Naunyn Schmiedebergs Arch. Pharmacol. [JOURNAL]
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200 papers
Parthenolide accelerates diabetic wound healing through the STAT3 and TNF-α/NF-kappaB pathways.
Song D, Zeng Z, Tang H … +5 more , Chen K, Li J, Liang Y, Lei X, Liu H
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42337164 · Publisher ↗
Diabetic wounds, a common complication of diabetes, can elicit intricate inflammatory responses and progressive tissue damage without proper treatment. Parthenolide (PTL), a natural compound isolated from the medicinal p...
Diabetic wounds, a common complication of diabetes, can elicit intricate inflammatory responses and progressive tissue damage without proper treatment. Parthenolide (PTL), a natural compound isolated from the medicinal plant feverfew (Tanacetum balsamita), possesses antitumor, anti-inflammatory, and antioxidant properties. This study seeks to elucidate the molecular mechanisms by which PTL promotes diabetic wound healing. Using network pharmacology and molecular docking, we identified TNF-α and STAT3 as potential targets of PTL. In diabetic mouse models, PTL promoted wound healing with a distinct dose-dependent effect. Both 100 µM and 200 µM PTL significantly accelerated mouse wound repair, while 50 µM PTL failed to exert stable therapeutic effects, likely due to insufficient concentration. Histological and immunological staining assays confirmed that PTL promoted wound healing by enhancing keratinocyte proliferation, angiogenesis, and the conversion of macrophages to the M2 type. Furthermore, in vitro experiments were carried out by stimulating RAW264.7 macrophages with LPS. Through CCK-8 assays, immunofluorescence staining, and Western blotting, we further demonstrated that PTL might modulate the STAT3 and TNF-α/NF-κB signalling pathways, as well as regulate phenotypic switching of macrophages in the inflammatory microenvironment. Collectively, PTL promotes wound healing in diabetic conditions, a mechanism that may be mediated by the regulation of the STAT3 and TNF-α/NF-κB signalling pathways and the facilitation of macrophage phenotypic switching to the M2 phenotype to modulate wound-site inflammatory responses. Thus, PTL emerges as a potential therapeutic candidate for improving the healing of diabetic wounds.
Protective effects of selenium and vitamin E supplementation on eryptosis, oxidative stress, and inflammation in end-stage renal disease patients.
Sharafi M, Dehghan G, Khosroshahi HT … +1 more , Majidi H
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42334563 · Publisher ↗
End-stage renal disease (ESRD) involves chronic microinflammation, oxidative stress, and increased red blood cell (RBC) destruction. This study examined their effects on erythrocyte integrity and oxidative stress in ESRD...
End-stage renal disease (ESRD) involves chronic microinflammation, oxidative stress, and increased red blood cell (RBC) destruction. This study examined their effects on erythrocyte integrity and oxidative stress in ESRD patients. Seventy ESRD patients were enrolled and received selenium (200 µg) and vitamin E (400 units) supplementation for 60 days. Phosphatidylserine exposure on RBCs was assessed to evaluate eryptosis. Serum levels of malondialdehyde (MDA), glutathione peroxidase (GPx) activity, ferritin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and iron (Fe) were measured. Statistical analyses were performed using a paired t-test or Wilcoxon signed-rank tests, as appropriate. The findings demonstrated that supplementation was associated with reductions in serum MDA (95% CI 0.89 to 1.05; P < 0.001), ferritin (95% CI 146.58 to 292.01; P < 0.001), IL-6 (95% CI 4.09 to 5.58; P < 0.001), and TNF-α levels (95% CI 9.20 to 10.64; P < 0.001), while increasing GPx activity (95% CI -5.04 to -3.86; P < 0.001). Numerical improvements were noted in RBC count, hemoglobin concentration, erythrocyte stability, and annexin V-positive erythrocytes; however, these changes were not statistically significant and should be considered exploratory. The results indicated that the tested supplements may reduce oxidative stress and inflammation in ESRD patients; however, the erythrocyte-related observations are preliminary and require validation in controlled studies.
Potential mechanism of Lactiflorin in treating ulcerative colitis via modulation of the PI3K/AKT pathway: a study integrating network analysis, bioinformatics analysis, and experimental evidence.
Zhang M, Li H, Yan N … +5 more , Meng M, Su X, Liu Y, Chen R, Yang J
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42331986 · Publisher ↗
This study is aimed at investigating the therapeutic effects and the relevant mechanisms of Lactiflorin in ulcerative colitis (UC) via a combination of various methodologies. The PI3K/AKT pathway identified through netwo...
This study is aimed at investigating the therapeutic effects and the relevant mechanisms of Lactiflorin in ulcerative colitis (UC) via a combination of various methodologies. The PI3K/AKT pathway identified through network pharmacology, and key pathways and therapeutic effects were validated by animal experiments, molecular docking, and molecular dynamics simulations. The experimental verification was performed using an acute colitis model induced by 2.5% dextran sulfate sodium. This study further explored whether the key bioactive components could improve intestinal barrier integrity and alleviate ulcerative colitis by inhibiting the PI3K/AKT signaling pathway. We performed hematoxylin and eosin staining, cytometric bead array, western blotting, and immunofluorescence. Network analysis identified 718 predicted drug targets, among which 264 were related to UC therapeutic targets. Animal experiments further confirmed the significant role of the key pathways and the effects of the pharmacological intervention. Molecular docking and dynamics simulations demonstrated Lactiflorin with a strong binding affinity to STAT3 (- 11.24 kcal/mol), AKT1 (- 15.61 kcal/mol), and PIK3R1 (- 11.95 kcal/mol). In vivo experiments, Lactiflorin improved the Disease Activity Index score and histopathological score in UC-modelled mice and suppressed the expression of pro-inflammatory cytokines including IL‑23, IL‑12p70, IL‑17A, and IL‑1α. Western blot and immunofluorescence results revealed that Lactiflorin inhibited the expression of AKT, STAT3, and PI3K proteins (P < 0.01). These findings suggest that Lactiflorin exerts potential therapeutic effects against UC through PI3K/AKT pathway.
