Pooja Singh, Vikas Kumar, Keun-Woo Lee, Jong Chan Hong
SHP2 belongs to a cytoplasmic non-receptor protein tyrosine phosphatase class. It plays a critical role in the development of various cancers, such as gastric cancer, leukemia, and breast cancer. Thus, SHP2 has gained the interest of researchers as a potential target for inhibiting tumor cell proliferation in SHP2-dependent cancers. This study employed pharmacophore-based virtual screening, molecular docking, molecular dynamic (MD) simulations, MM/PBSA, and principal component analysis (PCA), followed by ADME prediction. We selected three potential hits from a collective database of more than one million chemical compounds. The stability of these selected hit–protein complexes was analyzed using 500 ns MD simulations and binding free energy calculations. The identified hits Lig_1, Lig_6, and Lig_14 demonstrated binding free energies of −161.49 kJ/mol, −151.28 kJ/mol, and −107.13 kJ/mol, respectively, compared to the reference molecule (SHP099) with a ΔG of −71.48 kJ/mol. Our results showed that the identified compounds could be used as promising candidates for selective SHP2 allosteric inhibition in cancer.
{"title":"Discovery of Novel Allosteric SHP2 Inhibitor Using Pharmacophore-Based Virtual Screening, Molecular Docking, Molecular Dynamics Simulation, and Principal Component Analysis","authors":"Pooja Singh, Vikas Kumar, Keun-Woo Lee, Jong Chan Hong","doi":"10.3390/ph17070935","DOIUrl":"https://doi.org/10.3390/ph17070935","url":null,"abstract":"SHP2 belongs to a cytoplasmic non-receptor protein tyrosine phosphatase class. It plays a critical role in the development of various cancers, such as gastric cancer, leukemia, and breast cancer. Thus, SHP2 has gained the interest of researchers as a potential target for inhibiting tumor cell proliferation in SHP2-dependent cancers. This study employed pharmacophore-based virtual screening, molecular docking, molecular dynamic (MD) simulations, MM/PBSA, and principal component analysis (PCA), followed by ADME prediction. We selected three potential hits from a collective database of more than one million chemical compounds. The stability of these selected hit–protein complexes was analyzed using 500 ns MD simulations and binding free energy calculations. The identified hits Lig_1, Lig_6, and Lig_14 demonstrated binding free energies of −161.49 kJ/mol, −151.28 kJ/mol, and −107.13 kJ/mol, respectively, compared to the reference molecule (SHP099) with a ΔG of −71.48 kJ/mol. Our results showed that the identified compounds could be used as promising candidates for selective SHP2 allosteric inhibition in cancer.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"39 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141653748","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}
D. Hales, Cătălina Bogdan, L. Tefas, Andreea Cornilă, Maria-Andreea Chiver, I. Tomuțǎ, T. Casian, R. Iovanov, Gábor Katona, Rita Ambrus, Sonia Iurian
In recent years, solid dosage forms have gained interest in pediatric therapy because they can provide valuable benefits in terms of dose accuracy and stability. Particularly for orodispersible films (ODFs), the literature evidences increased acceptability and dose flexibility. Among the various available technologies for obtaining ODFs, such as solvent casting, hot-melt extrusion, and ink printing technologies, the solvent-free preparation methods exhibit significant advantages. This study investigated Vacuum Compression Molding (VCM) as a solvent-free manufacturing method for the preparation of flexible-dose pediatric orodispersible films. The experimental approach focused on selecting the appropriate plasticizer and ratios of the active pharmaceutical ingredient, diclofenac sodium, followed by the study of their impacts on the mechanical properties, disintegration time, and drug release profile of the ODFs. Additional investigations were performed to obtain insights regarding the solid-state properties. The ODFs obtained by VCM displayed adequate quality in terms of their critical characteristics. Therefore, this proof-of-concept study shows how VCM could be utilized as a standalone method for the production of small-scale ODFs, enabling the customization of doses to meet the individual needs of pediatric patients.
