Mahnoor Pasha, Ammara Zamir, M. Rasool, Hamid Saeed, Tanveer Ahmad, N. S. Alqahtani, Lamya Saif Alqahtani, F. Alqahtani
Physiologically based pharmacokinetic (PBPK) modeling is of great importance in the field of medicine. This study aims to construct a PBPK model, which can provide reliable drug pharmacokinetic (PK) predictions in both healthy and chronic kidney disease (CKD) subjects. To do so, firstly a review of the literature was thoroughly conducted and the PK information of vildagliptin was collected. PBPK modeling software, PK-Sim®, was then used to build and assess the IV, oral, and drug-specific models. Next, the average fold error, visual predictive checks, and predicted/observed ratios were used for the assessment of the robustness of the model for all the essential PK parameters. This evaluation demonstrated that all PK parameters were within an acceptable limit of error, i.e., 2 fold. Also to display the influence of CKD on the total and unbound AUC (the area under the plasma concentration–time curve) and to make modifications in dose, the analysis results of the model on this aspect were further examined. This PBPK model has successfully depicted the variations of PK of vildagliptin in healthy subjects and patients with CKD, which can be useful for medical practitioners in dosage optimization in renal disease patients.
{"title":"A Comprehensive Physiologically Based Pharmacokinetic Model for Predicting Vildagliptin Pharmacokinetics: Insights into Dosing in Renal Impairment","authors":"Mahnoor Pasha, Ammara Zamir, M. Rasool, Hamid Saeed, Tanveer Ahmad, N. S. Alqahtani, Lamya Saif Alqahtani, F. Alqahtani","doi":"10.3390/ph17070924","DOIUrl":"https://doi.org/10.3390/ph17070924","url":null,"abstract":"Physiologically based pharmacokinetic (PBPK) modeling is of great importance in the field of medicine. This study aims to construct a PBPK model, which can provide reliable drug pharmacokinetic (PK) predictions in both healthy and chronic kidney disease (CKD) subjects. To do so, firstly a review of the literature was thoroughly conducted and the PK information of vildagliptin was collected. PBPK modeling software, PK-Sim®, was then used to build and assess the IV, oral, and drug-specific models. Next, the average fold error, visual predictive checks, and predicted/observed ratios were used for the assessment of the robustness of the model for all the essential PK parameters. This evaluation demonstrated that all PK parameters were within an acceptable limit of error, i.e., 2 fold. Also to display the influence of CKD on the total and unbound AUC (the area under the plasma concentration–time curve) and to make modifications in dose, the analysis results of the model on this aspect were further examined. This PBPK model has successfully depicted the variations of PK of vildagliptin in healthy subjects and patients with CKD, which can be useful for medical practitioners in dosage optimization in renal disease patients.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"14 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141660999","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}
Xu Sun, Xushuang Jia, Zhaolin Tan, Dongmei Fan, Meiqi Chen, Ning Cui, Aidong Liu, Da Liu
Atherosclerosis (AS) is the formation of atherosclerotic plaques on the walls of the arteries, causing them to narrow. If this occurs in the coronary arteries, the blood vessels may be completely blocked, resulting in myocardial infarction; if it occurs in the blood vessels of the brain, the blood vessels may be blocked, resulting in cerebral infarction, i.e., stroke. Studies have shown that the pathogenesis of atherosclerosis involves the processes of inflammation, lipid infiltration, oxidative stress, and endothelial damage, etc. SIRT, as a key factor regulating the molecular mechanisms of oxidative stress, inflammation, and aging, has an important impact on the pathogenesis of plaque formation, progression, and vulnerability. Statistics show that AS accounts for about 50 per cent of deaths in Western countries. Currently, oral medication is the mainstay of AS treatment, but its development is limited by side effects, low bioavailability and other unfavourable factors. In recent years, with the rapid development of nano-preparations, researchers have combined statins and natural product drugs within nanopreparations to improve their bioavailability. Based on this, this paper summarises the main pathogenesis of AS and also proposes new oral nanoformulations such as liposomes, nanoparticles, nanoemulsions, and nanocapsules to improve their application in the treatment of AS.
