Mohamed Elsawalhy, Adel A-H Abdel-Rahman, Ebtesam A Basiony, Salma A Ellithy, Allam A Hassan, Eman S Abou-Amra, Abdelhamid Ismail, Abdulrahman A Almehizia, Mohamed A Al-Omar, Ahmed M Naglah, Nasser A Hassan
{"title":"Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors Based on the Pyridyl-Pyridazine Moiety for the Potential Treatment of Alzheimer's Disease.","authors":"Mohamed Elsawalhy, Adel A-H Abdel-Rahman, Ebtesam A Basiony, Salma A Ellithy, Allam A Hassan, Eman S Abou-Amra, Abdelhamid Ismail, Abdulrahman A Almehizia, Mohamed A Al-Omar, Ahmed M Naglah, Nasser A Hassan","doi":"10.3390/ph17101407","DOIUrl":"https://doi.org/10.3390/ph17101407","url":null,"abstract":"<p><p><b>Background</b>: Alzheimer's disease (AD) is characterized by cholinergic dysfunction, making the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) critical for improving cholinergic neurotransmission. However, the development of effective dual inhibitors remains challenging. <b>Objective</b>: This study aims to synthesize and evaluate novel pyridazine-containing compounds as potential dual inhibitors of AChE and BuChE for AD treatment. <b>Methods</b>: Ten novel pyridazine-containing compounds were synthesized and characterized using IR, <sup>1</sup>H NMR, and <sup>13</sup>C NMR. The inhibitory activities against AChE and BuChE were assessed in vitro, and pharmacokinetic properties were explored through in silico ADME studies. Molecular dynamics simulations were performed for the most active compound. <b>Results</b>: Compound <b>5</b> was the most potent inhibitor, with IC<sub>50</sub> values of 0.26 µM for AChE and 0.19 µM for BuChE, outperforming rivastigmine and tacrine, and showing competitive results with donepezil. Docking studies revealed a binding affinity of -10.21 kcal/mol to AChE and -13.84 kcal/mol to BuChE, with stable interactions confirmed by molecular dynamics simulations. In silico ADME studies identified favorable pharmacokinetic properties for compounds <b>5</b>, <b>8</b>, and <b>9</b>, with Compound 5 showing the best activity. <b>Conclusions</b>: Compound <b>5</b> demonstrates strong potential as a dual cholinesterase inhibitor for Alzheimer's disease, supported by both in vitro and in silico analyses. These findings provide a basis for further optimization and development of these novel inhibitors.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"17 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11510214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joonyoung Shin, Dong-Uk Kim, Gi-Sang Bae, Ji-Ye Han, Do-Won Lim, Young-Mi Lee, Eunjae Kim, Eunjeong Kwon, Dongwoon Han, Sungchul Kim
{"title":"Antidepressant-like Effects of <i>Cannabis sativa</i> L. Extract in an Lipopolysaccharide Model: Modulation of Mast Cell Activation in Deep Cervical Lymph Nodes and Dura Mater.","authors":"Joonyoung Shin, Dong-Uk Kim, Gi-Sang Bae, Ji-Ye Han, Do-Won Lim, Young-Mi Lee, Eunjae Kim, Eunjeong Kwon, Dongwoon Han, Sungchul Kim","doi":"10.3390/ph17101409","DOIUrl":"https://doi.org/10.3390/ph17101409","url":null,"abstract":"<p><strong>Background: </strong>Lipopolysaccharide (LPS)-induced neuroinflammation is a well-established model for studying depression-like behavior, driven by pro-inflammatory cytokines such as TNF-α and IL-1β. Mast cells (MCs) contribute to neuroinflammation by releasing mediators that exacerbate depressive-like symptoms. This study evaluates the antidepressant-like and anti-inflammatory effects of <i>Cannabis sativa</i> L. inflorescence extract (CSL) in an LPS-induced neuroinflammation model.</p><p><strong>Methods: </strong>Male C57BL/6 mice were intraperitoneally injected with CSL at doses of 10, 20, and 30 mg/kg, 30 min prior to LPS (0.83 mg/kg) administration. Depressive behaviors were assessed using the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). The neutrophil-to-lymphocyte ratio (NLR) was measured to assess systemic inflammation. Cytokine levels in the prefrontal cortex (PFC) were measured, and mast cell degranulation in the lymph nodes and dura mater was analyzed histologically (approval number: WKU24-64).