{"title":"Exploring Vacuum Compression Molding as a Preparation Method for Flexible-Dose Pediatric Orodispersible Films","authors":"D. Hales, Cătălina Bogdan, L. Tefas, Andreea Cornilă, Maria-Andreea Chiver, I. Tomuțǎ, T. Casian, R. Iovanov, Gábor Katona, Rita Ambrus, Sonia Iurian","doi":"10.3390/ph17070934","DOIUrl":"https://doi.org/10.3390/ph17070934","url":null,"abstract":"In recent years, solid dosage forms have gained interest in pediatric therapy because they can provide valuable benefits in terms of dose accuracy and stability. Particularly for orodispersible films (ODFs), the literature evidences increased acceptability and dose flexibility. Among the various available technologies for obtaining ODFs, such as solvent casting, hot-melt extrusion, and ink printing technologies, the solvent-free preparation methods exhibit significant advantages. This study investigated Vacuum Compression Molding (VCM) as a solvent-free manufacturing method for the preparation of flexible-dose pediatric orodispersible films. The experimental approach focused on selecting the appropriate plasticizer and ratios of the active pharmaceutical ingredient, diclofenac sodium, followed by the study of their impacts on the mechanical properties, disintegration time, and drug release profile of the ODFs. Additional investigations were performed to obtain insights regarding the solid-state properties. The ODFs obtained by VCM displayed adequate quality in terms of their critical characteristics. Therefore, this proof-of-concept study shows how VCM could be utilized as a standalone method for the production of small-scale ODFs, enabling the customization of doses to meet the individual needs of pediatric patients.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"3 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141652284","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}
S. Pescariu, Ahmed Elagez, Balaji Nallapati, F. Bratosin, Adina Bucur, A. Negru, L. Gaita, I. Citu, Z. Popa, Paula Irina Barata
Cardiovascular diseases (CVDs) constitute a significant cause of morbidity and mortality globally, particularly among individuals with type 2 diabetes mellitus (T2DM). Ertugliflozin, a Sodium-Glucose Co-transporter-2 (SGLT2) inhibitor, is hypothesized to confer cardiovascular protection; however, long-term follow-up studies are necessary to support the hypothesis. This systematic review was conducted to evaluate the cardiovascular effects of ertugliflozin in diabetic versus non-diabetic cohorts, focusing on major adverse cardiovascular events (MACEs), hospitalizations for heart failure, and cardiovascular mortality. Adhering to PRISMA guidelines, the review encompassed studies indexed in PubMed, Scopus, and Web of Science up to March 2024. Eligibility was restricted to studies involving T2DM patients undergoing ertugliflozin treatment with reported outcomes relevant to cardiovascular health. Out of 767 initially identified articles, 6 met the inclusion criteria. Data concerning hazard ratios (HR) and confidence intervals (CI) were extracted to compare the effects of ertugliflozin with those of a placebo or other standard therapies. The collective sample size across these studies was 8246 participants. Ertugliflozin was associated with a significant reduction in hospitalizations for heart failure relative to a placebo (HR 0.70, 95% CI 0.54–0.90, p < 0.05). Furthermore, when combined with metformin, ertugliflozin potentially reduced MACEs (HR 0.92, 95% CI 0.79–1.07), although this finding did not reach statistical significance. Importantly, for patients with pre-existing heart failure, ertugliflozin significantly decreased the exacerbations of heart failure (HR 0.53, 95% CI 0.33–0.84, p < 0.01). Overall, ertugliflozin markedly reduces hospitalizations due to heart failure in T2DM patients and may improve additional cardiovascular outcomes. These results endorse the integration of ertugliflozin into therapeutic protocols for T2DM patients at elevated cardiovascular risk and substantiate its efficacy among SGLT2 inhibitors. Continued investigations are recommended to delineate its long-term cardiovascular benefits in diverse patient populations, including the potential impact on arrhythmias.
心血管疾病（CVD）是全球发病率和死亡率的重要原因，尤其是在2型糖尿病（T2DM）患者中。据推测，钠-葡萄糖共转运体-2（SGLT2）抑制剂 Ertugliflozin 可保护心血管；然而，有必要进行长期随访研究来支持这一假设。本系统综述旨在评估厄曲酶在糖尿病与非糖尿病队列中对心血管的影响，重点关注主要不良心血管事件（MACE）、心衰住院率和心血管死亡率。根据 PRISMA 指南，该综述涵盖了截至 2024 年 3 月在 PubMed、Scopus 和 Web of Science 上收录的研究。研究对象仅限于接受厄曲替尼治疗的 T2DM 患者，并报告了与心血管健康相关的结果。在初步确定的 767 篇文章中，有 6 篇符合纳入标准。我们提取了有关危险比 (HR) 和置信区间 (CI) 的数据，以比较厄曲酶与安慰剂或其他标准疗法的效果。这些研究的总样本量为 8246 人。与安慰剂相比，厄曲酶联用可显著减少因心衰而住院的人数（HR 0.70，95% CI 0.54-0.90，P < 0.05）。此外，当与二甲双胍联用时，厄曲替尼有可能降低MACE（HR 0.92，95% CI 0.79-1.07），尽管这一结果未达到统计学意义。重要的是，对于已有心力衰竭的患者，厄曲利嗪可显著减少心力衰竭的加重（HR 0.53，95% CI 0.33-0.84，P < 0.01）。总体而言，厄曲利嗪可明显减少 T2DM 患者因心衰而住院的次数，并可改善其他心血管预后。这些结果支持将ertugliflozin纳入心血管风险较高的T2DM患者的治疗方案，并证实了其在SGLT2抑制剂中的疗效。建议继续进行研究，以确定其在不同患者群体中的长期心血管益处，包括对心律失常的潜在影响。
