Naunyn Schmiedebergs Arch. Pharmacol. [JOURNAL]
Sun
200 papers
Pharmacogenomic characterization of a uric acid metabolism-related signature associated with prognosis and drug sensitivity in gastric cancer.
Wu W, Wei Z
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42363944 · Publisher ↗
Gastric cancer (GC) remains a major cause of cancer-related mortality worldwide. Increasing evidence suggests that metabolic reprogramming contributes to GC progression, yet the prognostic significance of uric acid metab...
Gastric cancer (GC) remains a major cause of cancer-related mortality worldwide. Increasing evidence suggests that metabolic reprogramming contributes to GC progression, yet the prognostic significance of uric acid metabolism-related genes in GC remains unclear. This study aimed to characterize uric acid metabolism-related genes with prognostic and pharmacological relevance in gastric cancer and to explore their potential value for risk stratification and drug-response prediction. Differentially expressed genes between tumor and normal tissues were obtained from public databases and intersected with uric acid metabolism-related genes to identify candidate genes. Prognostic genes were screened using univariate Cox regression and machine learning algorithms, and a prognostic risk model was subsequently established. Patients were classified into high- and low-risk groups based on the risk score. Functional enrichment, somatic mutation, drug sensitivity, and single-cell transcriptomic analyses were further performed. RT-qPCR was used to validate gene expression in gastric cancer cell lines. A total of 657 candidate genes were identified from the intersection of 4514 differentially expressed genes and 3806 uric acid metabolism-related genes. Three genes, ABCG4, SERPINE1, and GPX3, were selected to construct the prognostic model. Patients in the high-risk group had significantly worse survival than those in the low-risk group. Multivariate Cox analysis showed that both risk score and age were independent prognostic factors for GC. Enrichment analysis indicated that pentose and glucuronate interconversions were significantly associated with the high-risk group. Drug sensitivity prediction showed lower predicted half-maximal inhibitory concentration (IC50) values for selected agents, including AZD8055, in the high-risk subgroup, suggesting a potential association with pharmacogenomic drug-response patterns. Single-cell analysis highlighted fibroblasts as a key cell population. RT-qPCR confirmed downregulation of ABCG4 and GPX3 and upregulation of SERPINE1 in GC cell lines. These findings identified prognostic features associated with uric acid metabolism in gastric cancer and suggest that ABCG4, SERPINE1, and GPX3 may be involved in metabolic dysregulation, matrix remodeling, and predicted pharmacogenomics response patterns.
Calcitriol and candesartan mitigate monosodium glutamate-exacerbated metabolic syndrome and MASLD/MASH in rats: modulation of GLuR5/Ketohexokinase/FoxO1 axis.
Zakaria EM, Mohamed MS, Ghareib SA … +3 more , Mohammed HO, Elbaramawi SS, Hassan NA
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42362764 · Publisher ↗
The widespread consumption of monosodium glutamate (MSG) is linked to serious health threats which would be magnified when accompanied by high-fat/high-sugar diets. This study investigated the metabolic and hepatic pertu...
The widespread consumption of monosodium glutamate (MSG) is linked to serious health threats which would be magnified when accompanied by high-fat/high-sugar diets. This study investigated the metabolic and hepatic perturbations of adding MSG to high fat/fructose diet in adult male rats and the possible ameliorative effects of calcitriol, and candesartan. Rats were fed high-fat/fructose diet plus sodium chloride (FF/NaCl) or MSG (FF/MSG) for 18 weeks, and were treated with either drug daily for the last 10 weeks. MSG exacerbated dyslipidemia, glucose intolerance, hypertension, and hepatic expression of mGLuR5 and ketohexoknase compared to NaCl. Both FF/NaCl and FF/MSG impaired hepatic insulin signaling biomarkers IRS-1 and Akt but MSG enhanced FoxO1 expression compared to NaCl. Furthermore, MSG exacerbated MASH hallmarks; steatosis, inflammation, and fibrosis. Both drugs mitigated most of the FF/MSG-induced metabolic and hepatic manifestations by downregulating mGLuR5, hetohexokinase, and FoxO1, beside their antioxidant, antiinflammatory, and antifibrotic effects. Calcitriol, and candesartan protect against MSG-induced hepatic derangements through downregulation of hepatic mGluR5, KHK, and FoxO1 expression in addition to their well-known anti-inflammatory and antifibrotic effects.
A selective low-dose cisplatin strategy enabled by melatonin and cannabinoids for targeting osteosarcoma and chondrosarcoma.
Aydın D, Pınarbaşı AK, Aslan K … +2 more , Aydın A, Canatan H
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42362763 · Publisher ↗
Therapeutic management of osteosarcoma and chondrosarcoma is limited by cisplatin (CP)-associated systemic toxicity and acquired chemoresistance. Strategies enabling effective dose reduction while maintaining antitumor a...