{"title":"Oral Nanoformulations in Cardiovascular Medicine: Advances in Atherosclerosis Treatment","authors":"Xu Sun, Xushuang Jia, Zhaolin Tan, Dongmei Fan, Meiqi Chen, Ning Cui, Aidong Liu, Da Liu","doi":"10.3390/ph17070919","DOIUrl":"https://doi.org/10.3390/ph17070919","url":null,"abstract":"Atherosclerosis (AS) is the formation of atherosclerotic plaques on the walls of the arteries, causing them to narrow. If this occurs in the coronary arteries, the blood vessels may be completely blocked, resulting in myocardial infarction; if it occurs in the blood vessels of the brain, the blood vessels may be blocked, resulting in cerebral infarction, i.e., stroke. Studies have shown that the pathogenesis of atherosclerosis involves the processes of inflammation, lipid infiltration, oxidative stress, and endothelial damage, etc. SIRT, as a key factor regulating the molecular mechanisms of oxidative stress, inflammation, and aging, has an important impact on the pathogenesis of plaque formation, progression, and vulnerability. Statistics show that AS accounts for about 50 per cent of deaths in Western countries. Currently, oral medication is the mainstay of AS treatment, but its development is limited by side effects, low bioavailability and other unfavourable factors. In recent years, with the rapid development of nano-preparations, researchers have combined statins and natural product drugs within nanopreparations to improve their bioavailability. Based on this, this paper summarises the main pathogenesis of AS and also proposes new oral nanoformulations such as liposomes, nanoparticles, nanoemulsions, and nanocapsules to improve their application in the treatment of AS.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"18 13","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141661631","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}
This research is based on three fundamental aspects of successful biosimilar development in the challenging biopharmaceutical market. First, biosimilar regulations in eight selected countries: Japan, South Korea, the United States, Canada, Brazil, Argentina, Australia, and South Africa, represent the four continents. The regulatory aspects of the countries studied are analyzed, highlighting the challenges facing biosimilars, including their complex approval processes and the need for standardized regulatory guidelines. There is an inconsistency depending on whether the biosimilar is used in a developed or developing country. In the countries observed, biosimilars are considered excellent alternatives to patent-protected biological products for the treatment of chronic diseases. In the second aspect addressed, various analytical AI modeling methods (such as machine learning tools, reinforcement learning, supervised, unsupervised, and deep learning tools) were analyzed to observe patterns that lead to the prevalence of biosimilars used in cancer to model the behaviors of the most prominent active compounds with spectroscopy. Finally, an analysis of the use of active compounds of biosimilars used in cancer and approved by the FDA and EMA was proposed.
这项研究基于在充满挑战的生物制药市场中成功开发生物仿制药的三个基本方面。首先，八个选定国家的生物仿制药法规：日本、韩国、美国、加拿大、巴西、阿根廷、澳大利亚和南非代表了四大洲。对所研究国家的监管方面进行了分析，强调了生物仿制药所面临的挑战，包括其复杂的审批程序和对标准化监管准则的需求。生物仿制药在发达国家还是发展中国家的使用情况并不一致。在观察到的国家中，生物仿制药被认为是治疗慢性病的受专利保护生物制品的最佳替代品。在第二个方面，分析了各种分析性人工智能建模方法（如机器学习工具、强化学习、有监督、无监督和深度学习工具），以观察导致生物仿制药在癌症中普遍使用的模式，从而利用光谱学对最突出的活性化合物的行为进行建模。最后，提出了对用于癌症并获得 FDA 和 EMA 批准的生物仿制药活性化合物使用情况的分析。
{"title":"Biosimilars in the Era of Artificial Intelligence—International Regulations and the Use in Oncological Treatments","authors":"T. G. Bas, V. Duarte","doi":"10.3390/ph17070925","DOIUrl":"https://doi.org/10.3390/ph17070925","url":null,"abstract":"This research is based on three fundamental aspects of successful biosimilar development in the challenging biopharmaceutical market. First, biosimilar regulations in eight selected countries: Japan, South Korea, the United States, Canada, Brazil, Argentina, Australia, and South Africa, represent the four continents. The regulatory aspects of the countries studied are analyzed, highlighting the challenges facing biosimilars, including their complex approval processes and the need for standardized regulatory guidelines. There is an inconsistency depending on whether the biosimilar is used in a developed or developing country. In the countries observed, biosimilars are considered excellent alternatives to patent-protected biological products for the treatment of chronic diseases. In the second aspect addressed, various analytical AI modeling methods (such as machine learning tools, reinforcement learning, supervised, unsupervised, and deep learning tools) were analyzed to observe patterns that lead to the prevalence of biosimilars used in cancer to model the behaviors of the most prominent active compounds with spectroscopy. Finally, an analysis of the use of active compounds of biosimilars used in cancer and approved by the FDA and EMA was proposed.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"53 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141660052","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}
