Pharmaceuticals最新文献

{"title":"Computational Assessment of CKP-25 Binding at Receptor-Recognition Interfaces Across Diverse Human Coronaviruses.","authors":"Angelos-Michail Papadopoulos, Spyros Petrakis, Federico Alvarez, Petros Daras","doi":"10.3390/ph19101664","DOIUrl":"10.3390/ph19101664","url":null,"abstract":"<p><p><b>Background/Objectives:</b> The continued emergence of novel coronaviruses motivates the search for small molecules that bind conserved features of the spike receptor-recognition interface across diverse species. CKP-25 was recently reported as a small-molecule inhibitor of the SARS-CoV-2 spike receptor-binding domain. This study aimed to assess computationally whether CKP-25 can maintain stable binding at receptor-recognition interfaces across phylogenetically diverse human coronaviruses. <b>Methods:</b> CKP-25 was docked to the spike receptor-binding regions of Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), and human coronaviruses NL63, 229E, and HKU1 (HCoV-NL63, HCoV-229E, and HCoV-HKU1). SARS-CoV-2 (PDB 6M0J), for which CKP-25 has documented antiviral activity, was processed identically and included as an experimentally validated reference system. Each selected complex was subjected to three independent 100 ns all-atom molecular dynamics (MD) simulations initialized with different random velocities. Binding stability was evaluated using protein and ligand root-mean-square deviation (RMSD), residue flexibility, radius of gyration, protein-ligand contact persistence, polar interactions, and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) calculations. <b>Results:</b> CKP-25 was retained at the targeted receptor-recognition interface in all three replicates for four of the five test targets-MERS-CoV, HCoV-NL63, SARS-CoV-1, and HCoV-HKU1-each of which reproducibly engaged the same aromatic and hydrophobic anchor residues in every independent run. HCoV-229E was the sole exception, the ligand relocating from its docked site in two of three replicates. Ligand RMSD plateaus were generally low, mostly below 2.0 Å. Contact analyses indicated a shared dependence on shape-complementary van der Waals packing involving hydrophobic and aromatic residues, including tyrosine- and tryptophan-rich anchoring environments. MM-GBSA estimates, averaged across replicates, ranged from -24.28 to -34.57 kcal/mol. No test target differed from the SARS-CoV-2 reference (-29.15±3.46 kcal/mol) by more than the replicate-to-replicate spread, with MERS-CoV and HCoV-NL63 giving the most favorable means. <b>Conclusions:</b> CKP-25 remained at the receptor-recognition interface of four of the five human coronaviruses tested, and it did so in all three replicates. In the SARS-CoV-2 control, the same pipeline independently reproduced the experimentally established binding mode, which supports the reliability of these predictions. HCoV-229E was the exception: the ligand left the docked site in two of the three replicates, and no contact was reproducible across all three repetitions. Experimental binding measurements and cell-based entry assays are required to test these predictions.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13708399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272310","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":"Effect of Probiotics on Stress Scores, Cortisol Levels, and Immune Functions in Moderately Stressed Adolescents and Young Adults: Results of a Feasibility Clinical Study.","authors":"Elena Y Enioutina, Manav Jain, Rachel Hudson, Brian Bradford, Kevin M Watt, Nicole L Mihalopoulos, Simon Brewer","doi":"10.3390/ph19101662","DOIUrl":"10.3390/ph19101662","url":null,"abstract":"<p><p><b>Background:</b> Stress can negatively affect immune system functions by regulating cytokine production. The purpose of this feasibility study was to investigate the effects of a probiotic supplement on stress, cortisol levels, and the immune functions of moderately stressed adolescents and young adults. <b>Methods:</b> A randomized, single-blind clinical trial was conducted at Primary Children's Hospital, Utah. Eighty-seven moderately stressed (Perceived Stress Score, PSS, 14-26) volunteers (12-20 years old) completed the study. Participants took