Synergistic targeting of NF-κB by cinnamic and p-coumaric acids: computational and DPPH radical scavenging assessment.
Gajbe JW, Madgulkar AR, Bhalekar MR … +3 more , Tawari SA, Chaudhari SY, Shingan AV
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42331985 · Publisher ↗
Nuclear factor-kappa B (NF-κB) is a key transcription factor implicated in inflammation, immune regulation, and cancer progression, making it an important target for antioxidant and anti-inflammatory therapy for acne. Th...
Nuclear factor-kappa B (NF-κB) is a key transcription factor implicated in inflammation, immune regulation, and cancer progression, making it an important target for antioxidant and anti-inflammatory therapy for acne. The present study evaluated the synergistic NF-κB inhibitory potential of cinnamic acid and p-coumaric acid (p-CA) through molecular docking analysis, followed by formulation development and antioxidant assessment. Molecular docking was performed using AutoDock Vina v1.2.6 to investigate binding affinity and interaction profiles. Individual formulations containing cinnamic acid (1%) and p-CA (1%), as well as an equimolar combined formulation (0.5% each), were developed using hydrogel and oleogel phases to obtain a bigel system. Antioxidant activity was determined using the DPPH radical scavenging assay. Docking studies demonstrated binding energies of - 4.046 kcal/mol and - 4.400 kcal/mol for cinnamic acid and p-CA, respectively, whereas the combined ligand complex exhibited an enhanced binding affinity of - 7.837 kcal/mol. The improved interaction was stabilized through hydrogen bonding and hydrophobic interactions involving key amino acid residues, including ARG54, LEU251, GLU341, and THR342. In the antioxidant assay at 250 μg/mL, p-CA and cinnamic acid exhibited 16.76% and 14.02% inhibition, respectively, IC50 value of the cinnamic acid, p-coumaric acid and combined was found to be 750 µg/mL, 1160 µg/ mL, 810 µg/mL, while the equimolar bigel formulation demonstrated significantly higher radical scavenging activity (19.95%-28.55%), suggesting a synergistic effect. This research indicates that the combination of cinnamic acid and p-CA enhances molecular interactions with the NF-κB p50 subunit and improves antioxidant activity compared with the individual compounds. These integrated in silico and experimental results support the potential application of this combination in the development of multi-targeted natural formulations.
An Italian regional analysis on chronic obstructive pulmonary disease (COPD): correct diagnosis and lifestyle play a fundamental role in supporting drug therapy and containing healthcare costs.
Ferrara F, De Berardinis F, Scognamiglio M … +1 more , Zovi A
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42331984 · Publisher ↗
Chronic obstructive pulmonary disease (COPD) represents a major global health burden, largely attributable to tobacco exposure, including emerging patterns such as early initiation and dual use with electronic cigarettes...
Chronic obstructive pulmonary disease (COPD) represents a major global health burden, largely attributable to tobacco exposure, including emerging patterns such as early initiation and dual use with electronic cigarettes. Early detection through spirometry in primary care remains suboptimal, potentially limiting timely identification of early disease stages, including Pre-COPD and Preserved Ratio Impaired Spirometry (PRISm). This study aimed to assess whether the implementation of a structured, spirometry-based COPD clinic within primary care networks (Aggregazioni Funzionali Territoriali, AFTs) may be associated with improved diagnostic appropriateness, more consistent therapeutic management, and more efficient use of healthcare resources. We conducted a retrospective observational analysis of routinely collected clinical data from approximately 30,000 patients across three AFTs in the Campania Region (Italy), each including about 10,000 individuals. One AFT was equipped with a dedicated respiratory clinic providing in-house spirometry performed by trained personnel, while the other two followed standard care pathways without structured respiratory services. Key variables included spirometry utilization, diagnostic confirmation of COPD, patterns of care, and selected indicators of healthcare use. In the two standard AFTs, COPD diagnoses were not supported by spirometric confirmation in approximately 65% and 70% of cases, respectively. In contrast, the AFT with a dedicated clinic showed a substantially higher use of spirometry (approximately 80% vs. 30-35%), predominantly performed within the primary care setting. This organizational model was associated with improved alignment between diagnosis and objective testing, and with indicators suggestive of better therapeutic adherence and more appropriate use of secondary care services. The integration of structured, spirometry-enabled respiratory services within primary care networks may contribute to more appropriate COPD diagnosis and management. While the availability of spirometry alone is insufficient, organizational models that incorporate trained personnel, standardized procedures, and coordinated care pathways could represent a potentially effective approach to addressing under- and misdiagnosis in COPD.
From network prediction to in vivo validation: luteolin attenuates cholestatic liver injury in association with PI3K/Akt/GSK-3β signalling modulation.
Wu Y, Gong S, Wu X … +3 more , Wang W, Zhang D, Jia J
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42331983 · Publisher ↗
Cholestatic liver disease (CLD) is characterized by inflammatory amplification, hepatic stellate cell activation and collagen deposition. Luteolin is a natural flavonoid with reported anti-inflammatory and anti-fibrotic...