</p><p><strong>Results: </strong>CSL significantly improved depressive-like behaviors and decreased the NLR, indicating reduced systemic inflammation. CSL also significantly reduced TNF-α and IL-1β levels in the PFC. Furthermore, CSL inhibited MC degranulation in the deep cervical lymph nodes and dura mater, with the strongest effects observed at 30 mg/kg.</p><p><strong>Conclusions: </strong>CSL demonstrated antidepressant-like and anti-inflammatory effects in an LPS-induced neuroinflammation model, likely through the modulation of cytokine expression and mast cell activity. These results suggest the potential of CSL as a therapeutic option for treating inflammation-related depression.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"17 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11510560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lignin: An Adaptable Biodegradable Polymer Used in Different Formulation Processes.","authors":"Andreea Creteanu, Claudiu N Lungu, Mirela Lungu","doi":"10.3390/ph17101406","DOIUrl":"https://doi.org/10.3390/ph17101406","url":null,"abstract":"<p><strong>Introduction: </strong>LIG is a biopolymer found in vascular plant cell walls that is created by networks of hydroxylated and methoxylated phenylpropane that are randomly crosslinked. Plant cell walls contain LIG, a biopolymer with significant potential for usage in modern industrial and pharmaceutical applications. It is a renewable raw resource. The plant is mechanically protected by this substance, which may increase its durability. Because it has antibacterial and antioxidant qualities, LIG also shields plants from biological and chemical challenges from the outside world. Researchers have done a great deal of work to create new materials and substances based on LIG. Numerous applications, including those involving antibacterial agents, antioxidant additives, UV protection agents, hydrogel-forming molecules, nanoparticles, and solid dosage forms, have been made with this biopolymer.</p><p><strong>Methods: </strong>For this review, a consistent literature screening using the Pubmed database from 2019-2024 has been performed.</p><p><strong>Results: </strong>The results showed that there is an increase in interest in lignin as an adaptable biomolecule. The most recent studies are focused on the biosynthesis and antimicrobial properties of lignin-derived molecules. Also, the use of lignin in conjunction with nanostructures is actively explored.</p><p><strong>Conclusions: </strong>Overall, lignin is a versatile molecule with multiple uses in industry and medical science.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"17 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11509946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Susmit Mhatre, Rai Anjali, Pulkit Sahai, John Auden, Somnath Singh, Ya Fatou Njie Mbye, Sunny E Ohia, Catherine A Opere
{"title":"Glutathione Modulates Hydrogen Sulfide Release and the Ocular Hypotensive Action of Diallyl Polysulfide Compounds.","authors":"Susmit Mhatre, Rai Anjali, Pulkit Sahai, John Auden, Somnath Singh, Ya Fatou Njie Mbye, Sunny E Ohia, Catherine A Opere","doi":"10.3390/ph17101408","DOIUrl":"https://doi.org/10.3390/ph17101408","url":null,"abstract":"<p><strong>Background: </strong>Hydrogen sulfide (H<sub>2</sub>S) is an endogenous transmitter with the potential to regulate aqueous humor dynamics and protect retinal neurons from degeneration. The aim of the present study was two-fold: (a) to evaluate the release of H<sub>2</sub>S from two polysulfides, diallyl disulfide (DADS), and diallyl trisulfide (DATS); and (b) to investigate their ocular hypotensive actions in normotensive male and female rabbits in the presence and absence of GSH.</p><p><strong>Materials and methods: </strong>H<sub>2</sub>S was quantified hourly for up to 6 h using a H<sub>2</sub>S-Biosensor (World Precision Instruments, Sarasota, Fl). Intraocular pressure (IOP) was assessed in normotensive New Zealand Albino rabbits using a pneumotonometer (model 30 classic; Reichert Ophthalmic Instruments, Depew, NY, USA).