either a probiotic blend containing three <i>Lactobacillaceae</i> strains or placebo capsules for 12 weeks. Participants' PSSs were evaluated following office visits at baseline, and after 8 and 12 weeks of supplementation. Participants' collected salivary samples were analyzed for cortisol, secretory IgA, and a panel of cytokines (IL-1β, IL-6, IL-8, TNF-α, and IL-10). <b>Results:</b> Both cohorts showed decreases in PSS and increases in morning salivary cortisol levels; the difference between cohorts was not statistically significant. Probiotics slowed the increase in cortisol levels and had a beneficial effect on cytokine production, with a statistically significant reduction in IL-1β levels compared to placebo (<i>p</i> = 0.03-0.004). A statistically significant, weak positive correlation between cortisol levels and IL-1β (r = 0.16, <i>p</i> = 0.015) has been observed. <b>Conclusions:</b> This study's results suggest that probiotic supplementation may influence cortisol dynamics and cytokine responses in moderately stressed adolescents and young adults, with IL-1β showing the most consistent between-cohort difference. These findings support further investigation of probiotic supplementation in more rigorously designed trials that account for the types of stress experienced by participants in early life and during the study.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13708308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272362","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":"Nelfinavir Synergizes with Cisplatin and Promotes GSDME-Associated Lytic Cell Death in Platinum-Resistant Ovarian Cancer Cells.","authors":"Benjamin N Forgie, Rewati Prakash, Desiree Marno, Farah H Abdalbari, Edith Zorychta, Abu Shadat M Noman, Alicia A Goyeneche, Lucy Gilbert, Julia V Burnier, Carlos M Telleria","doi":"10.3390/ph19101665","DOIUrl":"10.3390/ph19101665","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Platinum resistance limits the efficacy of ovarian cancer treatment and arises through multiple mechanisms, including enhanced DNA repair, activation of stress responses, and increased survival signaling. Nelfinavir (NFV), an HIV protease inhibitor with reported anti-tumor activity, is a candidate for drug repurposing, but its interaction with cisplatin (CDDP) in ovarian cancer has not been established. Here, we investigated whether NFV enhances CDDP cytotoxicity in platinum (Pt)-resistant ovarian cancer cells and characterized the associated cell death response. <b>Methods:</b> Drug interaction was assessed using cell vitality and viability assays and Loewe additivity modeling together with Bliss and ZIP analyses. Cell death was characterized by Annexin V/7-AAD staining, mitochondrial membrane potential analysis, lactate dehydrogenase (LDH) release, immunoblotting, pharmacological caspase inhibition, and bulk mRNA sequencing with differential expression and gene set enrichment analyses. <b>Results:</b> NFV synergistically enhanced CDDP cytotoxicity across three Pt-resistant ovarian cancer cell lines, reducing CDDP IC50 values by 4.2-5.8-fold and producing mean Loewe synergy scores of approximately 25-30. Combination treatment increased LDH release and was accompanied by caspase-8, caspase-3, PARP, and the pore-forming death effector gasdermin E (GSDME) cleavage. Caspase inhibition attenuated viability loss and GSDME processing. Transcriptomic analysis identified enrichment of stress- and death-associated programs, including the unfolded protein response (UPR), apoptosis, reactive oxygen species (ROS)-associated signaling, and TNF/NF-κB signaling. <b>Conclusions:</b> Together, these findings demonstrate a reproducible synergistic interaction between CDDP and NFV in Pt-resistant ovarian cancer cells and characterize an associated lytic cell death phenotype involving apoptotic signaling and accompanied by GSDME processing. These findings support further investigation of NFV as a repurposed combination partner to enhance CDDP cytotoxicity in Pt-resistant ovarian cancer.