Pharmaceuticals最新文献

{"title":"Silibinin Potentiates Antimicrobial Action and Reduces Staphyloxanthin in <i>Staphylococcus aureus</i>.","authors":"José Lima Pereira-Filho, Amanda Graziela Gonçalves Mendes, Carmem Duarte Lima Campos, Viviane da Silva Sousa Almeida, Aleania Polassa Almeida Pereira, Israel Viegas Moreira, Cinara Regina Aragão Vieira Monteiro, Louriane Nunes Gomes, Cristianne Roberta Rhoden, Antonio José Cantanhede-Filho, Lucilene Amorim Silva, Alberto Jorge Oliveira Lopes, Rafael Cardoso Carvalho, Valério Monteiro-Neto","doi":"10.3390/ph19040643","DOIUrl":"10.3390/ph19040643","url":null,"abstract":"<p><p><b>Background/Objectives:</b> The emergence of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) necessitates innovative strategies to overcome conventional resistance mechanisms. This study investigated the potential of the natural flavonolignan silibinin (SIL) as an antivirulence agent against <i>S. aureus</i>, with a particular emphasis on its putative multi-target antibacterial activity and its capacity to potentiate the effects of ciprofloxacin (CIP). <b>Methods:</b> The antibacterial and antivirulence properties of SIL were assessed using both in vitro and in silico approaches. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined, and its synergistic interaction with CIP was evaluated using checkerboard assays. Inhibition of biofilm formation, as well as disruption of established biofilms, was assessed using an MTT-based viability assay. Staphyloxanthin (STX) inhibition was examined through pigment extraction and spectrophotometric quantification of pathway intermediates. Molecular docking studies were conducted to predict the binding affinities of the compounds to key bacterial targets, while safety was evaluated through haemolytic and cytotoxicity assays. <b>Results:</b> SIL exhibited weak to moderate direct antibacterial activity (MICs of 256-512 µg/mL), which is characteristic of many natural product scaffolds. Notably, SIL potentiated the activity of CIP, reducing its MIC by up to fourfold against selected resistant strains of <i>S. aureus</i>. SIL significantly inhibited biofilm formation and disrupted established mature biofilms in a strain-dependent manner. In vitro metabolic profiling and in silico analyses provided mechanistic insights into the effects of SIL on STX biosynthesis. Precursor accumulation data suggest inhibition at the diapophytoene desaturase (CrtN) catalytic step, representing a potential mechanism not previously reported for flavonolignans. Molecular docking studies further predicted favourable binding affinities for CrtM and other key targets. Importantly, SIL exhibited no haemolytic activity and low cytotoxicity in macrophages at synergistic concentrations. <b>Conclusions:</b> This study provides evidence that SIL functions as a dual-action agent, potentiating ciprofloxacin efficacy while reducing STX production and inhibiting biofilm formation, thereby impairing key virulence mechanisms of <i>S. aureus</i>. These findings, together with its favourable safety profile, provide a strong rationale for the development of silibinin-based topical adjuvants to combat drug-resistant <i>Staphylococcus</i> infections in humans.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13119222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819753","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":"Analgesic and Anti-Inflammatory Activity of Ambroxol in the Treatment of Endometriosis: An Experimental Study in Wistar Rats.","authors":"Gustavo Medeiros Frota, Wilwana Guimarães Barbalho Santos, Joana Tenório-Meireles, Eduardo Rodrigues Silva, Amanda Tissore Forwille Reis, Rennan Abud Pinheiro Santos, Larissa Rodrigues de Sousa, Rafael Antônio Freire Carvalho, Joicy Cortez de Sá Sousa, Eduardo Martins de Sousa, Rafael de Abreu Lima, Rafael Cardoso Carvalho, Marcelo Souza de Andrade, João Batista Santos Garcia, Maria do Socorro de Sousa Cartágenes","doi":"10.3390/ph19040641","DOIUrl":"10.3390/ph19040641","url":null,"abstract":"<p><p><b>Background/Objective:</b> This study evaluated the analgesic and anti-inflammatory effects of ambroxol in an experimental model of endometriosis. <b>Methods:</b> Ambroxol was administered at doses of 10, 50, and 100 mg/kg (Abx 10, Abx 50, and Abx 100) by daily gavage for 21 days. A medroxyprogesterone-treated group (Progesterone) was included as a positive control. Pain was assessed using validated behavioral tests, including the Rat Grimace Scale (RGS), the von Frey test, and the rotarod test. Additionally, interleukin-1β (IL-1β) levels and total leukocyte counts were measured in peritoneal lavage fluid. The volumetric reduction in endometriotic implants was evaluated by ultrasonography, while histopathological analysis characterized inflammatory infiltrate and epithelial layer integrity using a standardized scoring system. <b>Results:</b> All ambroxol doses reduced spontaneous pain manifestations throughout the treatment. The mechanical withdrawal threshold significantly increased from the second week onward, and motor quality improved over the course of the study. A significant reduction in IL-1β levels compared with the negative control (Control(-)) was observed on day 21. Abx 50 and Abx 100 significantly reduced implant volumes (48.2% and 56.2%, respectively) and promoted marked disruption of the endometriotic epithelial layer. When compared with Progesterone, higher doses-particularly 100 mg/kg-demonstrated comparable efficacy. <b>Conclusions:</b> Taken together, these pleiotropic effects support the potential for drug repurposing in endometriosis.