Naunyn-Schmiedeberg's archives of pharmacology最新文献

{"title":"6-Shogaol attenuates cisplatin-induced gastrointestinal inflammation involving modulation of the putative mTOR/TFEB-mediated autophagy-lysosomal pathway.","authors":"Wenzhuo Zhang, Qingqing Liu, Chenglu Yang, Lei Feng, Yunjing He, Yujie Gao, Yusu Wang, Siyu Han, Yarong Zhai, Ke Nie","doi":"10.1007/s00210-026-05725-8","DOIUrl":"10.1007/s00210-026-05725-8","url":null,"abstract":"<p><p>Gastrointestinal (GI) inflammation is a predominant toxic side effect of cisplatin therapy in oncology patients. 6-Shogaol, among the most effective components derived from ginger, is effective in reducing inflammation, but its inhibitory effects on cisplatin-induced GI inflammation are unknown. This study investigates whether 6-shogaol control of cisplatin-induced GI inflammation is associated with the mTOR/TFEB-mediated autophagy-lysosomal pathway. GI inflammation was assessed by H&E staining and ELISA, while network pharmacology and molecular docking were employed to identify potential targets and mechanisms. Furthermore, the autophagy marker LC3 was detected by immunofluorescence, and the mTOR/TFEB pathway was evaluated by Western blot. 6-Shogaol treatment exerted therapeutic efficacy on GI inflammation via improving cisplatin-triggered reduction in body weight and ameliorated inflammatory pathological injury in mice, with decreased levels of IL-1β, IL-6, and TNF-α. Mechanistically, 6-shogaol increased LC3II/Ⅰ, CTSB, and LAMP1 protein expression; decreased p62 protein expression; and improved the autophagy-lysosomal pathway. Immunofluorescence confirmed increased LC3 expression, particularly at the high dose. Network pharmacology and molecular docking suggested that mTOR is a key putative target of 6-shogaol in the prevention and treatment of GI inflammation, and 6-shogaol treatment was associated with suppressed mTOR/TFEB phosphorylation and enhanced TFEB entry into the nucleus. These findings indicate that cisplatin-induced autophagy suppression and GI inflammation correlate with dysregulated mTOR/TFEB signaling, while 6-shogaol treatment was associated with attenuated GI injury in conjunction with modulation of the putative mTOR/TFEB-mediated autophagy-lysosomal pathway.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"21245-21262"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148497754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of essential drug lists: concordance, differences, and the need for core lists in times of crisis.","authors":"Lilly Josephine Bindel, Roland Seifert","doi":"10.1007/s00210-026-05698-8","DOIUrl":"10.1007/s00210-026-05698-8","url":null,"abstract":"<p><p>The prioritization of essential drugs is important for rational pharmacotherapy, public health, drug availability, and medical education. While the Model List of Essential Medicines (EML) of the World Health Organization (WHO) is considered the international reference, other drug lists focus on supply-related or educational purposes. Seven drug lists were compared. Drug names were extracted, harmonized, and analysed for their presence on each list. Assessed were the number of listings per drug, the concordance between the lists, and the comparison of the EML 2025 with other lists. In addition, frequently prescribed drugs in Germany were compared with the summarized drug list. In total, 1061 single drugs were identified. Most drugs were listed on one to three drug lists (n = 824; 77.6%), whereas 49 drugs were listed on six or seven lists. These highly concordant drugs mainly covered broad-use symptomatic care, long-term treatment of chronic disorders, and emergency situations. Several frequently prescribed drugs and relevant indication areas were not represented within the highly concordant core. Essentiality strongly depends on the purpose, scope, and regional context of a drug list. Broad concordance can support the relevance and recognition of established drugs across different contexts, but does not prove therapeutic value or essentiality. Therefore, comparison with other drug lists provides an additional perspective, but should be combined with drug-specific assessment of therapeutic value, safety, prescription relevance, feasibility, and global need. Especially in times of crisis, effort is needed for the development of national and international core essential drug lists.