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13708070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272312","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":"The Forgotten First Contact: The Oral Cavity as a Site of Local Biotransformation Shaping the Chemical Form of Polyphenolic Drugs and Dietary Compounds.","authors":"Caterina Nela Dumitru, Teodora Marcu, Alina Oana Dumitru, Mădălina Nicoleta Matei","doi":"10.3390/ph19101661","DOIUrl":"10.3390/ph19101661","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Polyphenols are dietary constituents and active substances in dosage forms applied locally in the mouth, yet their bioavailability is interpreted almost exclusively in terms of intestinal absorption and colonic microbial metabolism. This review examines the oral cavity as a site of local biotransformation, a compartment that can chemically modify polyphenols before absorption, and asks whether this conversion could be measured as a phenotype. <b>Methods:</b> Narrative synthesis is reported according to SANRA. Four databases were searched from inception to 31 August 2026. <b>Results:</b> Flavonoid glucosides are hydrolysed to aglycones within minutes of contact with saliva; anthocyanins are deglycosylated to cyanidin and converted to protocatechuic acid; epigallocatechin gallate is de-esterified. Local concentrations reach 2-145 μM, two orders of magnitude above plasma. Conversion capacity varied more than twenty-fold among 17 subjects in the only quantitative study. <b>Conclusions:</b> The oral cavity can alter the chemical form of the polyphenols presented to absorption. The orally transformed fraction of an ingested dose is small; a first-pass effect is not demonstrated, and the established consequences are local and qualitative. Oral metabotypes have not been demonstrated; the concept and its operational classification are proposed as hypotheses to be tested in adequately sized cohorts.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13708039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272384","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":"Nephron-Sparing Strategies for Tumor-Bearing Horseshoe Kidney: From Surgeries to Pharmaceuticals.","authors":"Meng-Zhen He, Hui Zhou","doi":"10.3390/ph19101660","DOIUrl":"10.3390/ph19101660","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Horseshoe kidney (HSK) is a type of congenital renal fusion anomaly with extreme anatomic complexity. The malrotation of kidneys and ureters and malformation and altered isthmus and vascular supply may boost several renal and extrarenal complications. Organ preservation of tumor-bearing HSK is rather difficult and only available in a small minority of patients. <b>Methods/Results:</b> This review introduces new advances for nephron-sparing surgical strategies for tumor-bearing HSK, such as super-selective artery clamping, ultrasound-guided renal artery balloon catheter occluded hybrid partial nephrectomy, and focal therapies. It also puts forward novel pharmaceuticals for kidney function preservation to alleviate ischemia-reperfusion injury and medications for neoadjuvant therapies. <b>Conclusions:</b> HSK possesses unique etiology, complex anatomic characteristics, and hidden complications. Renal function preservation is extremely important for tumor-bearing HSK. For long-term high-quality lifespan, precise preoperative planning, surgeon's versatility with multiple surgical techniques, and novel pharmaceuticals to avoid IRI are promising strategies for nephron-sparing surgery.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13708348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272326","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 Benzimidazol-2-Acetamide Derivatives as Submicromolar Casein Kinase 1δ Inhibitors with Favourable Predicted Drug-like Properties.","authors":"Costanza Ceni, Sara Calenda, Giulia Vagnoni, Elisa Marinari, Daniela Catarzi, Flavia Varano, Letizia Trevisan, Michelle Fornasier, Stephanie Federico, Giampiero Spalluto, Gianluca Novello, Veronica Salmaso, Stefano Moro, Martino Calamai, Vittoria Colotta","doi":"10.3390/ph19101666","DOIUrl":"10.3390/ph19101666","url":null,"abstract":"<p><p><b>Background/Objective:</b> Casein kinase 1δ (CK1δ) plays a central role in regulating circadian rhythms, DNA repair, apoptosis, and cell proliferation, and its dysregulation is associated with both cancer and