</p><p><strong>Results: </strong>In the presence of GSH, there was an increase in the in vitro release of H<sub>2</sub>S produced by DADS and DATS. Both DADS and DATS also caused a dose-dependent reduction in IOP in male and female rabbits, in both treated and untreated eyes. For instance, in male animals, the presence of GSH (3% and 5%) significantly (<i>p</i> < 0.05, <i>n</i> = 5) enhanced the ocular hypotensive action of DADS (2%) and DATS (2%) from 14.02 ± 2.89% to 18.67 ± 5.6% and from 16.22 ± 3.48 to 23.62 ± 5.79%, respectively.</p><p><strong>Conclusions: </strong>GSH enhanced both H<sub>2</sub>S release and ocular hypotensive action of the polysulfides in a manner that was dependent on the number of sulfur atoms present in each polysulfide. Furthermore, female animals were less sensitive to the IOP-lowering action of the polysulfides, when compared to their male counterparts.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"17 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11510538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marwa H Abdallah, Mona M Shahien, Hemat El-Sayed El-Horany, Enas Haridy Ahmed, Hanan M El-Nahas, Nourhan A Abdulla, Tarek M Ibrahim
{"title":"Evaluation of Mucoadhesive Nano-Bilosomal In Situ Gels Containing Anti-Psychotic Clozapine for Treatment of Schizophrenia: In Vitro and In Vivo Studies.","authors":"Marwa H Abdallah, Mona M Shahien, Hemat El-Sayed El-Horany, Enas Haridy Ahmed, Hanan M El-Nahas, Nourhan A Abdulla, Tarek M Ibrahim","doi":"10.3390/ph17101404","DOIUrl":"https://doi.org/10.3390/ph17101404","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Patients with schizophrenia have significant challenges in adhering to and complying with oral medicines, resulting in adverse consequences such as symptom worsening and psychotic relapse. <b>Methods:</b> This study aimed to develop clove oil-based bilosomes using definitive screening design (DSD) to maximize the anti-schizophrenic action of clozapine and promote its nose-to-brain delivery. The target was to optimize the physicochemical properties of bilosomes and incorporate them into mucoadhesive intranasal in situ gels, searching for augmented ex vivo and in vivo clozapine delivery. <b>Results:</b> The bilosomes' particle size was decreased by increasing the span, SDC, and clove oil amounts. In addition to using a high lipid amount, the aforementioned components also helped increase the entrapment efficiency values. Increased zeta potential was only observed by increasing surfactant amount and reducing clozapine concentration. After incorporation of optimized liquid clove oil-based bilosomes, which had a spherical nano-sized vesicular shape, into P 407-dependent gels, an HPMC (2% <i>w</i>/<i>w</i>)/P 407 (20% <i>w</i>/<i>w</i>)-containing formulation (G6) was selected as an optimized gel owing to its acceptable gelation time (13.28 s), gel strength (27.72 s), viscosity (12,766.67 cP), and mucoadhesive strength (4273.93 dyne/cm<sup>2</sup>). The optimized G6 exhibited higher J<sub>ss</sub> (50.86 μg/cm<sup>2</sup>·h<sup>-1</sup>) through the nasal mucosa compared to the control gel (23.03 μg/cm<sup>2</sup>·h<sup>-1</sup>). Compared to the control gel, G6 displayed higher relative bioavailability (491.37%) than a commercial tablet (264.46%). Following ELISA analysis, dopamine and serotonin were significantly reduced, while BDNF was remarkably increased after administration of optimized G6 into schizophrenic rats. <b>Conclusion:</b> Our study indicates the potential of intranasal bilosomal gels in upgrading the anti-schizophrenic and neuroprotective activity of clozapine.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"17 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11510079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Naourez Ktari, Wafa Gargouri, Lobna Jlaiel, Imen Trabelsi, Sirine Ben Slima, Sana Bardaa, Farida Bendali, Riadh Ben Salah