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"21077-21097"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148448170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Edaravone provides neuroprotection against chronic heat stress-induced behavioral dysfunction through adaptive proteomic remodeling.","authors":"Shab M M Alkhoujah, Ruba A Zenati, Munazza Ahmed, Sana'a Jaber, Ahmad Y Abuhelwa, Shereen M Aleidi, Shirin Farheen, Amgad Albohy, Omar F Khabour, Majed M Masadeh, Zainab M AlShareef, Yasser Bustanji, Karem H Alzoubi, Mohammad H Semreen","doi":"10.1007/s00210-026-05686-y","DOIUrl":"10.1007/s00210-026-05686-y","url":null,"abstract":"<p><p>Heat stress is an increasing global health concern associated with high mortality and multi-organ dysfunction. The brain is particularly vulnerable to heat stress, which can lead to behavioral impairments. At the molecular level, heat stress disrupts proteins involved in synaptic communication, mitochondrial function, and cellular homeostasis. Current treatments are mainly symptomatic, highlighting the need for targeted neuroprotective strategies. Edaravone, a potent free-radical scavenger with anti-inflammatory properties, has demonstrated neuroprotective effects in various neurological conditions. This study aimed to evaluate the neuroprotective effects of edaravone against heat stress-induced behavioral dysfunction and to investigate the underlying molecular mechanisms using proteomic analysis. Male Wistar rats (n = 54) were assigned to four groups: control, heat stress (HS), edaravone (Edv), and heat stress plus edaravone (HS + Edv). Heat stress exposure and edaravone treatment were administered for 12 weeks. Behavioral assessments, including radial arm water maze (RAWM), open field test (OFT), elevated plus maze (EPM), and tail suspension test (TST), were conducted. Proteomic analysis of the cortex, hippocampus, and cerebellum was performed using LC-MS/MS with a nanoElute-QTOF-MS system. Heat stress impaired memory retention and increased anxiety-like behavior, while evidence for depressive-like behavior was modest. Proteomic analysis revealed region-specific alterations, with the hippocampus showing the largest number of significantly altered proteins, while the cortex showed the strongest multivariate separation between groups. The HS + Edv group showed partial normalization of behavioral outcomes and modulation of key proteomic pathways, including improved mitochondrial function, reduced oxidative stress, and preservation of synaptic and cytoskeletal integrity. These findings suggest that edaravone attenuates heat stress-induced brain dysfunction by promoting adaptive proteomic remodeling rather than complete restoration.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"20843-20867"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of CXCL16/ADAM10 signaling in methotrexate-induced nephrotoxicity and its modulation by simvastatin.","authors":"Alulu Alradhi, Abdulrahman A Alelowi, Ahmad H Alhowail, Maha A Aldubayan, Mohamed S Abdel-Bakky","doi":"10.1007/s00210-026-05658-2","DOIUrl":"10.1007/s00210-026-05658-2","url":null,"abstract":"<p><p>Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive agent; however, one of clinical limitations of its use is renal toxicity. CXCL16 is a transmembrane chemokine that can be cleaved by ADAM family proteases, particularly ADAM10, to generate a soluble form that acts as a chemoattractant for CXCR6-expressing cells such as T lymphocytes. This process may contribute to inflammatory renal injury. This study investigated the role of CXCL16/ADAM10 in MTX-induced nephrotoxicity and assessed the renoprotective effects of simvastatin (SIM). Fifty male Wistar rats were randomly assigned to five groups: control, SIM (40 mg/kg), MTX (20 mg/kg) and two combination groups receiving MTX with SIM (10 or 40 mg /kg). SIM was administered orally for 10 days, while MTX was administered as a single i.p. dose on day 4. Hematological parameters, markers of renal function, and renal histopathology were assessed. In addition, the expression of CXCL16, ADAM10, CD3, and fibrinogen was evaluated. MTX administration significantly elevated renal function markers compared with the control and SIM groups. Histopathological analysis revealed glomerular atrophy and mononuclear inflammatory cell infiltration in MTX-treated rats. Moreover, MTX markedly increased the expression of CXCL16, ADAM10, CD3, and fibrinogen in the glomeruli and tubulointerstitial regions. Treatment with SIM significantly improved renal function markers, attenuated histopathological damage, and reduced the expression of these inflammatory and injury-related proteins. CXCL16 and its processing enzyme ADAM10 play important roles in MTX-induced renal toxicity. SIM demonstrated a dose-dependent protective effect against MTX-induced renal injury, likely through modulation of inflammatory pathways involving CXCL16/ADAM10 signaling.