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13118583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819617","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":"<i>Artemisia argyi</i> Levl.et Vant Extract (AALE) and Parthenolide Suppress Respiratory Syncytial Virus (RSV) via the RIG-I/TLR3 Pathway In Vivo and In Vitro.","authors":"Zeting Tan, Rongshun Liang, Adam Junka, Haoxuan Sun, Jie Jiang, Haojia Ma, Shisong Fang, Yanfang Sun","doi":"10.3390/ph19040640","DOIUrl":"10.3390/ph19040640","url":null,"abstract":"<p><p><b>Background</b>: Respiratory syncytial virus (RSV) is a leading global pathogen of acute lower respiratory tract infection, posing significant risks to infants, the elderly, and immunocompromised patients. <i>Artemisia argyi</i> Levl.et Vant Extract (AALE) and its active components have a variety of pharmacological effects, but their anti-RSV potential remains unclear. The aim of this study is to investigate the anti-RSV activity of AALE and parthenolide and its underlying mechanisms. <b>Methods</b>: Cell counting kit-8 (CCK-8) assay was used to determine the anti-RSV activities of AALE and parthenolide. Time-of-addition assay and phase of action analysis were used to explore the effect of drugs on the viral replication cycle. Quantitative polymerase chain reaction (qRCR), immunofluorescence (IF) and Western blot (WB) were used to investigate the effects of AALE and parthenolide on RSV-F gene and protein and on RIG-I/TLR-3 pathway related molecules in vitro. In vivo antiviral efficacy was verified by hematoxylin-eosin (HE) staining for lung histopathology, quantitative real-time PCR (qPCR) quantification of RSV-F, RIG-I, TLR-3, IRF3, IL-6, and IFN-β gene expression in lung tissues, and enzyme-linked immunosorbent assay (ELISA) for serum IL-6 and IFN-β levels. <b>Results</b>: AALE exhibited the strongest anti-RSV activity among the extracts (SI = 27.6), while parthenolide was the most potent monomeric compound (SI = 8.19). In vitro, both AALE and parthenolide were effective in the co-treatment and post-treatment models, reducing RSV-F gene and F protein levels in infected cells. Furthermore, they alleviated RSV infection by regulating RIG-I and TLR-3 pathway-related genes and proteins. In vivo, AALE and parthenolide suppressed lung index and RSV proliferation, attenuated lung injury, and down-regulated RIG-I, TLR-3, IRF3, IL-6, and IFN-β expression in the lungs of RSV-infected mice. <b>Conclusions</b>: AALE and its component parthenolide can inhibit the invasion and replication of RSV, making it a potential candidate for the treatment of RSV-related diseases.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13119100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819700","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":"Anti-Inflammatory Activities of Baobab Fruit Extracts in TNF-<i>α</i>/IFN-<i>γ</i>-Stimulated HaCaT Keratinocytes with LC-MS/MS and HPLC Profiling.","authors":"Shi-Heon Kang, Soon Yeong Park, Hoon Kim, Sanghyun Lee","doi":"10.3390/ph19040639","DOIUrl":"10.3390/ph19040639","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Atopic dermatitis (AD)-related skin inflammation involves the release of cytokines and chemokines from keratinocytes; therefore, keratinocyte-based models are widely used to evaluate the anti-inflammatory potential of botanical extracts. This study examined the relationship between phytochemical profiles and anti-inflammatory potential of baobab fruit 30% and 70% ethanol extracts (BE-30 and BE-70, respectively) in a TNF-<i>α</i>/IFN-<i>γ</i> (TI)-stimulated HaCaT keratinocyte model. <b>Methods</b>: The anti-inflammatory effects of both extracts were evaluated by measuring cytokine and chemokine secretion in TI-stimulated HaCaT cells. Phytochemical characterization was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and targeted high-performance liquid chromatography (HPLC). <b>Results</b>: Both extracts were non-cytotoxic. TI-stimulation markedly increased interleukin (IL)-6, IL-8 and monocyte chemotactic protein (MCP)-1 secretion, while BE-30 and BE-70 significantly reduced all three mediators in a dose-dependent manner. At comparable doses, BE-70 exhibited greater inhibition than BE-30. BE-30 showed a non-monotonic IL-8 response at low concentrations, whereas BE-70 consistently reduced IL-8 in a dose-dependent manner. LC-MS/MS profiling revealed a polyphenol-rich composition, including flavonol glycosides and related phenolic compounds. HPLC confirmed the presence of four marker analytes (procyanidin B2, epicatechin, rutin and tiliroside), which were enriched in BE-70. The content of these four polyphenols was 1.94-fold higher in BE-70. <b>Conclusions</b>: Baobab fruit extracts exhibit anti-inflammatory activity associated with polyphenols. These findings suggest that they could be used as analytical standards and in dermatological applications.