Naunyn Schmiedebergs Arch. Pharmacol. [JOURNAL]
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200 papers
Correction to: Repurposing doxycycline as an adjunct to sitagliptin in type 2 diabetes mellitus: a randomized controlled study on glycemic, inflammatory, and cardiometabolic outcomes.
El-Khateeb E, Khrieba MO, Badawoud AM … +20 more , Morsy AA, El-Hanafy AA, Hamza E, Habba E, El-Hanafy DA, Eltantawy N, Al-Dhelaan RA, Radwan KH, El-Sayed AA, Eladaroussay MM, Rizk KAK, Ebrahim MHE, Abd Elhameed AG, Erfan IA, Elkhodary NM, Elshorbagi N, Sami HM, Dewidar SA, Mahdy MA, Zakaria H
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42402494 · Publisher ↗
Abstract loading — click title to view on PubMed.
Donafenib suppresses glioblastoma progression: potential enhancement of therapeutic response in TMZ-resistant models.
Yazici E, Gezen A, Kalay M … +4 more , Kocak O, Oylumlu E, Simsek E, Tanriover G
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42402493 · Publisher ↗
Glioblastoma (GBM) is the most aggressive primary brain tumor of the central nervous system and remains largely incurable due to the development of resistance to temozolomide (TMZ). Aberrant activation of growth factor-m...
Glioblastoma (GBM) is the most aggressive primary brain tumor of the central nervous system and remains largely incurable due to the development of resistance to temozolomide (TMZ). Aberrant activation of growth factor-mediated signaling pathways, including VEGFR and MET, plays a critical role in GBM progression, highlighting the need for alternative therapeutic strategies. Donafenib (DNF) is a novel multikinase inhibitor targeting VEGFR, PDGFR, and RAF signaling pathways. In this study, we evaluated the effects of DNF on proliferation-associated signaling pathways in U87MG and T98G GBM cell lines. DNF treatment significantly reduced cell viability, colony formation, migration, and invasion. Moreover, immunocytochemical analyses revealed lower levels of immunoreactivity for several markers associated with tumor progression, including p-ERK, NF-κB p65, p-mTOR, p-MET, p-STAT3, and p-VEGFR, following DNF treatment. While PAMPA analysis indicated that DNF exhibits lower blood-brain barrier (BBB) permeability than TMZ, in silico modeling revealed that a substantial proportion of its metabolites may possess BBB-penetrating potential. Collectively, these findings suggest that DNF exerts antitumor effects in both TMZ-sensitive and TMZ-resistant GBM models and highlight its potential as a promising therapeutic candidate for further investigation.
1-Palmitoyl-4-piperidinopiperidine exhibits anticancer effects in murine triple-negative breast cancer EO771 cells associated with STAT3 signaling suppression.
Yoshioka H, Hamanaka J, Horiuchi A … +5 more , Horita H, Uno R, Noguchi A, Matsushita Y, Suzui M
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42400622 · Publisher ↗
Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options. An urgent need thus exists to develop novel therapeutic strategies to treat TNBC. We previously demonstrated that 1‑pa...
Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options. An urgent need thus exists to develop novel therapeutic strategies to treat TNBC. We previously demonstrated that 1‑palmitoyl‑4‑piperidinopiperidine (PPI), a derivative of palmitic acid, exerts anticancer effects against human colon carcinoma cells and human pancreatic ductal adenocarcinoma cells by inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation. To date, no studies have assessed PPI potency in murine TNBC EO771 cells. We examined cell viability after treatment with PPI for 48 h, and evaluated the expression levels of apoptosis- and cell cycle-related proteins using immunocytochemistry and western blotting. PPI inhibited cell proliferation in a dose-dependent manner, with an IC of 3.06 µM. PPI treatment was found to induce apoptosis. We also observed G1 cell cycle arrest as indicated by cyclin D1 and Cdk2 downregulation. Phosphorylated STAT3 levels and those of downstream proteins including CXCR4, MMP2, MMP9, TWIST, VEGF, and Vimentin, decreased following PPI treatment. STAT3 knockdown modestly reduced the sensitivity of EO771 cells to PPI, supporting partial involvement of STAT3 signaling in the anticancer effects of PPI. These results suggest that PPI exerts anticancer effects on EO771 cells that are associated with suppression of STAT3 signaling.
Rosmarinic acid inhibits norepinephrine-induced metastatic capacity of triple negative breast cancer cells by Src kinase inactivation.