{"title":"Examining the Impact of Ertugliflozin on Cardiovascular Outcomes in Patients with Diabetes and Metabolic Syndrome: A Systematic Review of Clinical Trials","authors":"S. Pescariu, Ahmed Elagez, Balaji Nallapati, F. Bratosin, Adina Bucur, A. Negru, L. Gaita, I. Citu, Z. Popa, Paula Irina Barata","doi":"10.3390/ph17070929","DOIUrl":"https://doi.org/10.3390/ph17070929","url":null,"abstract":"Cardiovascular diseases (CVDs) constitute a significant cause of morbidity and mortality globally, particularly among individuals with type 2 diabetes mellitus (T2DM). Ertugliflozin, a Sodium-Glucose Co-transporter-2 (SGLT2) inhibitor, is hypothesized to confer cardiovascular protection; however, long-term follow-up studies are necessary to support the hypothesis. This systematic review was conducted to evaluate the cardiovascular effects of ertugliflozin in diabetic versus non-diabetic cohorts, focusing on major adverse cardiovascular events (MACEs), hospitalizations for heart failure, and cardiovascular mortality. Adhering to PRISMA guidelines, the review encompassed studies indexed in PubMed, Scopus, and Web of Science up to March 2024. Eligibility was restricted to studies involving T2DM patients undergoing ertugliflozin treatment with reported outcomes relevant to cardiovascular health. Out of 767 initially identified articles, 6 met the inclusion criteria. Data concerning hazard ratios (HR) and confidence intervals (CI) were extracted to compare the effects of ertugliflozin with those of a placebo or other standard therapies. The collective sample size across these studies was 8246 participants. Ertugliflozin was associated with a significant reduction in hospitalizations for heart failure relative to a placebo (HR 0.70, 95% CI 0.54–0.90, p < 0.05). Furthermore, when combined with metformin, ertugliflozin potentially reduced MACEs (HR 0.92, 95% CI 0.79–1.07), although this finding did not reach statistical significance. Importantly, for patients with pre-existing heart failure, ertugliflozin significantly decreased the exacerbations of heart failure (HR 0.53, 95% CI 0.33–0.84, p < 0.01). Overall, ertugliflozin markedly reduces hospitalizations due to heart failure in T2DM patients and may improve additional cardiovascular outcomes. These results endorse the integration of ertugliflozin into therapeutic protocols for T2DM patients at elevated cardiovascular risk and substantiate its efficacy among SGLT2 inhibitors. Continued investigations are recommended to delineate its long-term cardiovascular benefits in diverse patient populations, including the potential impact on arrhythmias.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"87 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141657789","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}
Nicolò Reccardini, Maria Chernovsky, F. Salton, P. Confalonieri, L. Mondini, Mariangela Barbieri, A. Romallo, Marta Maggisano, C. Torregiani, P. Geri, Michael Hughes, C. Campochiaro, M. Confalonieri, A. Scarda, Umberto Zuccon, B. Ruaro
Idiopathic pulmonary fibrosis (IPF) is a rare and progressive interstitial lung disease characterized by irreversible distortion of lung architecture and subsequent loss of pulmonary function. Pirfenidone is an antifibrotic agent associated with increased progression-free survival and overall survival rates, but it carries multiple side effects. The aim of the study was to examine the efficacy and safety profile of pirfenidone in a real-life context, with a focus on the concomitant use of antithrombotic and/or anticoagulant treatments. The clinical and functional data (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], diffusing lung capacity for carbon monoxide [DLCO], and 6 min walking test distance [6MWD]) of all IPF patients treated with pirfenidone and referred to our two centers between 2019 and 2022 were retrospectively analyzed at baseline, 6 and 12 months after the start of treatment. A total of 55 IPF subjects undergoing pirfenidone treatment were included in the analysis (45.5% females, median [IQR] age at disease onset 68.0 [10.0] years, median [IQR] age at baseline 69.0 [10.8] years). Compared to baseline, at 12 months, FVC (86.0% vs. 80.0%; p = 0.023) and DLCO (44.0% vs. 40.0%; p = 0.002) were significantly reduced, while FEV1 (p = 0.304) and 6MWD (p = 0.276) remained stable; no significant change was recorded at 6 months. Most of the reported adverse events were mild or moderate. Gastrointestinal intolerance (9.1%) was the main cause of treatment discontinuation. A total of 5% of patients reported at least one minor bleeding event, although all episodes occurred in those receiving concomitant antithrombotic or anticoagulant. Overall, this real-life experience confirms the efficacy and safety profile of pirfenidone in the case of the concomitant use of antithrombotic and/or anticoagulant drugs.