Cholestatic liver disease (CLD) is characterized by inflammatory amplification, hepatic stellate cell activation and collagen deposition. Luteolin is a natural flavonoid with reported anti-inflammatory and anti-fibrotic activities. Here, network pharmacology, molecular docking and experimental analyses were integrated to examine the effects of luteolin in CLD, with a focus on PI3K/Akt/GSK-3β-associated signalling. Target prediction identified 181 putative luteolin targets and 4,403 CLD-related targets, with 88 overlapping genes. In a bile duct ligation (BDL) rat model, luteolin treatment was associated with lower serum injury indices, reduced histopathological damage, decreased collagen deposition and lower fibrosis-related readouts. Experimental analyses further showed that luteolin treatment was accompanied by lower phosphorylation-associated readouts along the PI3K/Akt/GSK-3β axis. Together, these findings support an association between luteolin treatment and attenuation of cholestatic liver injury and fibrosis, within a multi-target signalling context that includes PI3K/Akt/GSK-3β.
Integrated bioinformatics, single-cell analysis, and experimental validation identify quercetin as a potential therapeutic candidate for intervertebral disc degeneration.
Zhang F, Yang Y, Gou X … +4 more , Yuan X, Zhu N, Yin M, He H
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42329412 · Publisher ↗
Intervertebral disc degeneration (IVDD) is a major pathological basis of low back pain, but its molecular mechanisms remain incompletely understood. Identifying key genes and potential therapeutic compounds may provide n...
Intervertebral disc degeneration (IVDD) is a major pathological basis of low back pain, but its molecular mechanisms remain incompletely understood. Identifying key genes and potential therapeutic compounds may provide new insights into the progression and treatment of IVDD. The GSE70362 bulk transcriptomic dataset was analyzed to identify 352 differentially expressed genes between IVDD and control nucleus pulposus samples. These DEGs were integrated with WGCNA, PPI network analysis, and LASSO regression to screen candidate hub genes, including ZEB2, COL6A2, CCND1, RAP1A, and GATA3. Functional enrichment, immune infiltration, and single-cell RNA-seq analyses were performed to characterize their biological relevance. Quercetin was selected as a candidate compound for molecular docking prediction and in vitro validation in LPS-induced nucleus pulposus cells. A total of 352 differentially expressed genes were identified, including 142 upregulated and 210 downregulated genes in IVDD samples. WGCNA identified five IVDD-related modules containing 454 genes, and 154 overlapping genes were obtained after intersection with differentially expressed genes. Further screening identified five hub genes: ZEB2, COL6A2, CCND1, RAP1A, and GATA3. Functional enrichment analysis indicated that these genes were mainly associated with cellular stress responses, extracellular matrix remodeling, cellular senescence, p53 signaling, focal adhesion, Rap1 signaling, and inflammatory pathways. Immune infiltration analysis showed decreased Tr1 and Th2 cells and increased macrophage infiltration in IVDD samples. Single-cell analysis revealed marked heterogeneity among nucleus pulposus cells and demonstrated that several hub genes were distributed across distinct degenerative cell states. Molecular docking provided preliminary computational evidence that quercetin may have potential binding affinities with the five hub proteins. In vitro experiments further showed that quercetin improved cell viability, reduced LPS-induced cell injury, reversed the abnormal expression of ZEB2, CCND1, RAP1A, GATA3, and partially restored COL6A2 expression. This study identified ZEB2, COL6A2, CCND1, RAP1A, and GATA3 as potential hub genes involved in IVDD progression. The integrated bioinformatics, single-cell, molecular docking, and experimental results suggest that quercetin may exert protective effects against IVDD-like nucleus pulposus cell injury, accompanied by partial reversal of abnormal hub gene expression and improvement of cell survival. These findings provide a potential molecular basis for further investigation of quercetin as a candidate therapeutic agent for IVDD.
Acute and sub-acute toxicity assessment of tetrodotoxin in Sprague-Dawley rats following intramuscular injection.
Ren L, Zhou K, Xuan H … +11 more , Zhao X, Li L, Sun C, Zhang J, Tian Y, Li J, Dai X, Mao J, Yan L, Chen J, Zhu J
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42329411 · Publisher ↗
Tetrodotoxin (TTX) is a potent neurotoxin with therapeutic potential, particularly in the fields of analgesia, cancer pain treatment, and drug addiction therapy. However, its high toxicity and lack of antidotes limit its...
Tetrodotoxin (TTX) is a potent neurotoxin with therapeutic potential, particularly in the fields of analgesia, cancer pain treatment, and drug addiction therapy. However, its high toxicity and lack of antidotes limit its clinical application. This study evaluated the acute toxicity and sub-acute toxicity of TTX via intramuscular injection in Sprague-Dawley (SD) rats. The acute toxicity test employed the Bliss method to determine the median lethal dose (LD), with 10 rats per group (sex-balanced). Rats received a single intramuscular injection at doses of 8.2-20.0 μg/kg. The sub-acute toxicity study was conducted through daily intramuscular injections at doses of 1.5, 3.0, and 6.0 μg/kg/day for 28 consecutive days. Parameters, including body weight, food consumption, hematology, serum biochemistry, urinalysis, and histopathology, were assessed. Acute toxicity was characterized by squinting, reduced spontaneous activity, convulsions, hind limb rigidity, limb weakness, and mortality. In the sub-acute toxicity study, no toxicity-related changes associated with TTX treatment were observed in any dose group compared to controls, including in food consumption, hematology, urinalysis, and histopathological examination. Although statistically significant differences in body weight, serum biochemical, and organ weights were noted at certain time points in individual dose groups, these were not dose-dependent and were of minimal magnitude. The LD of TTX administered via a single intramuscular injection in SD rats was 13.1 μg/kg. In the sub-acute toxicity study, no adverse effects were observed up to the highest tested dose (6.0 μg/kg/day), which was therefore considered the no observed adverse effect level (NOAEL) under the conditions.
