Fundamental & Clinical Pharmacology最新文献

{"title":"Potentiating-antibiotic activity and absorption, distribution, metabolism, excretion and toxicity properties (ADMET) analysis of synthetic thiadiazines against multi-drug resistant (MDR) strains","authors":"Ana Carolina Justino de Araújo,&nbsp;Priscilla Ramos Freitas,&nbsp;Isaac Moura Araújo,&nbsp;Gustavo Miguel Siqueira,&nbsp;João Arthur de Oliveira Borges,&nbsp;Daniel Sampaio Alves,&nbsp;Gustavo Marinho Miranda,&nbsp;Igor José dos Santos Nascimento,&nbsp;João Xavier de Araújo-Júnior,&nbsp;Edeildo Ferreira da Silva-Júnior,&nbsp;Thiago Mendonça de Aquino,&nbsp;Francisco Jaime Bezerra Mendonça Junior,&nbsp;Emmanuel Silva Marinho,&nbsp;Helcio Silva dos Santos,&nbsp;Saulo Relison Tintino,&nbsp;Henrique Douglas Melo Coutinho","doi":"10.1111/fcp.12950","DOIUrl":"10.1111/fcp.12950","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Thiadiazines are heterocyclic compounds that contain two nitrogen atoms and one sulfur atom in their structure. These synthetic molecules have several relevant pharmacological activities, such as antifungal, antibacterial, and antiparasitic.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The present study aimed to evaluate the possible in vitro and in silico interactions of compounds derived from thiadiazines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The compounds were initially synthesized, purified, and confirmed through HPLC methodology. Multi-drug resistant bacterial strains of <i>Staphylococcus aureus</i> 10 and <i>Pseudomonas aeruginosa</i> 24 were used to evaluate the direct and modifying antibiotic activity of thiadiazine derivatives. ADMET assays (absorption, distribution, metabolism, excretion, and toxicity) were conducted, which evaluated the influence of the compounds against thousands of macromolecules considered as bioactive targets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>There were modifications in the chemical synthesis in carbon 4 or 3 in one of the aromatic rings of the structure where different ions were added, ensuring a variability of products. It was possible to observe results that indicate the possibility of these compounds acting through the cyclooxygenase 2 mechanism, which, in addition to being involved in inflammatory responses, also acts by helping sodium reabsorption. The amine group present in thiadiazine analogs confers hydrophilic characteristics to the substances, but this primary characteristic has been altered due to alterations and insertions of other ligands. The characteristics of the analogs generally allow easy intestinal absorption, reduce possible hepatic toxic effects, and enable possible neurological and anti-inflammatory action. The antibacterial activity tests showed a slight direct action, mainly of the IJ23 analog. Some compounds were able to modify the action of the antibiotics gentamicin and norfloxacin against multi-drug resistant strains, indicating a possible synergistic action.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Among all the results obtained in the study, the relevance of thiadiazine analogs as possible coadjuvant drugs in the antibacterial, anti-inflammatory, and neurological action with low toxicity is clear. Need for further studies to verify these effects in living organisms is not ruled out.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 1","pages":"84-98"},"PeriodicalIF":2.9,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10476927","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":"Preliminary evaluation of the efficacy and safety of brimonidine for deep sedation","authors":"Xiaohui Wang,&nbsp;Rui Zhang,&nbsp;Bin Chen,&nbsp;Ting Zhang,&nbsp;Xinghua Jin,&nbsp;Ping Gao","doi":"10.1111/fcp.12944","DOIUrl":"10.1111/fcp.12944","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Although brimonidine is currently used in the clinical treatment of glaucoma and rosacea, research of the deep sedative effect on animals after systemic administration is reported firstly and has shown promising results.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The median effective dose (ED₅₀), the median lethal dose (LD₅₀), and the therapeutic index of brimonidine for deep sedation and formalin stimulation assay were determined by various animal experiments. The effect of synergistic anesthesia in rabbits with brimonidine and chloral hydrate was preliminarily evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The ED₅₀ of brimonidine for highly effective sedation by intraperitoneal injection in rats was calculated to be 2.05 mg kg⁻¹ with a 95% confidence interval (CI) of 1.87 to 2.25 mg kg⁻¹. The ED₅₀ of brimonidine for deep sedation by intravenous and intrarectal injection in rabbits was calculated to be 0.087 mg kg⁻¹ with a 95% CI of 0.084 to 0.091 mg kg⁻¹ and 1.65 mg kg⁻¹ with a 95% CI of 1.43 to 1.91 mg kg⁻¹, respectively. The LD₅₀ of intraperitoneal brimonidine injection in rats was calculated to be 468 mg kg⁻¹ with a 95% CI of 441 to 497 mg kg⁻¹ and a therapeutic index of 228. Brimonidine has a certain analgesic and heart rate lowering effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The results confirmed that brimonidine has deep sedation and analgesic effects after systemic administration and has high safety. It can be used in combination with other types of sedative drugs to achieve better effects.