Jeong JH, Park HJ, Park SH
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42400621 · Publisher ↗
Chronic psychological stress promotes cancer metastasis through catecholamine-mediated activation of β-adrenergic signaling. This study aimed to evaluate the inhibitory effects of rosmarinic acid (RA) on norepinephrine (...
Chronic psychological stress promotes cancer metastasis through catecholamine-mediated activation of β-adrenergic signaling. This study aimed to evaluate the inhibitory effects of rosmarinic acid (RA) on norepinephrine (NE)-induced migration and invasion in triple-negative breast cancer (TNBC) cells and to elucidate the underlying molecular mechanisms. Cell viability was assessed using an MTT assay. Migration and invasion were evaluated by Transwell assays in MDA-MB-231 and BT-20 cells treated with NE in the presence or absence of RA. Src phosphorylation and EMT-related protein expression were analyzed by Western blotting. Molecular docking was performed to predict the binding of RA to Src kinase. Constitutively active Src transfection was used to confirm the role of Src. A network pharmacology-based analysis was conducted to identify RA-associated targets and enriched pathways. RA significantly suppressed NE-induced migration and invasion in TNBC cells. RA markedly reduced NE-induced Src phosphorylation, and docking analysis predicted stable binding of RA within the ATP-binding pocket of Src. Constitutive Src activation abrogated the anti-migratory and anti-invasive effects of RA, confirming Src as a key molecular target. RA also attenuated NE-induced EMT by reducing mesenchymal marker expression. Network pharmacology analysis revealed enrichment of RA-associated targets in cancer-related pathways and identified several hub genes that converge on Src-related signaling cascades. RA suppresses NE-induced metastatic phenotypes in TNBC cells primarily through inhibition of Src kinase and partial modulation of the EMT program, highlighting its potential as a therapeutic candidate for stress-associated TNBC metastasis.
A successful switch from rasagiline to safinamide in a 49-year-old female with early-onset Parkinson's disease: a case report and review of literature.
Plaut S, Carmi S, Barash Y
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42400620 · Publisher ↗
There is a significant clinical challenge in the decision-making process when transitioning between monoamine oxidase-B inhibitors due to the sparse literature and lack of established guidelines for those trying to find...
There is a significant clinical challenge in the decision-making process when transitioning between monoamine oxidase-B inhibitors due to the sparse literature and lack of established guidelines for those trying to find the balance between risk for serious drug adverse effects and symptom exacerbation in Parkinson's disease. This case report and literature review is motivated by the limited body of evidence and conflicting recommendations regarding safe and effective management of such a switch. We discuss the trade-off between avoiding possible life-threatening complications such as serotonin syndrome and hypertensive crisis, while at the same time aiming for minimal washout period to minimize motor symptom exacerbation. The case of a 49 year-old female patient with early-onset Parkinson's disease who was transitioned from 1 mg rasagiline to 50 mg safinamide with a three-day washout period is described; afterwards, we review the relevant literature and current recommendations. We believe this paper will be valuable to clinicians and researchers managing such scenarios, and perhaps motivate further larger sample size studies, or help inform best practices in the treatment of Parkinson's disease.
Overexpression of FTO ameliorates chronic glomerulonephritis by inhibiting glycolysis in glomerular mesangial cells associated with ADPGK mA modification.
Zhao S, Zheng W, Guo M … +2 more , Gao J, Zhuang X
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42399381 · Publisher ↗
This study aims to investigate the inhibitory effect of Fat mass and obesity-associated protein (FTO) overexpression on glycolysis in glomerular mesangial cells (GMCs) and its potential therapeutic impact on chronic glom...
This study aims to investigate the inhibitory effect of Fat mass and obesity-associated protein (FTO) overexpression on glycolysis in glomerular mesangial cells (GMCs) and its potential therapeutic impact on chronic glomerulonephritis (CGN). An adeno-associated virus (AAV9-FTO) was constructed to explore the protective role of FTO overexpression in CGN mice in vivo. Renal tissue pathology was assessed through haematoxylin and eosin (HE) staining, Masson's trichrome staining, and TUNEL staining. The expression of proliferation markers were analyzed by Western blot. GMCs proliferation was evaluated via EdU assay, and m⁶A modification of ADP Dependent Glucokinase (ADPGK) was quantified using methylated RNA immunoprecipitation followed by qPCR (MeRIP-qPCR). The impact of FTO overexpression on ADPGK mRNA stability was assessed through Actinomycin D assay. Additionally, real-time quantitative PCR (RT-qPCR) was used to assess ADPGK mRNA expression before and after mutation of the m⁶A site. Tissue staining results demonstrated that FTO overexpression ameliorates renal pathological progression in CGN mice. Both in vivo and in vitro experiments confirmed that FTO overexpression can reduce the expression levels of proliferation markers and also inhibit the expression of glycolysis markers. Mechanistic studies revealed that FTO overexpression suppresses the glycolytic process by downregulating ADPGK expression, thereby inhibiting abnormal proliferation of GMCs. Collectively, these findings demonstrate that FTO overexpression ameliorates CGN by inhibiting glycolysis in GMCs.