Ulcerative colitis: from molecular pathophysiology to management and the emerging role of natural and pharmacological drug candidates.
Sharata EE, Bakry T, Mohamed H … +5 more , Mohyeldin RH, Rofaeil RR, Hemeida RAM, Kotb ASM, Abdelnaser M
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42324373 · Publisher ↗
Ulcerative colitis (UC) is a chronic, relapsing, immune-mediated inflammatory disease of the colonic mucosa that imposes a substantial and growing global health burden. The pathophysiological basis of UC encompasses a mu...
Ulcerative colitis (UC) is a chronic, relapsing, immune-mediated inflammatory disease of the colonic mucosa that imposes a substantial and growing global health burden. The pathophysiological basis of UC encompasses a multifactorial interplay among genetic predisposition, dysregulated innate and adaptive immune responses, gut microbiome dysbiosis, epithelial barrier dysfunction, and environmental triggers. Despite considerable advances in therapeutic strategies over the past two decades ranging from aminosalicylates and corticosteroids to biologic agents targeting TNF-α, integrins, and the IL-12/23 axis, as well as small molecule modulators such as JAK inhibitors and sphingosine-1-phosphate receptor agonists-a substantial proportion of patients either fail to achieve remission or experience loss of response over time, underscoring the continued need for novel therapeutic approaches. This comprehensive review systematically addresses the definition, epidemiology, socioeconomic burden, and unmet clinical needs in UC. The molecular and cellular underpinnings of the disease are discussed in depth, including the roles of key signaling pathways, pattern recognition receptors, cytokine networks, and the gut-immune interface. Clinical features, diagnostic criteria, endoscopic and histological scoring systems, and validated disease activity indices are also described. Current pharmacological therapies are reviewed with regard to mechanisms of action, pivotal clinical trial data, and safety profiles. Emerging investigational strategies including precision biologic agents, next-generation small molecules, microbiome-based therapeutics, and cell and gene therapy approaches are evaluated within a translational framework. A curated synthesis of experimental models of UC induction in rodents is presented, followed by structured tabular summaries of selected naturally derived bioactive compounds and pharmacological drug candidates that have demonstrated protective efficacy in preclinical models of UC. Compounds were selected for tabular inclusion on the basis of three prespecified criteria: (i) availability of at least one peer-reviewed in vivo study conducted in a validated experimental colitis model (DSS, TNBS, and acetic acid); (ii) a clearly described and mechanistically plausible basis of action relevant to UC pathophysiology; and (iii) representation across the principal mechanistic clusters identified in this review. Application of these criteria to the studies included in the final review yielded 29 naturally derived bioactive compounds (Table 1) and 26 pharmacological drug candidates (Table 2) for structured synthesis.
MTA-NPs induce preferential cytotoxicity, oxidative DNA damage, and mitochondrial apoptosis in human Hep-G2 hepatocellular carcinoma cells.
Mohamed HRH, Diab SA, Mofadal JW … +6 more , Hamdy YW, Elnewihy BE, Haitham B, El-Sherif BMI, Diab A, Safwat G
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42324372 · Publisher ↗
Hepatocellular carcinoma is one of the most aggressive and fatal malignancies worldwide, and the limited efficacy and severe toxic side effects of conventional chemotherapy emphasize the urgent need for safer and more ef...
Hepatocellular carcinoma is one of the most aggressive and fatal malignancies worldwide, and the limited efficacy and severe toxic side effects of conventional chemotherapy emphasize the urgent need for safer and more effective therapeutic strategies. Nanotherapies have recently gained considerable attention due to their enhanced cellular uptake, improved bioavailability, and selective targeting of malignant cells. Although mineral trioxide aggregate nanoparticles (MTA-NPs) possess unique physicochemical and biological properties, their anticancer potential against hepatocellular carcinoma has not been fully explored. Accordingly, this study evaluated the cytotoxic activity and underlying molecular mechanisms of MTA-NPs in human hepatocellular carcinoma Hep-G2 cells, while simultaneously assessing their safety profile in normal human HFB4 melanocytes. The MTT assay results demonstrated that MTA-NPs exerted potent and selective cytotoxicity against Hep-G2 hepatocellular carcinoma cells, as demonstrated by a significant concentration-dependent decline in cancer cell viability and a markedly low IC50 value of 52.53 μg/ml. Conversely, exposure of normal HFB4 melanocytes to the same MTA-NPs concentrations resulted in only slight reductions in cell viability, primarily at the highest tested concentrations, with a substantially higher IC50 value of 239.30 μg/ml. These findings indicate the preferential anticancer activity of MTA-NPs toward Hep-G2 cells. Moreover, the calculated selectivity index of 4.55 further confirmed the selective cytotoxic potential of MTA-NPs against hepatocellular carcinoma Hep-G2 cells. Furthermore, exposure of Hep-G2 cancer cells to the IC50 concentration of MTA-NPs resulted in marked intracellular ROS overproduction, profound mitochondrial membrane depolarization, and severe genomic DNA damage, which collectively culminated in apoptotic cell death. qRT-PCR analysis further demonstrated significant downregulation of both the apoptotic p53 and mitochondrial ND3 gene expression levels, together with pronounced upregulation of the anti-apoptotic Bcl-2 gene. Collectively, these molecular alterations indicate the activation of a p53-independent mitochondria-mediated apoptotic pathway. In conclusion, MTA-NPs demonstrate potent and preferential anticancer activity against human hepatocellular carcinoma Hep-G2 cells by inducing ROS-mediated oxidative stress, genomic DNA instability, mitochondrial dysfunction, and p53-independent mitochondrial apoptosis. These findings highlight the promising therapeutic potential of MTA-NPs as a novel nanotherapeutic approach for hepatocellular carcinoma treatment. Nevertheless, additional in vitro and in vivo studies and comprehensive biosafety evaluations are still necessary prior to clinical application.
