Frontiers in Pharmacology最新文献

{"title":"Identification of human pregnane X receptor antagonists utilizing a high-throughput screening platform.","authors":"Caitlin Lynch, Ryan Margolis, Jacob Niebler, Jameson Travers, Srilatha Sakamuru, Tongan Zhao, Carleen Klumpp-Thomas, Ruili Huang, Menghang Xia","doi":"10.3389/fphar.2024.1448744","DOIUrl":"10.3389/fphar.2024.1448744","url":null,"abstract":"<p><p>Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor with a well-established role in regulating drug metabolism and clearance. Recent studies have shown that PXR is involved in cell proliferation, apoptosis, immune response, and energy homeostasis. It is important to identify compounds that may modulate PXR activity to prevent drug-drug interactions, distinguish chemicals which could potentially generate toxicity, and identify compounds for further development towards therapeutic usage. In this study, we have screened the National Center for Advancing Translational Sciences (NCATS) Pharmacologically Active Chemical Toolbox (NPACT) library, which consists of 5,099 unique pharmacologically active synthetic and naturally derived small molecules to identify PXR antagonists. Ninety-four compounds were identified as potential PXR antagonists through a primary screen and 66 were confirmed in a confirmation study. Of these compounds, twenty potential PXR antagonists, including gamma-secretase modulator 2 (GSM2) and fusidic acid, were selected for further study based on their efficacy, potency, and novelty. Their PXR inhibition abilities were assessed by examining their effects on cytrochrome P450 (CYP) 3A4 mRNA expression using metabolically competent HepaRG cells. Additionally, a pharmacological inhibition assay using various concentrations of rifampicin as a stimulator was performed in HepG2-<i>CYP3A4</i>-hPXR cells to confirm the activity of the 20 selected compounds against PXR. Finally, HepaRG cells were used to confirm PXR antagonism by verification of a concentration-dependent decrease of CYP3A4 when co-treated with the known PXR agonist, rifampicin. Additionally, the potent actives were further investigated using molecular docking to find the potential interactions of the novel ligands with the active sites of hPXR. To our knowledge from the current study, GSM2 and fusidic acid have been identified as novel PXR antagonists, which provides useful information for further investigation regarding possible drug-drug interactions, as well as the detection of potential therapeutic effects or other toxic consequences.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic effects of anlotinib and DDP on breast cancer: targeting the VEGF/JAK2/STAT3 axis.","authors":"Hongmei Zhang, Chunling Liu, Ye Jin, Zheng Wang, Yi Guan, Zhenxian Jia, Tong Cui, Zhi Zhang, Xuemei Zhang","doi":"10.3389/fphar.2024.1494265","DOIUrl":"10.3389/fphar.2024.1494265","url":null,"abstract":"<p><strong>Background: </strong>Anlotinib, a highly selective inhibitor of VEGFR2, has demonstrated significant anti-tumor effects in various cancers. However, its potential synergistic effects with DDP (cisplatin) in breast cancer (BRCA) remain to be fully elucidated. This study aims to discover the therapeutic efficacy of anlotinib on BRCA, specifically the synergistic effects with DDP, and to elucidate the underlying molecular mechanisms.</p><p><strong>Methods: </strong>BRCA cells were treated with anlotinib and/or DDP. The proliferation, migration and invasion capabilities of BRCA cells were evaluated using CCK-8 assays, cell cycle distribution, clone formation assays, wound healing assays and transwell assays. Cell apoptosis was detected by flow cytometry technique and Hoechst33342 fluorescence staining. The potential mechanism of anlotinib in the development of BRCA was predicted through bioinformatics analysis, and the mRNA or protein levels were subsequently quantified using qPCR, immunofuorescence and western blot. The anti-breast cancer efficacy of anlotinib was evaluated <i>in vivo</i> using a xenograft tumor model.