Therapeutic management of osteosarcoma and chondrosarcoma is limited by cisplatin (CP)-associated systemic toxicity and acquired chemoresistance. Strategies enabling effective dose reduction while maintaining antitumor activity are urgently required. This study investigated whether melatonin (MEL) and cannabinoids (CBD, THC) enhance CP efficacy through synergistic, multi-target mechanisms in osteosarcoma (MG63, Saos2) and chondrosarcoma (SW1353) cells, with normal fibroblast (FL) and osteoblast (HC) cells as controls. Cytotoxicity and antiproliferative effects were evaluated using MTT and LDH assays. Drug interactions were quantified via combination index (CI) and dose-reduction index (DRI) analyses. Apoptotic mechanisms were assessed by Casp3, Casp8, Casp9, and Bax gene expression, DNA fragmentation, DAPI nuclear staining, and Rhodamine-123-based mitochondrial membrane potential analysis. Anti-migratory and anti-invasive effects were examined using wound-healing and invasion assays. Molecular docking was performed to predict interactions with COX-2, MMPs, ADAMTS-5, and MAPK pathway proteins. Combination regimens, particularly THC + CP + MEL, and CP + MEL, demonstrated strong synergism (CI < 1) in SW1353 and Saos2 cells, enabling up to a 2.77 - 4.38-fold reduction in CP dose. Synergistic treatments significantly upregulated apoptotic markers and induced selective DNA fragmentation, chromatin condensation, and mitochondrial depolarization in cancer cells, while normal cells showed minimal alterations. Cannabinoids markedly suppressed migration and invasion, effects further enhanced in combination treatments. Docking analyses supported high-affinity multi-target interactions consistent with the observed biological responses. Collectively, melatonin enhances cannabinoid-mediated chemosensitization to cisplatin through selective, pro-apoptotic and anti-invasive mechanisms, supporting a low-dose, multi-target combinatorial strategy for bone sarcoma therapy.
Chrysophanol is associated with reduced inflammation and oxidative stress in sepsis-associated acute kidney injury.
Li X, Ouyang B, Zhang M … +8 more , Sun H, Ye H, You L, Yuan W, Wang H, Yang H, Xu K, Lei M
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42362762 · Publisher ↗
Sepsis-associated acute kidney injury (SA-AKI) is a common and severe complication in critically ill patients with high mortality, characterized by a dysregulated inflammatory response and oxidative stress. Chrysophanol...
Sepsis-associated acute kidney injury (SA-AKI) is a common and severe complication in critically ill patients with high mortality, characterized by a dysregulated inflammatory response and oxidative stress. Chrysophanol (CHR), a natural anthraquinone, has demonstrated anti-inflammatory properties in other septic conditions, but its role and mechanism in SA-AKI remain unclear. This study aimed to investigate the protective effects of CHR against SA-AKI and the underlying mechanisms. Cell viability, inflammatory cytokine expression (IL-6, IL-1β, TNF-α, MCP-1, IL-10), and intracellular reactive oxygen species (ROS) levels were assessed after CHR pretreatment. An in vivo model was established using LPS method. Renal injury was evaluated through histopathology (H&E, Masson's, TUNEL staining), renal function (serum creatinine and BUN), and systemic inflammation (serum IL-6, TNF-α, IL-10). In vitro, LPS significantly reduced HK-2 cell viability and increased the production of pro-inflammatory cytokines and ROS. CHR pretreatment restored cell viability, suppressed the mRNA levels of IL-6, IL-1β, TNF-α, and MCP-1, enhanced IL-10 expression, and reduced intracellular ROS levels. In vivo, LPS-induced mice exhibited severe renal pathological damage, apoptosis, collagen deposition, and elevated serum creatinine and BUN. CHR treatment attenuate these pathological changes, reduced renal injury scores and apoptosis, and improved renal function. Furthermore, CHR significantly decreased serum levels of pro-inflammatory IL-6 and TNF-α while increasing the anti-inflammatory cytokine IL-10 in LPS mice. Chrysophanol treatment is associated with improved cell survival, reduced inflammatory cytokine expression, and decreased oxidative stress in LPS-stimulated HK-2 cells and septic mice. These associations suggest a potential protective role of chrysophanol in SA-AKI, though the underlying molecular mechanisms require further investigation.
Synthesis and biological evaluation of benzyloxymethyl-substituted imidazo[1,2-a]pyridines as apoptosis-inducing anticancer agents through modulation of BCL-2/Bax signaling and caspase-3 activation.
Arzuk E, Pinar İ, Kuzu B
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42360416 · Publisher ↗
A novel series of benzyloxymethyl-substituted imidazo[1,2-a]pyridine derivatives (IPO1-IPO14) was designed, synthesized, and evaluated as potential anticancer agents. The compounds were synthesized via an efficient multi...
A novel series of benzyloxymethyl-substituted imidazo[1,2-a]pyridine derivatives (IPO1-IPO14) was designed, synthesized, and evaluated as potential anticancer agents. The compounds were synthesized via an efficient multistep strategy with satisfactory yields and structurally characterized by comprehensive H, C NMR, and LC-TOF analyses. Antiproliferative activities were evaluated against a panel of human cancer cell lines, including HepG2, A549, PC-3, MDA-MB-231, and MCF-7 cells; A549 non-small cell lung cancer and MDA-MB-231 triple-negative breast cancer cells showed the highest sensitivity. Among the tested compounds, IPO8, IPO9, IPO10, IPO11, and IPO13 demonstrated the strongest antiproliferative activity. IPO9 emerged as the most potent derivative, displaying significant cytotoxicity against A549 (IC = 3.84 µM) and MDA-MB-231 cells (IC = 9.69 µM), together with favorable selectivity profiles (SI = 23.02 and 15.31, respectively). Structure-activity relationship analysis revealed that para-alkoxy substitution enhanced antiproliferative potency and selectivity, whereas bulky aromatic or strongly electron-withdrawing substituents reduced biological activity. Mechanistic investigations suggested that the lead derivatives induced mitochondria-mediated intrinsic apoptosis through suppression of BCL-2, induction of Bax expression, elevation of the Bax/BCL-2 ratio, disruption of mitochondrial membrane potential, and activation of caspase-3. Among the tested compounds, IPO9 consistently produced the strongest pro-apoptotic effects and, in MDA-MB-231 cells, exhibited more pronounced modulation of several apoptosis-related markers than the positive control doxorubicin. Further molecular docking studies revealed favorable binding interactions of IPO9 within the BCL-2 binding pocket, providing computational support for the in vitro findings.
