Research in Pharmaceutical Sciences最新文献

{"title":"Mechanistic insights into sitagliptin's action in rat inflammatory bowel disease: involvement of the NO-cGMP-KATP pathway.","authors":"Hasti Dehestani, Behnam Ghorbanzadeh, Tarang Taghvaei Arabi, Mohammad Seydabadi, Fereshteh Beigom Talebpour Amiri, Ramin Ataee, Mohammad Shokati Sayyad, Sara Bayat, Gholamreza Houshmand","doi":"10.4103/RPS.RPS_14_26","DOIUrl":"https://doi.org/10.4103/RPS.RPS_14_26","url":null,"abstract":"<p><strong>Background and purpose: </strong>Inflammatory bowel disease (IBD) involves several intestinal disorders that lead to prolonged inflammation of the gastrointestinal tract. Sitagliptin is an antidiabetic drug that works by increasing incretin hormones. This study examined the effect of sitagliptin, as well as the contribution of the NO-cGMP-KATP channel pathway, in acetic acid-induced colitis.</p><p><strong>Experimental approach: </strong>To induce colitis in rats, 4% acetic acid was administered intrarectally. Subsequently, the animals were intraperitoneally pretreated with L-arginine, L-NAME, sildenafil, methylene blue, diazoxide, and glibenclamide for 3 consecutive days, 15 min before sitagliptin administration (90 mg/kg. p.o.). Finally, microscopic and macroscopic parameters and inflammatory indices, apoptotic gene expression, and histopathological observation were evaluated in colon tissue.</p><p><strong>Findings/results: </strong>The findings showed that sitagliptin diminished both the macroscopic and microscopic injuries caused by acetic acid and also decreased IL-1β and TNF-α levels and TNF-α gene expression. Moreover, it enhanced the gene expression of BCL2. The findings revealed that the effects of sitagliptin were significantly reduced by L-NAME (NOS inhibitor), methylene blue (guanylate cyclase inhibitor), and glibenclamide (ATP-sensitive potassium channel blocker). In addition, pretreatment with L-arginine, diazoxide, and sildenafil preserved the protective effect of sitagliptin.</p><p><strong>Conclusion and implications: </strong>Finally, this study revealed that sitagliptin effectively alleviated acetic acid-induced colonic tissue injury by reducing inflammation and regulating genes involved in apoptosis. The NO-cGMP-KATP channel pathway plays a significant role in mediating this protective effect.</p>","PeriodicalId":21075,"journal":{"name":"Research in Pharmaceutical Sciences","volume":"21 5","pages":"657-669"},"PeriodicalIF":2.3,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sitagliptin protects against bile duct ligation-induced cholemic nephropathy in male rats through modulation of inflammation, sestrin2, and the Nrf2/SOD pathway.","authors":"Mohammad Akhbari, Shadan Saberi, Mohammad Khaksari, Majid Askaripour, Elham Jafari","doi":"10.4103/RPS.RPS_101_25","DOIUrl":"https://doi.org/10.4103/RPS.RPS_101_25","url":null,"abstract":"<p><strong>Background and purpose: </strong>Cholestasis or bile duct ligation (BDL) could develop cirrhosis and may lead to other organ dysfunction, including the kidneys, which is called cholemic nephropathy (CN). Hyperbilirubinemia, bile acid accumulation, renal hypoperfusion, oxidative stress, and inflammation are implicated in the pathogenesis of CN. Sitagliptin is an oral antihyperglycemic drug with anti-inflammatory and anti-oxidative effects. Its effects on CN were unknown.</p><p><strong>Experimental approach: </strong>The BDL-induced CN model was performed in 35 male Wistar rats (200-250 g), which were divided into five groups (n = 7) as follows: sham group receiving distilled water as vehicle (sham + Veh), BDL group receiving vehicle (BDL + Veh), and BDL groups receiving sitagliptin at the doses of 10, 50, or 100 mg/kg/day by gavage for 14 days named BDL + Sit 10, BDL + Sit 50, and BDL + Sit 100, respectively. Aspartate transferase, alkaline phosphatase, total bilirubin (T-Bil), renal function biomarkers, creatinine (Cr) clearance, redox system status, TNF-α, and renal histopathology were evaluated.