</p><p><strong>Results: </strong>Our findings reveal that increased VEGFA expression in BRCA patients is associated with poorer prognosis, underscoring the need for targeted therapeutic strategies. We also demonstrate that both anlotinib and DDP independently inhibit BRCA cell growth, migration, and invasion, while their combination exhibits a synergistic effect, significantly enhancing the inhibition of these oncogenic processes. This synergy is further evident through the induction of apoptosis and autophagy in BRCA cells. Mechanistically, anlotinib's effectiveness is linked to its inhibition of the JAK2/STAT3 pathway, a critical axis in BRCA progression. <i>In vivo</i> study further support these results, showing that anlotinib markedly inhibits tumor growth in xenografted mice.</p><p><strong>Conclusion: </strong>This study confirms the efficacy of anlotinib or in combination with DDP and elucidates the mechanism behind anlotinib's effectiveness, highlighting its role in inhibiting the JAK2/STAT3 pathway.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The enigma of small heat shock protein phosphorylation.","authors":"Matthias Gaestel","doi":"10.3389/fphar.2024.1486245","DOIUrl":"10.3389/fphar.2024.1486245","url":null,"abstract":"","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The potential of natural products to inhibit abnormal aggregation of α-Synuclein in the treatment of Parkinson's disease.","authors":"Kaixia Yang, Zhongyue Lv, Wen Zhao, Guogang Lai, Cheng Zheng, Feiteng Qi, Cui Zhao, Kaikai Hu, Xiao Chen, Fan Fu, Jiayi Li, Guomin Xie, Haifeng Wang, Xiping Wu, Wu Zheng","doi":"10.3389/fphar.2024.1468850","DOIUrl":"10.3389/fphar.2024.1468850","url":null,"abstract":"<p><p>Parkinson's disease (PD), as a refractory neurological disorder with complex etiology, currently lacks effective therapeutic agents. Natural products (NPs), derived from plants, animals, or microbes, have shown promising effects in PD models through their antioxidative and anti-inflammatory properties, as well as the enhancement of mitochondrial homeostasis and autophagy. The misfolding and deposition of α-Synuclein (α-Syn), due to abnormal overproduction and impaired clearance, being central to the death of dopamine (DA) neurons. Thus, inhibiting α-Syn misfolding and aggregation has become a critical focus in PD discovery. This review highlights NPs that can reduce α-Syn aggregation by preventing its overproduction and misfolding, emphasizing their potential as novel drugs or adjunctive therapies for PD treatment, thereby providing further insights for clinical translation.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimutagenic and anticoagulant therapeutic effects of Ag/Ag₂O nanoparticles from <i>Olea europaea</i> leaf extract: mitigating metribuzin-induced hepato-and nephrotoxicity.","authors":"Manel Azzi, Ibtissam Laib, Abderrhmane Bouafia, Ifriqya Medila, Ali Tliba, Salah Eddine Laouini, Huda Alsaeedi, David Cornu, Mikhael Bechelany, Ahmed Barhoum","doi":"10.3389/fphar.2024.1485525","DOIUrl":"10.3389/fphar.2024.1485525","url":null,"abstract":"<p><strong>Background: </strong>Silver nanoparticles (Ag/Ag₂O NPs) have garnered attention for their potent antioxidant, antimicrobial, and anti-inflammatory properties, showing promise for therapeutic applications, particularly in mitigating chemical-induced toxicity.</p><p><strong>Objective: </strong>This study aimed to synthesize Ag/Ag₂O NPs using Olea europaea (olive) leaf extract as a green, eco-friendly reducing agent and evaluate their protective effects against metribuzin-induced toxicity in Wistar rats, focusing on oxidative stress, hematological parameters, and lipid profiles, with specific dose optimization.</p><p><strong>Methodology: </strong>Ag/Ag₂O NPs were synthesized using Olea europaea leaf extract, and their properties were confirmed via XRD, FTIR, SEM, EDS, and UV-visible spectroscopy. Wistar rats exposed to metribuzin (110 mg/kg/day) were treated with two doses of Ag/Ag₂O NPs (0.062 mg/kg and 0.125 mg/kg). Hematological and biochemical markers were assessed to evaluate the NPs' protective effects.</p><p><strong>Results: </strong>Physicochemical characterization confirmed the successful formation of Ag/Ag₂O NPs loaded with phytochemicals, exhibiting crystallite sizes of 23 nm and 19 nm, a particle size of 25 nm, and significant peaks in XRD, FTIR, and UV-Vis spectra indicating the formation of Ag/Ag₂O. Metribuzin exposure led to significant hematological disruptions (elevated WBC, reduced RBC and hemoglobin) and worsened lipid profiles (increased cholesterol, LDL, and triglycerides). The lower NP dose (0.062 mg/kg) improved WBC, RBC, hemoglobin, and platelet counts, normalized lipid levels, and positively influenced biochemical markers such as serum creatinine and uric acid. In contrast, the higher NP dose (0.125 mg/kg) showed mixed results, with some improvements but an increase in triglycerides and continued elevation of ASAT and ALAT enzyme levels.