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 1","pages":"139-151"},"PeriodicalIF":2.9,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10115867","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":"Human neutrophil elastase inhibitors: Classification, biological-synthetic sources and their relevance in related diseases","authors":"Jhonnatan Styver Ocampo-Gallego,&nbsp;David Pedroza-Escobar,&nbsp;Ana Ruth Caicedo-Ortega,&nbsp;María Teresa Berumen-Murra,&nbsp;Ana Lucía Novelo-Aguirre,&nbsp;Rebeca Denis de Sotelo-León,&nbsp;Dealmy Delgadillo-Guzmán","doi":"10.1111/fcp.12946","DOIUrl":"10.1111/fcp.12946","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Human neutrophil elastase is a multifunctional protease enzyme whose function is to break the bonds of proteins and degrade them to polypeptides or amino acids. In addition, it plays an essential role in the immune mechanism against bacterial infections and represents a key mediator in tissue remodeling and inflammation. However, when the extracellular release of this enzyme is dysregulated in response to low levels of its physiological inhibitors, it ultimately leads to the degradation of proteins, in particular elastin, as well as other components of the extracellular matrix, producing injury to epithelial cells, which can promote sustained inflammation and affect the innate immune system, and, therefore, be the basis for the development of severe inflammatory diseases, especially those associated with the cardiopulmonary system.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This review aims to provide an update on the elastase inhibitory properties of several molecules, either synthetic or biological sources, as well as their classification and relevance in related pathologies since a clear understanding of the function of these molecules with the inhibitory capacity of this protease can provide valuable information for the development of pharmacological therapies that manage to modify the prognosis and survival of various inflammatory diseases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Collected data from scientific databases, including PubMed, Google Scholar, Science Direct, Nature, Wiley, Scopus, and Scielo. Articles published in any country and language were included.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We reviewed and included 132 articles conceptualizing neutrophil elastase activity and known inhibitors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Understanding the mechanism of action of elastase inhibitors based on particular aspects such as their kinetic behavior, structure–function relationship, chemical properties, origin, pharmacodynamics, and experimental progress has allowed for a broad classification of HNE inhibitors.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 1","pages":"13-32"},"PeriodicalIF":2.9,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10054251","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":"Role of apoptosis and autophagy in folic acid-induced cytotoxicity of human breast cancer cells in vitro","authors":"Munevver Baran,&nbsp;Gozde Ozge Onder,&nbsp;Ozge Goktepe,&nbsp;Arzu Yay","doi":"10.1111/fcp.12948","DOIUrl":"10.1111/fcp.12948","url":null,"abstract":"<p>Obstacles to the successful treatment of breast cancer patients with chemotherapeutic agents can be overcome with effective new strategies. It is still unclear how folic acid affects the onset and spread of breast cancer. The purpose of this study was to determine how folic acid affected the apoptotic and autophagic pathways of the breast cancer cell lines MCF-7 and MDA-MB-231. In the present study, folic acid was applied to MCF-7 and MDA-MB-231 breast cancer cell lines at different concentrations and for different durations. MTT analysis was used to investigate cytotoxic activity. All groups underwent the Tunel staining procedure to identify apoptosis and the immunofluorescence staining approach to identify the autophagic pathway. 24-hour folic acid values were accepted as the most appropriate cytotoxic dose. In MCF-7, cell cycle arrest was observed in the S phase and MDA-MB-231 G1/G0 phases. When apoptotic TUNEL staining was evaluated in both cell lines, folic acid significantly increased apoptosis. While a significant difference was observed between the groups in terms of Beclin 1 immunoreactivity in the MDA-MB-231 cell line, there was no significant difference in the MCF-7 cell line. In addition, statistical significance was not observed LC3 immunoreactivity in both cell lines. In the study, it was observed that folic acid induced autophagy at the initial stage in the MDA-MB-231 cell line but had no inductive effect in the MCF-7 cell line. In conclusion, our findings showed that folic acid has a potential cytotoxic and therapeutic effect on MCF-7 and MDA-MB-231 breast cancer cell lines.