Naunyn Schmiedebergs Arch. Pharmacol. [JOURNAL]
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200 papers
Kaempferol: advances in biosynthesis, molecular mechanisms, and therapeutic applications.
Zaki ES, Sabry MO, Abou-Elazm FI … +5 more , El-Dessouki AM, Khalaf SS, Ramadan A, El-Shiekh RA, Aboutaleb AS
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42287316 · Publisher ↗
Kaempferol is a ubiquitous dietary flavonol found in fruits, vegetables, and medicinal plants, existing in both aglycone and glycosylated forms which contribute to its structural and functional diversity. This review pro...
Kaempferol is a ubiquitous dietary flavonol found in fruits, vegetables, and medicinal plants, existing in both aglycone and glycosylated forms which contribute to its structural and functional diversity. This review provides a comprehensive overview of kaempferol, focusing on its biosynthesis, pharmacokinetic challenges, and the mechanistic basis for its diverse pharmacological properties. Its biosynthesis originates from phenylalanine, with subsequent enzymatic modifications yielding derivatives of varying bioactivity. The principal mechanism of kaempferol is rooted in its potent antioxidant capacity, acting through both direct radical scavenging and the upregulation of the cytoprotective Nrf2 pathway. This redox modulation is intricately linked to its anti-inflammatory effects, which are mediated by the suppression of key signaling cascades including NF-κB, MAPKs, and STATs. In preclinical models, kaempferol demonstrates significant antidiabetic activity by activating AMPK and enhancing insulin sensitivity. Its anticancer properties are equally notable, involving the induction of apoptosis, cell cycle arrest, and inhibition of metastasis through the disruption of pathways such as PI3K/AKT and Wnt/β-catenin. Furthermore, it exhibits antimicrobial effects and hepatoprotective actions by modulating SIRT1/AMPK signaling. Despite these promising bioactivities, therapeutic translation is severely hampered by its poor aqueous solubility and extensive first-pass metabolism, which critically limit oral bioavailability. Consequently, while kaempferol is a compelling polypharmacological agent with the potential to address complex diseases, its unfavorable pharmacokinetic profile remains the critical bottleneck for clinical advancement. A promising direction for future research is to prioritize the development of advanced drug delivery systems and the execution of rigorous clinical trials to translate its extensive preclinical promise into validated clinical applications.
Immunopharmacological and structural design of a polyprotein based multi epitope vaccine against Powassan virus.
Kalsoom A, Abidi SH, Marwat SA … +8 more , Shabbir G, Naveed M, Mughal AMA, Majeed MN, Korany SM, Korany BM, Alzhrani K, Aziz T
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42287315 · Publisher ↗
Powassan virus (POWV) poses a growing neurotropic threat with limited immunopharmacological interventions, requiring the development of targeted vaccine strategies. The current study focuses on developing a specific vacc...
Powassan virus (POWV) poses a growing neurotropic threat with limited immunopharmacological interventions, requiring the development of targeted vaccine strategies. The current study focuses on developing a specific vaccine using bioinformatics tools to target T- and B-cell epitopes from a genome polyprotein sequence of POWV. Four vaccine constructs with possible immunogenic qualities were assembled. Two specific epitopes were selected from B-cell, and T-cell for each construct. The heat-labile enterotoxin S63 adjuvant was attached to the N-terminal, while the PADRE order and the His-tag were added to the C-terminal with appropriate linkers. The vaccine constructs showed 62%, 80%, 90%, and 72% of average global population coverage. The Ramachandran scores were observed to be ≥ 90%, and the instability index was 35.13, validating stable structures. Docking analysis showed strong affinity for V1-TLR7 (-1380), V2-TLR7 (-1615.7), V2-TLR8 (-1033.8), V3-TLR7 (-1692.7), V3-TLR8 (-1097.6), ACE (-1127.2), V4-TLR7 (-1689.4), and V4-TLR10 (-1240.8 kcal/mol) complexes, respectively. However, molecular dynamics simulations revealed a consistent interaction pattern for the complex TLR8-construct3. The vaccine constructs ligated into the pBR322 vector showed successful insertion and expression. A strong immune response was observed, with elevated IgM + IgG concentrations within 10 days of injection, which normalized by 30-35 days. In conclusion, the current research highlights the possibility of an innovative vaccine against the virus. To extend our efforts and bridge the gap between vaccine design and reducing the burden of POWV, further in vitro and in in vivo studies are necessary.
Vitexin-loaded phytosomes protect against high-fat diet-induced MASLD modulating PI3K/AKT/mTOR/SREBP-1c, Nrf2/HO-1, NF-κB/COX-2, and apoptotic pathways.
Hegazy AM, Al-Ghafari AB, Doghaither HAA … +5 more , Elmorsy EM, Ghaith MM, Alshammari AN, Alfayoumi MG, Hassan AME
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42283841 · Publisher ↗
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a progressive liver disorder driven by high-fat diet (HFD)-induced metabolic stress, oxidative damage, inflammation, and apoptosis. This study investiga...