Preferential enhancement of mitochondria-mediated apoptosis and modulation of metastasis-related markers by etoposide-loaded nanoparticles in breast cancer cell lines.
Bakar-Ates F, Sengel-Turk CT
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42399380 · Publisher ↗
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 delive...
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.
Modulation of the ACLY-AMPK axis by bempedoic acid suppresses NF-κB-driven inflammation, VEGF-Notch angiogenic crosstalk, and cell-cycle progression in Solid Ehrlich Carcinoma.
Saleh A, Raslan NA, Selim HMRM … +22 more , Farghly AM, Ali SK, Galal O, Barakat BM, Fayyad RM, Rizk SH, Elhusseiny SM, Badawy AI, Saadat HMF, Salem MA, Salama A, Aboelsoud HA, Ali MHH, Abd Allatif AAA, Mohamed MFA, Hanafy SM, Mohamed SM, Elashrey AM, Mousa SNM, Soliman WI, Motawei SM, El-Dessouki AM
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42397396 · Publisher ↗
This study examined whether bempedoic acid (BPA) suppresses SEC progression through an integrated pharmacological framework with toxicological relevance, targeting metabolic, inflammatory, oxidative, angiogenic, prolifer...
This study examined whether bempedoic acid (BPA) suppresses SEC progression through an integrated pharmacological framework with toxicological relevance, targeting metabolic, inflammatory, oxidative, angiogenic, proliferative, and apoptotic pathways. Fifty female Swiss albino mice were assigned to five groups (n = 10): normal control, untreated SEC control, SEC + bempedoic acid (10 or 30 mg/kg, orally), and SEC + doxorubicin (5 mg/kg, i.p.) three times weekly for two weeks as a reference chemotherapeutic comparator with established clinical toxicity relevance. After experiment completion, blood and tumor tissues were obtained for molecular assessment. SEC-bearing mice showed lipid dysregulation, with elevated ACLY, ACC, FASN, total cholesterol, and triglycerides, alongside suppressed AMPK. BPA counteracted these changes by inhibiting ACLY-driven lipogenesis and restoring AMPK-related signaling, thereby reducing NF-κB pathway activity and iNOS, IL-6, and TNF-α. It also attenuated oxidative stress, increasing SOD and lowering p-carbonyls. Moreover, BPA reduced VEGF, MMP-2, MMP-9, Hes-1, DLL4, Notch-1, and Jagged-1, indicating impaired angiogenic remodeling and endothelial differentiation. Decreased Cyclin-D1 and PCNA reflected reduced proliferation, while increased p53, Bax, and Caspase-3 indicated enhanced apoptosis. Histologically, BPA promoted dose-dependent tumor necrosis, reduced viable anaplastic cell clusters, and induced fibrovascular granulation tissue with peripheral inflammatory cell infiltration, indicating tumor regression and reparative remodeling. These findings provide preclinical evidence that BPA reduces SEC tumor burden by modulating the ACLY/AMPK-related metabolic pathway, accompanied by suppression of inflammatory, angiogenic, proliferative, survival, oxidative stress, and apoptosis-related dysregulation, supporting its repurposing potential as a multi-target therapeutic candidate for solid tumors.
Alamandine attenuates stress-induced inflammation, oxidative stress, and intestinal histopathological alterations in a chronic unpredictable mild stress model of depression.
Kilic A, Ipek BE, Cimen YA … +5 more , Yilmaz M, Cimen FBK, Hekimoglu ER, Demirci H, Ustunova S
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42393404 · Publisher ↗
Depression is increasingly recognized as a systemic disorder associated with chronic inflammation, oxidative stress, and disturbances in the gut-brain axis. This study aimed to investigate whether alamandine modulates ch...
