubule-targeting agents are needed to improve cancer treatment. The recent characterization of the anticancer alkaloid securinine as a tubulin-binding agent prompted us to explore the interaction of related monomeric and dimeric analogues with tubulin. The interaction between the α/β-tubulin dimer and alkaloids fluevirines A–F and flueggenines A–I, isolated from the bush Flueggea virosa (Roxb. ex Willd.) Royle, was investigated using molecular docking. Methods: Two molecular models were initially compared for the binding of securinine to α/β-tubulin. The pironetin-binding site model (5FNV) was selected for the subsequent docking analysis with all compounds. Empirical energies of interaction (ΔE) were measured and compared. Results: Fluevirine A has been identified as a potent tubulin binder. This dimeric alkaloid formed more stable complexes with tubulin than the monomeric counterparts, such as fluevirines B–D. The bis-indole derivative fluevirine E also provided more stable complexes than (nor)securinine. The study was extended to the dimeric alkaloids flueggenines A–I and three compounds were identified as potential tubulin binders: the polycyclic product flueggenine B, the norsecurinine-indole hybrid flueggenine E, and the norsecurinine dimer flueggenine I. This later compound proved to be well adapted to fit into the pironetin site of tubulin, extending its two norsecurinine units between the colchicine-binding area and the pironetin site, in close proximity to the pironetin-reactive cysteine-316 residue. Structure-binding relationships were delineated. Conclusions: The study identifies the dimeric alkaloids fluevirine A and flueggenine I as potential α-tubulin binding agents. For the first time, dimeric alkaloids including two C-C connected norsecurinine units are characterized as tubulin ligands. The study contributes to a better understanding of the mechanism of action of Flueggea alkaloids and should help the design of anticancer analogues targeting the pironetin site of α-tubulin.
目的：改善癌症治疗需要新的微管靶向药物。最近，抗癌生物碱 securinine 作为一种微管蛋白结合剂的表征促使我们探索相关单体和二聚体类似物与微管蛋白的相互作用。我们采用分子对接法研究了α/β-微管蛋白二聚体与从灌木 Flueggea virosa (Roxb. ex Willd.) Royle 中分离出来的生物碱 fluevirines A-F 和 flueggenines A-I 之间的相互作用。研究方法首先比较了两种securinine与α/β-tubulin结合的分子模型。在随后与所有化合物的对接分析中，选择了 pironetin 结合位点模型（5FNV）。测量并比较了相互作用的经验能量（ΔE）。结果Fluevirine A 被鉴定为一种强效的小管蛋白粘合剂。这种二聚生物碱与小管蛋白形成的复合物比单体化合物（如氟韦林 B-D）更稳定。双吲哚衍生物氟病毒因子 E 也能提供比 (nor)securinine 更稳定的复合物。研究扩展到了二聚生物碱氟矢车菊碱 A-I，并确定了三种化合物为潜在的小管蛋白结合剂：多环产物氟矢车菊碱 B、去甲琥珀酰-吲哚杂化物氟矢车菊碱 E 和去甲琥珀酰二聚物氟矢车菊碱 I。后一种化合物被证明能很好地适应微管蛋白的 pironetin 位点，在秋水仙碱结合区和 pironetin 位点之间延伸出两个去甲苏氨酸单元，非常靠近 pironetin 反应半胱氨酸-316 残基。对结构-结合关系进行了描述。结论：这项研究确定了二聚生物碱氟卫宁 A 和氟卫宁 I 是潜在的 α-管蛋白结合剂。这是首次将包括两个 C-C 连接的去甲嘌呤单位的二聚生物碱鉴定为微管蛋白配体。这项研究有助于人们更好地了解 Flueggea 生物碱的作用机制，并有助于设计以 α-微管蛋白的 pironetin 位点为靶点的抗癌类似物。
{"title":"Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study","authors":"Gérard Vergoten, Christian Bailly","doi":"10.37349/eds.2024.00047","DOIUrl":"https://doi.org/10.37349/eds.2024.00047","url":null,"abstract":"Aim: New microtubule-targeting agents are needed to improve cancer treatment. The recent characterization of the anticancer alkaloid securinine as a tubulin-binding agent prompted us to explore the interaction of related monomeric and dimeric analogues with tubulin. The interaction between the α/β-tubulin dimer and alkaloids fluevirines A–F and flueggenines A–I, isolated from the bush Flueggea virosa (Roxb. ex Willd.) Royle, was investigated using molecular docking. Methods: Two molecular models were initially compared for the binding of securinine to α/β-tubulin. The pironetin-binding site model (5FNV) was selected for the subsequent docking analysis with all compounds. Empirical energies of interaction (ΔE) were measured and compared. Results: Fluevirine A has been identified as a potent tubulin binder. This dimeric alkaloid formed more stable complexes with tubulin than the monomeric counterparts, such as fluevirines B–D. The bis-indole derivative fluevirine E also provided more stable complexes than (nor)securinine. The study was extended to the dimeric alkaloids flueggenines A–I and three compounds were identified as potential tubulin binders: the polycyclic product flueggenine B, the norsecurinine-indole hybrid flueggenine E, and the norsecurinine dimer flueggenine I. This later compound proved to be well adapted to fit into the pironetin site of tubulin, extending its two norsecurinine units between the colchicine-binding area and the pironetin site, in close proximity to the pironetin-reactive cysteine-316 residue. Structure-binding relationships were delineated. Conclusions: The study identifies the dimeric alkaloids fluevirine A and flueggenine I as potential α-tubulin binding agents. For the first time, dimeric alkaloids including two C-C connected norsecurinine units are characterized as tubulin ligands. The study contributes to a better understanding of the mechanism of action of Flueggea alkaloids and should help the design of anticancer analogues targeting the pironetin site of α-tubulin.