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a progressive liver disorder driven by high-fat diet (HFD)-induced metabolic stress, oxidative damage, inflammation, and apoptosis. This study investigated the hepatoprotective effects of vitexin (VX) and vitexin-loaded phytosomal nanoparticles (VX-PHY) in HFD-fed rats. Sixty male albino rats were randomly assigned to six groups: standard diet control, standard diet + VX, standard diet + VX-PHY, HFD only, HFD + VX, and HFD + VX-PHY. HFD feeding caused significant weight gain, elevated liver and fat indices, disrupted serum proteins, impaired liver function, and dysregulated lipid profiles. At the molecular level, HFD induced oxidative stress, depleting GSH and antioxidant enzymes while activating the Nrf2/HO-1 pathway. It also triggered hepatic inflammation via NF-κB/COX-2 signaling, increasing TNF-α, IL-1β, and IL-6, and promoted apoptosis by upregulating BAX, Caspase-3, Caspase-8, and downregulating BCL2. HFD additionally activated the PI3K/AKT/mTOR/SREBP-1c axis, enhancing AKT/mTOR phosphorylation, nuclear SREBP-1c, and lipogenic gene expression (FASN, ACC), contributing to hepatic lipid accumulation, which was effectively suppressed by VX-PHY, highlighting its superior anti-lipogenic effect compared with crude VX. VX-PHY co-treatment further enhanced antioxidant defenses, modulated Nrf2/HO-1, suppressed NF-κB/COX-2-mediated inflammation, and attenuated pro-apoptotic signaling, restoring these pathways to near-control levels. Histopathological and ultrastructural analyses confirmed reduced steatosis, hepatocyte ballooning, necrosis, and organelle damage in VX-PHY-treated rats. Overall, vitexin, particularly when delivered via phytosomal nanoparticles, exerts potent hepatoprotective effects in HFD-induced MASLD by simultaneously mitigating oxidative stress, inflammation, apoptosis, and lipid dysregulation via inhibition of PI3K/AKT/mTOR/SREBP-1c, highlighting the therapeutic potential of nanoparticle-based delivery for natural compounds like vitexin.
Identification of potential targets of kaempferol for the treatment of intervertebral disc degeneration based on network pharmacology and multi-omics analysis.
Cheng W, Yang L, Zhao L … +1 more , Jian J
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42283840 · Publisher ↗
Intervertebral disc degeneration (IVDD) is a leading cause of chronic disabling musculoskeletal disorders, with its incidence rising annually among the aging global population. This degenerative process is strongly linke...
Intervertebral disc degeneration (IVDD) is a leading cause of chronic disabling musculoskeletal disorders, with its incidence rising annually among the aging global population. This degenerative process is strongly linked to persistent functional impairment and reduced quality of life in patients, while placing a growing socioeconomic burden on global healthcare systems. Previous studies have demonstrated that kaempferol exerts potent anti-inflammatory effects by modulating pro-inflammatory cytokine expression and attenuating extracellular matrix degradation in degenerated intervertebral discs. However, the precise molecular targets responsible for its therapeutic effects remain unclear. This study integrated network pharmacology, molecular docking, bulk and single-cell transcriptomics, and experimental validation to identify the therapeutic targets of kaempferol in IVDD. Potential targets of kaempferol were predicted using the TCMSP, SwissTargetPrediction, and PharmMapper databases. IVDD-related targets were retrieved from the GeneCards, OMIM, and MalaCards databases. A protein-protein interaction (PPI) network was constructed using STRING and Cytoscape, followed by GO and KEGG enrichment analyses. Hub genes were identified via topological analysis. Molecular docking was conducted using AutoDock Vina. The expression patterns of core targets were validated using two GEO bulk RNA-seq datasets (GSE70362 and GSE147383), one single-cell RNA-seq dataset (GSE251686), and qRT-PCR in IL-1β-induced nucleus pulposus cells. Twenty-one common targets between kaempferol and IVDD were identified. Topological analysis identified three core hub genes-STAT1, CASP1, and NOX4-all significantly upregulated in IVDD tissues. Molecular docking revealed strong binding affinities between kaempferol and these targets, with binding energies ranging from - 6.7 to - 7.9 kcal/mol. Single-cell transcriptomics further confirmed their high expression in nucleus pulposus cells. qRT-PCR analysis demonstrated that kaempferol significantly downregulated STAT1, CASP1, and NOX4 mRNA expression; restored extracellular matrix components (COL2 and ACAN); and suppressed matrix-degrading enzymes (MMP3 and MMP13) in IL-1β-stimulated nucleus pulposus cells. These findings suggest that kaempferol exerts protective effects against IVDD by regulating STAT1, CASP1, and NOX4. The multi-target effects of kaempferol in IVDD provide novel insights and highlight its potential as a therapeutic candidate for IVDD treatment.
Evaluating the quality and reliability of DILI in Chinese videos on TikTok (Douyin) and BiliBili: cross-sectional content analysis study.
Nie R, Yu B, Wang H … +3 more , Qin S, Huai C, Li Z
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42283839 · Publisher ↗
This study is a cross-sectional analysis aimed at systematically evaluating the information quality and reliability of popular science content related to drug-induced liver injury (DILI) on the two major Chinese video pl...