</p><p><strong>Findings/results: </strong>BDL increased serum liver enzymes, T-Bil, Cr, urea, urine Cr, albumin to Cr ratio, and decreased Cr clearance. Also, BDL elevated renal sestrin2, malondialdehyde, TNF-α, renal index, and kidney tissue injury score, while reducing superoxide dismutase (SOD) activity, total antioxidant capacity, and nuclear factor erythroid 2-related factor 2 (Nrf2). Sitagliptin, especially at the low dose, reversed these effects.</p><p><strong>Conclusion and implications: </strong>Sitagliptin improved renal injury and function <i>via</i> ameliorating inflammation and oxidative stress by activating the Nrf2/SOD pathway in BDL rats. Sitagliptin might help treat renal complications in cirrhosis and liver diseases.</p>","PeriodicalId":21075,"journal":{"name":"Research in Pharmaceutical Sciences","volume":"21 5","pages":"605-617"},"PeriodicalIF":2.3,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ketotifen attenuates paraquat-induced nephrotoxicity in mice <i>via</i> suppression of oxidative stress and inflammation.","authors":"Ali Vadizadeh, Mahdieh Sadat Badiee, Ali Hasan Rahmani, Masoud Mahdavinia, Hadi Kalantar, Fereshtesadat Fakhredini, Sirous Rafiei Asl, Mohammad Javad Khodayar","doi":"10.4103/RPS.RPS_161_25","DOIUrl":"https://doi.org/10.4103/RPS.RPS_161_25","url":null,"abstract":"<p><strong>Background and purpose: </strong>Paraquat (PQ) is a toxic herbicide to humans and animals that causes kidney damage. Ketotifen (KTF) is a first-generation antihistamine and a potent mast cell stabilizer with antioxidant and anti-inflammatory properties. This study aimed to evaluate the protective effect of KTF against PQ-induced nephrotoxicity in mice by suppressing inflammation, oxidative stress, and inducible nitric oxide synthase (iNOS).</p><p><strong>Experimental approach: </strong>Thirty-five male NMRI mice were randomly divided into 5 groups (n = 7) as follows: control group receiving normal saline as vehicle (10 mL/kg/day, IP), KTF, PQ, PQ + KTF 2, and PQ + KTF 4 groups. PQ was administered as a single dose (30 mg/kg, IP) on day 4. The mice received KTF at the doses of 2 and 4 mg/kg/day, IP, for seven days. On the eighth day of the study, the mice were anesthetized, and their kidneys were removed. Then, oxidative stress and inflammation factors and iNOS protein expression were evaluated, and histological examinations were performed.</p><p><strong>Findings/results: </strong>KTF resulted in a significant decrease in blood urea nitrogen, creatinine, thiobarbituric acid-reactive substances, tumor necrosis factor alpha, and iNOS protein expression, and a significant increase in albumin, total thiol, and the activity of antioxidant enzymes including catalase, superoxide dismutase, and glutathione peroxidase in PQ-induced nephrotoxicity compared with the PQ group, which were confirmed by histopathological findings.</p><p><strong>Conclusion and implications: </strong>The results of this study showed that KTF could improve PQ-induced renal injury in mice by reducing oxidative stress, inflammation, and iNOS protein expression.</p>","PeriodicalId":21075,"journal":{"name":"Research in Pharmaceutical Sciences","volume":"21 5","pages":"645-656"},"PeriodicalIF":2.3,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thiolactomycin-based morpholino and piperidino conjugates: synthesis, antimalarial evaluation, and P<i>f</i>FAS-II inhibition.","authors":"Shaik Azeeza, M Shaheer Malik, Qazi Mohammad Sajid Jamal, Mufakham Ali Mohammad, Munirah M Al-Rooqi, Saeed S Samman, Shaikh Thoukhir Basha, Abdulrahman A Alsimaree, Ziad Moussa, Saleh A Ahmed, Ahmed Kamal","doi":"10.4103/RPS.RPS_187_25","DOIUrl":"https://doi.org/10.4103/RPS.RPS_187_25","url":null,"abstract":"<p><strong>Background and purpose: </strong>Malaria remains a formidable global healthcare challenge due to emerging drug-resistant Plasmodium spp., underscoring the urgent need for novel antimalarial scaffolds. Thiolactomycin, a FAS-II inhibitor, is a promising lead for structural optimization. This study aims to design, synthesize, and evaluate a series of thiomorpholino and piperidino conjugates bearing a thiolactone moiety as target-specific antimalarial agents.