{"title":"Pirfenidone in Idiopathic Pulmonary Fibrosis: Real-World Observation on Efficacy and Safety, Focus on Patients Undergoing Antithrombotic and Anticoagulant","authors":"Nicolò Reccardini, Maria Chernovsky, F. Salton, P. Confalonieri, L. Mondini, Mariangela Barbieri, A. Romallo, Marta Maggisano, C. Torregiani, P. Geri, Michael Hughes, C. Campochiaro, M. Confalonieri, A. Scarda, Umberto Zuccon, B. Ruaro","doi":"10.3390/ph17070930","DOIUrl":"https://doi.org/10.3390/ph17070930","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a rare and progressive interstitial lung disease characterized by irreversible distortion of lung architecture and subsequent loss of pulmonary function. Pirfenidone is an antifibrotic agent associated with increased progression-free survival and overall survival rates, but it carries multiple side effects. The aim of the study was to examine the efficacy and safety profile of pirfenidone in a real-life context, with a focus on the concomitant use of antithrombotic and/or anticoagulant treatments. The clinical and functional data (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], diffusing lung capacity for carbon monoxide [DLCO], and 6 min walking test distance [6MWD]) of all IPF patients treated with pirfenidone and referred to our two centers between 2019 and 2022 were retrospectively analyzed at baseline, 6 and 12 months after the start of treatment. A total of 55 IPF subjects undergoing pirfenidone treatment were included in the analysis (45.5% females, median [IQR] age at disease onset 68.0 [10.0] years, median [IQR] age at baseline 69.0 [10.8] years). Compared to baseline, at 12 months, FVC (86.0% vs. 80.0%; p = 0.023) and DLCO (44.0% vs. 40.0%; p = 0.002) were significantly reduced, while FEV1 (p = 0.304) and 6MWD (p = 0.276) remained stable; no significant change was recorded at 6 months. Most of the reported adverse events were mild or moderate. Gastrointestinal intolerance (9.1%) was the main cause of treatment discontinuation. A total of 5% of patients reported at least one minor bleeding event, although all episodes occurred in those receiving concomitant antithrombotic or anticoagulant. Overall, this real-life experience confirms the efficacy and safety profile of pirfenidone in the case of the concomitant use of antithrombotic and/or anticoagulant drugs.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"129 16","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141656462","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}
M. Kubeczko, Dorota Gabryś, A. Polakiewicz-Gilowska, Barbara Bobek-Billewicz, Michał Jarząb
Background. The use of locoregional radiotherapy (RT) in patients with advanced ER-positive, HER2-negative breast cancer remains a topic of ongoing debate. In this study, we aimed to evaluate the efficacy of locoregional RT in advanced breast cancer patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in a first-line setting. Methods. We conducted a retrospective analysis of patients diagnosed with advanced breast cancer between 2018 and 2023 who received treatment with CDK4/6i and underwent locoregional radiotherapy. Results. Among the 371 patients treated with CDK4/6i as part of their first-line therapy, 23 received locoregional RT either concurrently or sequentially with CDK4/6 inhibitors. Disease progression within the breast occurred in 19 patients (5.1%). Among these cases, five patients had previously undergone breast RT (5/23, 21.7%), while 14 did not (14/348, 4.0%, p = 0.004). All cases of local progression after RT followed palliative doses and were accompanied by early systemic progression. The 2-year PFS in the entire cohort of patients treated with locoregional RT was 65.7% (95% CI: 40.5–82.3%). Notably, patients who received higher RT doses had longer 2-year PFS (83.3%, 95% CI: 27.3–97.5%) than those with palliative RT doses (59.3%, 95% CI: 30.7–79.3%); however, the results were not statistically significant (p = 0.58). Furthermore, the 2-year local control in the entire cohort with locoregional RT was 73.0% (95% CI: 46.5–87.9%). Importantly, no local progression was observed after RT when using high doses. Conclusions. The addition of locoregional radiotherapy to first-line CDK4/6 inhibitors warrants further investigation across various clinical scenarios in advanced breast cancer. Palliative radiation regimens delivered early in breast oligoprogression may not always suffice, emphasizing the need for comprehensive studies in this context.
