Naunyn-Schmiedeberg's archives of pharmacology最新文献

{"title":"Cancer-associated fibroblast-secreted exosomal miR-454-3p inhibits lipid metabolism and ferroptosis in breast cancer by targeting ACSL4.","authors":"Yuanyuan Gao, Ying Huang, Yanjiao Zhao, Ping Hu","doi":"10.1007/s00210-024-03488-8","DOIUrl":"10.1007/s00210-024-03488-8","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) participate in the development of the tumor microenvironment through the secretion of exosomes. Acyl-CoA synthetase long-chain family member 4 (ACSL4) is an essential component of ferroptosis. However, the regulatory mechanism of ACSL4 in breast cancer remains unexplored. The study aimed to determine the influence of exosomal miR-454-3p from CAFs on lipid metabolism and ferroptosis. CAF-derived exosomes (CAF-exo) were isolated from breast cancer tissue of breast cancer patients and characterized using transmission electron microscopy (TEM) and Western blot. Luciferase reporter assay and RNA immunoprecipitation (RIP) were used to demonstrate the relationship between miR-454-3p and ACSL4. Cell viability and ferroptosis-related markers were detected by CCK-8 and Western blot. Malondialdehyde (MDA), glutathione (GSH), and iron levels were detected. Reverse transcription-quantitative PCR (RT-qPCR) and fluorescence in situ hybridization (FISH) were used to assess miR-454-3p expression. miR-454-3p and ACSL4 levels were abnormally expressed in breast cancer tissues. CAF-exo significantly enhanced cell viability and GSH levels and suppressed MDA, and iron levels. CAF-exo upregulated ferroptosis suppressor protein 1 (FSP1) and glutathione peroxidase 4 (GPX4) expression, and reduced ACSL4 levels. miR-454-3p was strongly expressed in CAF-exo, and exosomal miR-454-3p suppressed lipid metabolism and ferroptosis in breast cancer cells. The effects of miR-454-3p inhibitor on lipid metabolism and ferroptosis were eliminated by ACSL4 knockdown. CAF-secreted exosomal miR-454-3p inhibited lipid metabolism and ferroptosis by targeting ACSL4 in breast cancer. This study revealed a novel molecular mechanism that offers a potential therapeutic intervention in breast cancer treatment.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"3925-3937"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A promise of nose to brain delivery of bevacizumab intranasal sol-gel formulation substantiated in rat C6 glioma model.","authors":"Siddhesh Desai, Prajakta Thorat, Anuradha Majumdar","doi":"10.1007/s00210-024-03536-3","DOIUrl":"10.1007/s00210-024-03536-3","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Glioblastoma is one of the rapidly spreading cancers, with its potent malignancy often linked to pronounced angiogenesis within tumors. To mitigate this vascularization profile, bevacizumab (Avastin®), a monoclonal antibody, has been utilized for its antiangiogenic activity. However, its effectiveness is hindered by challenges in crossing the blood-brain barrier and the risk of off-target organ toxicity. Delivering drugs directly from the nose to the brain through the olfactory or trigeminal nerves bypassing the blood-brain barrier offers enhanced bioavailability and a more precise targeting strategy. To overcome these challenges, we aimed to develop bevacizumab in situ gel loaded mesoporous silica nanoparticles for intranasal delivery and further examine their pharmacokinetic and pharmacodynamic characteristics. The intranasal gel of mesoporous silica nanoparticles loaded with bevacizumab was optimized and formulated using a factorial and quality by design approach. In the case of bevacizumab mesoporous silica nanoparticles, lower particle size and most negative zeta potential were selected as quality target product profiles which is important for drug loading on the mesoporous silica nanoparticles and also transport of these nanoparticles across the nasal mucosa to the brain. A design space with a multidimensional combination of input variables and process parameters has been demonstrated to assure quality. To optimize the design space and achieve the desired quality standards, the base catalyst and surfactant concentration were chosen as the critical process parameters, while particle size and zeta potential were identified as the critical quality attributes. The novel formulation was assessed for physicochemical parameters such as particle size, zeta potential, entrapment efficiency, appearance, color, consistency, and pH. Additionally, studies on in vitro release, ex vivo permeation, stability, nasal toxicity, organ safety, and bioavailability were conducted. The efficacy study was conducted in an orthotopic murine glioblastoma rat model in which C6 Luc cells were instilled in the striatum of the rat's brain. In vivo, bioluminescence imaging of brain tumors was carried out to