</p><p><strong>Experimental approach: </strong>A series of thiolactomycin-based conjugates was synthesized, including intermediate <b>7b</b> and conjugate <b>4g</b>. Antimalarial activity was evaluated <i>in vitro</i> against the <i>Plasmodium falciparum</i> D10 strain. To elucidate the mechanism, multi-target docking studies of <b>7b</b> and <b>4g</b> were performed against key FAS-II enzymes, followed by 200 ns explicit-solvent MD simulations and MM-PBSA binding free energy calculations targeting <i>Pf</i>FabI. <i>In silico</i> pharmacokinetics and drug-likeness profiling of potent molecules were also carried out.</p><p><strong>Findings/results: </strong>Biological evaluation identified <b>7b</b> and <b>4g</b> as potent compounds with IC₅₀ values of 0.2 and 1.81 μM, respectively. However, the higher phenotypic potency of <b>7b</b> was accompanied by mutagenic liability (Ames positive) revealed by toxicological profiling. Conversely, <b>4g</b> exhibited superior binding affinity (-7.2 kcal/mol) against <i>Pf</i>FabI. MD simulations revealed an induced-fit stabilization of the <b>4g</b>-<i>Pf</i>FabI complex and the complex achieved superior binding free energy (Δ<i>G_Total</i> = -22.14 kcal/mol) compared to thiolactomycin.</p><p><strong>Conclusion and implications: </strong>Conjugate <b>4g</b> was identified as a safer potent compound from the series. MD simulation of the <b>4g</b>-<i>Pf</i>FabI complex revealed an induced fit stabilization involving persistent H-bonds that were absent in docking. These findings suggest <b>4g</b> as a promising molecule for further optimization.</p>","PeriodicalId":21075,"journal":{"name":"Research in Pharmaceutical Sciences","volume":"21 5","pages":"582-604"},"PeriodicalIF":2.3,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IGFBP3 and cisplatin synergistically suppress HeLa cell proliferation and migration through NRF2 inhibition.","authors":"Mahboube Rahmati Kukandeh, Ramin Ataee, Abouzar Bagheri, Elahe Gharehkhani, Mohammad Shokrzadeh","doi":"10.4103/RPS.RPS_212_25","DOIUrl":"https://doi.org/10.4103/RPS.RPS_212_25","url":null,"abstract":"<p><strong>Background and purpose: </strong>Cisplatin is a cornerstone of cervical cancer treatment, but chemoresistance and toxicity limit its efficacy. The NRF2-mediated antioxidant pathway contributes to cisplatin resistance. This study investigated whether insulin-like growth factor-binding protein 3 (IGFBP3) could enhance cisplatin efficacy by suppressing NRF2 signaling.</p><p><strong>Experimental approach: </strong>HeLa cervical cancer cells were treated with IGFBP3, cisplatin, or their combination. Cytotoxicity and drug synergy were evaluated using the MTT assay and combination index analysis. Oxidative stress markers and antioxidant enzyme activities were assessed. NRF2 protein expression was determined by Western blotting and ELISA. Cell migration was evaluated using a scratch assay, and NRF2 target gene expression was measured by RT-qPCR.</p><p><strong>Findings/results: </strong>IGFBP3 combined with cisplatin produced synergistic cytotoxicity (combination index <1). Compared with either monotherapy, the combination significantly suppressed NRF2 expression, increased oxidative stress, reduced antioxidant enzyme activities, and inhibited cell migration. Expression of NRF2 target genes, including HO-1, CAT, SOD, and GPX, was also downregulated.</p><p><strong>Conclusion and implications: </strong>IGFBP3 synergized with cisplatin to inhibit cervical cancer cell proliferation and migration, at least partly through suppression of the NRF2-mediated antioxidant pathway. IGFBP3 may therefore represent a promising chemosensitizing agent for overcoming cisplatin resistance and warrants further preclinical investigation.