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13118622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819627","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":"(5R)-5-Hydroxytriptolide (LLDT-8) Ameliorates Experimental Autoimmune Myositis via Suppression of the NLRC5/MHC-I Signaling Pathway.","authors":"Tingting Hao, Qing Qi, Cancan Xie, Li Chen, Meijuan Shao, Que Wang, Zemin Lin, Fenghua Zhu, Xiaoqian Yang, Shijun He, Jianping Zuo","doi":"10.3390/ph19040631","DOIUrl":"10.3390/ph19040631","url":null,"abstract":"<p><p><b>Background:</b> Idiopathic inflammatory myopathies (IIMs), characterized by muscle weakness and chronic inflammation, currently lack highly effective therapies. This study investigated the therapeutic potential and underlying mechanism of (5R)-5-hydroxytriptolide (LLDT-8), a triptolide derivative with reduced toxicity, using an experimental autoimmune myositis (EAM) mouse model and in vitro assays. <b>Methods:</b> Forty female BALB/c mice were randomly assigned to five groups: normal, vehicle, methylprednisolone (MP), LLDT-8 (0.0625 mg/kg), and LLDT-8 (0.125 mg/kg). EAM mice were treated with LLDT-8 (0.0625 or 0.125 mg/kg) or methylprednisolone as a positive control. Cellular experiments and molecular docking were performed to investigate potential mechanisms of LLDT-8. <b>Results:</b> LLDT-8 significantly attenuated clinicopathological features, including muscle weakness and pain sensitivity, while reducing serum levels of aspartate aminotransferase and lactate dehydrogenase. Histological analysis revealed that LLDT-8 reduced inflammatory cell infiltration and the presence of CD4⁺ and CD8⁺ T cells in muscle tissues. Mechanistically, LLDT-8 inhibited the expression of nucleotide-binding oligomerization domain receptor caspase recruitment domain 5 (NLRC5), a key transcriptional regulator of major histocompatibility complex-I (MHC-I). This suppression extended to downstream antigen presentation-related molecules, including the transporter associated with antigen processing and proteasome 20S subunit beta. Molecular docking further confirmed the high binding affinity of LLDT-8 to both NLRC5 and MHC-I. <b>Conclusions:</b> LLDT-8 alleviates inflammatory muscle injury by targeting the NLRC5/MHC-I signaling axis, suggesting it may be a promising therapeutic candidate for IIMs.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13119063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819703","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":"XGBPred-ACSM: A Hybrid Descriptor-Driven XGBoost Framework for Anticancer Small Molecule Prediction.","authors":"Priya Dharshini Balaji, Subathra Selvam, Anuradha Thiagarajan, Honglae Sohn, Thirumurthy Madhavan","doi":"10.3390/ph19040635","DOIUrl":"10.3390/ph19040635","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Cancer remains one of the leading global health burdens, mainly because of the lack of specificity and off-target toxicity associated with conventional therapeutic approaches. To move toward more efficient anticancer drug discovery, we have developed an advanced machine-learning-based architecture that allows for predictive modeling of anticancer small molecules. <b>Methods</b>: A total of 3600 compounds with experimentally validated IC₅₀ values were systematically processed to derive a comprehensive suite of molecular representations comprising 2D physicochemical descriptors, structural fingerprints, and hybrid descriptor sets generated via the Mordred and PaDEL frameworks. A total of six machine learning algorithms-Random Forest (RF), Extreme Gradient Boosting (XGB), Gradient Boosting (GB), Extra-Trees classifier (ET), Adaptive Boosting (AdaBoost), and Light Gradient Boosting Machine (LightGBM)-were trained and benchmarked via a rigorous model evaluation protocol incorporating 10-fold cross-validation along with multiple performance metrics. Ensemble voting strategies were also examined to assess potential performance. <b>Result</b>: Of all configurations, the XGB-Hybrid architecture emerged as the most robust and generalizable classifier with an AUC of 0.88 and accuracy of 79.11% on the independent test set. To ensure interpretability and mechanistic insight, SHAP-based feature analysis was conducted, by which feature contributions could be quantified and the molecular determinants most influential for anticancer activity discrimination were revealed. Altogether, the current study establishes an XGB-Hybrid framework as technically rigorous, interpretable, and high-performance predictive modeling with the ability to accelerate early-stage anticancer small molecule identification. <b>Conclusions</b>: The study has brought into focus the transformational effect of machine learning in modern computational oncology and rational drug design pipelines.