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"131 38","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141115055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The potent pain-relieving properties of opioids come at a steep price. Their addictive nature and side effects raise critical concerns in managing pain after surgical spine procedures. Postoperatively, spinal surgeries often accompany acute intense pain, which presents a significant challenge in optimal recovery. This paper reviews the historical approach to pain management in spine surgeries and expands on the use of alternatives and novel agents with reduced addictive potential. Additionally showcasing individualized multimodal strategies for postoperative pain management beyond pharmacological approaches such as cognitive behavioral therapy (CBT), physical therapy, and transcutaneous electrical nerve stimulation (TENS). Given the global opioid addiction crisis, there is a growing need for a fundamental shift towards safer and effective alternatives. Transitioning beyond opioid-centric practices in spinal surgery can optimize pain relief while improving patient outcomes and minimizing risk.
{"title":"Pain management for the neurosurgical patient in spinal procedures: overview of historic and new modalities","authors":"Ashley M. Carter, Samantha Yost, Jessica Tobin, Simran Phuyal, Brandon Lucke-Wold","doi":"10.37349/eds.2024.00046","DOIUrl":"https://doi.org/10.37349/eds.2024.00046","url":null,"abstract":"The potent pain-relieving properties of opioids come at a steep price. Their addictive nature and side effects raise critical concerns in managing pain after surgical spine procedures. Postoperatively, spinal surgeries often accompany acute intense pain, which presents a significant challenge in optimal recovery. This paper reviews the historical approach to pain management in spine surgeries and expands on the use of alternatives and novel agents with reduced addictive potential. Additionally showcasing individualized multimodal strategies for postoperative pain management beyond pharmacological approaches such as cognitive behavioral therapy (CBT), physical therapy, and transcutaneous electrical nerve stimulation (TENS). Given the global opioid addiction crisis, there is a growing need for a fundamental shift towards safer and effective alternatives. Transitioning beyond opioid-centric practices in spinal surgery can optimize pain relief while improving patient outcomes and minimizing risk.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"60 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141114080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
I. D. da Cruz, C. F. Teixeira, N. L. Pellenz, M. Mastella, V. Azzolin, Euler Esteves Ribeiro, F. Barbisan
Aim: The purpose of this study is to conduct a comprehensive investigation into the modulatory effects of Stryphnodendron adstringens (Mart.; S. adstringens), a Brazilian wound-healing plant, on the expression of inflammatory cytokines. This will be achieved using an in vitro protocol with the commercial macrophage cell line RAW 264.7. Methods: The macrophage inflammatory response was induced by the natural antigen phytohemagglutinin (PHA), with and without supplementation of different concentrations of S. adstringens extract. The effects on cell proliferation rate and the concentration and production of transcripts of pro-inflammatory cytokines interleukin 1β (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), as well as the anti-inflammatory cytokine IL-10, were assessed using spectrophotometric, immunoassay, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) techniques. Results: S. adstringens extract at all concentrations tested here reduced the cellular proliferation rate of activated macrophages. Extracts at concentrations of 0.49 mg/mL and 0.99 mg/mL decreased the protein and gene expression of pro-inflammatory cytokines, exhibiting the opposite effect concerning IL-10. Conclusions: The findings suggest that the wound-healing action of S. adstringens may encompass differential modulation of inflammation associated with tissue injury.