This study is a cross-sectional analysis aimed at systematically evaluating the information quality and reliability of popular science content related to drug-induced liver injury (DILI) on the two major Chinese video platforms, TikTok (Douyin) and BiliBili, and analyzing its content characteristics. On December 20, 2025, searches were conducted in the Chinese versions of the TikTok (Douyin) and BiliBili mobile applications using "" as the single keyword. Exclude content that does not meet the requirements based on the exclusion criteria, and ultimately retain the top 100 videos from each platform that meet the standards for analysis (N = 200). Two trained reviewers independently performed blinded assessments using the Global Quality Score (GQS), Journal of the American Medical Association (JAMA) benchmark criteria, and the modified DISCERN (mDISCERN) tool. Non-parametric tests were used to compare differences between groups, and Spearman correlation analysis was employed to explore the relationship between video characteristics and quality scores. User engagement metrics (likes, favorites, shares) for TikTok (Douyin) videos were significantly higher than those for BiliBili (p < 0.001). In terms of information quality, TikTok (Douyin) videos scored significantly higher than BiliBili on the GQS, JAMA, and mDISCERN scales (p < 0.001). There were differences in quality across content types: videos on "medication knowledge" received the highest mDISCERN reliability scores and "disease knowledge" videos scored higher in GQS practicality. Correlation analysis showed a weak positive correlation between user engagement metrics and mDISCERN scores. Among the 107 videos mentioning liver injury-related drugs, chemical drugs (antibacterial, chemotherapeutic, anti-tuberculosis drugs, and anti-inflammatory drugs) and traditional Chinese medicines (such as He Shou Wu) were mentioned most frequently. In this cross-sectional sample, TikTok (Douyin) videos demonstrated higher quality scores and user engagement than those on BiliBili, while professionals outperformed general users only on the JAMA criteria. Although some videos mentioned medications associated with liver injury, the information was generally oversimplified and biased toward trending topics. Hence, active information seekers should critically appraise the scientific soundness of medical short videos on platforms like TikTok and BiliBili before making healthcare decisions.
Artificial intelligence-powered chatbots for oral anticancer drug patient information: an assessment of quality.
Sametinger SM, Maas R, Nicolaus HF … +1 more , Andrikyan W
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42283838 · Publisher ↗
The increasing use of oral anticancer drugs (OADs) in cancer therapy shifts greater responsibility towards patients, thereby also placing a higher informational burden on them. While intensified pharmacological/pharmaceu...
The increasing use of oral anticancer drugs (OADs) in cancer therapy shifts greater responsibility towards patients, thereby also placing a higher informational burden on them. While intensified pharmacological/pharmaceutical care programs have proven beneficial for patients undergoing OAD treatment, their universal availability is currently limited. Given that patients frequently seek health information online, AI-powered chatbots may present a promising resource to address these increasing, yet often unmet information needs. This study aims to evaluate the readability, completeness of relevant information, and accuracy provided by AI-powered chatbots in response to patient questions about OAD treatment. Microsoft Bing's Copilot and Google's Gemini were queried in June 2024 on four patient questions regarding ten commonly prescribed and ten recently approved OADs in triplicate. Readability of chatbot answers was assessed using the Flesch reading-ease score (scale 0-100). Completeness of relevant information and accuracy were evaluated based on corresponding standardized written patient information materials. Both chatbots' answers demonstrated low readability according to the overall mean Flesch reading-ease scores of 38.8 (Copilot) and 50.9 (Gemini). Overall median completeness of relevant information of Copilot's and Gemini's answers was 61.1% (IQR, 35.3-78.7%) and 73.8% (IQR, 50.0-100.0%), respectively. Conversely, accuracy of chatbot answers was consistently high, with an overall median accuracy of 100.0% (IQR, 83.3-100.0%) for Copilot and 100.0% (IQR, 98.5-100.0%) for Gemini. AI-powered chatbots provide overall accurate information on OADs. However, their moderate completeness of relevant information and low readability may limit their current practical utility in meeting cancer patients' information need.
Clinical evaluation of adjunctive magnesium therapy in patients receiving antidepressants for depression-open label, nonrandomized clinical trial.
Siddique A, Naeem U, Khokhar MM … +3 more , Irshad M, Farooq T, Kanwal S
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42283837 · Publisher ↗
Depression causes distress, dysfunction, and disability in terms of physical, mental, and social wellbeing. The challenges of late presentation, no-compliance of patients, and time-lag of antidepressants persist, despite...
Depression causes distress, dysfunction, and disability in terms of physical, mental, and social wellbeing. The challenges of late presentation, no-compliance of patients, and time-lag of antidepressants persist, despite advances. The objective was to determine the efficacy of antidepressants in combination with magnesium, compared to antidepressant monotherapy for treating depression. Forty-four patients with depression (6A70, 6A71, and 6A72 according to ICD-11) were divided into two equal groups, in an open label nonrandomized clinical trial. All patients received evidence-based antidepressants (either escitalopram, sertraline, duloxetine, amitriptyline, or fluoxetine). The experimental group additionally received 800 mg of magnesium glycinate (112 mg elemental magnesium). The psychometric testing was done by Patient Health Questionnaire (PHQ-9) at days 0, 14, and 28. Primary outcome was to see improvement at day 28, while secondary outcomes included time lag and remission (PHQ-9 scores < 4) at day 14 and 28, respectively. Paired sample t-test and Student t-test were applied for within-group and between-group differences using SPSSv27.0. The p-value ≤ 0.05 was considered statistically significant. The improvement in the PHQ-9 scores in groups A and B was 26.42% and 72.17%, respectively, by day 28, and effect size (Cohen's d = 1.76) was in the favor of adjunct therapy. Group B showed 41.34% improvemnet and large effect size (d = 1.29) on day 14 as well. All these values were statistically significant (p ≤ 0.05). The remission rate (44 patients) was higher with adjunt therpay (10.23%), versus 2.27% with monotherapy. Adjunct antidepressant therapy with magnesium is a preliminary effective strategy for patients with depression, potentially augmenting treatment response and decreasing time lag of antidepressants. ClinicalTrials.gov ID: NCT05931965 ( https://clinicaltrials.gov/study/NCT05931965?cond=Depression&intr=magnesium,%20methylfolate,%20B12&rank=1 ), 14-06-2023 (retrospectively registered).
A hybrid PK/PD index for gentamicin dosing in premature neonates: a Monte Carlo simulation study.