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13118636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819728","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":"Theranostic vNAR-Based Immunoconjugates Achieve Selective Intracellular Cisplatin Delivery in Embedded 3D HER2-Positive Breast Cancer In Vitro Model.","authors":"Andrea C Alfonseca-Ladrón de Guevara, Alejandro Manzanares-Guzmán, Jessica A Badillo-Mata, Mirna Burciaga-Flores, Pavel H Lugo-Fabres, Tanya A Camacho-Villegas","doi":"10.3390/ph19040633","DOIUrl":"10.3390/ph19040633","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Precise intracellular delivery of chemotherapeutics remains a major challenge in HER2-positive breast cancer, where intratumoral heterogeneity and limited tissue penetration constrain efficacy. A key contributor is the tumor-restricted epidermal growth factor receptor variant III (EGFRvIII), a constitutively active, ligand-independent mutant generated by deletion of exons 2-7. Although classically associated with glioblastoma, lung (NSCLC), head/neck, and prostate cancers, EGFRvIII is also present in subsets of HER2-positive breast cancers, where low-abundance subclones drive aggressive phenotypes and attenuate therapeutic responses. HER2-EGFRvIII co-expression amplifies oncogenic signaling, supported by frequent co-expression in ErbB2-positive primary tumors and metastases, and by sustained receptor phosphorylation in the absence of EGFR gene amplification, depicting EGFRvIII as a compelling therapeutic target. <b>Methods</b>: We evaluated the shark-derived single-domain antibody vNAR R426 as a modular theranostic platform for receptor-mediated cisplatin delivery. Conjugation to cisplatin and fluorescein enabled simultaneous intracellular drug transport and immunofluorescence-based detection in EGFRvIII-positive SKBR3 cells and 3D spheroids. The compact vNAR-based immunoconjugates support efficient receptor recognition, internalization, and intracellular trafficking, features rarely achieved by conventional IgG antibodies. <b>Results</b>: vNAR_CDDP elicited robust, receptor-mediated cytotoxicity, achieving an IC₅₀ of 2.68 µM-approximately 50-fold lower than that of free cisplatin-while unconjugated vNAR maintained scaffold biocompatibility. In three-dimensional spheroid models, the theranostic vNAR (vNAR_CDDP+FITC) exhibited deep and uniform penetration throughout tumor-like architectures, with immunofluorescence intensity closely correlating with regions of intracellular drug delivery and the initiation of cytotoxic responses. Notably, cisplatin conjugation did not impair tissue diffusion or receptor engagement, facilitating effective payload delivery to both peripheral and central cell populations. <b>Conclusions</b>: By integrating tumor-restricted targeting and efficient intracellular drug delivery within a modular single-domain scaffold, vNAR R426 represents a next-generation theranostic platform capable of addressing intratumoral heterogeneity. This approach combines potent cytotoxic activity with immunofluorescence-based detection, thereby advancing the rational design of precision therapeutics for HER2-positive breast cancer.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13119102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819881","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":"Mechanism of Bao Jing Tablets in Chronic Prostatitis/Chronic Pelvic Pain Syndrome: Insights from Multi-Omics and Network Pharmacology.","authors":"Haitao Ge, Yan Zhang, Siqi Jin, Chen Wang, Fujiang Wang","doi":"10.3390/ph19040632","DOIUrl":"10.3390/ph19040632","url":null,"abstract":"<p><p><b>Background/Objectives</b>: To investigate the therapeutic potential and mechanistic basis of Bao Jing Tablet (BJT) for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) via an experimental autoimmune prostatitis (EAP) rat model, through integrating network pharmacology, metabolomics, proteomics, and animal experiments. <b>Methods</b>: UPLC-ZenoTOF 7600-MS/MS was used to analyze the chemical composition of BJT. The therapeutic effect of BJT was evaluated using an experimental autoimmune prostatitis (EAP) rat model. Lipid metabolomics, proteomics, and integrated network pharmacology analyses were performed to investigate the potential mechanisms and active components of BJT in treatment. <b>Results</b>: A total of 174 constituents were identified in BJT, among which 54 major active compounds were screened for further analysis. Network pharmacology and combined multi-omics analysis indicate that the protein targets of HIF-1α, Akt, and PI3K/Akt, as well as the Glycolysis pathway, play important roles in the improvement of CP/CPPS. <b>Conclusions</b>: Our results demonstrated that BJT was an effective drug to improve the development of CP/CPPS. This is associated with the PI3K/Akt-HIF-1α-Glycolysis pathways.