目的：本研究旨在全面调查巴西伤口愈合植物 Stryphnodendron adstringens（Mart.这项研究将采用商业巨噬细胞系 RAW 264.7 的体外实验方案来实现。研究方法用天然抗原植物血凝素（PHA）诱导巨噬细胞炎症反应，同时添加或不添加不同浓度的 S. adstringens 提取物。使用分光光度法、免疫测定法和定量反转录聚合酶链反应（qRT-PCR）技术评估了对细胞增殖率、促炎细胞因子白细胞介素 1β (IL-1β)、IL-6、肿瘤坏死因子-α (TNF-α)、干扰素-γ (IFN-γ)以及抗炎细胞因子 IL-10 的浓度和转录物产生的影响。结果显示所有测试浓度的 S. adstringens 提取物都能降低活化巨噬细胞的细胞增殖率。浓度为 0.49 毫克/毫升和 0.99 毫克/毫升的提取物可降低促炎细胞因子的蛋白和基因表达，而对 IL-10 则表现出相反的效果。结论研究结果表明，S. adstringens 的伤口愈合作用可能包括对组织损伤相关炎症的不同调节。
{"title":"Stryphnodendron adstringens have a modulatory effect on inflammatory cytokines markers of in vitro activated macrophages","authors":"I. D. da Cruz, C. F. Teixeira, N. L. Pellenz, M. Mastella, V. Azzolin, Euler Esteves Ribeiro, F. Barbisan","doi":"10.37349/eds.2024.00045","DOIUrl":"https://doi.org/10.37349/eds.2024.00045","url":null,"abstract":"Aim: The purpose of this study is to conduct a comprehensive investigation into the modulatory effects of Stryphnodendron adstringens (Mart.; S. adstringens), a Brazilian wound-healing plant, on the expression of inflammatory cytokines. This will be achieved using an in vitro protocol with the commercial macrophage cell line RAW 264.7. Methods: The macrophage inflammatory response was induced by the natural antigen phytohemagglutinin (PHA), with and without supplementation of different concentrations of S. adstringens extract. The effects on cell proliferation rate and the concentration and production of transcripts of pro-inflammatory cytokines interleukin 1β (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), as well as the anti-inflammatory cytokine IL-10, were assessed using spectrophotometric, immunoassay, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) techniques. Results: S. adstringens extract at all concentrations tested here reduced the cellular proliferation rate of activated macrophages. Extracts at concentrations of 0.49 mg/mL and 0.99 mg/mL decreased the protein and gene expression of pro-inflammatory cytokines, exhibiting the opposite effect concerning IL-10. Conclusions: The findings suggest that the wound-healing action of S. adstringens may encompass differential modulation of inflammation associated with tissue injury.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"117 15","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140987797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cyclophane-containing peptides comprise an important group of macrocyclic peptides with unique structural properties and pharmaceutical relevance. Darobactin A is a ribosomally synthesized and post-translationally modified peptide (RiPP) antibiotic, which features an unusual biscyclophane moiety formed via the class-defining ether crosslink in addition to a carbon-carbon (C-C) crosslink. Because darobactin-like peptides (daropeptides) are widespread in nature, further exploration of these emerging RiPP natural products featuring ether crosslinked cyclophane could facilitate the discovery and development of new bioactive peptides. This perspective provides updated insights into the biosynthesis and classification of daropeptides, highlighting the potential to manipulate daropeptide maturases to access novel bioactive peptide cyclophanes.