</p>","PeriodicalId":21075,"journal":{"name":"Research in Pharmaceutical Sciences","volume":"21 5","pages":"632-644"},"PeriodicalIF":2.3,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systems biology-driven drug repurposing in glioblastoma <i>via</i> antigen and pathway mapping.","authors":"Erfan Zaker, Negar Nouri, Parsa Pashangeh, Saeid Razavi Dizaji, Rahim Asghari, Akbar Davoodi, Ilnaz Rahimmanesh","doi":"10.4103/RPS.RPS_193_25","DOIUrl":"https://doi.org/10.4103/RPS.RPS_193_25","url":null,"abstract":"<p><strong>Background and purpose: </strong>Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options and poor patient survival. This study aimed to identify key genes and altered pathways in GBM and to explore potential drug-repurposing candidates using a systems biology approach.</p><p><strong>Experimental approach: </strong>We analyzed gene expression data from two public datasets (GSE4290 and GSE50161) using Transcriptome Analysis Console. These datasets included 102 GBM samples and 23 non-tumor brain samples. We identified differentially expressed genes using statistical thresholds. A protein-protein interaction network was built using STRING and analyzed in Cytoscape based on degree, betweenness, and closeness metrics. Pathway analysis was carried out using KEGG. Survival analysis was performed with GEPIA2. Drug-gene interactions were screened using DGIdb, and molecular docking was carried out for selected targets.</p><p><strong>Findings/results: </strong>A total of 1,704 upregulated and 1,345 downregulated genes were detected. Network analysis highlighted TP53, EGFR, CDC42, and STAT3 as central hub genes. Pathway analysis showed major changes in MAPK signaling, neuroactive ligand-receptor interaction, and extracellular matrix-receptor interaction. Higher expression of CDC42, EGFR, and TP53 was associated with shorter overall survival in GBM patients. Drug screening identified 28 approved compounds targeting six core genes. Docking analysis showed strong binding affinity for several candidates, with scores of -8.5 kcal/mol or lower.</p><p><strong>Conclusion and implications: </strong>This study identified important molecular targets and pathways in GBM and suggests several existing drugs with potential value for therapeutic repurposing. These findings may support future experimental and clinical studies in GBM treatment.</p>","PeriodicalId":21075,"journal":{"name":"Research in Pharmaceutical Sciences","volume":"21 5","pages":"682-701"},"PeriodicalIF":2.3,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, in vitro and in silico evaluation of quinazoline and triazoloquinazoline derivatives as PDE7A inhibitors.","authors":"Afaf A El-Malah, Magdy M Gineinah, Maan T Khayat, Thikryat Neamatallah, Amr Sonousi, Zeinab Mahmoud, Rasha A Hassan","doi":"10.4103/RPS.RPS_195_25","DOIUrl":"https://doi.org/10.4103/RPS.RPS_195_25","url":null,"abstract":"<p><strong>Background and purpose: </strong>Phosphodiesterase 7A (PDE7A) is an attractive therapeutic target for the treatment of inflammatory, autoimmune, and neurodegenerative disorders through modulation of intracellular cAMP levels. However, the development of highly potent and selective PDE7A inhibitors remains challenging. This study aimed to design, synthesize, and evaluate 2-chloroquinazoline and fused 1,2,4-triazolo[4,3-<i>c</i>]quinazoline derivatives as potential PDE7A inhibitors, supported by molecular docking, molecular dynamics simulations, and <i>in silico</i> toxicity prediction.</p><p><strong>Experimental approach: </strong>A series of 2-chloroquinazoline derivatives <b>4a-f</b> and their fused 1,2,4-triazolo[4,3-c]quinazoline counterparts <b>5a</b>-<b>d</b> were synthesized as phosphodiesterase 7A (PDE7A) inhibitors. The synthesized compounds were evaluated for their <i>in vitro</i> inhibitory activity against phosphodiesterase 7A (PDE7A) and were compared with theophylline and BRL50481, a selective PDE7 inhibitor.</p><p><strong>Findings/results: </strong>All compounds demonstrated enzyme inhibition ranging from 0.062 to 1.35 μM;. Derivatives <b>5c</b> and <b>5d</b> exhibited the most potent inhibitory effects, with IC₅₀ values of 0.076 and 0.062 μM;, respectively, and were not significantly different from BRL50481 (IC₅₀ = 0.034 μM;), while being significantly more potent than theophylline (IC₅₀ = 0.539 μM;). These compounds, together with <b>4c</b> and <b>5a</b>, showed superior inhibitory activity compared with theophylline. Molecular docking and molecular dynamics studies were performed to investigate binding interactions and stability within the PDE7A active site.