Sara M. Hassan, A. Farid, Siva S Panda, M. Bekheit, Holden Dinkins, W. Fayad, A. S. Girgis
Cancer remains a formidable global health challenge, with current treatment modalities such as chemotherapy, radiotherapy, surgery, and targeted therapy often hindered by low efficacy and adverse side effects. The indole scaffold, a prominent heterocyclic structure, has emerged as a promising candidate in the fight against cancer. This review consolidates recent advancements in developing natural and synthetic indolyl analogs, highlighting their antiproliferative activities against various cancer types over the past five years. These analogs are categorized based on their efficacy against common cancer types, supported by biochemical assays demonstrating their antiproliferative properties. In this review, emphasis is placed on elucidating the mechanisms of action of these compounds. Given the limitations of conventional cancer therapies, developing targeted therapeutics with enhanced selectivity and reduced side effects remains a critical focus in oncological research.
{"title":"Indole Compounds in Oncology: Therapeutic Potential and Mechanistic Insights","authors":"Sara M. Hassan, A. Farid, Siva S Panda, M. Bekheit, Holden Dinkins, W. Fayad, A. S. Girgis","doi":"10.3390/ph17070922","DOIUrl":"https://doi.org/10.3390/ph17070922","url":null,"abstract":"Cancer remains a formidable global health challenge, with current treatment modalities such as chemotherapy, radiotherapy, surgery, and targeted therapy often hindered by low efficacy and adverse side effects. The indole scaffold, a prominent heterocyclic structure, has emerged as a promising candidate in the fight against cancer. This review consolidates recent advancements in developing natural and synthetic indolyl analogs, highlighting their antiproliferative activities against various cancer types over the past five years. These analogs are categorized based on their efficacy against common cancer types, supported by biochemical assays demonstrating their antiproliferative properties. In this review, emphasis is placed on elucidating the mechanisms of action of these compounds. Given the limitations of conventional cancer therapies, developing targeted therapeutics with enhanced selectivity and reduced side effects remains a critical focus in oncological research.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"16 15","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141659890","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}
Danishuddin, Md Azizul Haque, M. Z. Malik, Rakesh Arya, Pooja Singh, Jeong-Sang Lee, Jong-Joo Kim, Keun-Woo Lee, T. Jung
Head and neck cancer ranks as the sixth-most common malignancy worldwide, characterized by high mortality and recurrence rates. Research studies indicate that molecular diagnostics play a crucial role in the early detection and prognostic evaluation of these diseases. This study aimed to identify potential biomarkers for head and neck cancer and elucidate their interactions with miRNAs and possible therapeutic drugs. Four drivers, namely, FN1, IL1A, COL1A1, and MMP9, were identified using network biology and machine learning approaches. Gene set variation analysis (GSVA) showed that these genes were significantly involved in different biological processes and pathways, including coagulation, UV-response-down, apoptosis, NOTCH signaling, Wnt-beta catenin, and other signal pathways. The diagnostic value of these hub genes was validated using receiver operating characteristic (ROC) curves. The top interactive miRNAs, including miR-128-3p, miR-218-5p, miR-214-3p, miR-124-3p, miR-129-2-3p, and miR-1-3p, targeted the key genes. Furthermore, the interaction between the key genes and drugs was also identified. In summary, the key genes and miRNAs or drugs reported in this study might provide valuable information for potential biomarkers to increase the prognosis and diagnosis of head and neck cancer.