Homocysteine-induced bone formation dysfunction reversed by icariin via the AKT/FOXO1 signaling pathway.
Chao S, Fu Y, Peng X … +8 more , Zhou Y, Xia J, Chen M, Li Y, Li S, Shi M, Xia X, Liu B
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42350823 · Publisher ↗
Elevated homocysteine (Hcy) is an independent osteoporosis (OP) risk factor via oxidative stress-induced bone formation dysfunction. Icariin (ICA) has ethnopharmacological bone-protective effects, but its mechanism again...
Elevated homocysteine (Hcy) is an independent osteoporosis (OP) risk factor via oxidative stress-induced bone formation dysfunction. Icariin (ICA) has ethnopharmacological bone-protective effects, but its mechanism against Hcy-induced damage remains unclear. This study aimed to confirm Hcy's causal role in OP and clarify ICA's reversal effect via the AKT/FOXO1 pathway. Mendelian randomization (MR) analyzed Hcy-OP causality. In vitro, Hcy-treated MC3T3-E1 cells (osteoblast model) were evaluated via CCK-8, ALP/alizarin red staining, MDA/SOD detection, and Western blot. Network pharmacology/molecular docking predicted key targets; PI3K inhibitor LY294002 verified the AKT pathway. In vivo, dexamethasone-induced OP mice were assessed via micro-CT, ELISA, HE staining, and Western blot/qPCR. MR confirmed elevated Hcy as an upstream OP risk factor. Hcy inhibited osteoblast function, while ICA reversed this by enhancing proliferation/differentiation (elevated ALP, osteogenic markers: BMP2/COL1/OPG/RUNX2), reducing oxidative stress (lower MDA, higher SOD), and activating AKT/FOXO1 via phosphorylation. In OP mice, ICA improved BMD/trabecular microarchitecture, elevated P1NP, reduced CTX-1, and upregulated osteogenic pathway markers. Hcy-induced bone formation dysfunction drives OP progression. ICA alleviates oxidative stress and activates AKT/FOXO1 to protect against Hcy-related OP, offering a potential therapeutic strategy.
Design and optimization of isoxsuprine-loaded novasomes for the attenuation of coronary artery disease in rats.
Fouad AG, Belal A, Bukhari SM … +5 more , Albezrah NKA, Alghamdi SSA, Aljahdali ATH, Alziyadi RH, El-Ela FIA
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42350822 · Publisher ↗
Worldwide, healthcare systems are increasingly overwhelmed by the significant burden of coronary artery disease (CAD). The risk of developing CAD is heightened in individuals with diabetes mellitus (DM). Isoxsuprine (IXP...
Worldwide, healthcare systems are increasingly overwhelmed by the significant burden of coronary artery disease (CAD). The risk of developing CAD is heightened in individuals with diabetes mellitus (DM). Isoxsuprine (IXP) is a potent beta receptor agonist and α1-adrenoreceptor antagonist. IXP exhibits various pharmacological effects, such as enhancing arterial blood flow, promoting glucose uptake, and providing antioxidant benefits. However, the limited utility of IXP is attributed to its low bioavailability, hepatic metabolism, and short half-life. The primary objectives of this study were to design a nasal spray containing IXP-loaded novasomes (ILN) for attenuating DM-associated CAD. The focus was on enhancing the efficacy, bioavailability, and sustained release behavior of IXP. Various ILNs have been optimized using Design Expert software. The optimal ILN formulation has been characterized in terms of zeta potential, particle size, release, permeation, and stability. Additionally, the bioavailability and efficacy of the nasal ILN formulation have been studied in albino Wistar rats. The optimal ILN formulation exhibited a significant (Student's t-test, p-value < 0.0001) 3.53-fold increase in the sustained release behavior of IXP, a 3.87-fold increase in its permeation, and a 3.72-fold enhancement in its bioavailability. Additionally, the nasal ILN formulation demonstrated significantly (one-way ANOVA, p-value < 0.0001) greater cardioprotective and antioxidant activities compared to both oral and nasal IXP solutions. These results were further validated by the histopathological examination. The results indicate that the nasal ILN spray demonstrates preclinical efficacy in a rat model, suggesting its potential as a candidate for attenuating DM-associated CAD.
Safranal improves the anticancer efficacy of sorafenib via transcriptomic reprogramming and metabolomic changes in a rat model of diethylnitrosamine-induced cirrhosis-hepatocellular carcinoma.