含环烷肽是一类重要的大环肽，具有独特的结构特性和药用价值。Darobactin A 是一种经核糖体合成和翻译后修饰的多肽（RiPP）抗生素，其特点是除了碳-碳（C-C）交联外，还通过定义类别的醚交联形成不寻常的双环烷分子。由于达罗巴肽类多肽（daropeptides）在自然界中广泛存在，进一步探索这些以醚交联环烷为特征的新兴 RiPP 天然产物，有助于发现和开发新的生物活性多肽。这一观点提供了关于达拉肽的生物合成和分类的最新见解，强调了操纵达拉肽成熟酶以获得新型生物活性肽环烷的潜力。
{"title":"Daropeptide natural products","authors":"Suze Ma, Sijia Guo, Wei Ding, Qi Zhang","doi":"10.37349/eds.2024.00042","DOIUrl":"https://doi.org/10.37349/eds.2024.00042","url":null,"abstract":"Cyclophane-containing peptides comprise an important group of macrocyclic peptides with unique structural properties and pharmaceutical relevance. Darobactin A is a ribosomally synthesized and post-translationally modified peptide (RiPP) antibiotic, which features an unusual biscyclophane moiety formed via the class-defining ether crosslink in addition to a carbon-carbon (C-C) crosslink. Because darobactin-like peptides (daropeptides) are widespread in nature, further exploration of these emerging RiPP natural products featuring ether crosslinked cyclophane could facilitate the discovery and development of new bioactive peptides. This perspective provides updated insights into the biosynthesis and classification of daropeptides, highlighting the potential to manipulate daropeptide maturases to access novel bioactive peptide cyclophanes.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":" 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140684053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qian Zhang, Ziyang Wang, Xiaohan Mei, Quan Chen, Chunqiu Zhang
Protein-protein interactions (PPIs) impersonate a significant role in many biological processes and are potential therapeutic targets in numerous human diseases. Stapled peptides, as the most promising therapeutic candidate for interfering with PPIs, have a higher degree of α-helicity, improved binding affinity, more resistance to proteolytic digestion, longer serum half-life, and enhanced cell permeability, which exhibits higher pharmacological activity compared with small molecule drugs and biologics. This review outlined the continuous progress of stapled peptides mainly concerning the design principle, structural stability, bioactivity, cell permeability, and potential applications in therapeutics, which is aimed at providing a broad reference for the design and exploration of stapled peptides with enhanced biological and pharmacokinetic properties as the next-generation therapeutic peptide drugs targeting various diseases.
{"title":"Stapled peptides: targeting protein-protein interactions in drug development","authors":"Qian Zhang, Ziyang Wang, Xiaohan Mei, Quan Chen, Chunqiu Zhang","doi":"10.37349/eds.2024.00041","DOIUrl":"https://doi.org/10.37349/eds.2024.00041","url":null,"abstract":"Protein-protein interactions (PPIs) impersonate a significant role in many biological processes and are potential therapeutic targets in numerous human diseases. Stapled peptides, as the most promising therapeutic candidate for interfering with PPIs, have a higher degree of α-helicity, improved binding affinity, more resistance to proteolytic digestion, longer serum half-life, and enhanced cell permeability, which exhibits higher pharmacological activity compared with small molecule drugs and biologics. This review outlined the continuous progress of stapled peptides mainly concerning the design principle, structural stability, bioactivity, cell permeability, and potential applications in therapeutics, which is aimed at providing a broad reference for the design and exploration of stapled peptides with enhanced biological and pharmacokinetic properties as the next-generation therapeutic peptide drugs targeting various diseases.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":" 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140685837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Five families of investigational products are in clinical investigation to slow or reverse normal aging processes [longevity candidates, mesenchymal stem cells, senolytics drugs, sirtuin activators, and nicotinamide adenine dinucleotide (NAD)+ precursors]. The longevity candidates, vitamin D and metformin, appear to significantly reduce all-cause mortality and prolong life expectancy. This should be confirmed by interventional studies. The mesenchymal stem cell family is the most advanced in clinical trial development [phase 2b randomized controlled trial (RCT)]. An allogeneic bone marrow stem cell preparation (Lomecel-B) reduced locomotor frailty in older people. The improvement in locomotion was modest. In the future, attempts could be made to improve potency through a precondition or genetic modification of naive bone marrow stem cells. Autologous adipose stem cell-assisted fat grafting increased graft survival, facial volume, and skin quality. The association of the senolytic drugs dasatinib and quercetin was well tolerated, with low brain penetration of dasatinib and undetectable levels of quercetin. The sirtuin-1 activator resveratrol (combined with physical exercise) improved physical function in older adults with physical limitations. The NAD+ precursor nicotinamide riboside improved physical exercise performance. In conclusion, Lomecel-B is the most advanced agent in clinical trial development for normal aging processes (phase 2b for locomotion frailty), followed by resveratrol and nicotinamide riboside.