{"title":"Unveiling the Mechanisms Underlying the Immunotherapeutic Potential of Gene–miRNA and Drugs in Head and Neck Cancer","authors":"Danishuddin, Md Azizul Haque, M. Z. Malik, Rakesh Arya, Pooja Singh, Jeong-Sang Lee, Jong-Joo Kim, Keun-Woo Lee, T. Jung","doi":"10.3390/ph17070921","DOIUrl":"https://doi.org/10.3390/ph17070921","url":null,"abstract":"Head and neck cancer ranks as the sixth-most common malignancy worldwide, characterized by high mortality and recurrence rates. Research studies indicate that molecular diagnostics play a crucial role in the early detection and prognostic evaluation of these diseases. This study aimed to identify potential biomarkers for head and neck cancer and elucidate their interactions with miRNAs and possible therapeutic drugs. Four drivers, namely, FN1, IL1A, COL1A1, and MMP9, were identified using network biology and machine learning approaches. Gene set variation analysis (GSVA) showed that these genes were significantly involved in different biological processes and pathways, including coagulation, UV-response-down, apoptosis, NOTCH signaling, Wnt-beta catenin, and other signal pathways. The diagnostic value of these hub genes was validated using receiver operating characteristic (ROC) curves. The top interactive miRNAs, including miR-128-3p, miR-218-5p, miR-214-3p, miR-124-3p, miR-129-2-3p, and miR-1-3p, targeted the key genes. Furthermore, the interaction between the key genes and drugs was also identified. In summary, the key genes and miRNAs or drugs reported in this study might provide valuable information for potential biomarkers to increase the prognosis and diagnosis of head and neck cancer.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"10 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141659314","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}
Emma Custers, D. Vreeken, Frank H. J. Schuren, T. J. van den Broek, Lieke van Dongen, B. Geenen, Ivo de Blaauw, M. Wiesmann, Eric J. Hazebroek, Robert Kleemann, Amanda J. Kiliaan
Obesity is a multifactorial disease associated with low-grade inflammation. The gut is thought to be involved in obesity-related inflammation, as it is continuously exposed to antigens from food, microbiota and metabolites. However, the exact underlying mechanisms are still unknown. Therefore, we examined the relation between gut pathology, microbiota, its metabolites and cytokines in adults with severe obesity. Individuals eligible for bariatric surgery were included. Fecal and plasma samples were collected at surgery timepoint, to assess microbiota and metabolite composition. Jejunal biopsies were collected during surgery and stained for cytotoxic T cells, macrophages, mast cells and tight junction component zonula occludens-1. Based on these stainings, the cohort was divided into four groups: high versus low intestinal inflammation and high versus low intestinal integrity. We found no significant differences in microbiota diversity between groups, nor for individual bacterial species. No significant differences in metabolites were observed between the intestinal inflammatory groups. However, some metabolites and cytokines differed between the intestinal integrity groups. Higher plasma levels of interleukin-8 and tauro-chenodeoxycholic acid were found, whereas isovaleric acid and acetic acid were lower in the high intestinal integrity group. As the results were very subtle, we suggest that our cohort shows very early and minor intestinal pathology.