{"title":"Locoregional Radiotherapy in Patients with Advanced Breast Cancer Treated with Cyclin-Dependent Kinase 4/6 Inhibitors Based on Real-World Data","authors":"M. Kubeczko, Dorota Gabryś, A. Polakiewicz-Gilowska, Barbara Bobek-Billewicz, Michał Jarząb","doi":"10.3390/ph17070927","DOIUrl":"https://doi.org/10.3390/ph17070927","url":null,"abstract":"Background. The use of locoregional radiotherapy (RT) in patients with advanced ER-positive, HER2-negative breast cancer remains a topic of ongoing debate. In this study, we aimed to evaluate the efficacy of locoregional RT in advanced breast cancer patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in a first-line setting. Methods. We conducted a retrospective analysis of patients diagnosed with advanced breast cancer between 2018 and 2023 who received treatment with CDK4/6i and underwent locoregional radiotherapy. Results. Among the 371 patients treated with CDK4/6i as part of their first-line therapy, 23 received locoregional RT either concurrently or sequentially with CDK4/6 inhibitors. Disease progression within the breast occurred in 19 patients (5.1%). Among these cases, five patients had previously undergone breast RT (5/23, 21.7%), while 14 did not (14/348, 4.0%, p = 0.004). All cases of local progression after RT followed palliative doses and were accompanied by early systemic progression. The 2-year PFS in the entire cohort of patients treated with locoregional RT was 65.7% (95% CI: 40.5–82.3%). Notably, patients who received higher RT doses had longer 2-year PFS (83.3%, 95% CI: 27.3–97.5%) than those with palliative RT doses (59.3%, 95% CI: 30.7–79.3%); however, the results were not statistically significant (p = 0.58). Furthermore, the 2-year local control in the entire cohort with locoregional RT was 73.0% (95% CI: 46.5–87.9%). Importantly, no local progression was observed after RT when using high doses. Conclusions. The addition of locoregional radiotherapy to first-line CDK4/6 inhibitors warrants further investigation across various clinical scenarios in advanced breast cancer. Palliative radiation regimens delivered early in breast oligoprogression may not always suffice, emphasizing the need for comprehensive studies in this context.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"74 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141658225","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}
Carlos Alberto-Silva, Brenda Rufino da Silva, Julio Cezar Araujo da Silva, Felipe Assumpção da Cunha e Silva, R. Kodama, Wilmar Dias da Silva, M. Costa, F. V. Portaro
Introduction. The proline-rich decapeptide 10c (Bj-PRO-10c; ENWPHPQIPP) from the Bothrops jararaca snake modulates argininosuccinate synthetase (AsS) activity to stimulate L-arginine metabolite production and neuroprotection in the SH-SY5Y cell line. The relationships between structure, interactions with AsS, and neuroprotection are little known. We evaluated the neuroprotective effects of Bj-PRO-10c and three other PROs (Bn-PRO-10a, Bn-PRO-10c > Bn-PRO-10a-MK > Bn-PRO-10a. The structure of PROs and their correlations with enzyme activity revealed that histidine (H5) and glutamine (Q7) in Bj-PRO-10c potentiated their affinity for AsS. Conclusions. Our investigation provides the first insights into the structure and molecular interactions of PROs with AsS, which could possibly further their neuropharmacological applications.
简介。来自两头蛇的富脯氨酸十肽 10c（Bj-PRO-10c；ENWPHPQIPP）能调节精氨酸琥珀酸合成酶（AsS）的活性，从而刺激 L-精氨酸代谢物的产生，并对 SH-SY5Y 细胞系产生神经保护作用。人们对结构、与 AsS 的相互作用以及神经保护之间的关系知之甚少。我们评估了 Bj-PRO-10c 和其他三种 PRO（Bn-PRO-10a、Bn-PRO-10c > Bn-PRO-10a-MK > Bn-PRO-10a）的神经保护作用。PROs的结构及其与酶活性的相关性显示，Bj-PRO-10c中的组氨酸（H5）和谷氨酰胺（Q7）增强了它们对AsS的亲和力。结论。我们的研究首次揭示了 PROs 的结构及其与 AsS 的分子相互作用，这可能会促进它们在神经药理学方面的应用。