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"20359-20373"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated transcriptomic and experimental validation reveal that N‑acetylcysteine ameliorates acute liver failure through multi‑target synergistic regulation of pyroptosis and related signaling networks.","authors":"Huazhu Wei, Shubing Yuan, Ziyuan Liang, Qinglan Shi","doi":"10.1007/s00210-026-05678-y","DOIUrl":"10.1007/s00210-026-05678-y","url":null,"abstract":"<p><p>Pyroptosis is a major contributor to the pathophysiology of acute liver failure (ALF), a condition with high mortality. Although N‑acetylcysteine (NAC) is used clinically for ALF, its mechanisms of regulating pyroptosis and multiple signaling pathways to achieve hepatoprotection remain incompletely understood. We integrated public transcriptomic data (GSE14668, GSE96851, GSE38941) and performed differential expression analysis, weighted gene co‑expression network analysis, protein-protein interaction network construction, and machine learning to identify ALF‑related pyroptosis signature genes. Network pharmacology and molecular docking were used to predict the core therapeutic targets and mechanisms of NAC. An in vitro cellular inflammation model (LPS/D‑GalN‑treated L02 hepatocytes) was established, and the effects of NAC on target proteins and signaling pathways were validated by CCK‑8, LDH release, Western blot, ELISA, and qPCR. Six core targets-IL18, BCL2, TLR4, CASP1, CCNB1, and CAV1-were identified. Molecular docking predicted binding affinities between NAC and these targets in the moderate range (- 4.2 to - 5.3 kcal/mol). In vitro, NAC (10 mM) significantly reduced total CASP1 and GSDMD protein levels. More importantly, we further assessed NLRP3 expression, cleaved caspase‑1 (p20 subunit), and the N‑terminal cleavage fragment of GSDMD (GSDMD‑NT); NAC markedly suppressed all three markers, providing direct evidence that it inhibits the canonical NLRP3/caspase‑1/GSDMD pyroptotic axis. NAC also restored BCL2, CCNB1, and CAV1 expression, reversed TLR4 overexpression, and normalized the LC3B‑II/I ratio and p62 levels, indicating restoration of autophagic flux. Compared with a pyroptosis inhibitor (Ac‑YVAD‑CMK), NAC showed superior efficacy in reversing TLR4 upregulation and cell‑cycle‑related protein abnormalities. NAC exerts a comprehensive hepatoprotective effect that surpasses that of a simple pyroptosis inhibitor by synergistically modulating pyroptosis, apoptosis, cell cycle, inflammatory recognition, and endocytosis pathways through multiple targets. These findings provide a theoretical foundation for expanding the clinical application of NAC in ALF.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"20649-20671"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148405274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological mechanisms of fisetin in neurodegenerative disorders: regulation of neuroinflammatory, oxidative, and autophagic pathways.","authors":"Anish Singh, Lovedeep Singh, Diksha Dalal","doi":"10.1007/s00210-026-05656-4","DOIUrl":"10.1007/s00210-026-05656-4","url":null,"abstract":"<p><p>Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and related progressive neurological conditions, are characterized by irreversible neuronal loss, cognitive impairment, and motor dysfunction. Accumulating evidence identifies chronic neuroinflammation as a critical contributor to disease initiation and progression. In particular, activation of the TLR-4/NF-κB signaling cascade in glial cells promotes excessive production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, together with induction of COX-2, iNOS, oxidative stress, and apoptosis, thereby exacerbating neuronal injury. Current pharmacotherapeutic strategies largely provide symptomatic benefit without effectively targeting the underlying pathogenic mechanisms. Fisetin, a naturally occurring flavonoid abundantly present in strawberries, apples, and persimmons, has recently attracted considerable attention owing to its pleiotropic neuroprotective properties. Experimental evidence indicates that fisetin suppresses TLR-4/NF-κB-mediated neuroinflammatory signaling, attenuates microglial activation, and enhances endogenous antioxidant defense through modulation of the Nrf2 pathway. Moreover, fisetin regulates apoptosis-associated mediators, thereby preserving neuronal integrity and survival. Notably, emerging studies demonstrate that fisetin-mediated inhibition of the TLR-4/Akt/mTOR signaling axis promotes autophagy-dependent α-syn clearance and neurogenesis, particularly in Parkinsonian models, highlighting its potential disease-modifying effects. These multifaceted pharmacological actions suggest that fisetin simultaneously targets interconnected inflammatory, oxidative, apoptotic, and proteostatic pathways implicated in neurodegeneration. Despite promising preclinical findings, additional investigations are required to elucidate its effects on inflammasome activation, glial cell crosstalk, pharmacokinetic behavior, and long-term clinical safety. Collectively, fisetin represents a promising multi-target therapeutic candidate for the management of inflammation-associated neurodegenerative disorders.