{"title":"Extraction, Purification, Characterization, and Wound Healing Effects of Novel Prickly Pear (<i>Opuntiaficus-indica</i> (L.) Mill.) Heteropolysaccharides.","authors":"Naourez Ktari, Wafa Gargouri, Lobna Jlaiel, Imen Trabelsi, Sirine Ben Slima, Sana Bardaa, Farida Bendali, Riadh Ben Salah","doi":"10.3390/ph17101410","DOIUrl":"https://doi.org/10.3390/ph17101410","url":null,"abstract":"<p><p><b>Background:</b> The present study undertakes the purification of a novel polysaccharide from Tunisian prickly pear <i>(Opuntiaficus-indica</i> (L.) Mill.) rackets (PPPRs) and the determination of its physicochemical properties, structure, antibacterial and antioxidant properties, as well as its in vitro and in vivo wound healing potential. <b>Methods:</b> The PPPR was structurally analyzed by Fourier Transform Infrared Spectroscopy (FTIR) and UV/Visible Spectroscopy, revealing characteristic bands of polysaccharides. According to thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and Gas Chromatography-Mass Spectrometry (GC-MS) analyses. <b>Results:</b> The crude PPPR is an heteropolysaccharide composed of glucose (62.4%), galactose (19.37%), mannose (10.24%), and rhamnose (7.98%), with an average molecular weight of 90.94 kDa. This novel polysaccharide exhibited notable antioxidant potential assessed by four different in vitro assays: the 2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay, ferric reducing power, ferrous chelating activity, and scavenging activity against 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS). In addition, the PPPR displayed high antibacterial activities with a MIC of 2.5 mg/mL against <i>Salmonella Typhimurium</i> and <i>Pseudomonas aeruginosa</i>, cytocompatibility properties, and non-cytotoxicity. Subsequently, the effect of the PPPR on skin wound healing was studied in a diabetic rat model induced by alloxan, revealing a significant acceleration in the wound healing process. This acceleration was evidenced by the expedited recovery of the dermis, increased formation of blood vessels, and enhanced tissue granulation. <b>Conclusion:</b> Therefore, the findings offer fresh perspectives on the creation of a potentially efficient and promising racket polysaccharide-based therapy for the treatment of persistent diabetic wounds.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"17 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11510737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Inhibitory Effect of Luteolin on Spike S1 Glycoprotein-Induced Inflammation in THP-1 Cells via the ER Stress-Inducing Calcium/CHOP/MAPK Pathway.","authors":"Sonthaya Umsumarng, Sivamoke Dissook, Punnida Arjsri, Kamonwan Srisawad, Pilaiporn Thippraphan, Apiwat Sangphukieo, Patcharawadee Thongkumkoon, Pornngarm Dejkriengkraikul","doi":"10.3390/ph17101402","DOIUrl":"https://doi.org/10.3390/ph17101402","url":null,"abstract":"<p><strong>Background/objectives: </strong>The global SARS-CoV-2 outbreak has escalated into a critical public health emergency, with the spike glycoprotein S1 subunit of SARS-CoV-2 (spike-S1) linked to inflammation in lung tissue and immune cells. Luteolin, a flavone with anti-inflammatory properties, shows promise, but research on its effectiveness against long-COVID-related inflammation and spike protein-induced responses remains limited. This study aims to elucidate the underlying mechanisms of inflammation in THP-1 cells induced by the spike-S1. Additionally, it seeks to assess the potential of luteolin in mitigating inflammatory responses induced by the spike-S1 in a THP-1 macrophage model.</p><p><strong>Methods: </strong>The gene expression profiles of spike-S1 in THP-1 cells were analyzed by transcriptome sequencing. The inhibitory effect of luteolin on ER stress and inflammation in spike-S1-induced THP-1 cells was investigated using Western blotting, RT-PCR, and ELISA.</p><p><strong>Results: </strong>The candidate genes (<i>CAMK2A</i>, <i>SIGLEC7</i>, <i>PPARGC1B</i>, <i>SEC22B</i>, <i>USP28</i>, <i>IER2</i>, and <i>TIRAP</i>) were upregulated in the spike-S1-induced THP-1 group compared to the control group. Among these, calcium/calmodulin-dependent protein kinase II alpha (CAMK2A) was identified as the most promising molecule in spike-S1-induced THP-1 cells. Our results indicate that the spike S1 significantly increased the expression of ER-stress markers at both gene and protein levels. Luteolin significantly reduced ER stress by decreasing the expression of ER-stress marker genes and ER-stress marker proteins (<i>p</i> < 0.01). Additionally, luteolin exhibited anti-inflammatory properties upon spike S1-induction in THP-1 cells by significantly suppressing IL-6, IL-8, and IL-1β cytokine secretion in a dose-dependent manner (<i>p</i> < 0.05). Furthermore, our results revealed that luteolin exhibited the downregulation of the MAPK pathway, as evidenced by modulating the phosphorylation of p-ERK1/2, p-JNK and p-p38 proteins (<i>p</i> < 0.05).