{"title":"Small Structural Differences in Proline-Rich Decapeptides Have Specific Effects on Oxidative Stress-Induced Neurotoxicity and L-Arginine Generation by Arginosuccinate Synthase","authors":"Carlos Alberto-Silva, Brenda Rufino da Silva, Julio Cezar Araujo da Silva, Felipe Assumpção da Cunha e Silva, R. Kodama, Wilmar Dias da Silva, M. Costa, F. V. Portaro","doi":"10.3390/ph17070931","DOIUrl":"https://doi.org/10.3390/ph17070931","url":null,"abstract":"Introduction. The proline-rich decapeptide 10c (Bj-PRO-10c; ENWPHPQIPP) from the Bothrops jararaca snake modulates argininosuccinate synthetase (AsS) activity to stimulate L-arginine metabolite production and neuroprotection in the SH-SY5Y cell line. The relationships between structure, interactions with AsS, and neuroprotection are little known. We evaluated the neuroprotective effects of Bj-PRO-10c and three other PROs (Bn-PRO-10a, <ENWPRPKIPP; Bn-PRO-10a-MK, <ENWPRPKIPPMK; and, Bn-PRO-10c, <ENWPRPKVPP) identified from Bitis nasicornis snake venom, with a high degree of similarity to Bj-PRO-10c, on oxidative stress-induced toxicity in neuronal PC12 cells and L-arginine metabolite generation via AsS activity regulation. Methods. Cell integrity, metabolic activity, reactive oxygen species (ROS) production, and arginase activity were examined after 4 h of PRO pre-treatment and 20 h of H2O2-induced damage. Results. Only Bn-PRO-10a-MK and Bn-PRO-10c restored cell integrity and arginase function under oxidative stress settings, but they did not reduce ROS or cell metabolism. The MK dipeptide in Bn-PRO-10a-MK and valine (V8) in Bn-PRO-10c are important to these effects when compared to Bn-PRO-10a. Bj-PRO-10c is not neuroprotective in PC12 cells, perhaps because of their limited NMDA-type glutamate receptor activity. The PROs interaction analysis on AsS activation can be rated as follows: Bj-PRO-10c > Bn-PRO-10c > Bn-PRO-10a-MK > Bn-PRO-10a. The structure of PROs and their correlations with enzyme activity revealed that histidine (H5) and glutamine (Q7) in Bj-PRO-10c potentiated their affinity for AsS. Conclusions. Our investigation provides the first insights into the structure and molecular interactions of PROs with AsS, which could possibly further their neuropharmacological applications.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"90 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141657752","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}
Hak-Dong Lee, Genevieve Tonog, N. Uy, Yunji Lee, Ki-Young Kim, Hangeun Kim, Sanghyun Lee
Since atopic dermatitis is an inflammatory skin disease, natural remedies, such as Filipendula glaberrima Nakai (FG), with anti-inflammatory properties are possible promising therapeutic options. This study aimed to investigate the therapeutic potential of FG extracts at different growth stages. Seven compounds were isolated from the FG leaf extracts using open-column chromatography, and they were analyzed using HPLC. The extracts were further evaluated for their total polyphenol and flavonoid content (TPC and TFC). The in vitro antioxidant properties of the FG extracts were evaluated using radical scavenging assays, whereas their anti-inflammatory activities were assessed by evaluating their ability to inhibit the production of inflammation-associated biomarkers using the Griess assay and ELISA, respectively. The MTT assay was used to evaluate the viability and cytotoxicity of the FG extracts in keratinocyte cell lines. The results showed that the full-flowering stage exhibited the highest TPC, TFC, and antioxidant activities, thus suggesting a positive correlation between these properties. All FG extracts showed significant anti-inflammatory activity by inhibiting the production of pro-inflammatory biomarkers in lipopolysaccharide-stimulated macrophages. Additionally, the FG extracts suppressed the production of cytokines and chemokines in keratinocytes, indicating their anti-atopic potential. HPLC analysis revealed that the full-flowering stage had the highest content of all the analyzed phytochemicals (gallic acid, (+)-catechin, hyperin, miquelianin, astragalin, afzelin, and quercetin). These results suggest that the full-flowering stage of FG is the most promising source for therapeutic applications owing to its superior phytochemical profile and biological activities. This study highlights the potential of FG extracts, particularly in its full-flowering stage, as a natural therapeutic agent for the management of inflammation-related diseases, and it can also serve as a reference for further research on FG.