Al Mansoori A, Baig B, Harati R … +8 more , Alhamidi RS, Hamza AA, Al-Salam S, Le A, Zhang C, Khare P, Hamoudi R, Amin A
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42350821 · Publisher ↗
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Sorafenib (SB) remains an option for advanced HCC in patients who cannot receive, or do not respond to, immunotherapy. Safranal (SF), a bioac...
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Sorafenib (SB) remains an option for advanced HCC in patients who cannot receive, or do not respond to, immunotherapy. Safranal (SF), a bioactive saffron compound, possesses anti-inflammatory and anticancer properties. This study evaluated SF with SB in a diethylnitrosamine-induced cirrhosis-HCC rat model. Rats were assigned to control, HCC, HCC + SB, HCC + SF, and HCC + SF + SB groups and treated for three weeks. Liver morphology, function, histology, apoptosis, cell proliferation, transcriptomics, and metabolomics analyses were assessed. Combination therapy inhibited hepatic nodules and restored liver architecture. Biochemical and histopathological analyses confirmed improved liver function, reduced fibrosis, vacuolation, and decreased α-SMA expression. Combined treatment improved apoptosis, antiproliferative effects and caused G2/M cell cycle arrest. Inflammatory markers (TNF-α, NF-κB, COX-2, MMP9, and β-catenin) were downregulated. Multiomics confirmed modulation of apoptosis, inflammation, oxidative stress, and metabolic pathways. SF potentiates a promising anti-HCC therapeutic efficacy of SB.
Study on the therapeutic effects of the primary active ingredients in cinnamon oil for constipation-predominant irritable bowel syndrome and their regulatory effects on the 5-HT signaling pathway and gut microbiota.
Peng W, Xu T, Zhang Z … +4 more , Cui L, Gu C, Sun X, Li H
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42347879 · Publisher ↗
Cinnamon oil exhibits therapeutic potential against constipation-predominant irritable bowel syndrome (IBS-C). This study aimed to evaluate the efficacy and mechanisms of its main components-cinnamaldehyde (CAL), cinnamy...
Cinnamon oil exhibits therapeutic potential against constipation-predominant irritable bowel syndrome (IBS-C). This study aimed to evaluate the efficacy and mechanisms of its main components-cinnamaldehyde (CAL), cinnamyl alcohol (COL), and trans-cinnamic acid (TCA)-in IBS-C. This study established an IBS-C mouse model using loperamide hydrochloride and restraint stress, and evaluated indicators such as body weight, the number of fecal pellets, fecal water content, visceral hypersensitivity, and small intestinal propulsion rate. The analysis was performed via HE staining, ELISA, Western blot, qRT-PCR, and 16S rRNA sequencing. All three components ameliorated low-grade immune cell infiltration in colonic tissue and reduced serum levels of IL-6, IL-8, and TNF-α. They also increased motilin (MTL) and acetylcholine (Ach) levels; all except trans-cinnamic acid low-dose (TCA-L) increased gastrin (Gas) levels, and all except TCA-L and trans-cinnamic acid high-dose (TCA-H) increased 5-HT levels. Cinnamaldehyde high-dose (CAL-H), cinnamyl alcohol high-dose (COL-H), and TCA-H upregulated the expression of tryptophan hydroxylase 1 (TPH1), serotonin transporter (SERT), and 5-hydroxytryptamine receptor 4 (5-HT4R) and partially modulated gut microbiota composition. CAL showed favorable effects under the present experimental conditions. The three components alleviated IBS-C symptoms partially through modulating the 5-HT signaling pathway and gut microbiota, with CAL showing the most pronounced effects under the present experimental conditions.
Integrated transcriptomic and in silico structural analysis identifies NFS1 and HSPA9 as potential regulators associated with mitochondrial ferroptosis and cell death resistance in colorectal cancer.
Liu Z, Xu X, Chen D … +6 more , Zhang L, Pan Y, Liu D, Shen M, Chen F, Chen M
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42347878 · Publisher ↗
Colorectal cancer (CRC) exhibits extensive metabolic reprogramming and resistance to regulated cell death, contributing to tumor progression and therapeutic failure. Ferroptosis, an iron-dependent and mitochondria-associ...
Colorectal cancer (CRC) exhibits extensive metabolic reprogramming and resistance to regulated cell death, contributing to tumor progression and therapeutic failure. Ferroptosis, an iron-dependent and mitochondria-associated form of cell death, has emerged as a potential therapeutic vulnerability; however, its integrated molecular regulation in CRC remains poorly understood. In this study, an integrative transcriptomic and in silico structural analysis was performed using two GEO datasets (GSE290002 and GSE65632). Differential expression analysis combined with curated mitochondrial and ferroptosis-related gene sets identified 69 mitochondrial ferroptosis-associated genes dysregulated in CRC. Functional enrichment analyses revealed significant involvement in oxidative phosphorylation, TCA cycle activity, iron-sulfur cluster assembly, and redox homeostasis. Protein-protein interaction and co-expression analyses identified HSPA9 and NFS1 as central hub genes associated with mitochondrial stress adaptation and ferroptosis resistance. Survival and stage-specific analyses further supported their prognostic significance in CRC progression. Structural and pathogenicity analyses of prioritized nsSNPs demonstrated that NFS1 variants may disrupt catalytic stability and ligand interactions, whereas HSPA9 variants predominantly affected conformational flexibility and protein-protein interaction interfaces. Collectively, these findings highlight mitochondrial ferroptosis dysregulation as a key mechanistic feature of colorectal cancer and identify HSPA9 and NFS1 as potential biomarkers and therapeutic targets. This study provides a comprehensive systems-level framework for understanding mitochondrial ferroptosis regulation and its translational relevance in CRC.