observe the tumor regression after treatment with the intranasal and intravenous bevacizumab formulation. Biochemical parameters and histopathology were performed for organ safety studies. The optimized intranasal formulation exhibited an average particle size of 318.8 nm and a zeta potential of - 14.7 mV for the mesoporous silica nanoparticles. The formulation also demonstrated an entrapment efficiency of 91.34% and a loading capacity of 45.67%. Further pharmacokinetic studies revealed that the optimized intranasal bevacizumab formulation achieved a significantly higher brain concentration Cmax = 147.9 ng/ml, indicating improved bioavailability compared to rats administered with intravenous bevacizumab formulation (BEVATAS®), which had a Cmax of 127.2 ng/ml. More","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"4123-4148"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chaetocin inhibits the progression of neuroblastoma by targeting JAK2/STAT3 signaling pathway in SH-SY5Y cells.","authors":"Ke Wang, Ye Li, Linlin Wang","doi":"10.1007/s00210-024-03426-8","DOIUrl":"10.1007/s00210-024-03426-8","url":null,"abstract":"<p><p>Chaetocin is a fungal mycotoxin that extensively found in various natural products and has anticancer and anti‑inflammatory activities. Herein, the anticancer effects of chaetocin against the progression of neuroblastoma were studied with SHSY-5Y human neuroblastoma cells and examined the underlying molecular mechanisms. The effects of chaetocin on cellular viability, apoptosis, cell migration, and invasion were investigated. The underlying mechanism of anticancer effects of chaetocin was found to mediate via activating JAK2/STAT3 signaling pathway. Furthermore, when SHSY-5Y cells were exposed to a higher concentration of chaetocin, the induction of cell apoptosis significantly increased by enhancing the expression of pro-apoptotic protein Bcl-2, resulting in anticancer activity against neuroblastoma. In addition, chaetocin significantly decreased the SHSY-5Y cell invasion and migration at 50 μM treatment. Moreover, it was shown that increasing chaetocin treatments greatly decreased the activity of proteins connected to the JAK2/STAT3 signaling pathway. In conclusion, chaetocin exhibits a diverse range of actions on neuroblastoma cells, including the inhibition of proliferation, induction of apoptosis, perturbation of cellular morphology, and modulation of critical signaling pathways, with a specific focus on the JAK/STAT3 pathway. These results contribute valuable insights that underscore the potential therapeutic utility of chaetocin in the context of neuroblastoma treatment, suggesting its multifaceted impact on key cellular processes involved in cancer progression.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"4237-4246"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contemporary and prospective use of azathioprine (AZA) in viral, rheumatic, and dermatological disorders: a review of pharmacogenomic and nanotechnology applications.","authors":"Gulshan Rathi, Prashant B Shamkuwar, Karishma Rathi, Ruchita Ranazunjare, Soham Kulkarni","doi":"10.1007/s00210-024-03569-8","DOIUrl":"10.1007/s00210-024-03569-8","url":null,"abstract":"<p><p>Azathioprine (AZA) has been extensively used for immunomodulatory effects in autoimmune disorders and transplantation. This article is proposed to review the contemporary and prospective use of AZA in viral, rheumatic, and dermatological disorders. The primary objective is to draw attention to possible developments in regards to AZA application in recent years, with an emphasis on the use of pharmacogenomics and nanotechnology to improve its efficacy in practice. This study reveals that AZA, having the active metabolites 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), may be useful in the treatment of systemic lupus erythematosus (SLE), pemphigus vulgaris, and psoriasis. Pharmacogenomic testing of thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) genotypes minimizes the occurrence of myelosuppression. Furthermore, new formulations of AZA using biocompatible polymers and nanoparticles for drug delivery were reported to improve its efficacy and lower systemic toxicity. This paper aims to establish the multifunctional nature of AZA in modern medicine, thus emphasizing its potential for other applications. Through the combination of pharmacogenomic analysis along with nanotechnology application, AZA makes the promise of enhancing patients' treatment efficacy and extending the stock of medical information available. These advancements offer new possibilities for application of precision medicine and improvements in the use of AZA therapy.