肥胖症是一种与低度炎症相关的多因素疾病。肠道被认为参与了与肥胖相关的炎症，因为它不断接触到来自食物、微生物群和代谢物的抗原。然而，其确切的内在机制仍然未知。因此，我们研究了重度肥胖成人的肠道病理、微生物群、其代谢物和细胞因子之间的关系。研究对象包括符合减肥手术条件的患者。在手术时间点收集粪便和血浆样本，以评估微生物群和代谢物组成。手术期间收集空肠活检组织，并对细胞毒性 T 细胞、巨噬细胞、肥大细胞和紧密连接成分 zonula occludens-1 进行染色。根据这些染色结果，样本被分为四组：肠道炎症程度高与低，肠道完整性程度高与低。我们发现各组之间的微生物群多样性和单个细菌种类没有明显差异。肠道炎症组之间的代谢物也无明显差异。不过，一些代谢物和细胞因子在肠道完整性组之间存在差异。在肠道完整性高的组别中，白细胞介素-8 和陶罗-去氧胆酸的血浆水平较高，而异戊酸和乙酸的血浆水平较低。由于结果非常微妙，我们认为我们的队列显示出非常早期和轻微的肠道病变。
{"title":"Impact of Microbiota and Metabolites on Intestinal Integrity and Inflammation in Severe Obesity","authors":"Emma Custers, D. Vreeken, Frank H. J. Schuren, T. J. van den Broek, Lieke van Dongen, B. Geenen, Ivo de Blaauw, M. Wiesmann, Eric J. Hazebroek, Robert Kleemann, Amanda J. Kiliaan","doi":"10.3390/ph17070918","DOIUrl":"https://doi.org/10.3390/ph17070918","url":null,"abstract":"Obesity is a multifactorial disease associated with low-grade inflammation. The gut is thought to be involved in obesity-related inflammation, as it is continuously exposed to antigens from food, microbiota and metabolites. However, the exact underlying mechanisms are still unknown. Therefore, we examined the relation between gut pathology, microbiota, its metabolites and cytokines in adults with severe obesity. Individuals eligible for bariatric surgery were included. Fecal and plasma samples were collected at surgery timepoint, to assess microbiota and metabolite composition. Jejunal biopsies were collected during surgery and stained for cytotoxic T cells, macrophages, mast cells and tight junction component zonula occludens-1. Based on these stainings, the cohort was divided into four groups: high versus low intestinal inflammation and high versus low intestinal integrity. We found no significant differences in microbiota diversity between groups, nor for individual bacterial species. No significant differences in metabolites were observed between the intestinal inflammatory groups. However, some metabolites and cytokines differed between the intestinal integrity groups. Higher plasma levels of interleukin-8 and tauro-chenodeoxycholic acid were found, whereas isovaleric acid and acetic acid were lower in the high intestinal integrity group. As the results were very subtle, we suggest that our cohort shows very early and minor intestinal pathology.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"23 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141661954","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}
Yucan Yang, Huizhi Chen, Yunjie Li, Junting Liang, Feng Huang, Liyan Wang, Huilai Miao, H. S. Nanda, Jin Wu, Xinsheng Peng, Yubin Zhou
An increasing number of novel biomaterials have been applied in wound healing therapy. Creating beneficial environments and containing various bioactive molecules, hydrogel- and extracellular vesicle (EV)-based therapies have respectively emerged as effective approaches for wound healing. Moreover, the synergistic combination of these two components demonstrates more favorable outcomes in both chronic and acute wound healing. This review provides a comprehensive discussion and summary of the combined application of EVs and hydrogels to address the intricate scenario of wounds. The wound healing process and related biological mechanisms are outlined in the first section. Subsequently, the utilization of EV-loaded hydrogels during the wound healing process is evaluated and discussed. The moist environment created by hydrogels is conducive to wound tissue regeneration. Additionally, the continuous and controlled release of EVs from various origins could be achieved by hydrogel encapsulation. Finally, recent in vitro and in vivo studies reported on hydrogel dressings loaded with EVs are summarized and challenges and opportunities for the future clinical application of this therapeutic approach are outlined.