</p><p><strong>Conclusions: </strong>The results from this study elucidate the mechanisms by which the spike S1 induces inflammation in THP-1 cells and supports the use of naturally occurring bioactive compounds, like luteolin, against inflammation-related SARS-CoV-2 infection.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"17 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11509993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yi Mou, Shuai Wen, Hong-Kai Sha, Yao Zhao, Li-Juan Gui, Yan Wang, Zheng-Yu Jiang
{"title":"Discovery and Development of Caffeic Acid Analogs as Versatile Therapeutic Agents.","authors":"Yi Mou, Shuai Wen, Hong-Kai Sha, Yao Zhao, Li-Juan Gui, Yan Wang, Zheng-Yu Jiang","doi":"10.3390/ph17101403","DOIUrl":"https://doi.org/10.3390/ph17101403","url":null,"abstract":"<p><p>Caffeic acid (CA) is a polyphenolic acid compound widely distributed in plant seeds. As natural compounds with high research interest, caffeic acid and its derivatives show good activity in the treatment of tumors and inflammation and have antibacterial properties. In recent years, caffeic acid derivatives have been studied extensively, and these derivatives fall roughly into three categories: (1) caffeic acid ester derivatives, (2) caffeic acid amide derivatives, (3) caffeic acid hybrids. These caffeic acid analogues exert mainly antibacterial and antioxidant activities. Among the caffeic acid analogues summarized in this paper, compounds <b>1g</b> and CAP10 have good activity against <i>Candida albicans</i>, and their MIC<sub>50</sub> is 32 µg/mL and 13 μM, respectively. In a DPPH assay, compounds <b>3k</b>, <b>5a</b>, CS2, Phellinsin A and <b>8j</b> showed strong antioxidant activity, and their IC<sub>50</sub> values are 18.6 μM, 67.85 μM, 40.29 μM, 0.29 ± 0.004 mM, 4774.37 ± 137.20 μM, respectively. Overall, compound CAP10 had the best antibacterial activity and compound <b>3k</b> had the best antioxidant activity. This paper mainly summarizes and discusses some representative caffeic acid analogs, hoping to provide better drug design strategies for the subsequent development of caffeic acid analogs.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"17 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11510674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Novel Deep Sea Isoindole Alkaloid FGFC1 Exhibits Its Fibrinolytic Effects by Inhibiting Thrombin-Activatable Fibrinolysis Inhibitor.","authors":"Haixing Zhang, Xiaozhen Diao, Tingting Jiang, Mingjun Wei, Yue Su, Jingjing Shen, Chunlin Bao, Wenhui Wu","doi":"10.3390/ph17101401","DOIUrl":"https://doi.org/10.3390/ph17101401","url":null,"abstract":"<p><strong>Background: </strong>The thrombin-activatable fibrinolysis inhibitor (TAFI) is an important regulator in the balance between blood clot formation (coagulation) and dissolution (fibrinolysis), which is mainly activated by thrombin bonded with thrombomodulin (TM).</p><p><strong>Methods: </strong>In this study, the investigation focused on the unique target TAFI of fungi fibrinolytic compound 1 (FGFC1), a novel fibrinolytic compound sourced from the deep sea. In this sense, the regulation of TAFI by FGFC1, in comparison to established TAFI inhibitors such as DS-1040 and PCTI in hPPP, was investigated, which was validated through the molecular docking of FGFC1 to TAFI. The inhibitory effect of FGFC1 on TAFI-mediating coagulation (ex vivo and in vitro) and its fibrinolytic effect (ex vivo) were investigated in hPPP and hCMEC/D3 cells, respectively, followed by SEM.