Promising natural agents in psychopharmacology described by Rhazes in Al-Hawi and Liber Almansoris: a ninth-century paradigm.
Ahansazan H, Ayati MH, Ince F … +1 more , Zargaran A
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42324371 · Publisher ↗
The synthesis of psychopharmaceuticals in the twentieth century marked the beginning of modern psychopharmacology, replacing earlier first-line psychiatric management that relied on psychosurgery, physical restraint, or...
The synthesis of psychopharmaceuticals in the twentieth century marked the beginning of modern psychopharmacology, replacing earlier first-line psychiatric management that relied on psychosurgery, physical restraint, or administering narcotics and sedatives, e.g., morphine and chloral, which suppressed psychotic outbreaks temporarily without addressing the origin. Chlorpromazine's effective management of psychosis in the early 1950s opened the door for non-surgical therapies, making psychopharmaceuticals the current first-line treatment. While modern psychopharmacology began in the 1950s, the history of psychopharmacology may extend back many years. The concept of treating patients by understanding the cause and healing the mind was also evident during the Islamic Golden Age (ninth to thirteenth century CE). One of the physicians in the field was Rhazes (865-925 CE), also known as Abu Bakr Muhammad ibn Zakariyya Al-Razi. Rhazes' contributions to both psychiatry and pharmacology make his work a subject for examining the roots of psychopharmacology. This study aims to explore Rhazes' pharmacological approaches for patients with mental illnesses, focusing on the conditions under which he prescribed herbs for neurological, psychological, and psychiatric issues. An analytical approach has been utilized to systematically extract data from Al-Hawi and Liber Almansoris concerning neurological, psychological, psychiatric, and behavioral conditions. For the next phase, another table was created to list each condition alongside its treatment and psychopharmacological classification based on the works of Rhazes. Based on the collected information from Rhazes' Al-Hawi and Liber Almansoris, each of the mentioned neurological, psychological, psychiatric, and behavioral conditions was categorized. Rhazes distinguished between different psychological conditions and avoided using a universal prescription. He also differentiated between conditions that necessitated pharmacological interventions and those that could be effectively addressed through lifestyle modifications, nutritional adjustments, or manual therapy (hands-on therapy techniques like massage for managing musculoskeletal problems). The current historical study indicates that the roots of psychopharmacology can be traced back to the ninth century, during which the physician Rhazes documented various psychological and psychiatric diseases in his works Al-Hawi and Liber Almansoris, along with their natural pharmacological treatments. This historical perspective can enhance our understanding of psychopharmacology and provide new insights for expanding the range of psychopharmacological agents. Clinical trial number: Not applicable.
Interplay between systemic immune-metabolic signatures and endometrial immune profiles in women with recurrent pregnancy loss.
Kamrani A, Pourvahdani S, Pirouzpanah M … +8 more , Salamati A, Hassanzadeh A, Baharaghdam S, Aghapour A, Mehdizadeh A, Akbari M, Heris JA, Yousefi M
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42324370 · Publisher ↗
Recurrent pregnancy loss (RPL) is a complex disorder fundamentally linked to immune dysregulation at the maternal-fetal interface. While endometrial immune profiling provides critical diagnostic insights for managing RPL...
Recurrent pregnancy loss (RPL) is a complex disorder fundamentally linked to immune dysregulation at the maternal-fetal interface. While endometrial immune profiling provides critical diagnostic insights for managing RPL, its clinical application is limited by the invasive nature of endometrial biopsies. This study aimed to identify non-invasive, serum-based immunological and metabolic markers that accurately reflect local endometrial immune profiles, facilitating a less-invasive risk assessment and patient categorization. The study enrolled 106 participants, including 81 women with RPL and 25 fertile controls. The specimens of endometrium by doing biopsy of IL-15/Fn-14, IL-18/TWEAK, and CD56 expression were analyzed to categorize patients as having balanced, highly dysregulated (over-activated) and lowly dysregulated immune profiles. For each patient, blood samples from the same time frame were processed for immune profile (Th1/Th2 ratio), non-specific immune cell populations (NK), a metabolic profile containing autoantibody levels, and a metabolic screening of adiponectin, prostaglandin E2 (PGE-2), insulin-like growth factor-1 (IGF-1), and total phospholipids. All control subjects exhibited a balanced endometrial immune profile. In contrast, approximately 71% of RPL patients demonstrated immune dysregulation, with 46.9% showing an over-activated profile and 24.7% a low-activated profile. Systemically, the high immune dysregulation group exhibited significantly elevated peripheral NK cell frequencies and Th1/Th2 ratios compared to the balanced group. Furthermore, this over-activated group demonstrated a substantially higher prevalence of serum autoantibodies. Metabolically, high immune dysregulation was associated with significantly decreased serum adiponectin and IGF-1 levels, alongside markedly elevated PGE-2 and total phospholipid concentrations. These findings suggest that systemic metabolic and immune biomarkers may potentially reflect local endometrial immune status in women with RPL. Although these serum markers demonstrate promise as minimally invasive tools for immune profiling, further large-scale validation and predictive studies are required before they can be introduced as reliable alternatives to endometrial biopsy in clinical practice.