越来越多的新型生物材料被应用于伤口愈合治疗。基于水凝胶和细胞外囊泡 (EV) 的疗法能创造有益的环境并含有各种生物活性分子，已分别成为伤口愈合的有效方法。此外，这两种成分的协同组合在慢性和急性伤口愈合中都显示出更有利的结果。本综述全面讨论和总结了如何结合应用 EVs 和水凝胶来应对伤口的复杂情况。第一部分概述了伤口愈合过程和相关生物机制。随后，评估并讨论了在伤口愈合过程中使用负载 EV 的水凝胶的情况。水凝胶创造的潮湿环境有利于伤口组织再生。此外，通过水凝胶封装，可以实现持续、可控地释放来自不同来源的 EV。最后，总结了最近有关负载 EVs 的水凝胶敷料的体外和体内研究报告，并概述了这种治疗方法未来临床应用的挑战和机遇。
{"title":"Hydrogel Loaded with Extracellular Vesicles: An Emerging Strategy for Wound Healing","authors":"Yucan Yang, Huizhi Chen, Yunjie Li, Junting Liang, Feng Huang, Liyan Wang, Huilai Miao, H. S. Nanda, Jin Wu, Xinsheng Peng, Yubin Zhou","doi":"10.3390/ph17070923","DOIUrl":"https://doi.org/10.3390/ph17070923","url":null,"abstract":"An increasing number of novel biomaterials have been applied in wound healing therapy. Creating beneficial environments and containing various bioactive molecules, hydrogel- and extracellular vesicle (EV)-based therapies have respectively emerged as effective approaches for wound healing. Moreover, the synergistic combination of these two components demonstrates more favorable outcomes in both chronic and acute wound healing. This review provides a comprehensive discussion and summary of the combined application of EVs and hydrogels to address the intricate scenario of wounds. The wound healing process and related biological mechanisms are outlined in the first section. Subsequently, the utilization of EV-loaded hydrogels during the wound healing process is evaluated and discussed. The moist environment created by hydrogels is conducive to wound tissue regeneration. Additionally, the continuous and controlled release of EVs from various origins could be achieved by hydrogel encapsulation. Finally, recent in vitro and in vivo studies reported on hydrogel dressings loaded with EVs are summarized and challenges and opportunities for the future clinical application of this therapeutic approach are outlined.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141662314","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}
Marco Alexander Valverde Akamine, Beatriz Moreira Ayub Ferreira Soares, João Paulo Mota Telles, Arthur Cicupira Rodrigues de Assis, Gabriela Nicole Valverde Rodriguez, Paulo Rogério Soares, W. A. Chalela, T. Scudeler
Background: Ischemic preconditioning (IP) is a powerful cellular protection mechanism. The cellular pathways underlying IP are extremely complex and involve the participation of cell triggers, intracellular signaling pathways, and end-effectors. Experimental studies have shown that sodium-glucose transport protein 2 (SGLT2) inhibitors promote activation of 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK), the main regulator of adenosine 5′-triphosphate homeostasis and energy metabolism in the body. Despite its cardioprotective profile demonstrated by numerous clinical trials, the results of studies on the action of SGLT2 inhibitors in IP are scarce. This study will investigate the effects of dapagliflozin on IP in patients with coronary artery disease (CAD). Methods: The study will include 50 patients with multivessel CAD, ischemia documented by stress testing, and preserved left ventricular ejection fraction (LVEF). Patients will undergo four exercise tests, the first two with a time interval of 30 min between them after washout of cardiovascular or hypoglycemic medications and the last two after 7 days of dapagliflozin 10 mg once a day, also with a time interval of 30 min between them. Discussion: The role of SGLT2 inhibitors on IP is not clearly established. Several clinical trials have shown that SGLT2 inhibitors reduce the occurrence cardiovascular events, notably heart failure. However, such studies have not shown beneficial metabolic effects of SGLT2 inhibitors, such as reducing myocardial infarction or stroke. On the other hand, experimental studies with animal models have shown the beneficial effects of SGLT2 inhibitors on IP, a mechanism that confers cardiac and vascular protection from subsequent ischemia–reperfusion (IR) injury. This is the first clinical study to evaluate the effects of SGLT2 inhibitors on IP, which could result in an important advance in the treatment of patients with stable CAD.
