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From Ethnopharmacology to Active Compound: Effects of Traditional Plant Extracts on Varicose Vein-Related Enzymes and Isolation of Active Flavonoids from Helichrysum plicatum DC. subsp. plicatum. 从民族药理学到活性化合物:传统植物提取物对蜡菊静脉曲张相关酶的影响及活性黄酮的分离。无性系种群。plicatum。
IF 4.3 3区 医学
Pharmaceuticals Pub Date : 2025-06-19 DOI: 10.3390/ph18060926
Tugsen Buyukyildirim, F Sezer Senol Deniz, Merve Yuzbasioglu Baran, Ece Salihoglu, Mustafa Abdullah Yilmaz, Osman Tugay
{"title":"From Ethnopharmacology to Active Compound: Effects of Traditional Plant Extracts on Varicose Vein-Related Enzymes and Isolation of Active Flavonoids from <i>Helichrysum plicatum</i> DC. subsp. <i>plicatum</i>.","authors":"Tugsen Buyukyildirim, F Sezer Senol Deniz, Merve Yuzbasioglu Baran, Ece Salihoglu, Mustafa Abdullah Yilmaz, Osman Tugay","doi":"10.3390/ph18060926","DOIUrl":"10.3390/ph18060926","url":null,"abstract":"<p><p><b>Background:</b> Varicose veins and chronic venous insufficiency are chronic venous disorders involving abnormalities in the venous system. Inflammation, an increase in proteolytic enzymes, and free radicals are important factors that play a role in the varicose vein pathology. <b>Methods:</b> In this study, the antioxidant properties and inhibitor activities of 17 plant extracts used to treat varicose veins in traditional medicine were evaluated against varicose veins-related enzymes (hyaluronidase, elastase, collagenase, lipooxygenase, prolylendopeptidase, and xanthine oxidase). The most effective compounds responsible for the activity of the <i>Helichrysum plicatum</i> subsp. <i>plicatum</i> extract were isolated by open column chromatography techniques. The active compounds were determined to be naringenin, apigenin, and luteolin by spectroscopic methods. In the activity-guided isolation study, the xanthine oxidase enzyme inhibition method was used. <b>Results:</b> The fractions containing naringenin and apigenin (IC<sub>50</sub> = 0.269 ± 0.009 µg/mL) and apigenin and luteolin (IC<sub>50</sub> = 0.285 ± 0.019 µg/mL) compounds showed synergistic and strong effects against xanthine oxidase and were found to be as active as the positive control allopurinol (IC<sub>50</sub> = 0.250 ± 0.006 µg/mL). In the LC-MS/MS analysis of the <i>Helichrysum plicatum</i> extract, quinic acid (22.649 mg compound/g extract), chlorogenic acid (14.573 mg/g extract), isoquercitrin (14.371 mg/g extract), cosmosin (9.885 mg/g extract), and astragalin (11.506 mg/g extract) were detected as the major components. Naringenin, apigenin, and luteolin were detected at concentrations of 1.457, 2.518, and 1.368 mg/g in the extract, respectively. <b>Conclusions:</b> In conclusion, it is predicted that the combination of naringenin, apigenin, and luteolin has a promising use as a conservative treatment option for diseases associated with varicose veins due to their synergistic effects with each other.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12195836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507740","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}
引用次数: 0
Prognostic Modeling of Deleterious IDUA Mutations L238Q and P385R in Hurler Syndrome Through Molecular Dynamics Simulations. 基于分子动力学模拟的有害IDUA突变L238Q和P385R在Hurler综合征中的预后建模
IF 4.3 3区 医学
Pharmaceuticals Pub Date : 2025-06-19 DOI: 10.3390/ph18060922
Madhana Priya Nanda Kumar, Esakki Dharsini Selvamani, Archana Pai Panemangalore, Sidharth Kumar Nanda Kumar, Vasundra Vasudevan, Magesh Ramasamy
{"title":"Prognostic Modeling of Deleterious IDUA Mutations L238Q and P385R in Hurler Syndrome Through Molecular Dynamics Simulations.","authors":"Madhana Priya Nanda Kumar, Esakki Dharsini Selvamani, Archana Pai Panemangalore, Sidharth Kumar Nanda Kumar, Vasundra Vasudevan, Magesh Ramasamy","doi":"10.3390/ph18060922","DOIUrl":"10.3390/ph18060922","url":null,"abstract":"<p><p>MPS I (Mucopolysaccharidosis type I) is a rare lysosomal storage disease originating from the deficiency of the enzyme alpha-L-iduronidase, encoded by the IDUA gene, which impairs the degradation of glycosaminoglycans (GAGs) and diminishes biological functioning across several organs. <b>Background:</b> Out of the eleven MPS disorders, MPS I includes three syndromes, of which the first, named Hurler syndrome, affects the most. <b>Methods:</b> Several in silico tools were used, such as ConSurf (73 