neurodegenerative diseases, making CK1δ an attractive therapeutic target. This study aimed to develop novel CK1δ inhibitors with favourable drug-like properties through the synthesis and biological evaluation of benzimidazol-2-acetamide derivatives. <b>Methods:</b> A novel series of benzimidazol-2-acetamide derivatives was synthesized, incorporating different substituents on the benzimidazole core (5-chloro, 5,6-dichloro, 5-nitro, and 5-cyano) and various saturated cyclic amines on the acetamide moiety. Compounds were evaluated for CK1δ inhibitory activity, while molecular docking and molecular dynamics simulations were performed to investigate their binding mode. In silico ADME predictions assessed pharmacokinetic properties, and cytotoxicity was evaluated in SH-SY5Y neuroblastoma cells. <b>Results:</b> The 5,6-dichloro derivatives <b>20</b> and <b>24</b>, bearing piperidin-4-ylmethanamine and morpholine moieties, respectively, displayed the highest CK1δ inhibitory activity (IC₅₀ = 0.172 and 0.223 μM). The 5-cyano analogue <b>22</b> also exhibited a good potency (IC₅₀ = 0.224 μM). Computational studies confirmed an ATP-competitive binding mode and highlighted the dynamic behaviour of the solvent-exposed substituents within the CK1δ binding site. Predicted pharmacokinetic properties suggested favourable oral absorption and blood-brain barrier penetration. Compounds <b>20</b>, <b>22</b>, and <b>24</b> showed no cytotoxicity in SH-SY5Y cells at concentrations up to 10 μM. <b>Conclusions:</b> The new benzimidazol-2-acetamide derivatives exhibited good inhibitor activity against CK1δ, favourable predicted ADME properties, and low cellular toxicity. The combined experimental and computational findings provide valuable insights for the further optimization of this scaffold toward the development of therapeutics for CK1δ-related diseases.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13708543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272339","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":"Trimetazidine in Heart Failure: From Metabolic Modulation to Clinical Outcomes-A Narrative Review.","authors":"Akshyaya Pradhan, Sudesh Prajapathi, Kunal Mahajan, Akash Batta, Marco Alfonso Perrone","doi":"10.3390/ph19101663","DOIUrl":"10.3390/ph19101663","url":null,"abstract":"<p><p>Heart Failure (HF) remains a leading cause of morbidity and mortality worldwide despite major advances in guideline-directed medical therapy. Metabolic remodeling with impaired myocardial energy utilization has emerged as an important therapeutic target in HF. Trimetazidine, a metabolic modulator that partially inhibits fatty acid beta-oxidation and favours glucose oxidation, enhances myocardial energy efficiency without changing systemic hemodynamics. This narrative review summarizes the molecular mechanisms underlying the cardioprotective effects of trimetazidine and critically evaluates the available clinical evidence supporting its use in HF. Experimental studies have shown that trimetazidine increases ATP production, maintains mitochondrial function, decreases oxidative stress, inhibits apoptosis of cardiomyocytes, regulates autophagy, and reduces myocardial inflammation and fibrosis. Clinical studies and meta-analyses have shown that adjunctive therapy with trimetazidine has been associated with improved left ventricular ejection fraction, ventricular remodeling, exercise capacity, New York Heart Association functional class, biomarkers of myocardial injury, and quality of life in patients with heart failure with reduced ejection fraction. The available evidence also indicates reductions in cardiovascular hospitalization and possibly all-cause mortality, but these findings are based primarily on relatively small randomized trials and pooled analyses, and need confirmation in adequately powered multicenter studies. The potential role of trimetazidine alongside contemporary therapies, including sodium-glucose cotransporter-2 inhibitors and other guideline-directed treatments, is also discussed. Overall, trimetazidine appears to be a promising adjunctive metabolic therapy that may complement existing pharmacological strategies in selected patients with heart failure (Central Illustration). Further large-scale clinical trials are needed to better define its place in contemporary HF management.