Protein phosphatase 2A impairs cardiac uptake of glucose in the mammalian heart.
Hadova K, Gündel D, Knieß T … +4 more , Brust P, Klimas J, Neumann J, Gergs U
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42347877 · Publisher ↗
Protein phosphatase 2A (PP2A) accounts for approximately half of all serine/threonine phosphatase activity in the mammalian heart. We hypothesised that PP2A, through dephosphorylation of key regulatory enzymes, modulates...
Protein phosphatase 2A (PP2A) accounts for approximately half of all serine/threonine phosphatase activity in the mammalian heart. We hypothesised that PP2A, through dephosphorylation of key regulatory enzymes, modulates cardiac glucose uptake and metabolism in vivo. Using positron emission tomography (PET), we studied the uptake of 2-[F]fluoro-2-deoxy-D-glucose ([F]FDG) in living mice with cardiac-specific overexpression of the catalytic subunit of PP2A (PP2A-TG) as well as in littermate controls (wild-type, WT). Additionally, we analysed the expression of enzymes and transcription factors involved in cardiac glucose metabolism. Cardiac glucose consumption was reduced by 41% (P < 0.05) in PP2A-TG mice relative to WT. Real-time quantitative polymerase chain reaction analysis revealed decreased gene expression of glycogen synthase 1 (- 26%, P < 0.05), glycogen phosphorylase (- 17%, P < 0.05), Mtor (-22%, P < 0.05), peroxisome proliferator-activated receptor gamma (Pparg), and its coactivator PGC-1α (-41% and - 28% respectively; both P < 0.05) in PP2A-TG hearts. Western blotting demonstrated increased protein expression of phosphoinositide 3-kinase (PI3K, 26%, P < 0.05), reduced expression of glycogen synthase (-34%, P < 0.05) and glycogen phosphorylase (-18%, P < 0.05), and enhanced phosphorylation of AKT (95%, P < 0.05) and glycogen synthase kinase-3β (GSK3β, 22%, P < 0.05) in PP2A-TG hearts. These findings indicate that PP2A impairs cardiac glucose metabolism in vivo through modulation of multiple components of glucose handling, including the PI3K/AKT signalling axis, glycogen metabolism, and PPARγ-dependent transcriptional regulation. The effects of PP2A appear to be predominantly indirect. Elevated PP2A expression may therefore be detrimental in heart failure by compromising myocardial energy production.
Integrated phenotypic-genotypic characterization of antimicrobial resistance in uropathogens: implications for targeted therapy in a North Indian cohort.
Mir TA, Shareef T, Lone SA … +3 more , Mir SA, Ahmad J, Ganai BA
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42347876 · Publisher ↗
Urinary tract infections (UTIs) are among the most common bacterial infections globally, increasingly driven by the continous emergence of multidrug-resistant (MDR) uropathogens that complicate empirical therapy. This st...
Urinary tract infections (UTIs) are among the most common bacterial infections globally, increasingly driven by the continous emergence of multidrug-resistant (MDR) uropathogens that complicate empirical therapy. This study employed an integrated phenotypic-genotypic approach to characterize antimicrobial resistance patterns and their therapeutic implications in a high-burden North Indian cohort. A prospective study was conducted from June 2024 to November 2025, including 1140 patients with suspected UTIs. Bacterial isolates were identified from patients with significant bacteriuria using biochemical characterization and 16S rRNA gene sequencing; and antimicrobial susceptibility testing of the isolates was performed according to CLSI 2024 guidelines. Molecular detection of key resistance and virulence determinants was carried out using PCR, and genotype-phenotype concordance was evaluated. Of 1140 samples, 354 showed bacterial growth, with a predominance in females (71.5%). Gram-negative pathogens constituted 68% of the isolates, dominated by Escherichia coli (46%), followed by Klebsiella pneumoniae and Pseudomonas aeruginosa. High resistance to first-line agents, including fluoroquinolones, β-lactams, and co-trimoxazole, was observed, whereas therapeutic efficacy was largely restricted to last-resort agents such as amikacin, fosfomycin, and polymyxin B. Among Gram-positive isolates, linezolid and vancomycin were found to be effective. Molecular analysis revealed a high prevalence of resistance genes, including that of blaCTX-M (in 42.4%), blaTEM (in 39.5%), and carbapenemase gene blaOXA-48 (in 25.4%) of the isolates, indicating widespread ESBL and emerging carbapenemase-mediated resistance. Addationally, aac(6')-Ib (56.5%) and fimH (66%) were also among the most frequently detected genes. Significant genotype-phenotype concordance (p < 0.05) supports the reliability of integrated profiling. These findings highlight the pharmacological challenges posed by MDR uropathogens and underscore the need to incorporate molecular diagnostics into routine workflows to enable precision therapy and strengthen antimicrobial stewardship strategies.
β-caryophyllene attenuates lead acetate-induced hepatotoxicity through regulation of oxidative stress, inflammation, and PI3K/AKT/mTOR signaling.