variants), Mutation Assessor (69 variants), PredictSNP, MAPP, PhDSNP, Polyphen-1, Polyphen-2, SIFT, SNAP, PANTHER, MetaSNP (24 variants); Missense 3D-DB (11 variants) and AlignGVGD (eight variants) for physicochemical properties; and I-Mutant, Mupro, CUPSAT, and INPS for stability predictions (four variants). <b>Results:</b> A molecular docking study was performed for the two variants: L238Q and P385R scored -7.22 and -7.05 kcal/mol, respectively, and the native scored -7.14 kcal/mol with IDR as the ligand. Molecular dynamics anticipated how these molecules fluctuate over a period of 100 nanoseconds. <b>Conclusions:</b> Alpha-L-iduronidase enzyme has a critical role in the lysosomal degradation of glycosaminoglycans. According to the comparative analysis of the three structures by MDS, P385R had the least stability in all aspects of the plots. Our study demonstrates that the mutation significantly alters protein stability and binding efficiency with the ligands.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12195877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507762","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}
引用次数: 0
Impact of Age and Menopausal Status on T-DM1 (Ado-Trastuzumab Emtansine) Treatment Outcomes in HER2-Positive Breast Cancer. 年龄和绝经状态对her2阳性乳腺癌T-DM1 (ado -曲妥珠单抗Emtansine)治疗结果的影响
IF 4.3 3区 医学
Pharmaceuticals Pub Date : 2025-06-19 DOI: 10.3390/ph18060931
Heves Surmeli, Deniz Isik, Oguzcan Kinikoglu, Yunus Emre Altintas, Ugur Ozkerim, Sıla Oksuz, Tugba Basoglu, Hatice Odabas, Nedim Turan
{"title":"Impact of Age and Menopausal Status on T-DM1 (Ado-Trastuzumab Emtansine) Treatment Outcomes in HER2-Positive Breast Cancer.","authors":"Heves Surmeli, Deniz Isik, Oguzcan Kinikoglu, Yunus Emre Altintas, Ugur Ozkerim, Sıla Oksuz, Tugba Basoglu, Hatice Odabas, Nedim Turan","doi":"10.3390/ph18060931","DOIUrl":"10.3390/ph18060931","url":null,"abstract":"<p><p><b>Background/Objectives</b>: HER2-positive breast cancer is an aggressive subtype with an established responsiveness to HER2-targeted therapies like ado-trastuzumab emtansine (T-DM1). However, inter-patient variability in treatment response and toxicity remains a challenge. Hormonal status, particularly menopausal state, may influence breast cancer behavior, therapeutic tolerance, and outcomes, yet data on its effect in patients treated with T-DM1 are scarce. This study aimed to evaluate whether menopausal status independently affects treatment response, side effects, and survival outcomes in HER2-positive breast cancer patients receiving T-DM1, accounting for the confounding role of age. <b>Methods</b>: This retrospective cohort study included 98 female patients with HER2-positive breast cancer treated with T-DM1: 53 premenopausal and 45 postmenopausal. The clinical characteristics, metastatic patterns, treatment history, T-DM1 outcomes, and toxicities were recorded. The statistical analysis included chi-square, <i>t</i>-tests, Mann-Whitney U tests, and Spearman's correlations. Partial correlation analyses were conducted to isolate the effect of menopausal status by controlling for age. <b>Results</b>: The postmenopausal patients showed higher rates of lung metastasis (42.2% vs. 20.8%) and mortality (60.0% vs. 39.6%) than premenopausal patients. However, no significant differences were found in the T-DM1 response or toxicity profiles. After adjusting for age, menopausal status had no independent association with the treatment outcomes or side effects. Age was the dominant factor influencing performance status, metastatic burden, and mortality risk. <b>Conclusions</b>: Menopausal status affects disease presentation but not T-DM1 efficacy or toxicity when age is accounted for. Treatment decisions should consider age and clinical profile rather than menopausal classification alone when managing HER2-positive breast cancer with T-DM1.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12196445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507668","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}
引用次数: 0
Pharmacotherapy of Neuropathic Pain. 神经性疼痛的药物治疗。
IF 4.3 3区 医学
Pharmaceuticals Pub Date : 2025-06-19 DOI: 10.3390/ph18060930
Sergio Marques Borghi