{"title":"Phytochemical Profile, Antioxidant, Anti-Atopic, and Anti-Inflammatory Activities of Filipendula glaberrima Nakai at Different Growth Stages","authors":"Hak-Dong Lee, Genevieve Tonog, N. Uy, Yunji Lee, Ki-Young Kim, Hangeun Kim, Sanghyun Lee","doi":"10.3390/ph17070928","DOIUrl":"https://doi.org/10.3390/ph17070928","url":null,"abstract":"Since atopic dermatitis is an inflammatory skin disease, natural remedies, such as Filipendula glaberrima Nakai (FG), with anti-inflammatory properties are possible promising therapeutic options. This study aimed to investigate the therapeutic potential of FG extracts at different growth stages. Seven compounds were isolated from the FG leaf extracts using open-column chromatography, and they were analyzed using HPLC. The extracts were further evaluated for their total polyphenol and flavonoid content (TPC and TFC). The in vitro antioxidant properties of the FG extracts were evaluated using radical scavenging assays, whereas their anti-inflammatory activities were assessed by evaluating their ability to inhibit the production of inflammation-associated biomarkers using the Griess assay and ELISA, respectively. The MTT assay was used to evaluate the viability and cytotoxicity of the FG extracts in keratinocyte cell lines. The results showed that the full-flowering stage exhibited the highest TPC, TFC, and antioxidant activities, thus suggesting a positive correlation between these properties. All FG extracts showed significant anti-inflammatory activity by inhibiting the production of pro-inflammatory biomarkers in lipopolysaccharide-stimulated macrophages. Additionally, the FG extracts suppressed the production of cytokines and chemokines in keratinocytes, indicating their anti-atopic potential. HPLC analysis revealed that the full-flowering stage had the highest content of all the analyzed phytochemicals (gallic acid, (+)-catechin, hyperin, miquelianin, astragalin, afzelin, and quercetin). These results suggest that the full-flowering stage of FG is the most promising source for therapeutic applications owing to its superior phytochemical profile and biological activities. This study highlights the potential of FG extracts, particularly in its full-flowering stage, as a natural therapeutic agent for the management of inflammation-related diseases, and it can also serve as a reference for further research on FG.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"142 29","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141656147","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}
Wenxuan Zhang, Zhenyi Wu, Zulifukeer Maituersong, Ting Wang, Yubin Su
Global bacterial infections are on the rise, and drug resistance to bacteria is gradually rendering existing antibiotics ineffective. Therefore, the discovery of new strategies is urgently needed. Cellular metabolism is a key factor in the regulation of bacterial drug resistance, which cannot be separated from the utilization of energetic substances, suggesting that energetic substances may be associated with bacterial drug resistance. In this study, we found that adenosine monophosphate (AMP) can enhance the bactericidal effect of gentamicin against gentamicin-resistant Staphylococcus aureus. This synergistic effect can be generalized for use with different antibiotics and Gram-positive or Gram-negative bacteria. We also validated that the mechanism of AMP reversal of antibiotic resistance involves enhancing the proton motive force via the tricarboxylic acid cycle to increase antibiotic uptake. Simultaneously, AMP increases oxidative stress-induced cell death. This study presents a strategy for adopting low-dose antibiotics to control drug-resistant bacteria, which is important for future drug development and bacterial control.
{"title":"Adenosine Monophosphate as a Metabolic Adjuvant Enhances Antibiotic Efficacy against Drug-Resistant Bacterial Pathogens","authors":"Wenxuan Zhang, Zhenyi Wu, Zulifukeer Maituersong, Ting Wang, Yubin Su","doi":"10.3390/ph17070933","DOIUrl":"https://doi.org/10.3390/ph17070933","url":null,"abstract":"Global bacterial infections are on the rise, and drug resistance to bacteria is gradually rendering existing antibiotics ineffective. Therefore, the discovery of new strategies is urgently needed. Cellular metabolism is a key factor in the regulation of bacterial drug resistance, which cannot be separated from the utilization of energetic substances, suggesting that energetic substances may be associated with bacterial drug resistance. In this study, we found that adenosine monophosphate (AMP) can enhance the bactericidal effect of gentamicin against gentamicin-resistant Staphylococcus aureus. This synergistic effect can be generalized for use with different antibiotics and Gram-positive or Gram-negative bacteria. We also validated that the mechanism of AMP reversal of antibiotic resistance involves enhancing the proton motive force via the tricarboxylic acid cycle to increase antibiotic uptake. Simultaneously, AMP increases oxidative stress-induced cell death. This study presents a strategy for adopting low-dose antibiotics to control drug-resistant bacteria, which is important for future drug development and bacterial control.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"70 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141658456","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}
David Aebisher, Iga Serafin, Katarzyna Batóg-Szczęch, Klaudia Dynarowicz, E. Chodurek, A. Kawczyk-Krupka, D. Bartusik-Aebisher
Photodynamic therapy (PDT) is a promising cancer treatment method that uses photosensitizing (PS) compounds to selectively destroy tumor cells using laser light. This review discusses the main advantages of PDT, such as its low invasiveness, minimal systemic toxicity and low risk of complications. Special attention is paid to photosensitizers obtained by chemical synthesis. Three generations of photosensitizers are presented, starting with the first, based on porphyrins, through the second generation, including modified porphyrins, chlorins, 5-aminolevulinic acid (ALA) and its derivative hexyl aminolevulinate (HAL), to the third generation, which is based on the use of nanotechnology to increase the selectivity of therapy. In addition, current research trends are highlighted, including the search for new photosensitizers that can overcome the limitations of existing therapies, such as heavy-atom-free nonporphyrinoid photosensitizers, antibody–drug conjugates (ADCs) or photosensitizers with a near-infrared (NIR) absorption peak. Finally, the prospects for the development of PDTs are presented, taking into account advances in nanotechnology and biomedical engineering. The references include both older and newer works. In many cases, when writing about a given group of first- or second-generation photosensitizers, older publications are used because the properties of the compounds described therein have not changed over the years. Moreover, older articles provide information that serves as an introduction to a given group of drugs.