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 1","pages":"126-138"},"PeriodicalIF":2.9,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10069986","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":"Can cannabidiol have an analgesic effect?","authors":"Bartłomiej Kulesza,&nbsp;Marek Mazurek,&nbsp;Jacek Kurzepa","doi":"10.1111/fcp.12947","DOIUrl":"10.1111/fcp.12947","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cannabis, more commonly known as marijuana or hemp, has been used for centuries to treat various conditions. Cannabis contains two main components cannabidiol (CBD) and tetrahydrocannabinol (THC). CBD, unlike THC, is devoid of psychoactive effects and is well tolerated by the human body but has no direct effect on the receptors of the endocannabid system, despite the lack of action on the receptors of the endocannabid system.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives and methods</h3>\u0000 \u0000 <p>We have prepared a literature review based on the latest available literature regarding the analgesic effects of CBD. CBD has a wide range of effects on the human body. In this study, we will present the potential mechanisms responsible for the analgesic effect of CBD. To the best of our knowledge, this is the first review to explore the analgesic mechanisms of CBD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results and conclusion</h3>\u0000 \u0000 <p>The analgesic effect of CBD is complex and still being researched. CBD models the perception of pain by acting on G protein-coupled receptors. Another group of receptors that CBD acts on are serotonergic receptors. The effect of CBD on an enzyme of potential importance in the production of inflammatory factors such as cyclooxygenases and lipoxygenases has also been confirmed. The presented potential mechanisms of CBD's analgesic effect are currently being extensively studied.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 1","pages":"33-41"},"PeriodicalIF":2.9,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10004065","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":"Evaluation of the anti-inflammatory effect of 1,4-dihydropyridine derivatives","authors":"Bruno Matheus Facchin,&nbsp;Tainá Larissa Lubschinski,&nbsp;Yeo Jim Kinoshita Moon,&nbsp;Paula Giarola Fragoso de Oliveira,&nbsp;Bianca Klafke Beck,&nbsp;Ziliani da Silva Buss,&nbsp;Luiz Antonio Escorteganha Pollo,&nbsp;Maique Weber Biavatti,&nbsp;Louis Pergaud Sandjo,&nbsp;Eduardo Monguilhott Dalmarco","doi":"10.1111/fcp.12945","DOIUrl":"10.1111/fcp.12945","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Inflammation is a physiological event that protects the organism against different factors that lead to loss of tissue homeostasis. Dihydropyridine (DHP) derivatives are heterocyclic compounds known for their different biological activities, including anti-inflammatory activities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To evaluate the anti-inflammatory activity of 1,4-dihydropyridine (1,4-DHP) derivatives using anti-inflammatory models in vitro, in RAW264.7 cells induced by lipopolysaccharide (LPS) and in vivo using the acute lung injury (ALI) model in mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Fifteen compounds derived from 1,4-DHP were tested in RAW264.7 cells for their cytotoxic effect and cell viability. Thereafter, only the six compounds that showed the highest cell viability were tested for the production or inhibition of the pro-inflammatory cytokine interleukin 6 (IL-6). The best compound (compound 4) was tested for its anti-inflammatory effects in vitro and in vivo, showing inhibition of nitric oxide (NO), pro-inflammatory cytokines, increased phagocytic activity, and an increase in IL-10 in vitro. In in vivo tests, compound 4 also reduces the levels of NO, myeloperoxidase (MPO) activity, leukocyte migration, and exudation, as well as reducing the levels of tumor necrosis factor-alpha (TNF-α) and IL-6 and preventing the loss in the lung architecture.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This compound showed important anti-inflammatory activity, with a significant ability to reduce the production of pro-inflammatory mediators and increase the phagocytic activity of macrophages and anti-inflammatory mediator secretion (IL-10). These findings led us to hypothesize that this compound can repolarize the macrophage response to an anti-inflammatory profile (M2). Moreover, it was also able to maintain its anti-inflammatory activity in vivo experiments.