{"title":"Pharmacotherapy of Neuropathic Pain.","authors":"Sergio Marques Borghi","doi":"10.3390/ph18060930","DOIUrl":"10.3390/ph18060930","url":null,"abstract":"<p><p>Despite advances in recent decades, the management of neuropathic pain remains one of the greatest challenges in modern clinical medicine [...].</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12196152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507755","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}
引用次数: 0
Development of Mannitol-Based Microparticles for Dry Powder Inhalers: Enhancing Pulmonary Delivery of NSAIDs. 用于干粉吸入器的甘露醇基微粒的开发:增强非甾体抗炎药的肺部输送。
IF 4.3 3区 医学
Pharmaceuticals Pub Date : 2025-06-19 DOI: 10.3390/ph18060923
Petra Party, Zsófia Ilona Piszman, Rita Ambrus
{"title":"Development of Mannitol-Based Microparticles for Dry Powder Inhalers: Enhancing Pulmonary Delivery of NSAIDs.","authors":"Petra Party, Zsófia Ilona Piszman, Rita Ambrus","doi":"10.3390/ph18060923","DOIUrl":"10.3390/ph18060923","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Chronic lung diseases are among the leading causes of death worldwide. In the treatment of these diseases, non-steroidal anti-inflammatory drugs can be effective. We have previously developed an excipient formulation alongside a modern manufacturing protocol, which we aim to further investigate. We have chosen two new model drugs, meloxicam (MX) and its water-soluble salt, meloxicam-potassium (MXP). The particles in dry powder inhaler (DPI) formulation were expected to have a spherical shape, fast drug release, and good aerodynamic properties. <b>Methods:</b> The excipients were poloxamer-188, mannitol, and leucine. The samples were prepared by spray drying, preceded by solution preparation and wet grinding. Particle size was determined by laser diffraction, shape by scanning electron microscopy (SEM), crystallinity by powder X-ray diffraction (PXRD), interactions by Fourier-transform infrared spectroscopy (FT-IR), in vitro drug dissolution by paddle apparatus, and in vitro aerodynamic properties by Andersen cascade impactor and Spraytec<sup>®</sup> device. <b>Results:</b> We achieved the proper particle size (<5 μm) and spherical shape according to laser diffraction and SEM. The XRPD showed partial amorphization. FT-IR revealed no interaction between the materials. During the in vitro dissolution tests, more than 90% of MX and MXP were released within the first 5 min. The best products exhibited an aerodynamic diameter of around 4 µm, a fine particle fraction around 50%, and an emitted fraction over 95%. The analysis by Spraytec<sup>®</sup> supported the suitability for lung targeting. <b>Conclusions:</b> The developed preparation process and excipient system can be applied in the development of different drugs containing DPIs.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12195923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507688","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}
引用次数: 0
Influence of Tariquidar, an ABC Transporter Inhibitor, on the Ca2+-Dependent Mitochondrial Permeability Transition Pore. ABC转运蛋白抑制剂Tariquidar对Ca2+依赖性线粒体通透性过渡孔的影响。
IF 4.3 3区 医学
Pharmaceuticals Pub Date : 2025-06-19 DOI: 10.3390/ph18060924
Tatiana A Fedotcheva, Alexey G Kruglov, Nadezhda I Fedotcheva
{"title":"Influence of Tariquidar, an ABC Transporter Inhibitor, on the Ca<sup>2+</sup>-Dependent Mitochondrial Permeability Transition Pore.","authors":"Tatiana A Fedotcheva, Alexey G Kruglov, Nadezhda I Fedotcheva","doi":"10.3390/ph18060924","DOIUrl":"10.3390/ph18060924","url":null,"abstract":"<p><p><b>Background</b>: Tariquidar (Tq) is an inhibitor of the multidrug resistance (MDR) proteins relevant to ATP-binding cassette transporters (ABC transporters), which suppresses the ATP-dependent efflux of a variety of hydrophilic and amphipathic compounds, including anticancer drugs. Tq is a representative of a new generation of MDR inhibitors with high affinity to ABC proteins. However, there are still no data on the possible effect of Tq on mitochondria as an important target in the regulation of cell death or survival. <b>Methods</b>: We investigated the influence of Tq on the Ca<sup>2+</sup>-dependent mitochondrial permeability transition pore (mPTP). The effect of Tq was assessed using several parameters, including the calcium load, membrane potential, and mitochondrial swelling. To evaluate the specific targets of Tq, selective inhibitors of components of the mitochondrial pore were used, including adenine nucleotides, carboxyatractylozide (Catr) and bongkrekic acid (BA), oligomycin, and