</p><p><strong>Conclusion: </strong>Ag/Ag₂O NPs synthesized via green methods using olive leaf extract effectively mitigated metribuzin-induced toxicity, especially at lower doses, by improving oxidative stress markers and hematological and biochemical profiles. Dose optimization is crucial to maximize therapeutic benefits and minimize adverse effects, underscoring their potential in treating chemical-induced toxicity.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tilianin suppresses NLRP3 inflammasome activation in myocardial ischemia/reperfusion injury via inhibition of TLR4/NF-κB and NEK7/NLRP3.","authors":"Suyue Yin, Kaixi Han, Di Wu, Zihan Wang, Ruifang Zheng, Lianhua Fang, Shoubao Wang, Jianguo Xing, Guanhua Du","doi":"10.3389/fphar.2024.1423053","DOIUrl":"10.3389/fphar.2024.1423053","url":null,"abstract":"<p><p>Tilianin, a flavonoid compound derived from <i>Dracocephalum moldavica</i> L., is recognized for its diverse biological functionalities, in particular alleviating myocardial ischemia-reperfusion injury (MIRI). There is ample evidence suggesting that the NLRP3 inflammasome has a significant impact on the development of MIRI. In this study, rats undergoing the ligation and subsequent release of the left anterior descending (LAD) coronary artery and H9c2 cardiomyocytes subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) were used to investigate the effects of tilianin on NLRP3 inflammasome and its anti-MIRI mechanisms. Upon reperfusion, the rats were intraperitoneally injected with tilianin at doses of 3, 10, 30 mg/kg. H9c2 cells were treated with tilianin at concentrations of 10, 30, and 50 μg/mL. Echocardiography, TTC staining and TUNEL staining demonstrated that tilianin remarkably improved cardiac function and mitigated myocardial damage in MIRI rats. Additionally, notable inflammatory response reduction by tilianin was evidenced by subsequent hematatoxylin-eosin (HE) staining, inflammatory cytokines assay, and quantitative proteomics. Further western blotting analysis and immunofluorescence staining showed tilianin decreased the levels of TLR4, p-NF-κB, NLRP3, and ASC in MIRI rats and H9c2 cells exposed to OGD/R, alongside a significant reduction in cleaved gasdermin D, mature IL-1β and IL-18. Molecular docking, cellular thermal shift assay (CETSA) and co-immunoprecipitation (co-IP) assay revealed that tilianin impeded the interaction between NLRP3 and NEK7. Taken together, tilianin protects cardiomyocytes from MIRI by suppressing NLRP3 inflammasome through the inhibition of the TLR4/NF-κB signaling pathway and the disruption of the NEK7/NLRP3 interface. These findings underscore the potential of tilianin as a promising therapeutic candidate for MIRI.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of fermentation on the constituents in the branches and leaves of <i>Taxus media</i> and non-small cell lung cancer.","authors":"Xing Guo, Rui-Sheng Wang, Zhen-Ling Zhang, Hong-Wei Zhang, Sheng-Chao Wang, Shuai Zhang, Ya-Ning Wu, Ya-Jing Li, Jun Yuan","doi":"10.3389/fphar.2024.1449498","DOIUrl":"10.3389/fphar.2024.1449498","url":null,"abstract":"<p><strong>Introduction: </strong>Non-small cell lung cancer (NSCLC) is a prominent lung cancer disease worldwide. Currently, commonly used methods, such as surgery and radiotherapy, have significant side effects. Traditional Chinese medicine (TCM) has become a research hotspot because of its safe and effective characteristics. The branches and leaves of <i>Taxus media</i> are abundant in antitumor active compounds, and there has been no research conducted as yet regarding its anti-lung cancer molecular mechanism.</p><p><strong>Objective: </strong>The aim of this study is to investigate the antitumor activity of two samples before and after fermentation of <i>T. media</i>, and to research the molecular mechanism of its inhibitory effect on NSCLC.</p><p><strong>Methods: </strong>The chemical composition of pre-fermentation <i>T. media</i> (TM) and post-fermentation <i>T. media</i> qu (TMQ) were investigated using UHPLC-Q-Qrbitrap HRMS and high-performance liquid chromatography (HPLC). The anti-lung cancer activities of TM and TMQ were compared using an A549-induced tumor mouse model. An enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (H&E) staining, immunohistochemistry, and immunofluorescence were used to determine the of TMQ mechanism of action.