Emerging role of plant-based compounds as ferroptosis modulators in breast cancer.
Pandey P, Mallick MN, Ali S … +5 more , Verma M, Lakhanpal S, Sharma S, Khan MM, Khan F
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42322357 · Publisher ↗
Ferroptosis is a specialized form of regulated cell death that is dependent on intracellular iron and is characterized by excessive lipid peroxidation, accumulation of lipid peroxides, and increased intracellular iron le...
Ferroptosis is a specialized form of regulated cell death that is dependent on intracellular iron and is characterized by excessive lipid peroxidation, accumulation of lipid peroxides, and increased intracellular iron levels. This process is regulated through complex and tightly coordinated molecular mechanisms involving multiple signaling pathways and regulatory proteins, including key antioxidant defense components such as glutathione peroxide 4 (GPX4) and ferroptosis suppressor protein-1 (FSP-1). Increasing experimental evidences suggested that modulation of ferroptosis pathway might offer a potent target for breast cancer management, as ferroptosis dysregulation has been strongly associated with tumor invasion, progression, and drug resistance. Current cancer treatment strategies including surgery, chemotherapy, radiation therapy have detrimental effects on cancer patients. Therefore, it is highly needed to focus on safe and effective therapeutics like natural compounds for cancer therapy. These compounds have shown the significance of ferroptosis-mediated cell death, thereby providing drug candidate for developing ferroptosis-inducing agents. Current research studies suggested that numerous plant-based compounds have strong anticancer potential via ferroptosis induction in breast carcinoma. However, these results are dependent upon preclinical experimentation and lacking validation of long-term clinical research. Thus, this review is designed to provide a mechanistic overview of plant-derived natural compounds by targeting ferroptosis pathway specifically in breast cancer. This could help the researchers working in medicinal chemistry field and pharmacology to better understand the mechanism of action of these compounds against breast carcinoma and provide an alternative approach to treat breast cancer.
Novel fenoterol derivatives as suppressors of ERK1/2 phosphorylation in melanoma.
Wójcik J, Wnorowska S, Miziewicz W … +7 more , Tassinari G, Misiurek G, Kostecki R, Małek A, Boguszewska-Czubara A, Wainer IW, Wnorowski A
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42322356 · Publisher ↗
Melanoma is a highly aggressive cancer with limited therapeutic options. In melanoma cell lines, βAR activation leads to the suppression of pro-proliferatory MAPK/ERK signaling. This suggests that fenoterol, a potent βAR...
Melanoma is a highly aggressive cancer with limited therapeutic options. In melanoma cell lines, βAR activation leads to the suppression of pro-proliferatory MAPK/ERK signaling. This suggests that fenoterol, a potent βAR agonist, can be useful in the treatment of melanoma. Here, we investigated the structure-activity relationship (SAR) of fenoterol derivatives for βAR-depedent ERK suppression. We used the UACC-647 human-derived melanoma cell line to screen a panel of chiral compounds based on the fenoterol scaffold. The levels of phosphoactive ERK1/2 were quantified by immunoblotting. Anti-tumorigenic activity of the drugs was assessed using MTS assay and zebrafish xenograft model. (R,R') stereoisomers of fenoterol derivatives exhibited the highest suppression of ERK phosphorylation, followed by (R,S') and (S,R') isomers, with (S,S') isomers being the least active, mirroring trends observed in βAR binding and cAMP accumulation. SAR analysis revealed that modifications to the α' alkyl chain and the 4'-hydroxy moieties significantly affected ERK-inhibitory activity of fenoterol derivatives. (R,R')-4'-hydroxy-1-naphthylfenoterol [(R,R')-HNF] was the most active inhibitor of ERK activation with an IC of 0.03 nM. However, it showed minimal anti-proliferative activity in the zebrafish xenograft model. In contrast, (R,R')-4'-methoxy-1-naphthylfenoterol [(R,R')-MNF], a weaker ERK inhibitor (IC = 0.17 nM), significantly reduced cell viability in vitro (IC = 14.07 µM) and tumor growth in vivo. SAR for fenoterol-mediated ERK inhibition in melanoma was defined, highlighting the importance of the (R,R') stereochemistry. Crucially, potent ERK inhibition does not directly predict anti-tumorigenic activity, as shown by (R,R')-HNF. The pronounced anti-proliferatory effect of (R,R')-MNF, despite weaker ERK inhibition, implies additional mechanisms beyond ERK modulation.
Drug-induced gingival overgrowth: evaluation of an online survey.
Ried PFG, Seifert R
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42321579 · Publisher ↗
Drug-induced gingival overgrowth (DIGO) is becoming an increasingly important issue due to high prescription rates of inducing pharmaceuticals. Therefore, the main focus of this study was to determine what experiences de...
Drug-induced gingival overgrowth (DIGO) is becoming an increasingly important issue due to high prescription rates of inducing pharmaceuticals. Therefore, the main focus of this study was to determine what experiences dentists in Germany have had with DIGO and which active ingredients cause this ADR in their patients. The conducted online survey was sent to all 17 German dental associations asking them to forward the survey to their members. Five associations complied with the request. Out of 25,562 dentists who were potentially eligible, 118 questionnaires were evaluated, resulting in a response rate of 0.46%. Furthermore, the 24 questions were designed to shed light on the frequency with which this adverse drug reaction (ADR) occurs, as well as patient factors, treatment strategies and potential risks. Amlodipine, nifedipine and ciclosporin were cited as the most frequent triggers of DIGO. In addition, no gender-specific differences were found among the affected patients. Sixty-nine percent of respondents were able to successfully treat this condition, using the following treatment options in descending order: "oral hygiene instruction", "change in medication", and "surgical procedures". Accordingly, it is difficult to determine a precise prevalence with which a particular active substance leads to gingival overgrowth. It is therefore advisable to specify a narrow percentage range with which the prevalence can be reliably described. In addition, the underlying parameters of the source under consideration should be examined very carefully, as different sources may come to very different results.