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 1","pages":"168-182"},"PeriodicalIF":2.9,"publicationDate":"2023-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9957375","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":"Synthesis, spectroscopic characterization, and antibacterial activity of chalcone (2E)-1-(3′-aminophenyl)-3-(4-dimethylaminophenyl)-prop-2-en-1-one against multiresistant Staphylococcus aureus carrier of efflux pump mechanisms and β-lactamase","authors":"Larissa da Silva,&nbsp;Isydório Alves Donato,&nbsp;Suieny Rodrigues Bezerra,&nbsp;Hélcio Silva dos Santos,&nbsp;Paulo Nogueira Bandeira,&nbsp;Maria Thalia Ramos do Nascimento,&nbsp;Jesyka Macêdo Guedes,&nbsp;Priscila Ramos Freitas,&nbsp;Ana Carolina Justino de Araújo,&nbsp;Thiago Sampaio de Freitas,&nbsp;Henrique Douglas Melo Coutinho,&nbsp;Yedda Maria Lobo Soares de Matos,&nbsp;Lígia Cláudia Castro de Oliveira,&nbsp;Francisco Assis Bezerra da Cunha","doi":"10.1111/fcp.12938","DOIUrl":"10.1111/fcp.12938","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The bacterium <i>Staphylococcus</i> aureus has stood out for presenting a high adaptability, acquiring resistance to multiple drugs. The search for natural or synthetic compounds with antibacterial properties capable of reversing the resistance of <i>S. aureus</i> is the main challenge to be overcome today. Natural products such as chalcones are substances present in the secondary metabolism of plants, presenting important biological activities such as antitumor, antidiabetic, and antimicrobial activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>In this context, the aim of this work was to synthesize the chalcone (2<i>E</i>)-1-(3'-aminophenyl)-3-(4-dimethylaminophenyl)-prop-2-en-1-one with nomenclature CMADMA, confirm its structure by nuclear magnetic resonance (NMR), and evaluate its antibacterial properties.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The synthesis methodology used was that of Claisen-Schmidt, and spectroscopic characterization was performed by NMR. For microbiological assays, the broth microdilution methodology was adopted in order to analyze the antibacterial potential of chalcones and to analyze their ability to act as a possible inhibitor of β-lactamase and efflux pump resistance mechanisms, present in S. aureus strain K4100.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results obtained show that CMADMA does not show direct antibacterial activity, expressing a MIC of ≥1024 μg/mL, or on the enzymatic mechanism of β-lactamase; however, when associated with ethidium bromide in efflux pump inhibition assays, CMADMA showed promising activity by reducing the MIC of the bromide from 64 to 32 μg/mL.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We conclude that the chalcone synthesized in this study is a promising substance to combat bacterial resistance, possibly acting in the inhibition of the QacC efflux pump present in <i>S. aureus</i> strain K4100, as evidenced by the reduction in the MIC of ethidium bromide.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 1","pages":"60-71"},"PeriodicalIF":2.9,"publicationDate":"2023-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10235164","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":"Dihydroartemisinin inhibits angiogenesis in breast cancer via regulating VEGF and MMP-2/-9","authors":"Qi Rao,&nbsp;He Yu,&nbsp;Ruochan Li,&nbsp;Bin He,&nbsp;Yuxue Wang,&nbsp;Xiaohong Guo,&nbsp;Gang Zhao,&nbsp;Fenghua Wu","doi":"10.1111/fcp.12941","DOIUrl":"10.1111/fcp.12941","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Dihydroartemisinin (DHA) is an artemisinin derivative known for its antimalarial properties. It has also shown potential as an anti-tumor and anti-angiogenic agent. However, its specific role in inhibiting angiogenesis in breast cancer is not well understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We aimed to investigate the anti-angiogenesis effect of DHA on breast cancer and explore its potential as a therapeutic drug. Our objectives were to assess the impact of DHA on neovascularization induced by MDA-MB-231 cells, evaluate its effects on vessel sprout and tube-formation in vascular endothelial cells, and analyze the expression of key angiogenesis-related proteins.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using a chicken chorioallantoic membrane (CAM) model, we cultured MDA-MB-231 cells and treated them with DHA. We assessed neovascularization and cultured vascular endothelial cells with DHA-treated cell media to evaluate vessel sprout and tube-formation. Protein expression levels of VEGF, MMP-2, and MMP-9 were analyzed using Western blotting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>DHA significantly attenuated neovascularization induced by MDA-MB-231 cells. It also suppressed vessel sprout and tube-formation of HUVEC cells when exposed to DHA-treated cell media. Furthermore, DHA downregulated the expression of VEGF, MMP-2, and MMP-9 proteins. Mechanistically, DHA inhibited the phosphorylation of PI3K, AKT, ERK, and NF-κB proteins in tumor cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study provides evidence of the inhibitory effect of DHA on breast cancer angiogenesis. These findings support the potential of DHA as an anti-breast cancer drug and warrant further investigation for its therapeutic applications.