Alfaifi KA, Alsaedi SA, Aseeri MA … +6 more , Alkheliwi MM, Althukair AA, Alzaidi AA, Alfaifi SK, Alfaifi FK, Alfaifi SA
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42283836 · Publisher ↗
Gentamicindosing in premature neonates remains challenging due to developmental pharmacokinetic variability and augmented renal clearance. Conventional PK/PD targets such as Cmax/MIC and AUC/MIC capture distinct pharmaco...
Gentamicindosing in premature neonates remains challenging due to developmental pharmacokinetic variability and augmented renal clearance. Conventional PK/PD targets such as Cmax/MIC and AUC/MIC capture distinct pharmacodynamic dimensions but fail to integrate efficacy and toxicity simultaneously (Craig 1998; Sime and Roberts 2020). A Monte Carlo simulation of 3000 premature neonates was conducted using published pharmacokinetic parameters (Germovsek et al. 2019; Smith et al. 2011). A Hybrid PK/PD Index (H-index) integrating peak exposure, cumulative exposure, and toxicity constraints was evaluated across clinically relevant MIC values (0.5-2 mg/L). The H-index demonstrated improved joint probability of target attainment (PTA) compared with standard dosing, with enhanced robustness across MIC variability and reduced exposure dispersion. At MIC 2 mg/L, PTA increased from 40 to 65%. The proposed Hybrid PK/PD index (H-index) provides a conceptually integrated framework for optimizing gentamicin dosing in premature neonates under simulated conditions. While these in silico findings suggest enhanced target attainment, prospective clinical validation in real-world neonatal cohorts is warranted.
Integrative transcriptomic and bioinformatic analyses predict candidate EMT-related genes in sepsis-associated acute lung injury.
Liu J, Chen Y, Peng H … +4 more , Xu Z, Wang Y, Zhang L, Wang H
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42283835 · Publisher ↗
Sepsis-associated acute lung injury (sepsis-ALI) is a complex pathological condition; its underlying mechanisms remain mostly obscure. Thus, in this study, we aimed to explore potential candidate molecular markers, infer...
Sepsis-associated acute lung injury (sepsis-ALI) is a complex pathological condition; its underlying mechanisms remain mostly obscure. Thus, in this study, we aimed to explore potential candidate molecular markers, infer the regulatory signaling pathways, and describe the immunological profiles of sepsis-ALI. We developed a comprehensive bioinformatics analytical workflow by combining human transcriptome datasets with single-cell RNA sequencing databases and applied the ComBat algorithm to remove batch effects. A hierarchical gene screening process, incorporating the support vector machine, least absolute shrinkage and selection operator, and random forest machine learning algorithms, was applied. Five epithelial-mesenchymal transition (EMT)-related candidate genes (AURKA, MYB, CCNA2, CD24, and TYMS) were suggested across these algorithms. These candidate genes, which are involved in histone phosphorylation signaling, were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Single-sample gene set enrichment analysis was used to profile immune cell infiltration patterns, which led to the identification of seven differentially abundant immune cell populations. CellChat analysis suggested the MIF-(CD74 + CXCR4) axis serves as a putative mediator of intercellular communication based on ligand‑receptor expression patterns in sepsis-ALI. Pseudo-time trajectory analysis revealed that CD24 expression and MYB expression are associated with EMT progression and display stage‑specific functional relevance along the inferred cellular trajectory. Together, these integrative multi-resolution transcriptomic analysis findings describe EMT-related molecular characteristics, stage-specific regulatory pathways, and immune processes in sepsis-ALI. It is noteworthy that all these results are hypothesis-generating and derived solely from bioinformatics analyses without experimental validation. Identification of candidate genes and the putative role of the MIF-(CD74 + CXCR4) axis provides preliminary insights into sepsis-ALI pathophysiology; these findings will serve as a basis for further experimental research to develop potential precision-based and stage-specific experimental treatment strategies for sepsis-ALI in the future.
Luteolin ameliorates cigarette smoke-induced chronic obstructive pulmonary disease by modulating gut and lung microbiota and amino acid metabolism in C57Bl/6 mice.
Jian T, Huang J, Zhang F … +9 more , Zhang W, Zhou L, Niu G, Lv H, Gai Y, Zhang S, Li W, Ding X, Chen J
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42283834 · Publisher ↗
Exposure to cigarette smoke (CS) is a potent and major risk factor for chronic obstructive pulmonary disease (COPD). Luteolin (Lut), a flavonoid found in many edible plants, has displayed therapeutic effects on COPD; how...
Exposure to cigarette smoke (CS) is a potent and major risk factor for chronic obstructive pulmonary disease (COPD). Luteolin (Lut), a flavonoid found in many edible plants, has displayed therapeutic effects on COPD; however, the underlying mechanisms are not well comprehended. In this study, C57Bl/6 J mice were exposed to CS combined with lipopolysaccharide (LPS) to induce COPD. Examination of the levels of inflammatory markers, including TNF-α, IL-1β, IL-6, IL-18, NO, and LPS, revealed that CS exposure caused significant lung injury and inflammatory reactions, while treatment with Lut (50 and 100 mg/kg/day) significantly reversed these trends. 16S rRNA sequencing showed that mice exposed to CS not only decreased the richness and composition of the lung microbiota, but also affected the gut microbiota. Lut treatment increased the richness and modulated the composition. Lut treatment altered the abundance of Pseudomonas, Streptococcus, and Actinomyces in the lung microbiota, as well as Actinobacteria, Helicobacter, and Coprococcus in the gut microbiota. Moreover, targeted metabolomics of amino acids showed seven amino acids, which were significantly altered by Lut, including serine (Ser), threonine (Thr), asparagine (Asn), glutamine (Gln), glutamic acid (Glu), histidine (His), and tyrosine (Tyr). Our study suggests that the protection effect of Lut on CS-induced COPD probably relies on the modulation of gut and lung microbiota and amino acid metabolism.