Disproportionality analysis of drug-associated tinnitus safety signals: a 43-year pharmacovigilance study.
Narasimhaswamy N, Ganesan S, Poojar B
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42321578 · Publisher ↗
Drug-induced tinnitus is a prevalent yet under-characterised adverse drug reaction. No prior study has systematically screened the FDA Adverse Event Reporting System (FAERS) for drug-tinnitus disproportionality signals u...
Drug-induced tinnitus is a prevalent yet under-characterised adverse drug reaction. No prior study has systematically screened the FDA Adverse Event Reporting System (FAERS) for drug-tinnitus disproportionality signals using a rigorous, deduplication-validated framework. A case/non-case pharmacovigilance study was conducted using 53,243 tinnitus-associated individual case safety reports from the FAERS Public Dashboard (1983-2025). Following four-tier deduplication, the reporting odds ratio (ROR) was computed for 900 eligible active ingredients (N ≥ 10 ICSRs; signal criterion: ROR > 1, lower 95% CI > 1, Yates-corrected p < 0.05). Bayesian sensitivity analyses applied. Seventy-four. positive disproportionality signals were identified (8.2%; ROR 1.29-10.71). The strongest signal was diphenhydramine citrate/ibuprofen (ROR 10.71), followed by chloroquine phosphate (9.28). Signals spanned seven ATC Level-1 classes; the nervous system class contributed most signal drugs (n = 12). BCPNN positive 48/74 signals (64.9%; Spearman ρ = 0.997 vs ROR). Median reporting delay was 169 days (IQR 56-446). BH-FDR sensitivity analysis (q ≤ 0.05, m = 900) retained 60 signals, all BCPNN-corroborated. This 43-year analysis identifies 74 positive drug-associated tinnitus signals, including novel immunobiologic (guselkumab, lifitegrast) and cardiovascular (lovastatin, terazosin) associations without current audiological labelling warnings. The delayed onset profile implicates cumulative cochlear injury mechanisms. These findings provide an actionable basis for regulatory prioritisation and prospective audiological safety research for drug classes where audiological monitoring protocols are currently absent.
Palmitic acid in cancer research: mechanistic insights from in vitro and in vivo studies.
Nazir MM, Muzaffar S, Muzammil S … +1 more , Ashraf A
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42319420 · Publisher ↗
Palmitic acid (PA), a long-chain saturated fatty acid abundantly present in dietary lipids and endogenous metabolic pathways, has traditionally been associated with metabolic dysregulation. However, emerging experimental...
Palmitic acid (PA), a long-chain saturated fatty acid abundantly present in dietary lipids and endogenous metabolic pathways, has traditionally been associated with metabolic dysregulation. However, emerging experimental evidence has revealed a contrasting role for PA in cancer biology. This review critically summarizes recent in vitro and in vivo studies investigating the anticancer potential of PA across multiple malignancies, including gastric, breast, colorectal, prostate, and endometrial cancers. Accumulating data demonstrate that PA suppresses tumor cell proliferation, induces apoptosis and autophagy, and inhibits invasion and metastasis through modulation of key molecular pathways such as STAT3, PI3K/Akt, ER stress signaling, and cell cycle regulators. In addition, PA-based delivery systems and combination strategies have shown enhanced antitumor efficacy by promoting macrophage repolarization and improving chemotherapeutic outcomes. Despite these findings, the anticancer effects of PA appear to be highly context-dependent, influenced by concentration, exposure duration, and tumor type. Collectively, this review highlights the mechanistic basis and therapeutic relevance of PA in cancer models while emphasizing the need for careful interpretation and further validation before clinical translation.
Naringenin ameliorates postmenopausal osteoporosis by inhibiting BMSC oxidative stress via the PI3K/AKT/NRF2 pathway.
Zhang Y, Cao S, Li D … +5 more , Jing X, Zheng J, Xu Z, Wang Y, Yin W
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42319419 · Publisher ↗
Oxidative stress plays a critical role in the pathogenesis of various bone diseases, particularly osteoporosis. Naringenin, a small molecule compound confirmed to possess antioxidative stress properties, exerts anti-infl...
Oxidative stress plays a critical role in the pathogenesis of various bone diseases, particularly osteoporosis. Naringenin, a small molecule compound confirmed to possess antioxidative stress properties, exerts anti-inflammatory effects in multiple diseases and can ameliorate osteoporotic symptoms. However, the precise mechanism by which Naringenin treats osteoporosis remains unclear. This study investigates the mechanism by which Naringenin inhibits oxidative stress in Bone Marrow Mesenchymal Stem Cells (BMSCs) to treat postmenopausal osteoporosis (PMOP). A mouse model of postmenopausal osteoporosis (PMOP) was established by ovariectomy (OVX). Micro-computed tomography (micro-CT) and histological staining were used to evaluate the therapeutic efficacy of naringenin against PMOP. Network pharmacology and molecular docking were applied to explore the underlying mechanism of naringenin in the treatment of PMOP. Cell counting kit-8 (CCK-8) assay, alkaline phosphatase (ALP) staining, Alizarin Red S (ARS) staining, Western blot and immunofluorescence staining were performed to investigate the effects and mechanisms of naringenin on relieving oxidative stress in bone marrow mesenchymal stem cells (BMSCs) and ameliorating PMOP. Naringenin alleviated bone loss caused by postmenopausal osteoporosis and upregulated the expression of BCL-2, RUNX2 and NRF2 in BMSCs within bone tissues. In the hydrogen peroxide (HO)-induced BMSC injury model, naringenin activated the PI3K/AKT/NRF2 signaling pathway, thereby inhibiting oxidative stress-mediated cell apoptosis and the decline in osteogenic differentiation capacity. Treatment with a PI3K/AKT inhibitor reversed these beneficial effects, confirming the specificity of this signaling pathway. Naringenin treats postmenopausal osteoporosis by inhibiting BMSC oxidative stress via the PI3K/AKT/NRF2 pathway, presenting a potential new target for osteoporosis therapy.