Manavoğlu Kirman E, Bolat İ, Karaarslan T … +2 more , Tekin S, Atasever A
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42347875 · Publisher ↗
Lead acetate (PbAc) is an environmental toxicant known to induce liver injury through oxidative stress, inflammation, and apoptosis. This study aimed to investigate the potential hepatoprotective effects of β-caryophylle...
Lead acetate (PbAc) is an environmental toxicant known to induce liver injury through oxidative stress, inflammation, and apoptosis. This study aimed to investigate the potential hepatoprotective effects of β-caryophyllene (BCP), a natural sesquiterpene with antioxidant and anti-inflammatory properties, against PbAc-induced hepatotoxicity and to explore the underlying molecular mechanisms. Sixty male Sprague-Dawley rats were randomly assigned to five groups: control, BCP200, PbAc, PbAc + BCP100, and PbAc + BCP200. PbAc was used to induce hepatotoxicity, while BCP was administered at doses of 100 and 200 mg/kg. Serum liver enzymes (ALT, AST, ALP, and GGT), oxidative stress parameters (MDA, SOD, and GSH), and inflammatory cytokines (TNF-α, IL-1β, and IL-6) were evaluated. Immunohistochemical and immunofluorescence analyses were performed to assess Nrf2, HO-1, Sirt1, Keap1, and 8-OHdG expression. In addition, the mRNA expression of PI3K, AKT, mTOR, Bax, Bcl-2, and Caspase-3 was determined by qRT-PCR, and histopathological examinations of liver tissue were conducted. PbAc exposure significantly increased serum liver enzyme levels, lipid peroxidation, and pro-inflammatory cytokines while reducing antioxidant defense markers. It also suppressed Nrf2/HO-1 signaling and PI3K/AKT/mTOR gene expression, accompanied by increased Bax and Caspase-3 and decreased Bcl-2 expression, indicating enhanced apoptosis. Histopathological analysis confirmed severe hepatic degeneration and necrosis. BCP treatment significantly attenuated these alterations by reducing oxidative stress and inflammatory responses, restoring Nrf2/HO-1 signaling, improving PI3K/AKT/mTOR pathway activity, and regulating apoptosis-related gene expression. These findings suggest that β-caryophyllene may exert protective effects against PbAc-induced hepatotoxicity through modulation of oxidative stress, inflammation, cell survival signaling, and apoptosis pathways, highlighting its potential as a supportive therapeutic candidate for heavy metal-induced liver injury.
Quercetin derivatives from Camellia sinensis for the discovery of anticancer compound against P-glycoprotein-mediated multidrug resistance: a computational approach.
Mishra SK, Alfuhayr T, Subba A … +5 more , Siddiquee NH, Sourav SH, Hani U, Zaki MEA, Georrge JJ
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42347874 · Publisher ↗
Cancer is an ongoing severe health complication and public health concern. Efforts have been made to overcome this; however, the emergence of multidrug resistance (MDR) remains a major hurdle for available therapies, lim...
Cancer is an ongoing severe health complication and public health concern. Efforts have been made to overcome this; however, the emergence of multidrug resistance (MDR) remains a major hurdle for available therapies, limiting their effectiveness. Therefore, in this study, an AI-integrated computational framework was employed to identify a promising compound from Camellia sinensis targeting P-glycoprotein and enhance its binding affinity based on dynamic insights. Camellia sinensis, also known as green tea, is one of the well-known plants for its anticancer properties. A total of 209 compounds from Camellia sinensis were curated and screened, of which 32 compounds were prioritized based on the drug-likeness screening and selected for molecular docking analysis. Among the screened compounds, quercetin exhibited the highest docking score toward P-glycoprotein, with a docking score of - 7.751 kcal/mol. Subsequently, quercetin was further optimized and enhanced through the AI-based approach, resulting in five derivatives, among which Q5 was found to be most suitable and had the enhanced docking score compared to the parent compound, i.e., - 7.832 kcal/mol. The ADME analysis of both compounds was performed, and the AI-derived lead showed more promising drug-like properties than quercetin. Additionally, the molecular dynamics simulation was performed for 500 ns, along with post-simulation analysis, including RMSD, RMSF, PCA, and MMGBSA. The analysis demonstrated the minimal RMSD fluctuations and maintained conformational integrity, along with retention of binding stability with a moderate redistribution throughout the simulation period, showing the complex's reliable stability. Additionally, the DFT analysis was accomplished to examine the electronic properties of the AI-derived lead (Q5). Collectively, based on the computational analysis, the study demonstrates that the AI-enhanced quercetin derivative, Q5, is promising and can serve as a potential lead compound. However, the experimental evaluation is required to ensure the efficacy and safety of the AI-enhanced lead.
Targeting NOX4 with Quercetagetin-PLGA nanomaterials: a novel therapeutic strategy for Alzheimer's disease.
Jiang Z, Zhang J, Zhang X … +6 more , Xie C, Chen X, Ma G, Lu X, Ai Y, Jia T
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42343047 · Publisher ↗
This study aims to address NOX4 (NADPH oxidase 4)-driven oxidative injury in Alzheimer's disease (AD) and the poor bioavailability of the natural flavonoid Quercetagetin, we developed an α7 nicotinic acetylcholine recept...