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"21701-21712"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148405229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lapatinib mitigates acetic acid-induced ulcerative colitis and hepatic damage in rats.","authors":"Abdullah S Al-Resheedi, Hoda E Kafl, Ghada M Suddek","doi":"10.1007/s00210-026-05680-4","DOIUrl":"10.1007/s00210-026-05680-4","url":null,"abstract":"<p><p>Ulcerative colitis (UC) is an inflammatory condition of the colon. In some cases, current treatments produce no response or may not be enough for remission, fostering a need for more effective medications. Tyrosine kinase inhibitors have shown to be effective in some inflammatory diseases. This study aimed to investigate the potential protective effect of lapatinib (LAP), a dual tyrosine kinase inhibitor, against acetic acid (AA)-induced UC in rats. Four groups were formed from twenty-four rats (6 rats each) as control, AA, AA + LAP (50 mg/kg) and AA + LAP (75 mg/kg). LAP (50 or 75 mg/kg/day) was administered orally for 7 days prior to induction of UC. On the 8th day, UC was induced by instillation of AA (4%) intrarectally. The rats were sacrificed 1 day following UC induction, colons and livers were collected for biochemical, histopathological and immunohistochemical examination. LAP markedly alleviated histological damage of both the colon and the liver. LAP effectively reduced the oxidative stress status by diminishing MDA, upregulating GSH and Nrf2 contents and enhancing SOD activity in colonic and hepatic tissues. Mechanistically, LAP significantly suppressed NF-κB p65 and TNF-α, pJAK2, pSTAT3 and the proinflammatory cytokines IL-17 and IL-23. Additionally, it decreased apoptosis by downregulating caspase-3 expression in colonic and hepatic tissues. Conclusion: LAP prevented AA-induced colitis and associated hepatic damage in rats, at least partially, via targeting IL-23/IL-17/JAK2/STAT3 axis., inhibiting NF-κB/TNF-α pathway, enhancement of Nrf2-mediated antioxidant defense, and suppression of caspase-3-dependent apoptosis.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"21099-21117"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated bulk and single-cell transcriptomic analyses and experimental validation reveal the pathogenic role of chondrocyte pyroptosis in osteoarthritis and the therapeutic potential of curcumin via its targeted modulation.","authors":"Juan Huang, Chi Zhang, Qingchuan He, Yuan Chen, Ruyan Chen, Shibin Yang","doi":"10.1007/s00210-026-05721-y","DOIUrl":"10.1007/s00210-026-05721-y","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage destruction. Emerging evidence suggests that chondrocyte pyroptosis, a pro-inflammatory programmed cell death pathway, contributes to OA pathogenesis. However, the molecular mechanisms underlying pyroptosis in OA and potential therapeutic interventions remain incompletely understood. Bulk RNA-seq datasets (GSE114007 and GSE254844) were analyzed to identify differentially expressed genes (DEGs) and co-expression modules via DESeq2 and WGCNA. Shared key DEGs (SKDEGs) were subjected to GO and KEGG enrichment analyses to reveal relevant pathways. Pyroptosis-related DEGs (PRDEGs) were intersected with SKDEGs and used for drug prediction in EnrichR. Predicted compounds were further examined for potential targets using TCMSP, HIT, and SwissTargetPrediction databases to identify hub genes. Single-cell RNA-seq data (GSE169454) were analyzed to determine the cellular localization, differential expression, and pathway activity of hub genes. Finally, in vitro experiments with primary human normal and OA chondrocytes were performed to validate the effects of the identified compound on cell proliferation and pyroptosis. Analysis of bulk RNA-seq data identified 146 SKDEGs, with pyroptosis emerging as the most significantly enriched pathway. Six PRDEGs were identified, and curcumin was predicted as a key therapeutic compound. Intersection of curcumin targets with PRDEGs revealed four hub genes (CASP1, IL1B, IL18, NLRP3), all upregulated in OA. Single-cell analysis confirmed that these hub genes were predominantly expressed in OA-associated chondrocyte subtypes, with increased pathway activity and expression along pseudotime trajectories. In vitro, curcumin (10 µM) promoted chondrocyte proliferation and significantly suppressed the mRNA and protein expression of the hub genes, indicating inhibition of pyroptosis. Chondrocyte pyroptosis is a critical contributor to OA progression, and curcumin can alleviate OA by targeting pyroptosis-related pathways. This integrative study provides mechanistic insights and a potential therapeutic strategy for OA.