Integrated network toxicology and experimental validation to investigate potential mechanisms associated with aspartame-induced malignant phenotypic changes in colorectal cancer.
Liu Q, Yu D, Qiao L … +6 more , Wang N, Fan W, Wei T, Tian Z, Ma X, Xie X
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42319418 · Publisher ↗
To investigate the potential molecular mechanisms underlying aspartame (APM)-induced malignant phenotypic changes in colorectal cancer (CRC). Candidate targets of APM were identified by integrating the ChEMBL, SwissTarge...
To investigate the potential molecular mechanisms underlying aspartame (APM)-induced malignant phenotypic changes in colorectal cancer (CRC). Candidate targets of APM were identified by integrating the ChEMBL, SwissTargetPrediction, and SEA databases. Differential expression analysis was performed using transcriptomic data from The Cancer Genome Atlas (TCGA) CRC cohort, followed by weighted gene co-expression network analysis (WGCNA) to identify key modules associated with CRC. The intersection of differentially expressed genes (DEGs), key module genes, and candidate APM targets was used to identify shared APM-CRC candidate genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, machine learning, SHAP-based interpretability analysis, molecular docking, and molecular dynamics simulations were then conducted to identify key feature genes and evaluate their potential interactions with APM. Finally, EdU, CCK-8, ROS fluorescence staining, and Western blot assays were performed in HCT116 and SW480 cells to validate the effects of APM on CRC cell proliferation, oxidative stress, and epithelial-mesenchymal transition (EMT)-related molecular alterations. A total of 4790 DEGs were identified between CRC and normal tissues, and WGCNA further identified key modules significantly associated with the tumor phenotype. Intersection analysis yielded 1003 CRC-related candidate genes and 26 shared APM-CRC candidate genes. Enrichment analysis indicated that these genes were mainly involved in extracellular matrix remodeling, regulation of cell adhesion, glutathione metabolism, and xenobiotic metabolism. Machine learning combined with SHAP analysis ultimately identified SLC7A5, MMP3, ITGA2, CAPN2, and BACE2 as key feature genes. Molecular docking and molecular dynamics simulations suggested that APM could potentially interact with all five key proteins, with MMP3 and ITGA2 showing relatively stronger binding affinity. In vitro experiments showed that APM increased the proliferation of HCT116 and SW480 cells, elevated intracellular ROS levels, and was associated with decreased E-cadherin expression and increased N-cadherin and Vimentin expression. These findings suggest that APM exposure may be associated with increased CRC cell proliferation and EMT-related molecular alterations, accompanied by changes in oxidative stress-related processes, extracellular matrix remodeling, and abnormal cell adhesion. SLC7A5, MMP3, ITGA2, CAPN2, and BACE2 may represent APM-responsive candidate molecules involved in these cellular responses.
Molecular mechanism by which perfluorooctane sulfonate regulates the initiation and progression of prostate cancer via the ENTPD5-adenine axis.
Lei Y, Lei P, Shen G … +4 more , Li X, Tang H, Wang R, Dai Y
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42319417 · Publisher ↗
Perfluorooctane sulfonate (PFOS), a persistent member of the per- and polyfluoroalkyl substances family, has been increasingly associated with adverse carcinogenic effects; however, the molecular basis by which PFOS may...
Perfluorooctane sulfonate (PFOS), a persistent member of the per- and polyfluoroalkyl substances family, has been increasingly associated with adverse carcinogenic effects; however, the molecular basis by which PFOS may contribute to prostate cancer (PCa) initiation and progression remains poorly defined. In this study, we aimed to systematically elucidate the mechanisms underlying PFOS-associated prostate carcinogenesis, with particular emphasis on the identification of actionable molecular targets and metabolically relevant pathways. By integrating network toxicology, transcriptomic differential analysis, weighted gene co-expression network analysis, multi-algorithm machine learning, single-cell and spatial transcriptomics, metabolomics, and structural modeling, we identified a four-gene core signature consisting of APOF, B3GAT1, CGREF1, and ENTPD5. Among these candidates, ENTPD5 emerged as the most prominent PFOS-associated target, showing marked enrichment in epithelial compartments across both single-cell and spatial datasets. Further integrative analyses converged on purine metabolism as a shared pathogenic vulnerability, and increased ENTPD5 expression was accompanied by elevated adenine abundance, supporting the existence of an ENTPD5-centered metabolic axis. Molecular docking and molecular dynamics simulations further suggested stable binding of PFOS to ENTPD5. In addition, immunohistochemical evidence consistently confirmed ENTPD5 upregulation in prostate cancer tissues. Collectively, our findings support a PFOS-ENTPD5-adenine mechanistic axis that may promote prostate cancer initiation and progression through purine metabolic reprogramming, and provide a potential foundation for the development of exposure-related biomarkers and preventive intervention targets in PCa.
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