</p><p><strong>Conclusion and implications: </strong>Compounds <b>5c</b> and <b>5d</b> displayed high binding affinity and stability within the active site. Their interactions with key amino acid residues support their potential as effective PDE7A inhibitors. Predicted toxicity data indicated a favorable safety profile across 30 toxicity endpoints, supporting their further development.</p>","PeriodicalId":21075,"journal":{"name":"Research in Pharmaceutical Sciences","volume":"21 5","pages":"702-715"},"PeriodicalIF":2.3,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the molecular mechanisms underlying the neuroprotective potential of ellagic acid in scopolamine-induced learning and memory dysfunction.","authors":"Arezoo Rajabian, Amir Hossein Assaran, Farshad Mirzavi, Mahsan Akbarian, Hossein Salmani, Farimah Beheshti, Seyed Hamidreza Rastegar-Moghaddam, Rasul Saberi, Amin Azadmanesh, Mahmoud Hosseini","doi":"10.4103/RPS.RPS_104_25","DOIUrl":"https://doi.org/10.4103/RPS.RPS_104_25","url":null,"abstract":"<p><strong>Background and purpose: </strong>Scopolamine-induced memory impairment is widely used as an experimental model of cognitive dysfunction. Natural compounds with antioxidant and anti-inflammatory properties, such as ellagic acid (EA), have shown neuroprotective potential; however, their effects on cholinergic signaling and neurotrophic factors remain underexplored. This study aimed to investigate the effects of EA on cognitive performance, oxidative stress, neuroinflammation, and cholinergic markers in scopolamine-treated rats.</p><p><strong>Experimental approach: </strong>Fifty adult male Wistar rats were divided into control, scopolamine (Scop, 2 mg/kg, i.p.), Scop + EA (25 or 50 mg/kg, orally), and Scop + donepezil (2 mg/kg, orally) groups. Cognitive functions were assessed using the MWM and PA tests. Biochemical assays measured hippocampal and cortical levels of MDA, thiols, SOD, CAT, and AChE activity. In addition, hippocampal BDNF concentration and mRNA expression of pro-inflammatory cytokines, AChE, and CHRM1 were quantified.</p><p><strong>Results/findings: </strong>Scopolamine administration significantly impaired learning and memory in both MWM and PA tests, increased oxidative stress markers, reduced antioxidant enzyme activities, decreased hippocampal BDNF levels, and upregulated pro-inflammatory cytokines, AChE mRNA levels, and decreased CHRM1 mRNA expression. EA treatment (particularly at 50 mg/kg) significantly improved behavioral performance, restored antioxidant balance, enhanced BDNF expression, reduced AChE activity, and downregulated cytokine and AChE mRNA expression, while increasing CHRM1 mRNA expression, with effects comparable to those of donepezil.</p><p><strong>Conclusion and implications: </strong>EA attenuates scopolamine-induced memory deficits, accompanied by improvements in oxidative stress markers, neuroinflammatory gene expression, and cholinergic parameters. These findings suggest a potential neuroprotective role of EA; however, the underlying mechanisms remain speculative.</p>","PeriodicalId":21075,"journal":{"name":"Research in Pharmaceutical Sciences","volume":"21 5","pages":"566-581"},"PeriodicalIF":2.3,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of PIM-1 kinase inhibitors from marine natural products through machine learning and structure-based screening.","authors":"Bishal Budha, Arjun Acharya, Madan Khanal, Luthfi Ahmad Muchlashi, Prisma Trida Hardani, Rudy Salam","doi":"10.4103/RPS.RPS_159_25","DOIUrl":"https://doi.org/10.4103/RPS.RPS_159_25","url":null,"abstract":"<p><strong>Background and purpose: </strong>PIM-1 kinase, a serine/threonine kinase implicated in several cancers, has emerged as a promising yet underexplored target for anticancer therapy. This study aimed to identify the potential of PIM-1 inhibitors from marine natural products by integrating machine learning (ML)-based quantitative structure-activity relationship (QSAR) modeling with structure-based virtual screening.