背景：缺血预处理（IP）是一种强大的细胞保护机制。缺血预处理的细胞通路极其复杂，涉及细胞触发器、细胞内信号通路和终效应器的参与。实验研究表明，钠-葡萄糖转运蛋白 2（SGLT2）抑制剂可促进 5′-腺苷单磷酸（AMP）激活蛋白激酶（AMPK）的活化，AMPK 是体内腺苷 5′-三磷酸平衡和能量代谢的主要调节因子。尽管大量临床试验证明 SGLT2 抑制剂具有保护心脏的作用，但有关其在 IP 中作用的研究结果却很少。本研究将探讨达帕格列净对冠状动脉疾病（CAD）患者 IP 的影响。研究方法研究将包括 50 名患有多支血管并发症（CAD）、压力测试显示存在缺血且左心室射血分数（LVEF）保持不变的患者。患者将接受四次运动测试，前两次测试间隔时间为 30 分钟，测试前应停用心血管或降糖药物；后两次测试间隔时间为 30 分钟，测试前应服用达帕格列净 10 毫克，每天一次，共服用 7 天。讨论SGLT2 抑制剂对 IP 的作用尚未明确。一些临床试验显示，SGLT2 抑制剂可减少心血管事件的发生，尤其是心力衰竭。然而，这些研究并未显示 SGLT2 抑制剂对代谢产生有益影响，如减少心肌梗死或中风。另一方面，动物模型实验研究表明，SGLT2 抑制剂对 IP 有益，这种机制可保护心脏和血管免受随后的缺血再灌注（IR）损伤。这是第一项评估 SGLT2 抑制剂对 IP 影响的临床研究，可能会为稳定型 CAD 患者的治疗带来重要进展。
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Kerra™, a Thai traditional herbal medicine derived from the “Tak-Ka-Si-La Scripture” and composed of nine medicinal plants, has demonstrated potential antiviral properties against HIV. This study investigated the inhibitory effects of Kerra™ on HIV-1 reverse transcriptase (RT) and its ability to prevent pseudo-HIV viral infection in HEK293 cells. The results showed that Kerra™ extract achieved a 95.73 ± 4.24% relative inhibition of HIV-1 RT, with an IC50 value of 42.66 ± 8.74 µg/mL. Docking studies revealed that key phytochemicals in Kerra™, such as oleamide, formononetin, and biochanin A, interact with several residues in the RT non-nucleoside binding pocket, contributing to their inhibitory effects. Furthermore, Kerra™ was able to reduce pseudo-HIV infection in HEK293 cells at a concentration of 10 µg/mL, suggesting its potential as a supplementary treatment for HIV.
Kerra™ 是一种泰国传统草药，源自《Tak-Ka-Si-La 经》，由九种药用植物组成，具有潜在的抗 HIV 病毒特性。本研究调查了 Kerra™ 对 HIV-1 逆转录酶（RT）的抑制作用及其在 HEK293 细胞中预防假性 HIV 病毒感染的能力。结果表明，Kerra™ 提取物对 HIV-1 RT 的相对抑制率为 95.73 ± 4.24%，IC50 值为 42.66 ± 8.74 µg/mL。对接研究显示，Kerra™中的主要植物化学物质，如油酰胺、甲萘素和生物香豆素A，与RT非核苷结合袋中的几个残基相互作用，从而产生抑制作用。此外，当 Kerra™ 的浓度为 10 µg/mL 时，它还能减少 HEK293 细胞中的假性 HIV 感染，这表明它具有作为 HIV 辅助疗法的潜力。
{"title":"Anti-Human Immunodeficiency Virus-1 Property of Thai Herbal Extract Kerra™","authors":"Siriwan Saehlee, Supaphorn Seetaha, Wiwat Klankaew, Pussadee Srathong, K. Choowongkomon, Khuanjarat Choengpanya","doi":"10.3390/ph17070917","DOIUrl":"https://doi.org/10.3390/ph17070917","url":null,"abstract":"Kerra™, a Thai traditional herbal medicine derived from the “Tak-Ka-Si-La Scripture” and composed of nine medicinal plants, has demonstrated potential antiviral properties against HIV. This study investigated the inhibitory effects of Kerra™ on HIV-1 reverse transcriptase (RT) and its ability to prevent pseudo-HIV viral infection in HEK293 cells. The results showed that Kerra™ extract achieved a 95.73 ± 4.24% relative inhibition of HIV-1 RT, with an IC50 value of 42.66 ± 8.74 µg/mL. Docking studies revealed that key phytochemicals in Kerra™, such as oleamide, formononetin, and biochanin A, interact with several residues in the RT non-nucleoside binding pocket, contributing to their inhibitory effects. Furthermore, Kerra™ was able to reduce pseudo-HIV infection in HEK293 cells at a concentration of 10 µg/mL, suggesting its potential as a supplementary treatment for HIV.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"104 34","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141666398","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}
Ting Lei, Chang Jiang, Li Zhao, Jizhou Zhang, Qing Xiao, Yanhong Chen, Jie Zhang, Chunquan Zhou, Gong Wang, Jing Han