Depression is increasingly recognized as a systemic disorder associated with chronic inflammation, oxidative stress, and disturbances in the gut-brain axis. This study aimed to investigate whether alamandine modulates chronic stress-induced alterations in the intestine and liver by assessing histopathological changes, inflammatory responses, and oxidative stress parameters in a chronic unpredictable mild stress (CUMS) model. Male rats were exposed to CUMS for 35 days, and the effects of Alamandine and the Mas receptor antagonist A779 were evaluated. Serum inflammatory cytokines (TNF-α, IL-6), liver cytokines (IL-6, IL-1β), oxidative stress markers including superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA), as well as biochemical parameters (AST, ALT, total protein) were analyzed. Histopathological examination of intestinal and colonic tissues was also performed. CUMS significantly increased serum cortisol and pro-inflammatory cytokines, indicating systemic inflammation, while elevated IL-6 and IL-1β levels in liver tissue suggested a localized inflammatory response. Oxidative stress findings showed impaired antioxidant defense and increased lipid peroxidation. Despite these changes, AST, ALT, and total protein levels remained unchanged, indicating no overt hepatic injury. Histologically, CUMS caused intestinal villus degeneration, inflammatory infiltration, and reduced goblet cell numbers, whereas the colon exhibited milder epithelial alterations. Alamandine treatment attenuated inflammatory and oxidative responses and improved intestinal mucosal integrity, with partial restoration of goblet cells. These findings suggest that alamandine attenuates chronic stress-induced inflammatory, oxidative, and histopathological alterations in intestinal and hepatic tissues. The results further support a potential protective role of the RAS pathway in peripheral tissue injury associated with chronic stress.
Rudolf Buchheim Award 2026: solanidine as a dietary derived CYP2D6 biomarker.
Müller JP
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42393403 · Publisher ↗
The German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT) is annually awarding the Rudolf Buchheim Award. This year the Rudolf Buchheim Award was awarded to Julian Peter Müller for outstanding w...
The German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT) is annually awarding the Rudolf Buchheim Award. This year the Rudolf Buchheim Award was awarded to Julian Peter Müller for outstanding work of a young researcher in the field of clinical pharmacology. He investigated the performance and applicability of the novel CYP2D6 biomarker solanidine. CYP2D6 is a genotypic and phenotypic highly variable drug-metabolizing enzyme involved in the metabolism of about 20% of commonly used drugs. Variability in CYP2D6 activity may lead to pronounced interindividual deviations in the pharmacokinetics of its drug substrates, potentially leading to adverse events or therapy failure. CYP2D6 genotyping allows to predict metabolizer phenotypes, e.g., poor, intermediate, normal or ultrarapid, but cannot take into account additional variation due to co-medication or other factors. In the awarded work he could demonstrate that a single plasma sample is sufficient for accurate CYP2D6 phenotyping, and that by using solanidine, CYP2D6 phenoconversion, a genotype-phenotype mismatch, due to polypharmacy can be elucidated. The use of the CYP2D6 biomarker solanidine allows to study non-genetic variation of CYP2D6 activity and opens up new possibilities in personalized medicine. Application of solanidine phenotyping may help to understand factors of CYP2D6 phenoconversion and may be applied with patients to optimize therapy decisions and to improve outcomes and safety.
Integrative multi-omics analysis identifies SELL and PRF1 as key immune biomarkers and therapeutic targets in tuberculosis.
Tarkina T, Ali A, Ali SL … +5 more , Waseem T, Azanbayeva D, Kotlyarova T, Jetpisbayeva Z, Tsoy N
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42393402 · Publisher ↗
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains a major global health burden, with host immune responses critically influencing disease progression and treatment outcomes. In this study, we perfor...