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13118977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819630","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":"Inflammation-Driven JNK Activation Promotes EMT and Metastasis in Gastric Cancer and Is Attenuated by Huangjin Shuangshen Granules.","authors":"Shuo Zhang, Chen Huang, Zhiyuan Song, Jiaheng Lou, Jingcheng Zhang, Sicheng Zhao, Tao Jiang, Guangji Zhang","doi":"10.3390/ph19040636","DOIUrl":"10.3390/ph19040636","url":null,"abstract":"<p><p><b>Background:</b> Gastric cancer (GC) is characterized by aggressive invasion and early peritoneal dissemination, which are strongly driven by chronic inflammation and epithelial-mesenchymal transition (EMT). c-Jun N-terminal kinase (JNK), a stress-responsive serine/threonine kinase within the mitogen-activated protein kinase (MAPK) family, integrates inflammatory cues to promote EMT and metastasis. Huangjin Shuangshen granules (HJSS) is a multi-component traditional Chinese medicine (TCM) formula derived from Simiao Yong'an Decoction and clinically used as an adjuvant therapy for GC. However, whether HJSS restrains inflammation-driven metastasis through modulation of JNK-associated EMT signaling remains unclear. <b>Methods:</b> The anti-metastatic efficacy of HJSS was evaluated using integrated in vivo and in vitro models, combined with transcriptomics, network pharmacology and molecular validation. <b>Results:</b> HJSS markedly attenuated LPS-induced metastatic behavior and inflammatory activation. Multilevel analyses converged on MAPK8/JNK as a central regulatory node. HJSS reversed EMT progression and inhibited nuclear phosphorylation of JNK without affecting its upstream kinases. Thermal-shift assays and molecular docking supported potential target engagement of HJSS-derived constituents, including possible interactions with JNK-related signaling targets. Pharmacologic reactivation of JNK partially abrogated the inhibitory effects of HJSS, confirming JNK-dependent action. <b>Conclusions:</b> HJSS suppresses inflammation-driven GC metastasis primarily by attenuating JNK-associated EMT, potentially through modulation of JNK activation by its bioactive constituents. These findings provide mechanistic insight into HJSS as a low-toxicity anti-metastatic strategy and support further exploration of its active constituents.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13119064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819681","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":"When Red Blood Cells Meet Carbon Monoxide: Yin and Yang in Medicines and Pharmaceuticals.","authors":"Taisei Nagasaki, Victor Tuan Giam Chuang, Masaki Otagiri, Kazuaki Taguchi","doi":"10.3390/ph19040634","DOIUrl":"10.3390/ph19040634","url":null,"abstract":"<p><p>Carbon monoxide (CO) is a poisonous gas because it disrupts functional oxygen transport of red blood cell (RBC) by binding heme of hemoglobin with high affinity. Contrarily, endogenous CO, which is constantly generated in the process of heme degradation by heme oxygenase, functions as a gaseous mediator necessary for maintaining physiological homeostasis. This toxicological (Yin) and physiological (Yang) duality presents a distinctive problem in medical and pharmaceutical applications, prompting the central question of this review: How can strict control over CO's exposure dynamics, magnitude, kinetics, and tissue context be achieved to enable its safe therapeutic use? Here, we integrate the Yin and Yang of CO through an innovative exposure-engineering framework, leveraging the inherent RBC characteristics to offer a novel conceptualization for therapeutic development. We highlight the role of native RBCs as a biologically grounded platform that can convert hemoglobin binding-classically viewed as the basis of CO toxicity-into a measurable and controllable buffering mechanism. Then, reconciling the Yin and Yang of CO based on RBCs enables medical and pharmaceutical modulation that is attractive for clinical situations, therapeutics and diagnostics. Finally, we discuss key translational challenges-local concentration control, patient-specific risk stratification, manufacturability and critical quality attributes, and regulatory positioning-and outline how quantifiable exposure control can enable the safe clinical development of RBC-based CO therapy.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13118589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818919","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}