Drug repurposing in KRAS G12C-mutant NSCLC: a focus on resistance mechanisms and clinical strategies.
Jain A, Rosell R, Dharmashekara C … +7 more , Shreevatsa B, González-Cao M, Shivakumar A, Kollur SP, Prasad A, Shivamallu C, Prasad MNN
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42283833 · Publisher ↗
KRAS G12C-mutant non-small cell lung cancer (NSCLC) has transitioned from a therapeutically problematic disease to a precision-targetable cancer, anchored by the landmark approvals of sotorasib and adagrasib. Yet despite...
KRAS G12C-mutant non-small cell lung cancer (NSCLC) has transitioned from a therapeutically problematic disease to a precision-targetable cancer, anchored by the landmark approvals of sotorasib and adagrasib. Yet despite these advances, responses remain limited in duration and multiple mechanisms of rapid adaptive resistance emerge under inhibitor pressure. These resistance mechanisms define a therapeutic vulnerability map that can be addressed by repurposing approved agents with established safety profiles. This review emphasises the current understanding of KRAS G12C biology, integrates updated phase 3 clinical data and next-generation inhibitor pipelines through early 2026, and presents a mechanism-stratified drug repurposing framework that links validated bypass mechanisms to FDA-approved or clinically available compounds amenable to rapid combination trials. We further highlight patient-derived 3D models, multi-omics technologies, and ctDNA-guided monitoring as essential translational platforms. Finally, we propose an integrated translational roadmap that combines mechanistic insights with clinical innovation, offering new directions for precision therapy and improved patient outcomes in KRAS-driven NSCLC.
Alzheimer's disease-cancer research (inception to 2025): trends, themes, translational pathways, and insights from highly cited studies.
Taha MME, Abdelwahab SI, Alshahrani S … +4 more , Jali AM, Qadri M, Alarifi A, Al-Shamsi HO
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42274769 · Publisher ↗
Alzheimer's disease-cancer research (ADCR) has gained increasing attention due to paradoxical epidemiological associations and shared yet oppositely regulated biological mechanisms; however, the field lacks an integrated...
Alzheimer's disease-cancer research (ADCR) has gained increasing attention due to paradoxical epidemiological associations and shared yet oppositely regulated biological mechanisms; however, the field lacks an integrated synthesis of its intellectual and thematic structure. This study comprehensively mapped the longitudinal evolution, collaboration patterns, and conceptual architecture of ADCR. Scopus-indexed articles published between 1968 and 2025 were retrieved using a structured TITLE-ABS-KEY search strategy. Bibliometric indicators were analyzed using the Bibliometrix R package (Biblioshiny), and network, density, overlay, and thematic visualizations were generated using VOSviewer. Analyses included productivity trends, citation impact, collaboration networks, institutional and author performance, Bradford's and Lotka's laws, keyword co-occurrence, thematic evolution, and strategic mapping. The dataset comprised 7460 publications, with an annual growth rate of 11.98% and 24.79% international collaboration. Scientific output and citation impact were dominated by North America, Europe, and East Asia, led by the USA (2418 documents; 121,747 citations) and China (1406 documents; 40,410 citations). Thematically, Alzheimer's disease-centered neuroinflammatory mechanisms emerged as the principal motor theme, while cancer persisted as a foundational but less cohesive domain. Temporal analyses indicated a transition from early mechanistic fragmentation to consolidated interdisciplinary research, accompanied by the recent rise of molecular docking, machine learning, and network pharmacology. Collectively, ADCR is evolving into a mature, integrative field characterized by methodological innovation and growing translational convergence between neurodegeneration and oncology.
Immunopharmacological design of a multi-epitope vaccine targeting sarbecovirus Spike glycoprotein.
Aziz T, Alshehri MA, Aljumaa MA … +2 more , Alzhrani K, Tombozara N
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42274768 · Publisher ↗
Sarbecoviruses pose a continued pharmacological and immunological challenge due to their zoonotic potential and high genetic variability, demanding broadly protective vaccine strategies with conserved viral antigens. Thi...
Sarbecoviruses pose a continued pharmacological and immunological challenge due to their zoonotic potential and high genetic variability, demanding broadly protective vaccine strategies with conserved viral antigens. This study aimed to design a broad-spectrum multi-epitope vaccine predicted to neutralize potential future spillovers of Horseshoe bat sarbecoviruses, a likely evolutionary forebear. Using a reverse vaccinology pipeline, priority was given to high-affinity CTL, HTL, and B-cell epitopes from the Spike glycoprotein that had conserved antigenicity throughout the Sarbecovirus subgenus. A multi-epitope vaccine strategy was employed to enhance broad immunogenicity against conserved sarbecovirus regions. Being stable, soluble, and non-allergenic, the final chimeric construct showed a good physicochemical profile. Analysis of population coverage revealed that the chosen epitopes might technically stimulate an immunological reaction in almost 96.89% of the global population, hence reducing HLA-restriction bias. Structural modeling utilizing AlphaFold 3 exposed a native-like fold, which was confirmed by molecular docking with the human ACE2 receptor. The high binding affinity (energy score - 1484.7 kcal/mol) and unique interfacial interactions imply the vaccine can successfully emulate the viral pathogen, hence stopping viral entry. Later in silico immune simulations forecast a powerful Th1-polarized response distinguished by high IFN-gamma concentrations and the fast development of immunological memory. At last, virtual cloning into the pET-28a( +) vector and codon optimization verified the possibility of high-yield expression in E. coli. Further experimental validation is required to confirm its immunogenicity and protective efficacy.