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains a major global health burden, with host immune responses critically influencing disease progression and treatment outcomes. In this study, we performed an integrative multi-cohort analysis combining transcriptomics, SNP-based structural evaluation, and molecular docking to identify key immune regulators and potential therapeutic targets. Transcriptomic datasets from macrophage and patient-derived samples were analyzed to identify differentially expressed genes, followed by functional enrichment and network-based analyses to identify key immune regulators. Non-synonymous SNPs (nsSNPs) were evaluated using multiple predictive tools (SIFT, PolyPhen-2, CADD, REVEL, MetaLR, Mutation Assessor), while structural impacts were assessed using DUET and Project HOPE. A total of 162 DEGs were identified, significantly enriched in immune-related pathways including cytokine signaling, receptor activity, and host defense responses. Five hub genes SELL, CD19, CD27, PRF1, and KLRK1 were prioritized, with SELL and PRF1 demonstrating the highest regulatory importance. Structural and functional analyses identified six deleterious nsSNPs in SELL (G169E, W309R, W247R) and PRF1 (V419G, V482G, P459S), all predicted to destabilize protein structure and impair immune function. Molecular docking and MM/GBSA analyses revealed favorable and energetically stable interactions between selected immunomodulatory compounds and both wild-type and mutant protein structures. Key ligand-residue interactions supported the potential of these compounds to modulate SELL- and PRF1-associated immune pathways. Notably, mutant variants showed enhanced ligand binding, with BIMOSIAMOSE displaying the highest affinity in SELL W309R (- 6.92 kcal/mol) and PRF1 mutants (- 5.35 kcal/mol), suggesting mutation-induced alterations in binding pocket conformation. Unlike previous single-cohort or single-method studies in tuberculosis, this work employs a multi-cohort, systems-level integrative framework to identify robust host immune signatures. By combining transcriptomic meta-analysis across diverse infection models with protein-protein interaction network prioritization, regulatory network inference, genetic variant impact assessment, and structure-based computational validation, we identified conserved immune-associated genes, particularly SELL and PRF1, as central regulatory nodes in tuberculosis pathogenesis. The integration of structural modeling, molecular docking, and molecular dynamics simulations further strengthens the mechanistic plausibility of these candidates. This multi-layered strategy provides a comprehensive framework for prioritizing biologically consistent biomarkers and therapeutic targets in tuberculosis, offering a systems-level perspective beyond traditional single-omics approaches.
Topical ronomilast alone or combined with clobetasol ameliorates imiquimod-induced psoriasis in mice.
Jasim HS, Hameed MF
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42390545 · Publisher ↗
Psoriasis is a chronic autoinflammatory skin disease lacking curative options. Ronomilast is a novel PDE4i inhibitor with potent anti-inflammatory properties. To evaluate the therapeutic efficacy of topical ronomilast, a...
Psoriasis is a chronic autoinflammatory skin disease lacking curative options. Ronomilast is a novel PDE4i inhibitor with potent anti-inflammatory properties. To evaluate the therapeutic efficacy of topical ronomilast, alone and combined with clobetasol, in an imiquimod (IMQ)-induced psoriasis mouse model. Fifty BALB/c male albino mice were randomly assigned to five groups (n = 10): healthy control, imiquimod-induced, clobetasol-treated (0.05%), ronomilast-treated (0.3%), and combination-treated (ronomilast 0.15% + clobetasol 0.025%). Psoriasis-like lesions were induced by daily topical application of 5% imiquimod for five consecutive days. Treatments were applied topically 3 h after imiquimod. Skin samples were analyzed for IL-17A and IL-23 levels via ELISA, TNF-α expression via immunohistochemistry, and histopathological changes. In silico molecular docking with PDE4B and PDE4D targets was also conducted. Ronomilast significantly reduced IL-17A and IL-23 levels compared to the induction group. The combination therapy produced the greatest reduction in IL-17A and IL-23. TNF-α expression scores were also significantly decreased by ronomilast and the combination relative to the induction group, consistent with histopathological improvements. Molecular docking demonstrated that ronomilast has higher binding affinity than roflumilast for PDE4B and comparable affinity for PDE4D. Topical ronomilast alone or combined with clobetasol, substantially ameliorates psoriasiform dermatitis by inhibiting key inflammatory cytokines. These results strengthen its prospects as an antipsoriatic candidate; nonetheless, more clinical investigations are necessary to validate its effectiveness and safety in humans.
Role of CXCL16/ADAM10 signaling in methotrexate-induced nephrotoxicity and its modulation by simvastatin.
Alradhi A, Alelowi AA, Alhowail AH … +2 more , Aldubayan MA, Abdel-Bakky MS
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42390544 · Publisher ↗
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...
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.
Molecular insights into the anti-COVID-19 activity of reduced (quinol) and oxidized (quinone) forms of coenzyme Q10.
Hegde M, Kumar V, Gupta D … +7 more , Ishida Y, Terao K, Kaul SC, Vrati S, Sundar D, Wadhwa R, Kunnumakkara AB
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42390543 · Publisher ↗
Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, was declared a global pandemic by the World Health Organization in March 2020 and rapidly emerged as a systemic mitochondrial disorder rather than a pure respira...
Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, was declared a global pandemic by the World Health Organization in March 2020 and rapidly emerged as a systemic mitochondrial disorder rather than a pure respiratory illness. The disease disrupts mitochondrial bioenergetics, redox balance, and electron transport, with significant impairment of the quinone-quinol pool. Coenzyme Q10 (CoQ10), a central component of the mitochondrial respiratory chain, shuttles electrons between complexes I/II and III through dynamic interconversion between its oxidized quinone (CoQ; QN) and reduced quinol (CoQH; QL) forms. COVID-19 patients exhibit reduced endogenous CoQ10 levels, defective oxidative phosphorylation, and excessive oxidative stress, linking QN-QL imbalance to inflammation, thrombosis, fatigue, and multi-organ dysfunction. Restoration of mitochondrial redox cycling through CoQ10 supplementation or QN-based bioactive compounds has therefore gained attention as a therapeutic strategy. In this study, we investigated the effects of mitochondrial CoQ10 redox forms on key factors involved in COVID-19 infection using computational analyses and human oral squamous cell carcinoma (HSC3)-based assays. Molecular docking analyses demonstrated that QN binds more strongly than QL to host cell receptors (AR, ACE2, and TMPRSS2), which are key regulators of viral infection. However, cell-based experiments revealed similar effects of both compounds on cell viability, clonogenicity, and the expression of host cell receptors ACE2 and TMPRSS2. Furthermore, similar effects of QN and QL were observed in cells exposed to oxidative, metal, and hypoxic stress. Higher, but not lower, nontoxic concentrations of both compounds led to comparable downregulation of host cell receptors. In contrast, lower doses of QN and QL similarly protected cells against oxidative, metal, and hypoxia stress. These findings suggest that both forms exert similar modulatory effects on host cell receptors and stress-responsive pathways implicated in SARS-CoV-2 pathogenesis, supporting their potential as candidates for further investigation.
Young Investigator Award 2026: Integrative mechanistic insights into YAP/TAZ-mediated angiogenesis and its therapeutic implications.
Wibowo YC
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42390542 · Publisher ↗
The Young Investigator Award or "Nachwuchspreis der DGPT" (formerly the Fritz Külz Award) is awarded by the German Society for Experimental and Clinical Pharmacology and Toxicology (Deutsche Gesellschaft für experimentel...
The Young Investigator Award or "Nachwuchspreis der DGPT" (formerly the Fritz Külz Award) is awarded by the German Society for Experimental and Clinical Pharmacology and Toxicology (Deutsche Gesellschaft für experimentelle und klinische Pharmakologie und Toxikologie e.V./DGPT) to young scientists in recognition of their outstanding work in experimental pharmacology and toxicology. The Young Investigator Award in 2026 was awarded to Dr. Dr. Yohanes Cakrapradipta Wibowo from the Medical Faculty Mannheim of Heidelberg University for his previous PhD research, which was supervised by the late Prof. Dr. Thomas Wieland. In this work, Dr. Wibowo uncovered a new mechanistic insight into angiogenesis and proposed a therapeutic strategy for treating pathological angiogenesis. This article provides an overview of Dr. Wibowo's research.
Investigation of the cytotoxic and apoptotic effects of propylthiouracil-loaded mesoporous nanoparticles on Ehrlich ascites tumor cells.
Şeflek HN, Erbayram FZ, Ertuş EB … +3 more , Mutlu EG, Alpa Ş, Türkoğlu FN
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42387199 · Publisher ↗
This study investigated the cytotoxic and apoptotic effects of propylthiouracil (PTU) loaded on mesoporous silica nanoparticles (MSN) in Ehrlich ascites tumor (EAT) cells. EAT cells were incubated with PTU, blank MSN, an...
This study investigated the cytotoxic and apoptotic effects of propylthiouracil (PTU) loaded on mesoporous silica nanoparticles (MSN) in Ehrlich ascites tumor (EAT) cells. EAT cells were incubated with PTU, blank MSN, and PTU + MSN combinations for 24, 48, and 72 h, and cytotoxicity was assessed using the XTT assay, with IC values calculated. The combination treatment showed lower IC values and stronger time- and dose-dependent cytotoxic effects compared with single treatments. qPCR analyses suggested that PTU + MSN treatment was associated with increased Bax expression and decreased anti-apoptotic Bcl-2 and Bcl-xL expression, indicating activation of apoptotic signaling. Elevated caspase-9 and p53 expression suggested involvement of the intrinsic apoptotic pathway, while increased caspase-8 expression indicated possible contribution of the extrinsic pathway. Reduced mTOR and p70S6K expression was associated with suppression of cell proliferation and survival signaling. Overall, these findings suggest that MSN-based delivery may enhance the anticancer effects of PTU, highlighting its potential as a therapeutic strategy in cancer research.