Clematis Florida (CF) is a folk medicinal herb in the southeast of China, which is traditionally used for treating osteoarticular diseases. However, the mechanism of its action remains unclear. The present study used network pharmacology and experimental validation to explore the mechanism of CF in the treatment of rheumatoid arthritis (RA). Liquid chromatography–mass spectrometry (LC-MS/MS) identified 50 main compounds of CF; then, their targets were obtained from TCMSP, ETCM, ITCM, and SwissTargetPrediction databases. RA disease-related targets were obtained from DisGeNET, OMIM, and GeneCards databases, and 99 overlapped targets were obtained using a Venn diagram. The protein–protein interaction network (PPI), the compound–target network (CT), and the compound–potential target genes–signaling pathways network (CPS) were constructed and analyzed. The results showed that the core compounds were screened as oleanolic acid, oleic acid, ferulic acid, caffeic acid, and syringic acid. The core therapeutic targets were predicted via network pharmacology analysis as PTGS2 (COX-2), MAPK1, NF-κB1, TNF, and RELA, which belong to the MAPK signaling pathway and NF-κB signaling pathway. The animal experiments indicated that topical application of CF showed significant anti-inflammatory activity in a mouse model of xylene-induced ear edema and had strong analgesic effect on acetic acid-induced writhing. Furthermore, in the rat model of adjuvant arthritis (AA), topical administration of CF was able to alleviate toe swelling and ameliorate joint damage. The elevated serum content levels of IL-6, COX-2, TNF-α, IL-1β, and RF caused by adjuvant arthritis were reduced by CF treatment. Western blotting tests showed that CF may regulate the ERK and NF-κB pathway. The results provide a new perspective for the topical application of CF for treatment of RA.
{"title":"Exploring the Mechanism of Topical Application of Clematis Florida in the Treatment of Rheumatoid Arthritis through Network Pharmacology and Experimental Validation","authors":"Ting Lei, Chang Jiang, Li Zhao, Jizhou Zhang, Qing Xiao, Yanhong Chen, Jie Zhang, Chunquan Zhou, Gong Wang, Jing Han","doi":"10.3390/ph17070914","DOIUrl":"https://doi.org/10.3390/ph17070914","url":null,"abstract":"Clematis Florida (CF) is a folk medicinal herb in the southeast of China, which is traditionally used for treating osteoarticular diseases. However, the mechanism of its action remains unclear. The present study used network pharmacology and experimental validation to explore the mechanism of CF in the treatment of rheumatoid arthritis (RA). Liquid chromatography–mass spectrometry (LC-MS/MS) identified 50 main compounds of CF; then, their targets were obtained from TCMSP, ETCM, ITCM, and SwissTargetPrediction databases. RA disease-related targets were obtained from DisGeNET, OMIM, and GeneCards databases, and 99 overlapped targets were obtained using a Venn diagram. The protein–protein interaction network (PPI), the compound–target network (CT), and the compound–potential target genes–signaling pathways network (CPS) were constructed and analyzed. The results showed that the core compounds were screened as oleanolic acid, oleic acid, ferulic acid, caffeic acid, and syringic acid. The core therapeutic targets were predicted via network pharmacology analysis as PTGS2 (COX-2), MAPK1, NF-κB1, TNF, and RELA, which belong to the MAPK signaling pathway and NF-κB signaling pathway. The animal experiments indicated that topical application of CF showed significant anti-inflammatory activity in a mouse model of xylene-induced ear edema and had strong analgesic effect on acetic acid-induced writhing. Furthermore, in the rat model of adjuvant arthritis (AA), topical administration of CF was able to alleviate toe swelling and ameliorate joint damage. The elevated serum content levels of IL-6, COX-2, TNF-α, IL-1β, and RF caused by adjuvant arthritis were reduced by CF treatment. Western blotting tests showed that CF may regulate the ERK and NF-κB pathway. The results provide a new perspective for the topical application of CF for treatment of RA.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"119 36","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141665499","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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