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 Jun · PMID 42271067 · Publisher ↗
Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, β-cell dysfunction, and chronic low-grade inflammation. Doxycycline exhibits anti-inflammatory properties, suggesting potential benefit as an adjunc...
Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, β-cell dysfunction, and chronic low-grade inflammation. Doxycycline exhibits anti-inflammatory properties, suggesting potential benefit as an adjunctive therapy in T2DM. To evaluate the efficacy and safety of adjunctive doxycycline in patients with T2DM receiving sitagliptin. In this randomized controlled trial, 57 patients with T2DM were assigned to receive sitagliptin alone (n = 29) or sitagliptin plus doxycycline (n = 28) for 12 weeks. Glycemic indices, insulin sensitivity measures, lipid profile, cardiometabolic risk indices, and inflammatory markers were assessed before and after treatment. Parametric outcomes were analyzed using analysis of covariance (ANCOVA) adjusted for baseline values, while non-parametric biomarkers were analyzed using Hodges-Lehmann estimators. Multivariable linear regression identified independent determinant of treatment response. Between-group comparisons for secondary outcomes were adjusted using the Benjamini-Hochberg false discovery rate. Both groups showed significant within-group improvements in body weight, glycemic indices, lipid profile, and inflammatory markers (p < 0.05). However, the combination therapy demonstrated superior outcomes. Significant reductions were observed in fasting blood glucose (adjusted mean difference: - 6.20 mg/dL, p = 0.034), fasting insulin (- 2.02 μIU/mL, p = 0.008), HOMA-IR (- 0.83, p < 0.001), and HbA1c (- 1.25%, p < 0.001), along with increased insulin sensitivity (QUICKI: + 0.0086, p < 0.001). Cardiometabolic parameters were also significantly improved, including total cholesterol (- 14.0 mg/dL, p = 0.030), triglycerides (- 11.6 mg/dL, p = 0.007), LDL-C (- 14.4 mg/dL, p < 0.001), and HDL-C (+ 4.8 mg/dL, p = 0.030). Risk indices (AI, CVRI, CRR) showed marked reductions (all p < 0.05). Inflammatory biomarkers were associated with improvements with combination therapy, including reductions in MMP-9 (p = 0.030) and CRP (p = 0.002). Regression analysis identified doxycycline treatment as an independent determinant of improvement in most outcomes, including HbA1c, HOMA-IR, QUICKI, lipid indices, and MMP-9. FDR correction confirmed the robustness of these findings. Correlation analyses revealed strong associations between insulin resistance markers and cardiometabolic indices. Adverse events were mild and comparable between groups. The addition of doxycycline to sitagliptin appears to improve glycemic control, insulin sensitivity, cardiometabolic risk profile, and inflammatory status in T2DM, without increasing adverse effects. These findings are exploratory and should be confirmed in larger trials with longer follow-up. CLINICAL TRIAL IDENTIFIER: NCT06329882.
Delirium in older hospitalized patients: a decade-later study highlighting medical and medication-related etiologies beyond muscarinic antagonism.
Kaur U, Agrahari J, Velmurugan A … +10 more , Pandey A, Rai M, Prasad KK, Lahari TSS, Varshney T, Majumdar S, Pandey S, Pooja GS, Singh A, Chakrabarti SS
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42268391 · Publisher ↗
Delirium in older adults is often due to an acute infectious insult or metabolic dysfunction. Traditionally, muscarinic antagonists have been implicated in delirium, but the association remains inconsistent. The delirium...
Delirium in older adults is often due to an acute infectious insult or metabolic dysfunction. Traditionally, muscarinic antagonists have been implicated in delirium, but the association remains inconsistent. The delirium-producing effects of medications require a multifaceted understanding that goes beyond their anticholinergic actions and simultaneously considers other medical etiologies. The current study is a subgroup analysis of an 18-month prospective study on dyselectrolytemia conducted in the Department of Geriatric Medicine in a tertiary North Indian hospital. Findings are compared with those of a decade-old study from a non-geriatric service at the same hospital. Among 411 admissions, delirium occurred in 26.5% and was multifactorial in 64.2%. Infections and acute kidney injury were the leading causes. Medications were involved in 23.9%. Medication-induced delirium cases were related to severe hyponatremia or hypernatremia and direct neurological effects, in addition to usual antimuscarinic actions. However, at the study population level, while 3.3-fold higher odds of delirium were observed in patients aged 80 and above, no association was observed with the number of medications or with medications with strong anticholinergic potential. Increasing age was the strongest independent risk factor for delirium. A higher rate of medication-related causes was identified compared to past data from the same center, but different setups preclude any definite conclusions. Medication-induced delirium had a favorable outcome and was reversible in the majority. The study reinforces the role of meticulous medication review in therapeutic decision-making for older persons. The absence of an association with anticholinergic medications may be due to differences in population characteristics, limited statistical power of the study design, and evolving prescribing trends. The delirium-producing risk of individual medication classes warrants further larger studies.
Epilepsy-induced heart damage and sudep risk: ion channelopathies, calcium homeostasis, and the therapeutic potential of resveratrol.