Curcumin analogues suppress cellular pro-inflammatory mediators and reduce edema.
Ullah K, Zhu W, Shah SWA … +7 more , Hussain H, Ullah A, Khan FA, Khan NM, Khan NU, Ahmad S, Xu G
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42387198 · Publisher ↗
Inflammation is a normal physiological response to adverse stimuli mediated by numerous pro-inflammatory cytokines and signaling pathways. Although curcumin modulates key inflammatory pathways, the role of its analogues...
Inflammation is a normal physiological response to adverse stimuli mediated by numerous pro-inflammatory cytokines and signaling pathways. Although curcumin modulates key inflammatory pathways, the role of its analogues in inflammation is not fully elucidated. This study explores the anti-inflammatory potential of curcumin analogues (K1-K4) in vitro and in vivo models. Four curcumin analogues (K1-K4) were successfully synthesized and assessed for their anti-inflammatory efficacy at doses of 10 and 20 mg/kg body weight. All the curcumin analogues, particularly K1 and K4 demonstrated significant attenuation of absolute post-injection carrageenan-induced paw edema in mice, exhibiting a significant response at both doses. The maximum inhibition of paw edema was achieved after 2 h, i.e., 62.45% for K1 and 62.09% for K4 at a dose of 20 mg/kg compared to diclofenac (66.10%). The analogues markedly ameliorated ear edema and prominently alleviated the absolute post-injection paw edema mediated by histamine in mice. Among the analogues, K1 and K4 exhibited the highest activity and markedly attenuated the edema in all models. Mechanistically, the curcumin analogues except K2 significantly downregulated iNOS, COX2, and p-p65 protein levels in RAW264.7 cells. The mRNA expression of inflammatory cytokines was also notably diminished in RAW264.7 cells. Moreover, K1 was observed to affect markers associated with apoptosis among the curcumin analogues. The findings demonstrate that curcumin analogues suppress key pro-inflammatory mediators in cells and reduce edema in vivo, highlighting their preliminary anti-inflammatory activity in acute inflammation models.
Integrating network pharmacology, molecular dynamics, and in vitro assays to unveil the mechanism of costunolide against gastric cancer.
Zhu C, Chen Q, Li Y … +7 more , Wu H, Ming Q, Ma M, Mu J, Long X, Yang X, Zhang X
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42387197 · Publisher ↗
Gastric cancer (GC) stands as a major contributor to global cancer deaths. Due to tumor heterogeneity and drug resistance, current treatments remain unsatisfactory, highlighting the urgent need for novel targeted therape...
Gastric cancer (GC) stands as a major contributor to global cancer deaths. Due to tumor heterogeneity and drug resistance, current treatments remain unsatisfactory, highlighting the urgent need for novel targeted therapeutics. Costunolide (Cos), a natural sesquiterpene lactone, has shown notable anticancer activity. However, its primary upstream molecular target in GC remains unclear. We integrated network pharmacology (NP), molecular docking, molecular dynamics (MD) simulations, and in vitro assays to investigate the mechanisms of Cos against GC. NP analysis recognized ERBB2 as a core target and suggested that Cos may exert its pharmacological function through the PI3K/AKT and MAPK signaling pathways. Molecular docking showed strong binding between Cos and ERBB2, and MD simulations further supported the stability of the complex. In vitro evaluations demonstrated that Cos exhibits strong anti-proliferative effects against NCI-N87 and HGC-27 cell lines, in addition to stimulating programmed cell death. Western blot analysis revealed regulatory changes in apoptosis-related factors and key components of the ERBB2/PI3K/AKT/MAPK signaling cascades. Rescue experiments confirmed the pivotal role of ERBB2: overexpression of ERBB2 attenuated the effects induced by Cos, whereas knockdown of ERBB2 enhanced its activity. Collectively, these results suggest that Cos promotes programmed cell death in GC through the inhibition of ERBB2 and the subsequent attenuation of its downstream PI3K/AKT and MAPK signaling. This work provides a mechanistic basis for developing Cos as a potential therapeutic solution for GC.