cyclosporine A. <b>Results</b>: Tq decreased the calcium retention capacity, activated mitochondrial swelling, and lowered the influence of ADP and ATP, the inhibitors of the Ca<sup>2+</sup>-induced pore opening, at their low concentrations. These effects of Tq were observed in both calcium-load and swelling assays, thus mimicking the effect of Catr, a selective inhibitor of adenine nucleotide translocase (ANT). Tq also decreased the protective effect of BA, an inhibitor of ANT and mPTP, on the calcium retention capacity of mitochondria. Further, Tq dose-dependently decreased the inhibitory effect of a low ATP concentration but not of high concentrations, at which the effect of Tq was activated by oligomycin, an inhibitor of F-ATP synthase. <b>Conclusions</b>: The influence of Tq extends to mitochondria, specifically to the regulation of membrane permeability, promoting the activation of pore opening, probably through an interaction with ANT, a component of the pore-forming complex. The effect of Tq on the opening of mPTP is strongly dependent on the concentrations of adenine nucleotides and, consequently, on the functional state of mitochondria. The direct influence of Tq on mitochondria can be considered as a new activity that promotes the sensitization of cells to various treatments and stimuli.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12196283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507750","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}
引用次数: 0
In Vivo PK-PD and Drug-Drug Interaction Study of Dorzagliatin for the Management of PI3Kα Inhibitor-Induced Hyperglycemia. Dorzagliatin治疗PI3Kα抑制剂诱导的高血糖的体内PK-PD和药物相互作用研究。
IF 4.3 3区 医学
Pharmaceuticals Pub Date : 2025-06-19 DOI: 10.3390/ph18060927
Guanqin Jin, Kewei Zheng, Shihuang Liu, Huan Yi, Wei Wei, Congjian Xu, Xiaoqiang Xiang, Yu Kang
{"title":"In Vivo PK-PD and Drug-Drug Interaction Study of Dorzagliatin for the Management of PI3Kα Inhibitor-Induced Hyperglycemia.","authors":"Guanqin Jin, Kewei Zheng, Shihuang Liu, Huan Yi, Wei Wei, Congjian Xu, Xiaoqiang Xiang, Yu Kang","doi":"10.3390/ph18060927","DOIUrl":"10.3390/ph18060927","url":null,"abstract":"<p><p><b>Objectives:</b> The anticancer effects of PI3Kα inhibitors (PI3Ki) are constrained by their hyperglycemic side effects, while the efficacy of conventional hypoglycemic agents, such as insulin, metformin, and SGLT-2 inhibitors, in mitigating PI3Ki-induced hyperglycemia remains suboptimal. Dorzagliatin, a novel glucokinase activator, has been approved in China for the management of hyperglycemia, offering a promising alternative. This study aims to investigate the pharmacokinetic properties and potential mechanisms of drug interactions of dorzagliatin in the regulation of PI3K-induced hyperglycemia. <b>Methods:</b> Plasma concentrations of WX390, BYL719, and Dorz in mice were measured using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Pharmacokinetic (PK) parameters and PK/PD models were derived by using Phoenix WinNonlin 8.3.5 software. Blood glucose levels at various time points and tumor volume changes over a four-week period were assessed to explore the interactions when PI3Ki were combined with dorzagliatin. <b>Results:</b> The results indicated that, compared to the Dorz group, the combination groups (Dorz + BYL719, Dorz + WX390) exhibited increases in AUC0→t of dorzagliatin by 41.65% and 20.25%, and in C<sub>max</sub> by 33.48% and 13.32%, respectively. In contrast, co-administration of these PI3Ki with dorzagliatin resulted in minimal increase in their plasma exposure. The combination therapy group (Dorz+BYL719) exhibited superior antitumor efficacy compared to the BYL719 group. <b>Conclusions</b>: Our findings indicate that the drug-drug interactions (DDIs) between dorzagliatin and multiple PI3Ki (including WX390 and BYL719) may partially account for the enhanced antitumor efficacy observed in the combination therapy group compared to PI3Ki monotherapy. This interaction may be explained by the inhibition of P-glycoprotein (P-gp) and the pharmacological mechanism of dorzagliatin regarding the activation of insulin regulation.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12196043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507746","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}
引用次数: 0