目前有五种在研产品[长寿候选药物、间充质干细胞、衰老药物、sirtuin 激活剂和烟酰胺腺嘌呤二核苷酸（NAD）+ 前体]正在接受临床研究，以延缓或逆转正常衰老过程。长寿候选药物维生素 D 和二甲双胍似乎能显著降低全因死亡率并延长预期寿命。这一点应通过干预研究加以证实。间充质干细胞家族是临床试验发展最前沿的[2b期随机对照试验（RCT）]。异体骨髓干细胞制剂（Lomecel-B）减轻了老年人的运动虚弱。对运动能力的改善不大。未来，可尝试通过对天真骨髓干细胞进行先决条件或基因修饰来提高其效力。自体脂肪干细胞辅助脂肪移植提高了移植存活率、面部容积和皮肤质量。衰老药物达沙替尼和槲皮素的联合用药耐受性良好，达沙替尼的脑穿透率低，而槲皮素的含量则检测不到。sirtuin-1激活剂白藜芦醇（与体育锻炼相结合）可改善身体机能受限的老年人的身体机能。NAD+前体物烟酰胺核苷可改善体育锻炼表现。总之，Lomecel-B 是针对正常衰老过程（运动虚弱的 2b 阶段）进行临床试验开发的最先进药物，其次是白藜芦醇和烟酰胺核苷。
{"title":"Clinical studies with drugs and biologics aimed at slowing or reversing normal aging processes—emerging results and future perspectives","authors":"Ricardo P. Garay","doi":"10.37349/eds.2024.00040","DOIUrl":"https://doi.org/10.37349/eds.2024.00040","url":null,"abstract":"Five families of investigational products are in clinical investigation to slow or reverse normal aging processes [longevity candidates, mesenchymal stem cells, senolytics drugs, sirtuin activators, and nicotinamide adenine dinucleotide (NAD)+ precursors]. The longevity candidates, vitamin D and metformin, appear to significantly reduce all-cause mortality and prolong life expectancy. This should be confirmed by interventional studies. The mesenchymal stem cell family is the most advanced in clinical trial development [phase 2b randomized controlled trial (RCT)]. An allogeneic bone marrow stem cell preparation (Lomecel-B) reduced locomotor frailty in older people. The improvement in locomotion was modest. In the future, attempts could be made to improve potency through a precondition or genetic modification of naive bone marrow stem cells. Autologous adipose stem cell-assisted fat grafting increased graft survival, facial volume, and skin quality. The association of the senolytic drugs dasatinib and quercetin was well tolerated, with low brain penetration of dasatinib and undetectable levels of quercetin. The sirtuin-1 activator resveratrol (combined with physical exercise) improved physical function in older adults with physical limitations. The NAD+ precursor nicotinamide riboside improved physical exercise performance. In conclusion, Lomecel-B is the most advanced agent in clinical trial development for normal aging processes (phase 2b for locomotion frailty), followed by resveratrol and nicotinamide riboside.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140716697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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