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13708437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272429","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":"Detachable Modular Blood-Brain Barrier-on-a-Chip with a Concentration Gradient Generator for Stepwise Inflammation Modeling and Drug Evaluation.","authors":"Zezhi Li, Haizhu Meng, Xinmeng Liao, Shuqi Wang, Dan Hu, Lijuan Chen, Yuanhang Chang, Junwei Zhao, Xiang Li, Jianping Xie","doi":"10.3390/ph19101655","DOIUrl":"10.3390/ph19101655","url":null,"abstract":"<p><p><b>Background/Objectives</b>: The blood-brain barrier (BBB) is compromised in many neurological disorders, yet in vitro models rarely reproduce graded inflammatory stimulation of brain endothelial cells in vivo. This study developed a detachable, modular BBB-on-a-chip for stepwise inflammation modeling with multi-marker readout, and compared the anti-inflammatory efficacy of quercetin (QUER) and kaempferol (KAE). <b>Methods</b>: The chip combines a Christmas-tree concentration gradient generator with a four-channel culture module, fabricated separately and assembled on demand for stepwise seeding, exposure, dosing, and sampling. hCMEC/D3 cells were exposed to a TNF-α gradient (0-30 ng/mL); extracellular ATP, ROS, NO, cytokines, ZO-1, and ICAM-1 were monitored over 48 h. Transcriptomics and network pharmacology were integrated with molecular docking and 100 ns molecular dynamics simulations; QUER and KAE were administered gradient-wise (0-20 μM), with dexamethasone as a control. <b>Results</b>: The TNF-α gradient induced time- and concentration-dependent injury, with ATP and IL-8 responding at 8 h, ROS and NO at 12 h, and IL-1β, IL-6, and tight-junction impairment later, yielding spatiotemporally resolved readouts across four parallel channels. Ten hub inflammatory genes, including <i>ICAM1</i>, were identified, and network pharmacology nominated QUER. QUER was predicted to bind ICAM-1 more strongly than KAE, its structural analog differing by one B-ring hydroxyl group; gradient administration confirmed QUER suppressed ICAM-1 expression and inflammatory mediator release at lower concentrations. <b>Conclusions</b>: The detachable modular design makes multi-step inflammation modeling and gradient-based anti-inflammatory evaluation convenient on a single chip; QUER's consistent advantage over KAE across binding calculations and functional assays supports a structure-activity relationship consistent with ICAM-1 engagement.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13708139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272280","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":"Niosomal Mexiletine Attenuates Rotenone-Induced Parkinsonism via Modulation of the circDLGAP4/miR-134-5p/p-CREB Axis and Restoration of Mitochondrial-Autophagic Homeostasis.","authors":"Eman M Raafat, Fares Farhan Alanazi, Sarah Khalifah Alanazi, Yara E Mansour, Mohammed S Teiama, Shimaa K Mohamed","doi":"10.3390/ph19101654","DOIUrl":"10.3390/ph19101654","url":null,"abstract":"<p><p><b>Background</b>: Parkinson's disease (PD) is distinguished by progressive dopaminergic degeneration driven by the convergence of oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired autophagy. Mexiletine (Mexil), which has demonstrated antioxidant properties, has not been systematically investigated yet for its potential to mitigate mitochondrial-dysfunction-related neurodegeneration in PD. Using an integrated computational and experimental approach, we characterized, for the first time, the neuroprotective mechanisms of Mexil's action against rotenone (Rot)-induced Parkinsonism and employed niosomes as a nanocarrier platform to enhance mexil delivery and augment its neuroprotective potential in a Parkinson's disease model. <b>Methods</b>: Molecular docking identified candidate molecular targets underlying niosomal Mexil's neuroprotective potential. Sprague-Dawley male rats were assigned to control, Rot, and Rot plus niosomal Mexil (30 and 50 mg/kg) groups. Motor performance was evaluated, while dopaminergic degeneration, oxidative stress, neuroinflammation, mitochondrial