{"title":"Photodynamic Therapy in the Treatment of Cancer—The Selection of Synthetic Photosensitizers","authors":"David Aebisher, Iga Serafin, Katarzyna Batóg-Szczęch, Klaudia Dynarowicz, E. Chodurek, A. Kawczyk-Krupka, D. Bartusik-Aebisher","doi":"10.3390/ph17070932","DOIUrl":"https://doi.org/10.3390/ph17070932","url":null,"abstract":"Photodynamic therapy (PDT) is a promising cancer treatment method that uses photosensitizing (PS) compounds to selectively destroy tumor cells using laser light. This review discusses the main advantages of PDT, such as its low invasiveness, minimal systemic toxicity and low risk of complications. Special attention is paid to photosensitizers obtained by chemical synthesis. Three generations of photosensitizers are presented, starting with the first, based on porphyrins, through the second generation, including modified porphyrins, chlorins, 5-aminolevulinic acid (ALA) and its derivative hexyl aminolevulinate (HAL), to the third generation, which is based on the use of nanotechnology to increase the selectivity of therapy. In addition, current research trends are highlighted, including the search for new photosensitizers that can overcome the limitations of existing therapies, such as heavy-atom-free nonporphyrinoid photosensitizers, antibody–drug conjugates (ADCs) or photosensitizers with a near-infrared (NIR) absorption peak. Finally, the prospects for the development of PDTs are presented, taking into account advances in nanotechnology and biomedical engineering. The references include both older and newer works. In many cases, when writing about a given group of first- or second-generation photosensitizers, older publications are used because the properties of the compounds described therein have not changed over the years. Moreover, older articles provide information that serves as an introduction to a given group of drugs.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"94 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141658035","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}
Yeoum Choi, Jung-Mo Yang, C. Jeong, Sujin Shin, Junkyu Park, Kyungjin Lee, Ju-Hyun Cho
The incidence of cardiovascular diseases, such as high blood pressure, is increasing worldwide, owing to population aging and irregular lifestyle habits. Previous studies have reported the vasorelaxant effects of Prunus yedoensis bark methanol extract. However, various solvent extracts of P. yedoensis bark and their vascular relaxation mechanisms have not been sufficiently studied. We prepared extracts of P. yedoensis bark using various solvents (water, 30% ethanol, and 70% ethanol). P. yedoensis bark 30% ethanol extract (PYB-30E) decreased the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin in human umbilical vein endothelial cells (HUVECs) activated with 200 ng/mL TNF-α. Additionally, PYB-30E showed vasodilatory effects on isolated rat aortic rings. This was confirmed to be the result of the activation of the NO/cGMP pathway, regulation of non-selective calcium-activated K+ channels, and calcium channel blockade. Additionally, PYB-30E significantly reduced systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR). Taken together, our results indicated that PYB-30E is a candidate functional material with preventive and therapeutic effects against hypertension.
{"title":"Prunus yedoensis Bark Downregulates the Expression of Cell Adhesion Molecules in Human Endothelial Cell Lines and Relaxes Blood Vessels in Rat Aortic Rings","authors":"Yeoum Choi, Jung-Mo Yang, C. Jeong, Sujin Shin, Junkyu Park, Kyungjin Lee, Ju-Hyun Cho","doi":"10.3390/ph17070926","DOIUrl":"https://doi.org/10.3390/ph17070926","url":null,"abstract":"The incidence of cardiovascular diseases, such as high blood pressure, is increasing worldwide, owing to population aging and irregular lifestyle habits. Previous studies have reported the vasorelaxant effects of Prunus yedoensis bark methanol extract. However, various solvent extracts of P. yedoensis bark and their vascular relaxation mechanisms have not been sufficiently studied. We prepared extracts of P. yedoensis bark using various solvents (water, 30% ethanol, and 70% ethanol). P. yedoensis bark 30% ethanol extract (PYB-30E) decreased the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin in human umbilical vein endothelial cells (HUVECs) activated with 200 ng/mL TNF-α. Additionally, PYB-30E showed vasodilatory effects on isolated rat aortic rings. This was confirmed to be the result of the activation of the NO/cGMP pathway, regulation of non-selective calcium-activated K+ channels, and calcium channel blockade. Additionally, PYB-30E significantly reduced systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR). Taken together, our results indicated that PYB-30E is a candidate functional material with preventive and therapeutic effects against hypertension.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141660506","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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