</p><p><strong>Results: </strong>FGFC1 solutions ranging from 0.023 to 0.736 mM effectively inhibited TAFI activation. Notably, the 0.023 mM concentration demonstrated significant suppression, comparable to DS-1040 and PCTI. These inhibitory effects of FGFC1 (0.023-0.368 mM) were further validated through the enhancement in TAFI (TAFIa) activation by fibrins in the coagulum prior to proteolysis, resulting in the cleavage of TAFIa from 33 kDa to 28 kDa. Furthermore, these regulatory effects of FGFC1 on TAFI were demonstrated to have minimal association with TM-mediated control, as confirmed through a molecular docking analysis. FGFC1 (0.023-0.092 mM) was suggested to have obstructive effects on TAFI-mediated coagulation in the hPPP, which was demonstrated by the inhibition of clot aggregation, protein crystallization, and platelet anchoring, as observed through SEM. Simultaneously, FGFC1 (0.023 to 0.368 mM) significantly enhanced TAFI-mediated fibrinolysis, which was also supported by increased levels of t-PA, u-PA, and plasmin.</p><p><strong>Conclusions: </strong>From the above findings, FGFC1 is identified as a novel dual-target bioactive compound participating in blood formation/dissolution that demonstrates anti-coagulation and fibrinolytic effects by regulating TAFI activation, inhibiting TAFIa-fibrin combination, and initiating proteolysis. It also provided convincing evidence that TAFI plays a critical role in thrombolysis as a molecular link between coagulation and fibrinolysis. Furthermore, the application of FGFC1 was indicated as a potential therapeutic strategy in thromboembolic and hemorrhagic diseases.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"17 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11510285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lindalva Maria de Meneses Costa Ferreira, Naila Ferreira da Cruz, Desireé Gyles Lynch, Patrícia Fagundes da Costa, Claudio Guedes Salgado, José Otávio Carréra Silva-Júnior, Alessandra Rossi, Roseane Maria Ribeiro-Costa
{"title":"Hydrogel Containing Propolis: Physical Characterization and Evaluation of Biological Activities for Potential Use in the Treatment of Skin Lesions.","authors":"Lindalva Maria de Meneses Costa Ferreira, Naila Ferreira da Cruz, Desireé Gyles Lynch, Patrícia Fagundes da Costa, Claudio Guedes Salgado, José Otávio Carréra Silva-Júnior, Alessandra Rossi, Roseane Maria Ribeiro-Costa","doi":"10.3390/ph17101400","DOIUrl":"https://doi.org/10.3390/ph17101400","url":null,"abstract":"<p><strong>Background: </strong>Skin injury affects the integrity of the skin structure and induces the wound healing process, which is defined by a well-coordinated series of cellular and molecular reactions that aim to recover or replace the injured tissue. Hydrogels are a group of promising biomaterials that are able to incorporate active ingredients for use as dressings. This study aimed to synthesize hydrogels with and without propolis extract and evaluate their physical characteristics and biological activities in vitro for potential use as active dressings in the treatment of skin lesions.</p><p><strong>Methods: </strong>The antifungal [<i>Candida albicans</i> (<i>C. albicans</i>) and <i>Candida tropicalis</i> (<i>C. tropicalis</i>)] and antibacterial [<i>Staphylococcus aureus</i> (<i>S. aureus</i>), <i>Pseudomonas aeruginosas</i> (<i>P. aeruginosas</i>) and <i>Escherichia coli</i> (<i>E. coli</i>)] activity was assessed by the microdilution method in plates and antioxidant potential by the reduction of the phosphomolybdate complex.</p><p><strong>Results: </strong>The hydrogels showed good water absorption capacity, high solubility, and high gel fraction, as well as good porosity, water retention, and vapor transmission rates. They revealed a totally amorphous structure. The extract and the hydrogels containing the propolis extract (1.0% and 2.5%) did not inhibit fungal growth. However, they showed antibacterial activity against strains of <i>S. aureus</i> and <i>P. aeruginosas</i>. Regarding the <i>E. coli</i> strain, only the extract inhibited its growth. It showed good antioxidant activity by the evaluation method used.</p><p><strong>Conclusions: </strong>Therefore, the hydrogels containing propolis extract can be a promising alternative with antibacterial and antioxidant action for use as dressings for the treatment of skin lesions.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"17 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11510207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}