This study aims to address NOX4 (NADPH oxidase 4)-driven oxidative injury in Alzheimer's disease (AD) and the poor bioavailability of the natural flavonoid Quercetagetin, we developed an α7 nicotinic acetylcholine receptor (α7-nAChR)-targeted, Quercetagetin-loaded PLGA nanocarrier (PLGA@Quercetagetin@α7-nAChR) for receptor-mediated delivery, NOX4 suppression, and neuroprotection. Using the GSE97760 dataset, bioinformatic screening combined with LASSO regression was performed to identify candidate targets. Single-cell RNA sequencing (scRNA-seq) with pseudotime analysis was applied to delineate cell type-resolved and trajectory-associated expression patterns. Nanoparticles were fabricated by a double-emulsion method and characterized for physicochemical properties. In an Aβ-induced HT-22 neuronal injury model, genetic perturbation, western blotting, and flow cytometry were used to validate the pathogenic role of NOX4 and to evaluate the pharmacological efficacy of the nanoplatform. NOX4 emerged as the key gene, showing enriched expression in oligodendrocytes and endothelial cells and an increase along the inferred disease-associated trajectory. In vitro, Aβ stimulation upregulated NOX4, whereas NOX4 knockdown or Quercetagetin treatment alleviated Aβ-induced cytotoxicity and apoptosis. The nanoparticles exhibited an average diameter and sustained drug release over 72 h. α7-nAChR targeting enhanced neuronal uptake by ~ fivefold, markedly reduced NOX4 mRNA levels, and decreased the apoptotic rate from 18.3% to 5.0%. Notably, encapsulation also mitigated the hepatorenal toxicity observed with high-dose free Quercetagetin. These in vitro findings suggest NOX4 as a potential target in AD, and the PLGA@Quercetagetin@α7-nAChR nanoplatform shows improved cellular uptake and reduced short-term toxicity compared to free drug. However, claims regarding brain targeting and translational potential are limited by the absence of in vivo validation, non-targeted controls, drug exposure normalization, and key formulation parameters (e.g., encapsulation efficiency). Future in vivo studies are required to substantiate this targeted strategy for AD.
Bridging evidence and practice in heart failure care: barriers and pragmatic solutions to guideline-directed medical therapy implementation in India and other low-resource settings.
Maryam
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42343046 · Publisher ↗
Heart failure with reduced ejection fraction (HFrEF) remains a leading cause of morbidity, hospitalization, and mortality in low- and middle-income countries (LMICs). Guideline-directed medical therapy (GDMT) including a...
Heart failure with reduced ejection fraction (HFrEF) remains a leading cause of morbidity, hospitalization, and mortality in low- and middle-income countries (LMICs). Guideline-directed medical therapy (GDMT) including angiotensin receptor-neprilysin inhibitors (ARNIs), evidence-based beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose co-transporter 2 (SGLT2) inhibitors has consistently demonstrated reductions in mortality and heart failure (HF) hospitalizations. Despite strong evidence, real-world implementation of GDMT in LMICs remains suboptimal. This article synthesizes published evidence and expert experience to identify barriers to GDMT implementation in India and comparable LMIC settings and to propose pragmatic, resource-aligned strategies to improve uptake. Relevant English-language literature (2015-2025) was identified through PubMed, Google Scholar, and guideline repositories (ESC, ACC/AHA/HFSA, CSI). Search terms included "heart failure," "GDMT," "LMIC," "India," "implementation barriers," and "pharmacist-led care." Key guidelines, randomized trials, observational studies, registries, and relevant reviews were included. Barriers span economic constraints, limited insurance coverage, high out-of-pocket costs, low health literacy, cultural beliefs, fragmented follow-up, limited access to specialized HF services, inconsistent drug availability, and clinician-level knowledge-practice gaps. Evidence from observational studies and implementation reports supports early low-dose combination GDMT, simplified titration pathways, pharmacist- and nurse-led follow-up models, task-shifting, and telemedicine-enabled monitoring as feasible strategies in LMIC settings. Bridging the evidence-practice gap for GDMT in LMICs requires coordinated, multi-level interventions tailored to resource constraints. Strengthening team-based care and aligning policy with essential HF therapies can substantially improve outcomes and equity.
Timing and severity of acute kidney injury in hospitalized adults receiving vancomycin plus NKCC inhibitor with or without piperacillin-tazobactam.
Ishaqui AA, Tripathi R, Tripathi P … +3 more , Alqahtani SS, Makeen HA, Orayj K
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42343045 · Publisher ↗
Acute kidney injury (AKI) is a common and clinically important complication in hospitalized adults receiving nephrotoxic therapies. This study aimed to compare the incidence, timing, and severity of creatinine-defined AK...