</p><p><strong>Results: </strong>The results indicated that TM and TMQ contained 83 compounds, consisting primarily of flavonoids, organic acids, and taxanes. Both taxanes and flavonoids in TMQ were higher than that in TM. Both TM and TMQ effectively inhibited the tumor growth in non-small cell lung cancer (NSCLC), and the inhibition rate was greater in TMQ (57.24%) than in TM (49.62%). TMQ administration downregulated the tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and the glutathione (GSH) level and upregulated interferon-γ (IFN-γ), reactive oxygen species (ROS), and malondialdehyde (MDA) levels in the serum of tumor mice. TMQ treatment also increased the protein expression of Bax, Caspase-3, and Beclin-1 in tumor tissues. In contrast, the bcl-2, PI3K, Ki67, ULK1, and mTOR protein levels were suppressed by TMQ. Protein assay analyses reemphasized the superior antitumor effect of TMQ over TM. These cumulative findings demonstrated that the mechanism of action of TMQ was closely related to the activation of transcriptional misregulation in the cancer pathway that inhibited the cholinergic synaptic, AMPK, and PI3K/Akt/mTOR signaling pathways.</p><p><strong>Conclusion: </strong>This study demonstrated that fermentation increased the active ingredient contents and antitumor effects of <i>T. media</i>. In addition, post-fermentation TMQ was superior to TM as a herbal medicine for NSCLC treatment.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clopidogrel ameliorates high-fat diet-induced hepatic steatosis in mice through activation of the AMPK signaling pathway and beyond.","authors":"Ting Tai, Yuan-Yuan Shao, Yu-Qi Zheng, Li-Ping Jiang, Hao-Ru Han, Na Yin, Hao-Dong Li, Jin-Zi Ji, Qiong-Yu Mi, Li Yang, Lei Feng, Fu-Yang Duan, Hong-Guang Xie","doi":"10.3389/fphar.2024.1496639","DOIUrl":"10.3389/fphar.2024.1496639","url":null,"abstract":"<p><strong>Introduction: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) frequently confers an increased risk of vascular thrombosis; however, the marketed antiplatelet drugs are investigated for the prevention and treatment of MASLD in patients with these coexisting diseases.</p><p><strong>Methods: </strong>To determine whether clopidogrel could ameliorate high-fat diet (HFD)-induced hepatic steatosis in mice and how it works, mice were fed on normal diet or HFD alone or in combination with or without clopidogrel for 14 weeks, and primary mouse hepatocytes were treated with palmitate/oleate alone or in combination with the compounds examined for 24 h. Body weight, liver weight, insulin resistance, triglyceride and total cholesterol content in serum and liver, histological morphology, transcriptomic analysis of mouse liver, and multiple key MASLD-associated genes and proteins were measured, respectively.</p><p><strong>Results and discussion: </strong>Clopidogrel mitigated HFD-induced hepatic steatosis (as measured with oil red O staining and triglyceride kit assay) and reduced elevations in serum aminotransferases, liver weight, and the ratio of liver to body weight. Clopidogrel downregulated the expression of multiple critical lipogenic (<i>Acaca</i>/<i>Acacb</i>, <i>Fasn</i>, <i>Scd1</i>, <i>Elovl6</i>, <i>Mogat1</i>, <i>Pparg</i>, <i>Cd36</i>, and <i>Fabp4</i>), profibrotic (<i>Col1a1</i>, <i>Col1a2</i>, <i>Col3a1</i>, C<i>ol4a1</i>, <i>Acta2</i>, and <i>Mmp2</i>), and proinflammatory (<i>Ccl2</i>, <i>Cxcl2</i>, <i>Cxcl10</i>, <i>Il1a</i>, <i>Tlr4</i>, and <i>Nlrp3</i>) genes, and enhanced phosphorylation of AMPK and ACC. However, compound C (an AMPK inhibitor) reversed enhanced phosphorylation of AMPK and ACC in clopidogrel-treated primary mouse hepatocytes and alleviated accumulation of intracellular lipids. We concluded that clopidogrel may prevent and/or reverse HFD-induced hepatic steatosis in mice, suggesting that clopidogrel could be repurposed to fight fatty liver in patients.