dysfunction, and autophagy were assessed biochemically, histopathologically, and immunohistochemically. <b>Results</b>: Docking revealed promising interactions between Mexil and both phosphorylated cAMP response element-binding protein (p-CREB) and alpha-synuclein, with binding scores of -5.2 and -4.9 kcal/mol, respectively. Niosomal Mexil improved motor function, restored dopamine and tyrosine hydroxylase levels, and curtailed alpha-synuclein accumulation. Most notably, niosomal Mexil engaged a previously unexplored circular RNA DLGAP4/microRNA-134-5p/p-CREB axis, promoted mitochondrial biogenesis via the phosphorylated AMP-activated protein kinase (p-AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/sirtuin-1 (SIRT-1) pathway, and rebalanced mitochondrial dynamics. These changes were accompanied by restored autophagic axis and suppressed oxidative stress and inflammation. <b>Conclusions</b>: Niosomal Mexil confers neuroprotection against Rot-induced Parkinsonism by orchestrating oxidative, mitochondrial, autophagic, and inflammatory pathways, positioning it as a mechanistically novel disease-modifying candidate warranting further preclinical evaluation in PD.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13708736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272305","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":"Codeine and Testosterone Concentration Patterns During Co-Administration of Codeine and Testosterone Undecanoate in Male Wistar Rats.","authors":"Murat Ünalmış, Çiğdem Karakükçü, Mükerrem Betül Yerer, Hatice Duman Saraçoğlu","doi":"10.3390/ph19101653","DOIUrl":"10.3390/ph19101653","url":null,"abstract":"<p><p><b>Background:</b> Three widely separated sampling days cannot establish conventional pharmacokinetic parameters. We therefore examined exploratory whole-blood codeine and plasma total-testosterone concentration patterns during co-administration of codeine and testosterone undecanoate in male Wistar rats. <b>Methods:</b> Thirty-two rats were allocated to saline (S), codeine (C), testosterone undecanoate (T), or combined codeine plus testosterone undecanoate (CT) groups (eight animals per group). Codeine (10 mg/kg by oral gavage) was administered once daily from Day 0 through Day 5 (six total doses) and testosterone undecanoate (100 mg/kg intramuscularly) on Day 3. On Day 0, whole blood was collected two hours after codeine administration; therefore, Day 0 was a post-dose sampling point rather than a pre-dose baseline. No codeine was administered on Day 6; the Day 6 sample was collected after completion of the six-dose treatment schedule. Codeine dose volumes were adjusted according to each rat's baseline body weight. Measurements unavailable because of insufficient sample volume were treated as missing without imputation. Codeine was quantified only in C and CT; the corresponding model therefore estimated the association of adding testosterone undecanoate among codeine-treated animals rather than a full factorial drug-drug interaction. <b>Results:</b> All 14 available Day 0 samples had instrument-reported whole-blood codeine concentrations (range, 0.339-4.705 ng/mL), consistent with their post-dose status. The C-versus-CT group-by-day test using all instrument-reported values yielded Wald chi-square = 8.487 (df = 2, <i>p</i> = 0.014). With the verified LOQ of 0.25 ng/mL, only CT7 Day 14 (0.08 ng/mL) was below the LOQ while remaining above the LOD of 0.07 ng/mL; excluding this observation yielded Wald chi-square = 7.856 (df = 2, <i>p</i> = 0.020). Plasma testosterone availability varied by group and day (<i>n</i> = 3-8); the raw-scale group-by-day test was <i>p</i> = 0.0076, whereas the log-scale sensitivity test was <i>p</i> = 0.052. <b>Conclusions:</b> The observed numerical patterns are exploratory. Sparse sampling, one below-LOQ codeine value, an influential CT7 observation, unequal plasma-testosterone availability, and sensitivity to analytical and modeling choices prevent causal, pharmacokinetic, metabolic, endocrine-mechanistic, or clinical conclusions.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13708289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272346","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}