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"3183-3197"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha-lipoic acid, as an effective agent against toxic elements: a review.","authors":"Farzad Vafaee, Mahla Derakhshani, Mahboobeh Ghasemzadeh Rahbardar, Hossein Hosseinzadeh","doi":"10.1007/s00210-024-03576-9","DOIUrl":"10.1007/s00210-024-03576-9","url":null,"abstract":"<p><p>This review aims to evaluate the efficacy of alpha-lipoic acid (ALA) in combating toxic elements, such as aluminum, arsenic, lead, mercury, and cadmium. The primary research question addressed is whether ALA can effectively mitigate the toxic effects of these metals through its antioxidant and chelating properties. Articles published between 1995 and 2024 were collected from Scopus, PubMed, Google Scholar, and Web of Science. Using Boolean (AND and OR), English-language publications were selected based on medical subject headings, titles, or abstracts that contained keywords related to ALA, metals, toxicity, antioxidants, and chelation. ALA supplementation significantly enhances cellular defense mechanisms and antioxidant enzyme activity. It effectively mitigates the adverse effects of aluminum exposure, counters arsenic toxicity in various cells and organs, and reduces cadmium toxicity, resulting in lower mortality rates among treated groups. Although ALA acts as a lead chelator, its efficacy is less than standard chelators. In the case of mercury, ALA shows beneficial effects in long-term therapy, although its capacity to reduce mercury concentration is limited. Overall, ALA emerges as a promising alternative for alleviating metal toxicity by enhancing antioxidant defenses, chelating toxic metals, and reversing their harmful effects. Further research in this area is encouraged to explore the full potential of ALA in mitigating the toxic effects of metals on biological systems.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"3345-3372"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the impact of miRNAs on gouty arthritis: diagnostic significance and therapeutic opportunities.","authors":"Sherif S Abdel Mageed, Hanan Elimam, Ahmed E Elesawy, Ahmed I Abulsoud, Ahmed Amr Raouf, Manar Mohammed El Tabaa, Osama A Mohammed, Mohamed Bakr Zaki, Mai A Abd-Elmawla, Walaa A El-Dakroury, Safwat Abdelhady Mangoura, Mahmoud A Elrebehy, Mohammed S Elballal, Aya A Mohamed, Alaa Ashraf, Mustafa Ahmed Abdel-Reheim, Ali M S Eleragi, Hussein Abdellatif, Ahmed S Doghish","doi":"10.1007/s00210-024-03603-9","DOIUrl":"10.1007/s00210-024-03603-9","url":null,"abstract":"<p><p>Gouty arthritis is a prevalent inflammatory illness. Gout attacks begin when there is an imbalance in the body's uric acid metabolism, which leads to urate buildup and the development of the ailment. A family of conserved, short non-coding RNAs known as microRNAs (miRNAs) can regulate post-transcriptional protein synthesis by attaching to the 3' untranslated region (UTR) of messenger RNA (mRNA). An increasing amount of research is pointing to miRNAs as potential players in several inflammatory diseases, including gouty arthritis. miRNAs may influence the progression of the disease by regulating immune function and inflammatory responses. This review mainly focused on miRNAs and how they contribute to gouty arthritis. It also looked at how miRNAs could be used as diagnostic, prognostic, and potential therapeutic targets.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"3433-3450"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Flavopiridol: a promising cyclin-dependent kinase inhibitor in cancer treatment.","authors":"Uttam Singh Baghel, Priyanka Kriplani, Neelam M Patel, Manpreet Kaur, Kapil Sharma, Monika Meghani, Abhay Sharma, Deeksha Singh, Bhawani Singh, William N Setzer, Javad Sharifi-Rad, Daniela Calina","doi":"10.1007/s00210-024-03599-2","DOIUrl":"10.1007/s00210-024-03599-2","url":null,"abstract":"<p><p>Flavopiridol, a synthetic flavonoid derived from rohitukine, stands out as a powerful cyclin-dependent kinase (CDK) inhibitor with significant anticancer properties. Its action mechanisms involve inducing cell cycle arrest, triggering apoptosis, and inhibiting transcription across various cancer types. Despite these promising effects, flavopiridol's clinical use has been hampered by issues related to toxicity and drug resistance. This study aims to comprehensively review flavopiridol's mechanisms of action, structure-activity relationships, synthetic derivatives, pharmacokinetics, and its potential role in clinical applications, with a focus on how combination therapies can enhance its efficacy and address resistance challenges in cancer treatment. A thorough analysis of key studies was performed, examining flavopiridol's anticancer properties, emphasizing its structure-activity relationships, synthetic modifications, and clinical outcomes. The anticancer effects of flavopiridol are primarily driven by its