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 1","pages":"113-125"},"PeriodicalIF":2.9,"publicationDate":"2023-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9870113","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":"Paclitaxel alters melanogenesis and causes pigmentation in the skin of gynecological cancer patients","authors":"Paula Montero,&nbsp;Celia Sanz,&nbsp;Jose Alejandro Pérez-Fidalgo,&nbsp;Martín Pérez-Leal,&nbsp;Javier Milara,&nbsp;Julio Cortijo","doi":"10.1111/fcp.12943","DOIUrl":"10.1111/fcp.12943","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Paclitaxel (PTX) is a microtubule-stabilizing antineoplastic that has been shown to damage healthy tissues like the skin. Hyperpigmentation can be found among the adverse effects caused by PTX, but the literature is limited and the mechanisms driving PTX-induced pigmentary alterations are unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study aimed to describe the pigmentary alterations caused by PTX and to determine the effects of PTX on melanocytes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Pigmentary skin alterations were measured in 20 gynecological cancer patients under PTX treatment by using specific probes, which determine the melanin index and the pigmentation level. Melanocytes were incubated with paclitaxel to analyze melanogenesis markers gene expression, melanin content, and transcription factors activation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Paclitaxel induced alterations in the skin pigmentation with no visible clinical manifestations. Gynecological cancer patients under paclitaxel treatment had an increase in the melanin index and pigmentation levels. In vitro, PTX exposure to melanocytes increased the expression of melanogenesis markers, melanin content, and induced activation of ERK and MITF.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The results suggest that PTX alters pigmentation in patients with no clinically visible manifestations, and these alterations might be driven by its capacity to stimulate melanogenesis on melanocytes through the MITF activation pathway.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 1","pages":"183-191"},"PeriodicalIF":2.9,"publicationDate":"2023-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.12943","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9912671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro anti-trypanosomal activity of synthetic nitrofurantoin-triazole hybrids against Trypanosoma species causing human African trypanosomosis","authors":"Anna Seetsi,&nbsp;David D. N'da,&nbsp;Nthatisi Molefe-Nyembe,&nbsp;Keisuke Suganuma,&nbsp;Tsepo Ramatla,&nbsp;Oriel Thekisoe","doi":"10.1111/fcp.12940","DOIUrl":"10.1111/fcp.12940","url":null,"abstract":"<p>Human African trypanosomosis (HAT) which is also known as sleeping sickness is caused by <i>Trypanosoma brucei gambiense</i> that is endemic in western and central Africa and <i>T. b. rhodesiense</i> that is endemic in eastern and southern Africa. Drugs used for treatment against HAT first stage have limited effectiveness, and the second stage drugs have been reported to be toxic, expensive, and have time-consuming administration, and parasitic resistance has developed against these drugs. The aim of this study was to evaluate the anti-trypanosomal activity of nitrofurantoin-triazole hybrids against <i>T. b. gambiense</i> and <i>T. b. rhodesiense</i> parasites in vitro. This study screened 19 synthesized nitrofurantoin-triazole (NFT) hybrids on two strains of human trypanosomes, and cytotoxicity was evaluated on Madin-Darby bovine kidney (MDBK) cells. The findings in this study showed that an increase in the chain length and the number of carbon atoms in some n-alkyl hybrids influenced the increase in anti-trypanosomal activity against <i>T. b. gambiense</i> and <i>T. b. rhodesiense</i>. The short-chain n-alkyl hybrids showed decreased activity compared to the long-chain n-alkyl hybrids, with increased activity against both <i>T. b. gambiense</i> and <i>T. b. rhodesiense</i>. Incorporation of additional electron-donating substituents in some NFT hybrids showed increased anti-trypanosomal activity than to electron-withdrawing substituents in NFT hybrids. All 19 NFT hybrids tested displayed better anti-trypanosomal activity against <i>T. b. gambiense</i> than <i>T. b. rhodesiense</i>. The NFT hybrid no. 16 was among the best performing hybrids against both <i>T. b. gambiense</i> (0.08 ± 0.04 μM) and <i>T. b.rhodesiense</i> (0.11 ± 0.06 μM), and its activity might be influenced by the introduction of fluorine in the para-position on the benzyl ring. Remarkably, the NFT hybrids in this study displayed weak to moderate cytotoxicity on MDBK cells. All of the NFT hybrids in this study had selectivity index values ranging from 18 to greater than 915, meaning that they were up to 10–100 times fold selective in their anti-trypanosomal activity. The synthesized NFT hybrids showed strong selectivity &gt;10 to <i>T. b. gambiense</i> and <i>T. b. rhodesiense</i>, which indicates that they qualify from the initial selection criteria for potential hit drugs.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 1","pages":"72-83"},"PeriodicalIF":2.9,"publicationDate":"2023-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.12940","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9955223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}