NEU1-Mediated Extracellular Vesicle Glycosylation in Alzheimer's Disease: Mechanistic Insights into Intercellular Communication and Therapeutic Targeting. neu1介导的阿尔茨海默病细胞外囊泡糖基化:细胞间通讯和治疗靶向的机制见解
IF 4.3 3区 医学
Pharmaceuticals Pub Date : 2025-06-19 DOI: 10.3390/ph18060921
Mohd Adnan, Arif Jamal Siddiqui, Fevzi Bardakci, Malvi Surti, Riadh Badraoui, Mitesh Patel
{"title":"NEU1-Mediated Extracellular Vesicle Glycosylation in Alzheimer's Disease: Mechanistic Insights into Intercellular Communication and Therapeutic Targeting.","authors":"Mohd Adnan, Arif Jamal Siddiqui, Fevzi Bardakci, Malvi Surti, Riadh Badraoui, Mitesh Patel","doi":"10.3390/ph18060921","DOIUrl":"10.3390/ph18060921","url":null,"abstract":"<p><p>Alzheimer's disease (AD), a progressive neurodegenerative disorder, is marked by the pathological accumulation of amyloid-β plaques and tau neurofibrillary tangles, both of which disrupt neuronal communication and function. Emerging evidence highlights the role of extracellular vesicles (EVs) as key mediators of intercellular communication, particularly in the propagation of pathological proteins in AD. Among the regulatory factors influencing EV composition and function, neuraminidase 1 (NEU1), a lysosomal sialidase responsible for desialylating glycoproteins has gained attention for its involvement in EV glycosylation. This review explores the role of NEU1 in modulating EV glycosylation, with particular emphasis on its influence on immune modulation and intracellular trafficking pathways and the subsequent impact on intercellular signaling and neurodegenerative progression. Altered NEU1 activity has been associated with abnormal glycan profiles on EVs, which may facilitate the enhanced spread of amyloid-β and tau proteins across neural networks. By regulating glycosylation, NEU1 influences EV stability, targeting and uptake by recipient cells, primarily through the desialylation of surface glycoproteins and glycolipids, which alters the EV charge, recognition and receptor-mediated interactions. Targeting NEU1 offers a promising therapeutic avenue to restore EV homeostasis and reduces pathological protein dissemination. However, challenges persist in developing selective NEU1 inhibitors and effective delivery methods to the brain. Furthermore, altered EV glycosylation patterns may serve as potential biomarkers for early AD diagnosis and monitoring. Overall, this review highlights the importance of NEU1 in AD pathogenesis and advocates for deeper investigation into its regulatory functions, with the aim of advancing therapeutic strategies and biomarker development for AD and related neurological disabilities.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12196356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507725","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}
引用次数: 0
TrypPROTACs Unlocking New Therapeutic Strategies for Chagas Disease. 为恰加斯病开启新的治疗策略
IF 4.3 3区 医学
Pharmaceuticals Pub Date : 2025-06-19 DOI: 10.3390/ph18060919
Ana Luísa Rodriguez Gini, Pamela Souza Tada da Cunha, Emílio Emílio João, Chung Man Chin, Jean Leandro Dos Santos, Esteban Carlos Serra, Cauê Benito Scarim
{"title":"TrypPROTACs Unlocking New Therapeutic Strategies for Chagas Disease.","authors":"Ana Luísa Rodriguez Gini, Pamela Souza Tada da Cunha, Emílio Emílio João, Chung Man Chin, Jean Leandro Dos Santos, Esteban Carlos Serra, Cauê Benito Scarim","doi":"10.3390/ph18060919","DOIUrl":"10.3390/ph18060919","url":null,"abstract":"<p><p>Chagas disease, caused by the protozoan parasite <i>Trypanosoma cruzi</i> (<i>T. cruzi</i>), continues to pose significant public health challenges due to the toxicity, poor tolerability, and limited efficacy of current treatments. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) represents a novel therapeutic avenue by leveraging the ubiquitin-proteasome system to selectively degrade essential parasite proteins. This review introduces the conceptual framework of \"TrypPROTACs\" as a prospective strategy for <i>T. cruzi</i>, integrating a comprehensive analysis of druggable targets across critical biological pathways, including ergosterol biosynthesis, redox metabolism, glycolysis, nucleotide synthesis, protein kinases, molecular chaperones such as heat shock protein 90 (Hsp90), and epigenetic regulators such as <i>T. cruzi</i> bromodomain factor 3 (TcBDF3). It is important to note that no TrypPROTAC compound has yet been synthesized or experimentally validated in <i>T. cruzi</i>; the approach discussed herein remains theoretical and forward-looking. Representative inhibitors for each target class are compiled, highlighting potency, selectivity, and structural features relevant to ligand design. We also examine the parasite's ubiquitination machinery and compare it to the human system to identify putative E3 ubiquitin ligases. Key aspects of linker engineering and ternary complex stabilization are discussed, alongside potential validation techniques such as the cellular thermal shift assay (CETSA) and bioluminescence resonance energy transfer (NanoBRET). Collectively, these insights outline a roadmap for the rational design of TrypPROTACs and support the feasibility of expanding targeted protein degradation strategies to neglected tropical diseases.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12196504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507814","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}
引用次数: 0
Stable Gastric Pentadecapeptide BPC 157 as a Therapy and Safety Key: A Special Beneficial Pleiotropic Effect Controlling and Modulating Angiogenesis and the NO-System. 稳定的胃五肽bpc157作为一种治疗和安全关键:一种控制和调节血管生成和no系统的特殊有益多效效应。
IF 4.3 3区 医学
Pharmaceuticals Pub Date : 2025-06-19 DOI: 10.3390/ph18060928
Predrag Sikiric, Sven Seiwerth, Anita Skrtic, Mario Staresinic, Sanja Strbe, Antonia Vuksic, Suncana Sikiric, Dinko Bekic, Dragan Soldo, Boris Grizelj, Luka Novosel, Lidija Beketic Oreskovic, Ivana Oreskovic, Mirjana Stupnisek, Alenka Boban Blagaic, Ivan Dobric
{"title":"Stable Gastric Pentadecapeptide BPC 157 as a Therapy and Safety Key: A Special Beneficial Pleiotropic Effect Controlling and Modulating Angiogenesis and the NO-System.","authors":"Predrag Sikiric, Sven Seiwerth, Anita Skrtic, Mario Staresinic, Sanja Strbe, Antonia Vuksic, Suncana Sikiric, Dinko Bekic, Dragan Soldo, Boris Grizelj, Luka Novosel, Lidija Beketic Oreskovic, Ivana Oreskovic, Mirjana Stupnisek, Alenka Boban Blagaic, Ivan Dobric","doi":"10.3390/ph18060928","DOIUrl":"10.3390/ph18060928","url":null,"abstract":"<p><p>Although approached through many concepts, the pleiotropic healing issue, specifically, maintaining/reestablishing tissue integrity, remains a central challenge in pharmacology, particularly when the process is misdirected or not properly controlled. Robert and Szabo's concept of cytoprotection holds that innate cell (epithelial (Robert), endothelial (Szabo)) integrity and protection/maintenance/reestablishment in the stomach is translated to other organ therapy (cytoprotection → organoprotection) via the cytoprotection agent's effect. Therefore, we defend stable gastric pentadecapeptide BPC 157 therapy's efficacy and pleiotropic beneficial effects, along with its high safety (LD1 not achieved), against speculation of its negative impact, speculation of angiogenesis toward tumorigenesis, increased NO and eNOS, damaging free radical formation, and neurodegenerative diseases (Parkinson's disease and Alzheimer's disease). Contrarily, in wound healing and general healing capabilities, as reviewed, as a cytoprotective agent and native cytoprotection mediator, BPC 157 controls angiogenesis and the NO-system's healing functions and counteracts the pathological presentation of neurodegenerative diseases in acknowledged animal models (i.e., Parkinson's disease and Alzheimer's disease), and it presents prominent anti-tumor potential in vivo and in vitro. BPC 157 resolved cornea transparency maintenance, cornea healing \"angiogenic privilege\" (vs. angiogenesis/neovascularization/tumorigenesis), and it does not produce corneal neovascularization but rather opposes it. Per Folkman's concept, it demonstrates an anti-tumor effect in vivo and in vitro. BPC 157 exhibits a distinctive effect on the NO-level (increase vs. decrease), always combined with the counteraction of free radical formation, and, in mice and rats, BPC 157 therapy counteracts Parkinson's disease-like and Alzheimer's disease-like disturbances. Thus, BPC 157 therapy means targeting angiogenesis and NO's cytotoxic and damaging actions but maintaining, promoting, or recovering their essential protective functions.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12195719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507785","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}
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