inhibition of CDKs, induction of apoptosis, promotion of oxidative stress, and antiangiogenic activity. Modifications in its chemical structure, especially in the D ring, have shown a significant impact on its CDK inhibitory potency. Several synthetic derivatives have also demonstrated enhanced anticancer activity. While preclinical models highlight flavopiridol's potential in treating cancers such as leukemia and solid tumors, clinical trials have brought attention to its limitations, particularly regarding toxicity and resistance. However, flavopiridol remains a promising candidate for cancer therapy, especially when used in combination with other treatments. Future research efforts should focus on refining its therapeutic profile, minimizing toxicity, and investigating synergistic treatment combinations, including those with immunotherapy. Understanding the mechanisms of resistance and discovering predictive biomarkers will be crucial for its effective integration into clinical practice.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"3489-3511"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic potential of synthetic and natural iron chelators against ferroptosis.","authors":"Nupura Manish Prabhune, Bilal Ameen, Sudharshan Prabhu","doi":"10.1007/s00210-024-03640-4","DOIUrl":"10.1007/s00210-024-03640-4","url":null,"abstract":"<p><p>Ferroptosis, a regulated form of cell death, is characterized by iron accumulation that results in the production of reactive oxygen species. This further causes lipid peroxidation and damage to the cellular components, eventually culminating into oxidative stress. Recent studies have highlighted the pivotal role of ferroptosis in the pathophysiological development and progression of various diseases such as β-thalassemia, hemochromatosis, and neurodegenerative disorders like AD and PD. Extensive efforts are in progress to understand the molecular mechanisms governing the role of ferroptosis in these conditions, and chelation therapy stands out as a potential approach to mitigate ferroptosis and its related implications in their development. There are currently both synthetic and natural iron chelators that are being researched for their potential as ferroptosis inhibitors. While synthetic chelators are relatively well-established and studied, their short plasma half-life and toxic side effects necessitate the exploration and identification of natural products that can act as efficient and safe iron chelators. In this review, we comprehensively discuss both synthetic and natural iron chelators as potential therapeutic strategies against ferroptosis-induced pathologies.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"3527-3555"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Next-generation cancer nanotherapeutics: Pluronic^® F127 based mixed micelles for enhanced drug delivery.","authors":"Krishna Bhalodi, Charmy Kothari, Shital Butani","doi":"10.1007/s00210-024-03582-x","DOIUrl":"10.1007/s00210-024-03582-x","url":null,"abstract":"<p><p>Cancer, projected to become the second leading cause of mortality globally, underscores the critical need for precise drug delivery systems. Nanotechnology, particularly micelles, has emerged as a promising avenue. These nano-sized colloidal dispersions (< 100 nm) utilize amphiphilic molecules featuring a hydrophilic tail and hydrophobic core, facilitating efficient drug encapsulation and delivery. Pluronic^® F127, a triblock copolymer (PEO₁₀₁-PPO₅₆-PEO₁₀₁), has emerged as a promising drug carrier due to its non-ionic, less-toxic nature, which prolongs drug circulation time and improves drug delivery across blood-brain and intestinal barriers. Mixed micelles, formed using Pluronic^® F127 combined with other polymers, surfactants, and drugs, enhance drug solubility, stability, and targeted delivery. This review highlights the key features of mixed micelles, including enhanced pharmacokinetics and targeting abilities, folic acid (FA) conjugation strategies, superior cytotoxicity with reduced side effects, overcoming multidrug resistance, and versatility across various cancer types and compounds. Additionally, the potential for clinical translation of Pluronic^® F127-based mixed micelle in cancer treatment is discussed, addressing current challenges and paving the way for optimized applications.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"3241-3270"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Effect of EMB-FUBINACA on brain endothelial cell angiogenesis: expression analysis of angiogenic markers.","authors":"Laith Al-Eitan, Hana Abu Kharmah","doi":"10.1007/s00210-025-03969-4","DOIUrl":"10.1007/s00210-025-03969-4","url":null,"abstract":"","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"4667"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}