Akgun-Unal N, Unal O, Tiryaki ES … +4 more , Akkoca A, Simsek S, Gulbahce-Mutlu E, Ayyildiz M
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42268390 · Publisher ↗
Epilepsy is a worldwide health issue associated with cardiac-related conditions and Sudden Unexpected Death in Epilepsy (SUDEP). The pathophysiology of SUDEP involves structural fibrosis of the myocardium, a calcium imba...
Epilepsy is a worldwide health issue associated with cardiac-related conditions and Sudden Unexpected Death in Epilepsy (SUDEP). The pathophysiology of SUDEP involves structural fibrosis of the myocardium, a calcium imbalance, and dysfunction of the autonomic nervous system. The objective of this investigation was to examine cardiac damage resulting from epilepsy triggered by the Pentylenetetrazol (PTZ) kindling rat model at a dosage of 35 mg/kg administered intraperitoneally, and to assess the therapeutic benefits of Resveratrol (RSV) at a dosage of 5 mg/kg. Cardiac function was evaluated using isolated papillary muscle recordings. Damage to the structure was assessed by Sirius Red staining and general tissue morphology. Molecular analyses encompassed qPCR (SERCA2a, CACNA1G, HCN2, CAS3/9) and immunofluorescence (SIRT1, Caspase-3, S100α) in conjunction with the total Ca⁺ content. PTZ kindling enhanced seizure severity and overall spike number on ECoG. Functionally, contractile force (CF), contractile power (AUC), and contraction/relaxation velocities (± dF/dt) were decreased in the PTZ group compared to the Sham group at 3, 4, and 5 Hz frequencies. Contraction duration (CT) was significantly prolonged at 5 Hz, whereas no significant change was observed in relaxation time (RT). Histopathology revealed degeneration and substantial myocardial scarring. At a molecular level, PTZ decreased SERCA 2a mRNA expression (p < 0.0001) while increasing total calcium content (p < 0.0001) and pro-apoptotic markers (Caspase-3/9). Furthermore, the protective SIRT1 protein signal intensity was substantially reduced. RSV therapy resulted in a reduction of seizure severity by 2.54 ± 0.13 and also ameliorated cardiac function. Mechanistically, RSV recovered expression of SERCA2a (p < 0.0001), reduced fibrosis/apoptosis, and reactivated the anti-apoptotic SIRT1 pathway. These findings show that RSV ameliorates epilepsy-induced cardiac injury and has the potential to serve as an effective supportive treatment against SUDEP-related heart dysfunction by regulating calcium levels and activating anti-apoptotic pathways.
Oxidative stress, antioxidant depletion, and DNA damage in post-COVID-19 patients: evidence of a disrupted redox network and loss of age-dependent antioxidant compensation.
Dikshit N, Tripathi SK, Bajpai J … +11 more , Verma A, Ansari KM, Kaur C, Jahan I, Verma SK, Kumar S, Kushwaha RAS, Garg R, Srivastava A, Bajaj D, Katiyar A
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42268389 · Publisher ↗
The relationship between oxidative stress and viral infections is well established, yet data on the redox consequences of COVID-19 beyond the acute phase remain sparse. We conducted a comprehensive assessment of oxidativ...
The relationship between oxidative stress and viral infections is well established, yet data on the redox consequences of COVID-19 beyond the acute phase remain sparse. We conducted a comprehensive assessment of oxidative stress biomarkers, antioxidant defences, and DNA damage in post-COVID patients, and examined whether COVID-19 infection disrupts the normal architecture of the antioxidant network. In this single-centre, cross-sectional, case-control study, 40 symptomatic post-COVID patients and 40 age- and sex-matched healthy controls were recruited from the Department of Respiratory Medicine, King George's Medical University, Lucknow, India. Blood levels of lipid peroxidation (LPO), total antioxidant activity (TAA), superoxide dismutase (SOD), and glutathione reductase (GR) were measured. DNA damage was quantified using the alkaline comet assay. Data were analysed using Mann-Whitney U tests and Spearman rank correlations. Post-COVID patients showed profound antioxidant depletion: TAA was reduced by 60.8% (median 51.7 vs 224.3 mM; p < 0.001; Cohen's d = 1.57), SOD by 34.0% (p < 0.001; d = 0.58), and GR by 35.0% (p < 0.001; d = 0.65). LPO was elevated but did not reach significance after correction for non-normality (p = 0.254), though it correlated significantly with radiographic severity (ρ = 0.403; p = 0.010) and was markedly elevated in patients with neurological involvement (2486.6 nmole/ml; p = 0.008). DNA damage was significantly increased across all comet parameters (% Tail DNA: + 24.0%; p < 0.001; d = 0.82). A novel finding was that the physiological age-dependent increase in TAA observed in controls (ρ = 0.425; p = 0.006) was abolished in patients (ρ = - 0.061; p = 0.707). Inter-marker correlation analysis revealed a rewiring of the antioxidant network, with breakdown of the normal LPO-TAA feedback relationship and emergence of SOD-TAA co-depletion. Post-COVID patients exhibit severe antioxidant depletion, significant DNA damage, and disruption of the normal redox network architecture. These findings provide a biochemical rationale for antioxidant-targeted therapeutic strategies in post-COVID management.
Ameliorative effect of Nano berberine in bleomycin- induced lung fibrosis in male rats.
Morsy WA, Heibashy DMI, Eissa SM … +1 more , Elshafiey SH
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42268388 · Publisher ↗
Pulmonary fibrosis is a progressive and fatal lung disease characterized by excessive extracellular matrix deposition. Bleomycin (BLM)-induced pulmonary fibrosis is a widely used experimental model that replicates key pa...