Isatin-based oxime ethers as anticancer agents against human colorectal carcinoma.
Rajesh SM, N PA, C VKD … +5 more , Srinivasa SM, Swaroop TR, Suresh RN, Rangappa S, Rangappa KS
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42384169 · Publisher ↗
Colorectal cancer is one of the leading causes of cancer-related deaths and ranks third among them. Our efforts to develop new anticancer agents to treat this disease resulted in the synthesis of new isatin-based oxime e...
Colorectal cancer is one of the leading causes of cancer-related deaths and ranks third among them. Our efforts to develop new anticancer agents to treat this disease resulted in the synthesis of new isatin-based oxime ethers. The cytotoxic effects of these compounds against HCT116 were analyzed using MTT and Trypan Blue dye exclusion assays. A compound 10d has emerged as a lead compound with IC value of 22.31 ± 1.23 µM. Even though this molecule is two-fold less active than reference drug 5-fluorouracil (5-FU), the pharmacophore of the compound 10d would be considered for future derivatisation as a notable anticancer agent, due to its safety profile against normal cell line HEK. The anticancer effect of compound 10d against colon cancer cells was demonstrated by cell shrinkage and detachment observed under bright-field microscopy. Furthermore, Hoechst/propidium iodide (PI) staining and acridine orange (AO)/PI staining analysis confirmed the induction of cell death. Treatment with compound 10d restrains colony formation ability and mitigates the migratory potential of colon cancer cells as observed by both foci formation and migration assay. Finally, we elucidated the possible mode of action of the lead molecule by in-silico analysis using molecular docking studies. Results unveiled that the lead compound exhibits anticancer potential probably by targeting Human Tankyrase-2 and Bruton's tyrosine kinase with high docking scores, as evident by in-silico modelling. The binding affinity of synthetic compounds against the protein targets 5BXU and 7LTZ was assessed by molecular docking experiments. The compound 10d demonstrated the greatest affinity for both targets (- 8.8 and - 7.9 kcal/mol, respectively), whereas other compounds showed favourable binding energies. These findings suggest that compound 10d may serve as a promising lead for further biological evaluation.
Canonical Wnt pathway mediates catalpol-induced epithelial differentiation of porcine metanephric mesenchymal cells.
Ji P, Xie Y, Geng G … +5 more , Guo W, Bi J, Han B, Wang X, Fu B
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jul · PMID 42384168 · Publisher ↗
Kidney tissue injury is clinically very common, and how to effectively repair renal damage is a critical scientific issue that urgently requires attention. This study focuses on exploring alternative therapeutic strategi...
Kidney tissue injury is clinically very common, and how to effectively repair renal damage is a critical scientific issue that urgently requires attention. This study focuses on exploring alternative therapeutic strategies for renal repair. Specifically, it aims to compare the differentiation capabilities of metanephric mesenchymal cells (MMC), bone marrow mesenchymal stem cells (BMSC), and adipose-derived mesenchymal stem cells (AMSC) into epithelial cells, and to investigate the role and mechanism of catalpol, an active component of the traditional Chinese medicine Rehmannia glutinosa, in enhancing the epithelial differentiation of MMC. The epithelial differentiation potential of AMSC, BMSC, and MMC was compared under epithelial induction medium with or without catalpol supplementation. MMC were cultured in epithelial induction medium, and the expression of epithelial marker E-Cadherin, mesenchymal markers α-SMA and renal epithelial-specific marker AQP2 were assessed using Western Blot and immunofluorescence staining to evaluate the epithelial differentiation capacity of MMC and the enhancing effect of catalpol. RNA-seq was performed to identify signaling pathways activated by catalpol in MMC. The canonical Wnt pathway inhibitor MSAB was added to determine whether the pro-epithelial differentiation effect of catalpol was inhibited. AMSC and BMSC exhibited limited epithelial differentiation potential, which was not enhanced by catalpol. Under epithelial induction medium, MMC differentiated into epithelial cells, with increased expression of E-Cadherin and decreased expression of α-SMA. Catalpol further enhanced this effect and promoted the expression of the renal epithelial marker AQP2. RNA-seq revealed that the canonical Wnt pathway was activated in MMC. The pro-epithelial differentiation effect of catalpol was inhibited by MSAB, accompanied by decreased expression of E-Cadherin and AQP2 and increased expression of α-SMA. Catalpol promotes the differentiation of MMC into renal epithelial cells by activating the canonical Wnt pathway.
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