Acute kidney injury (AKI) is a common and clinically important complication in hospitalized adults receiving nephrotoxic therapies. This study aimed to compare the incidence, timing, and severity of creatinine-defined AKI in patients receiving vancomycin plus Na-K-2Cl cotransporter (NKCC) inhibitor only vs vancomycin plus NKCC inhibitor plus piperacillin-tazobactam. A retrospective observational cohort study was performed using MIMIC-IV version 3.1. Adult hospital admissions with qualifying exposure within the first 48 h of hospitalization were included. Group A comprised patients receiving vancomycin plus NKCC inhibitor only, and group B comprised patients receiving vancomycin plus NKCC inhibitor plus piperacillin-tazobactam. AKI was defined using KDIGO serum creatinine criteria. Multivariable logistic regression was used to evaluate any AKI, early AKI, and stage 2-3 AKI after adjustment for baseline renal risk and illness severity. The final analytic cohort included 5204 hospitalizations, with 4632 in group A and 572 in group B. Any AKI occurred in 28.0% of group A and 29.2% of group B, early AKI in 23.1% and 24.8%, and stage 2-3 AKI in 9.3% and 12.8%, respectively. Median time to AKI was similar at approximately 21.7 h in both groups. After adjustment, group B was not independently associated with any AKI (OR = 1.034), early AKI (OR = 1.115), or stage 2-3 AKI (OR = 1.107). Higher baseline creatinine, chronic kidney disease, mechanical ventilation, hypotension, liver disease, and sepsis were stronger predictors of renal outcomes. In hospitalized adults already receiving vancomycin and NKCC inhibitors, addition of piperacillin-tazobactam was not independently associated with higher odds of creatinine-defined AKI after adjustment. The observed crude excess in severe AKI and worse hospital outcomes appeared to reflect a sicker clinical phenotype rather than a clear independent nephrotoxic effect.
Revisiting endometriosis management: Polyphenols as alternative therapeutic candidates.
Pant A, Moar K, Hooda R … +1 more , Maurya PK
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42340393 · Publisher ↗
Endometriosis (EM) is a common gynecological disorder imposing a considerable burden on the quality of life of women through chronic pain, infertility, and other clinical manifestations. The effectiveness of management o...
Endometriosis (EM) is a common gynecological disorder imposing a considerable burden on the quality of life of women through chronic pain, infertility, and other clinical manifestations. The effectiveness of management options for EM is limited by substantial side effects associated with current treatment options, including hormonal therapies and surgery, increasing the need for an alternative approach associated with fewer adverse effects. Polyphenols, a wide class of naturally occurring bioactive compounds, have generated considerable attention due to their antioxidant, anti-inflammatory, and anti-proliferative properties. This structured narrative review highlights the therapeutic potential of polyphenols, focusing on their ethnopharmacological relevance and providing valuable insights into these natural compounds to be used as an alternative therapeutic approach for managing endometriosis. A comprehensive literature search was conducted across databases, including PubMed, Web of Science, and Scopus, with studies on polyphenol interventions in EM models. Data were analyzed for mechanisms such as antioxidant, anti-proliferative, anti-inflammatory, apoptotic effects, and others associated with endometriosis pathology. The existing evidence indicates that polyphenols can mitigate endometriosis-related outcomes, including inflammation, pain, lesion growth, and invasion in experimental models of endometriosis. However, the majority of the evidence available comes from rodent models, high-dose in vitro research, and immortalized cell lines, all of which have significant translational constraints and might not accurately represent the complexity of human disease. Additionally, there are very few clinical trials assessing the safety and effectiveness of polyphenols in endometriosis patients. In our opinion, polyphenols hold significant promise as adjunct therapies for EM. However, further large-scale clinical trials are essential to validate efficacy, optimize dosing, and establish safety profiles in diverse patient populations.
Retraction Note: UBE2D3 regulated by WTAP-mediated m6A modification inhibits temozolomide chemosensitivity in glioblastoma.
Bao J, Sun R, Pan Z … +1 more , Wei S
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42337166 · Publisher ↗
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Potential targets of baicalein in macrophages revealed by bulk and single cell RNA sequencing analysis.
Li P, Hu J, Zhang Y … +1 more , Bai X
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42337165 · Publisher ↗
Excessive inflammation drives organ dysfunction and high mortality in life-threatening conditions such as sepsis. Baicalein, a bioactive flavonoid, possesses well-recognized anti-inflammatory properties, yet its molecula...
Excessive inflammation drives organ dysfunction and high mortality in life-threatening conditions such as sepsis. Baicalein, a bioactive flavonoid, possesses well-recognized anti-inflammatory properties, yet its molecular targets in macrophages and potential systemic immunomodulatory effects on peripheral blood immune cells under hyperinflammatory conditions remain poorly characterized. Our previous studies demonstrated that baicalein alleviates hepatic inflammation in mice with non-alcoholic fatty liver disease (NAFLD) and inhibits NF-κB nuclear translocation in RAW264.7 macrophages. Here, by integrating network pharmacology, molecular docking, bulk RNA sequencing of macrophages, and single-cell RNA sequencing of peripheral blood from sepsis patients, we identified JAK2, SRC, TP53, MAPK3, AKT1, HSP90AA1, and ESR1 as potential core targets of baicalein in macrophages, and validated that the JAK2-STAT3 and NF-κB pathways might be the key downstream regulatory axes of its anti-inflammatory effects. Furthermore, we revealed that baicalein may modulate, based on single-cell expression signatures, the inflammatory phenotype of multiple peripheral blood immune cell populations, including monocytes, T cells, B cells, and granulocyte-monocyte progenitors, suggesting a potential systemic anti-inflammatory effect that requires experimental validation in human cells. Collectively, our findings elucidate the potential molecular targets of baicalein in macrophages and its multi-cellular immunoregulatory mechanisms under hyperinflammation, providing novel mechanistic insights for the clinical application of baicalein in inflammatory diseases.
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