</p><p><strong>Experimental approach: </strong>Eleven ML models were developed and evaluated using experimentally validated ChEMBL data. The best-performing model was used to screen the Chemical Marine Natural Product Database (CMNPD), yielding 15 candidate compounds. Molecular docking prioritized four hits based on similarity of binding interactions at the catalytic site to the co-crystallized reference ligand, rather than on docking score alone. These hits were further assessed using 100 ns molecular dynamics (MD) simulations and MM/GBSA binding free-energy calculations. ADMET profiling was also performed to evaluate pharmacokinetic and toxicity properties.</p><p><strong>Findings/results: </strong>Among the screened compounds, Hit-1 (CMNPD11687) emerged as the lead candidate. It showed stable binding throughout MD simulations, with an average RMSD of 4.10 ± 1.67 Å, low atomic fluctuations (RMSF), and favorable binding free energy (ΔG-_Total = -18.45 ± 2.70 kcal/mol). Hit-1 also maintained key protein-ligand interactions more consistently than the other hits. ADMET analysis predicted favorable drug-like and non-toxic properties.</p><p><strong>Conclusion and implications: </strong>These findings identified CMNPD11687 as a promising marine-derived scaffold for PIM-1 inhibition and demonstrated the value of combining ML-driven screening with molecular simulation to accelerate early-stage anticancer drug discovery.</p>","PeriodicalId":21075,"journal":{"name":"Research in Pharmaceutical Sciences","volume":"21 5","pages":"618-631"},"PeriodicalIF":2.3,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aptamer targeting proprotein convertase subtilisin/kexin type 9: <i>in vivo</i> efficacy in a hypercholesterolemic rat model.","authors":"Yaser Eshaghi Milasi, Fariba Sakhaei, AbbasAli Palizban","doi":"10.4103/RPS.RPS_242_25","DOIUrl":"https://doi.org/10.4103/RPS.RPS_242_25","url":null,"abstract":"<p><strong>Background and purpose: </strong>Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a key therapeutic target for lowering low-density lipoprotein cholesterol (LDL-C). This study aimed to evaluate the LDL-C-lowering efficacy of a PCSK9-targeting aptamer (AP-1) in a hypercholesterolemic rat model.</p><p><strong>Experimental approach: </strong>Wistar male rats (n = 48) were divided into 8 groups (n = 6): normal control, negative control, positive control receiving atorvastatin (4 mg/kg body weight) plus ezetimibe (1 mg/kg BW), and a PBS vehicle group. Experimental groups received the aptamer intraperitoneally at 1, 3, and 8 μM;, and one group received 3 μM; aptamer combined with atorvastatin (4 mg/kg BW). Hypercholesterolemia was induced for over 90 days, followed by a 4-week treatment period. Serum lipid parameters, including triglycerides (TG), total cholesterol (T-Chol), LDL-C, and atherogenic indices, were assessed.</p><p><strong>Findings/results: </strong>TG, 143.2 ± 16.44 vs. 109 ± 23.05 mg/dL; T-Chol, 88 ± 3.11 vs. 80 ± 7.16 mg/dL, and LDL-C, 19.4 ± 1.12 vs. 14.5 ± 1.56 mg/dL, levels were significantly increased in the hypercholesterolemic rat model compared to the normal group. Treatment with the 3 μM; aptamer produced the most pronounced lipidlowering effects, significantly reducing TG, 95.2 ± 8.76 vs. 143.2 ± 16.44 mg/dL; T-Chol, 61.2 ± 5.11 vs. 88 ± 3.11 mg/dL, and LDL-C, 11.4 ± 0.75 vs. 19.4 ± 1.12 compared to the hypercholesterolemic control group. Furthermore, the atherogenic index of plasma, remnant cholesterol, and Castelli risk index-II were reduced significantly.</p><p><strong>Conclusion and implications: </strong>AP-1 aptamer-mediated PCSK9 inhibition significantly improved lipid profiles and atherogenic indices, supporting aptamers as a viable alternative to monoclonal antibody-based PCSK9 inhibition.</p>","PeriodicalId":21075,"journal":{"name":"Research in Pharmaceutical Sciences","volume":"21 5","pages":"670-681"},"PeriodicalIF":2.3,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}