Pulmonary fibrosis is a progressive and fatal lung disease characterized by excessive extracellular matrix deposition. Bleomycin (BLM)-induced pulmonary fibrosis is a widely used experimental model that replicates key pathological features of the human disease. Berberine (Brb), a natural phytochemical, exhibits anti-inflammatory and immunomodulatory properties. However, its clinical application is restricted by poor bioavailability. Nano-formulation of Brb (Nano-Brb) may enhance its therapeutic potential. Therefore, this study aimed to evaluate the protective effects of Nano-Brb against BLM-induced pulmonary fibrosis in rats and to elucidate the underlying biochemical, histopathological, immunohistochemical, and molecular mechanisms. Thirty adult male albino rats were randomly assigned into six groups: control, Brb-treated (100 mg/kg body weight), Nano-Brb-treated (100 mg/kg body weight), BLM-treated (single intratracheal dose of 5 mg/kg body weight), BLM + Brb, and BLM + Nano-Brb. Nano-Brb significantly attenuated BLM-induced pulmonary fibrosis, as evidenced by reduced pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-4 (IL-4), interleukin-13 (IL-13), and tumor necrosis factor-alpha (TNF-α), as well as decreased matrix metalloproteinases (MMPs). It also modulated nuclear factor kappa B (NF-κB) and transforming growth factor-beta (TGF-β) signaling and reduced collagen type I (Col-I) and collagen type III (Col-III), connective tissue growth factor (CTGF), and neutrophil elastase (NE). Histopathological, histochemical, and immunohistochemical investigations confirmed marked improvement in lung architecture. Furthermore, Nano-Brb reduced transforming growth factor-beta 1 (TGF-β1) expression and upregulated pulmonary sirtuin 3 (SIRT3) gene expression. The present results suggest that Nano-Brb enhanced the lung's architecture and functional performance by modulating inflammatory cytokines, oxidative stress, gene expression, and histopathological damage.
Risk factors for immune checkpoint inhibitor-related interstitial lung disease: a retrospective cohort study.
Amemiya T, Suzuki H
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42262534 · Publisher ↗
Immune checkpoint inhibitors (ICIs) for cancer treatment show a high incidence of immune-related adverse events (irAEs), among which severe interstitial lung disease (ILD) can be fatal, requiring prompt identification an...
Immune checkpoint inhibitors (ICIs) for cancer treatment show a high incidence of immune-related adverse events (irAEs), among which severe interstitial lung disease (ILD) can be fatal, requiring prompt identification and management. This study aimed to identify pre-treatment risk factors associated with ICI-induced ILD. Medical records of patients who received ICIs were retrospectively reviewed. Age, sex, body weight, primary tumor type, ICI agent, PD-L1 status, disease stage, line of treatment, and laboratory parameters measured before treatment initiation were collected. Smoking history and prior diagnoses of chronic obstructive pulmonary disease and ILD were recorded. Patients who developed ILD were compared with those who did not. Elevated pre-treatment C-reactive protein (CRP) levels (odds ratio [OR] = 1.877; 95% confidence interval [CI] = 1.238-2.845; p = 0.003) and increased monocyte counts (OR = 23.509; 95% CI = 1.375-4.020 × 10; p = 0.029) were potential risk factors for ILD development following ICI therapy. A multivariable logistic regression model incorporating pre-ICI CRP levels and monocyte counts was constructed to predict ILD risk. The receiver operating characteristic analysis of this model yielded an area under the curve of 0.808 with a sensitivity of 92.0% and a specificity of 63.9%. Elevated pre-treatment levels of CRP and monocytes were significantly associated with the subsequent ILD development in patients treated with ICIs. These findings underscore the importance of close monitoring for pulmonary toxicity in patients with elevated CRP and monocyte counts before initiating ICI therapy.
Nitric oxide in neuroinflammation and neurodegeneration: dual roles, inflammasome crosstalk, and biomarker opportunities.
Korade G, Kharat S, Rathi K
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42262533 · Publisher ↗
Nitric oxide is a short-lived gas that plays a critical role in numerous physiological processes, including vascular regulation, neurotransmission, and immune responses. In the CNS NO's role is complex, as it can both pr...
Nitric oxide is a short-lived gas that plays a critical role in numerous physiological processes, including vascular regulation, neurotransmission, and immune responses. In the CNS NO's role is complex, as it can both protect and damage neurons. Microglia, the brain's resident macrophages, produce excessive NO in response to stimuli like endotoxins and cytokines, leading to chronic inflammation and neuronal damage associated with neurodegenerative diseases such as Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis. NO's dual role as a pro-inflammatory and anti-inflammatory mediator is intricately linked to its impact on neuronal health and disease progression. This review is aimed at summarizing and critically discussing the roles of NO in neuroinflammation, neurodegeneration, inflammasome regulation, and related therapeutic perspectives. A narrative literature review was conducted using electronic databases (e.g. PubMed and Google Scholar) to identify experimental and clinical studies on NO, neuroinflammation, neurodegenerative diseases, inflammasomes, and related biomarkers and therapies, with emphasis on mechanistic and translational work. Research into NO's effects on inflammasomes, key components of the innate immune system, reveals that NO can inhibit inflammasome activation, influencing inflammatory responses. Despite progress, challenges remain, including the need for cell-type-specific models, advanced technological approaches, and the development of selective NO modulators. Overall, current evidence indicates that NO exerts both neuroprotective and neurotoxic effects in the CNS, mediated by its complex interactions with neural, glial, and immune pathways. Future research should focus on the dual nature of NO, explore lesser-known inflammasomes, and incorporate human-centric models to develop targeted therapies.
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