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"21263-21281"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preferential enhancement of mitochondria-mediated apoptosis and modulation of metastasis-related markers by etoposide-loaded nanoparticles in breast cancer cell lines.","authors":"Filiz Bakar-Ates, Ceyda Tuba Sengel-Turk","doi":"10.1007/s00210-026-05676-0","DOIUrl":"10.1007/s00210-026-05676-0","url":null,"abstract":"<p><p>Etoposide is a widely used chemotherapeutic agent whose clinical application is limited by systemic toxicity and suboptimal intracellular delivery. Lipid-polymer hybrid nanoparticles have emerged as promising drug delivery systems that combine structural stability with enhanced cellular interaction. This study aimed to evalute the apoptotic and metastasis-related effects of etoposide-loaded lipid-polymer hybrid nanoparticles (ET-NPs) against human breast cancer cells. ET-NPs were synthesized and characterized, and their biological effects were compared with free etoposide in MCF-7 and MDA-MB-231 breast cancer cell lines. Cell viability was assessed using the MTT assay. Cell cycle distribution, Annexin V binding activity, mitochondrial membrane potential, and caspase activation were analyzed by flow cytometry based Muse Cell Analyzer. MMP-2 and MMP-9 mRNA levels were determined by quantitative real-time PCR. ET-NPs significantly enhanced the cytotoxic and pro-apoptotic effects of etoposide in both breast cancer cell lines. Annexin V analysis demonstrated increased apoptotic cell populations following ET-NP treatment compared with free etoposide. ET-NP also induced significant mitochondrial membrane depolarization, caspase activation, and G2/M phase arrest. Furthermore, ET-NP significantly exerted potential anti-metastatic activity indicating a preferential antitumor effect in MCF-7 cells compared with MDA-MB-231 cells. The findings of this study demonstrate that lipid-polymer hybrid nanoparticle-mediated delivery enhances the anticancer efficacy of etoposide in breast cancer cells by potentiating apoptotic signaling and suppressing metastasis-related gene expression. ET-NP may therefore represent a promising nanotherapeutic strategy for improving breast cancer treatment outcomes.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"20477-20492"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simvastatin enhances the antitumor activity of temsirolimus through AMPK-associated metabolic modulation in clear-cell renal cell carcinoma.","authors":"Hsuan-Yu Chen, Chien-Jui Cheng, Te-Hsing Hsu, Szu-Yu Tung, Fang-Ning Chou, Mantosh Kumar Satapathy, Shu-Hui Juan","doi":"10.1007/s00210-026-05733-8","DOIUrl":"10.1007/s00210-026-05733-8","url":null,"abstract":"<p><p>Clear-cell renal cell carcinoma (ccRCC) is characterized by VHL-associated metabolic reprogramming, including enhanced glycolysis and lipid biosynthesis, which may create therapeutic vulnerabilities. However, mTOR inhibitors such as temsirolimus often show limited efficacy due to adaptive metabolic compensation. We investigated whether simvastatin-induced metabolic stress enhances sensitivity to mTOR inhibition in a context-dependent manner in ccRCC. VHL-mutant (A498) and VHL-wild-type (Caki1) ccRCC cells were treated with simvastatin and temsirolimus, alone or in combination. Cell viability, colony formation, migration, Seahorse metabolic flux analysis, and Western blotting were performed. Mechanistic studies included shRNA-mediated knockdown of LKB1/AMPKα1/α2 and pharmacological modulation using Compound C and AICAR. Antitumor efficacy was evaluated in a Caki1 subcutaneous xenograft model in nude mice. Temsirolimus induced modest growth inhibition, whereas simvastatin produced stronger dose- and time-dependent effects. Combination treatment (simvastatin 2.5 µM + temsirolimus 100 nM) further reduced cell viability. Interaction analysis revealed a cell-dependent response, with synergism in A498 cells (combination index (CI), 0.31-0.77) and antagonistic-to-additive effects in Caki1 cells (CI, 1.6-2.7). Mechanistically, simvastatin activated LKB1-AMPK signaling, suppressed AKT/mTOR activity, reduced glycolysis (↓pPFKFB2), increased FBP1 expression, and downregulated lipid biosynthesis enzymes (FASN, SCD), thereby promoting ER stress and apoptosis. In vivo, combination therapy significantly suppressed tumor growth compared with monotherapy and alleviated temsirolimus-induced hypercholesterolemia without apparent toxicity. Simvastatin-induced metabolic perturbation enhances mTOR inhibition in a cell-dependent manner, supporting dual metabolic targeting as a potential therapeutic strategy in ccRCC.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"21639-21652"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148579470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}