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Plukenetia volubilis</i> leaves as source of anti-<i>Helicobacter pylori</i> agents.","authors":"Aditya Tan, Katia Castanho Scortecci, Nathalia Maira Cabral De Medeiros, Wirginia Kukula-Koch, Thomas J Butler, Sinéad Marian Smith, Fabio Boylan","doi":"10.3389/fphar.2024.1461447","DOIUrl":"10.3389/fphar.2024.1461447","url":null,"abstract":"<p><strong>Introduction: </strong><i>Helicobacter pylori</i> infection is a major issue worldwide, with widespread prevalence, combined with its link to gastritis, peptic ulcers, gastric cancer, and mucosa-associated lymphoid tissue (MALT) lymphoma. Meanwhile, effectiveness of current treatment protocols is limited by increasing antibiotic resistance and patient compliance issues due to long regimens and side effects. <i>Plukenetia volubilis</i>, or sacha inchi, is a valuable source of bioactive molecules. However, studies on its antimicrobial activity, especially against <i>H. pylori</i>, are lacking.</p><p><strong>Methods: </strong>In this study, the anti-<i>H. pylori</i> activity of <i>P. volubilis</i> leaves water extract was explored using <i>in vitro</i> and <i>in silico</i> approaches. High-Performance Liquid Chromatography coupled to Electrospray Ionisation and Quadrupole Time-of-Flight Mass Spectrometry (HPLC-ESI- QTOF-MS-MS) analysis of the water extract from the leaves was used to characterise the chemical composition of the plant and allowed identification of some flavonoids, such as astragalin, and some phenolic compounds. Then, high-speed counter current chromatography (HSCCC) was used to fractionate the ethyl acetate partition obtained from the water extract from the leaves.</p><p><strong>Results and discussion: </strong>The presence of flavonoids derived from kaempferol was confirmed and astragalin was isolated for the first time in <i>P. volubilis</i>. The <i>P. volubilis</i> water infusion, ethyl acetate extract and the isolated astragalin exhibited anti-bacterial activity against <i>H. pylori</i> J99 and two clinical isolates (e.g., minimum inhibitory concentrations of 0.53, 0.51 and 0.49 μg/mL, respectively, for clarithromycin-resistant clinical isolate SSR366). Then, using molecular docking for potential protein targets for <i>H. pylori</i>, it was verified that astragalin could interact with these proteins by <i>in silico</i> analysis.</p><p><strong>Conclusion: </strong>These findings highlight that <i>P. volubilis</i> and astragalin produce a bacteriostatic activity against <i>H. pylori</i> and may have potential to be used in treatment against <i>H. pylori</i>, after further research.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Febuxostat-induced agranulocytosis in a pediatric hematopoietic stem cell transplant recipient: Case Report and literature review.","authors":"Debora Curci, Stefania Braidotti, Natalia Maximova","doi":"10.3389/fphar.2024.1478381","DOIUrl":"10.3389/fphar.2024.1478381","url":null,"abstract":"<p><p>This report describes a pediatric case of isolated agranulocytosis occurring months after hematopoietic stem cell transplantation (HSCT). Secondary cytopenia, or secondary transplant failure, affects 10%-25% of HSCT recipients, with potential triggers including viral infection, graft-versus-host disease (GVHD), sepsis, and certain medications. Viral reactivation was ruled out based on negative PCR results, while GVHD and sepsis were ruled out based on the patient's clinical presentation. The patient, who received an HLA 10/10 unrelated donor T-cell transplant, underwent standard myeloablative conditioning to minimize the risk of graft rejection. However, agranulocytosis persisted even after discontinuation of myelotoxic drugs such as valganciclovir and ruxolitinib. Further investigation revealed that the patient had been taking febuxostat, which was subsequently discontinued, leading to a recovery of the neutrophil count. The European Medicines Agency lists agranulocytosis as a rare side effect of febuxostat. The effect of candidate genes and variants involved in febuxostat pharmacokinetics and pharmacodynamics was done using the Pharmacogenomics Knowledge Base (PharmGKB) to accurately evaluate an individual's risk for neutropenia. This case suggests that genetic variants in renal transporters <i>ABCG2</i> (exonic non-synonymous variant, rs2231137), <i>SLC29A1</i> (rs747199 and rs628031), and <i>ABCC4</i> (3'UTR SNP, rs3742106 and rs11568658) may contribute to drug-induced agranulocytosis. This finding underscores the importance of genetic profiling in the management of patients undergoing HSCT to prevent adverse drug reactions.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}