Naunyn Schmiedebergs Arch. Pharmacol. [JOURNAL]
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200 papers
Efficacy and safety of baloxavir marboxil vs. oseltamivir in Chinese outpatients with influenza B: an IPTW-adjusted real-world cohort study.
Gong Z, Yu X, Han Q … +4 more , Lu L, Liu Y, Pei B, Wang Z
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42319416 · Publisher ↗
Baloxavir marboxil (baloxavir) shows satisfactory efficacy and safety for treating influenza, particularly influenza A. However, real-world evidence for influenza B in Chinese populations is scarce. This study aimed to e...
Baloxavir marboxil (baloxavir) shows satisfactory efficacy and safety for treating influenza, particularly influenza A. However, real-world evidence for influenza B in Chinese populations is scarce. This study aimed to explore the efficacy and safety of baloxavir vs. oseltamivir in Chinese outpatients with influenza B. This real-world cohort study included 811 outpatients with influenza B between November 2023 and January 2024, comprising 394 patients in the baloxavir group and 417 patients in the oseltamivir group. Inverse probability of treatment weighting (IPTW) was applied to minimize potential confounding and achieve covariate balance. In both unweighted and IPTW-weighted cohorts, time to fever resolution was shorter in the baloxavir group (median: 24.0 h) compared with the oseltamivir group (median: 48.0 h) (both P < 0.001). In both cohorts, the baloxavir group (median: 120.0 h) had a shorter time to symptom resolution than the oseltamivir group (median: 168.0 h) (both P < 0.001). Due to residual imbalance, time from symptom onset to antiviral initiation was adjusted for in the multivariable Cox model. After adjustment, the baloxavir group remained associated with faster fever resolution and symptom resolution (all P < 0.001). The incidence of any adverse events was lower in the baloxavir group than in the oseltamivir group (3.6% vs. 10.3%) (P < 0.001). Headache was more frequent (1.3% vs. 0.0%), whereas nausea (0.0% vs. 6.7%) and vomiting (0.0% vs. 6.5%) were less frequent in the baloxavir group vs. the oseltamivir group (all P < 0.05). Baloxavir achieves faster fever resolution and symptom resolution, with a better safety profile in Chinese outpatients with influenza B.
Fluoxetine attenuates hepatic ischemia-reperfusion injury through antioxidant, anti-inflammatory and anti-apoptotic mechanisms.
Işık M, Şahin G, Kervancıoğlu G … +3 more , Yaman MO, Yelmen N, Güner İ
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42319415 · Publisher ↗
Hepatic ischemia-reperfusion injury is a major clinical problem associated with liver surgery, trauma, and transplantation, characterized by oxidative stress, inflammation, microcirculatory dysfunction, and apoptosis. Fl...
Hepatic ischemia-reperfusion injury is a major clinical problem associated with liver surgery, trauma, and transplantation, characterized by oxidative stress, inflammation, microcirculatory dysfunction, and apoptosis. Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to exert antioxidant, anti-inflammatory, and antiapoptotic effects. The present study aimed to investigate the potential protective effects of fluoxetine against experimental hepatic ischemia-reperfusion injury in rats. Male Wistar rats were randomly assigned to three groups: control, ischemia-reperfusion and fluoxetine-treated ischemia-reperfusion (n = 7 each). Hepatic ischemia-reperfusion injury was induced by infrarenal abdominal aortic cross-clamping for 60 min followed by 120 min of reperfusion. Fluoxetine (20 mg/kg/day, intraperitoneal) was administered for three consecutive days prior to ischemia. Oxidative stress markers, antioxidant parameters, inflammatory and anti-inflammatory cytokines, apoptotic markers, and specific tissue injury biomarkers were measured in liver homogenates using ELISA. Histopathological alterations were evaluated by light microscopy. Ischemia-reperfusion significantly increased oxidant markers, inflammatory cytokines, NF-κB activation, apoptotic indices, liver enzyme levels, and histological damage, while reducing antioxidant capacity. Fluoxetine treatment markedly restored antioxidant defenses, suppressed oxidative stress, inflammation, apoptosis, and microcirculatory injury, and significantly improved histopathological findings compared with the untreated ischemia-reperfusion group. Fluoxetine exerts a protective effect against hepatic ischemia-reperfusion injury through antioxidant, anti-inflammatory and antiapoptotic mechanisms, suggesting its potential as a therapeutic agent in conditions associated with hepatic ischemia-reperfusion.
Repurposing approved drugs as ferroptosis modulators: a critical review of clinical trials in cancer and neurodegeneration.
Zayed M, Massoud A, Elwakeel E … +5 more , Ezzat P, Alammar Y, El-Wahab NAA, Afifi RW, Jeong BH
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42319414 · Publisher ↗
Ferroptosis is a regulated form of cell death that depends on iron and is marked by lipid peroxidation and the inactivation of glutathione peroxidase 4. It has emerged as a pathway of broad relevance to cancer and neurod...
Ferroptosis is a regulated form of cell death that depends on iron and is marked by lipid peroxidation and the inactivation of glutathione peroxidase 4. It has emerged as a pathway of broad relevance to cancer and neurodegenerative disease. Preclinical studies have identified potent ferroptosis inducers (System Xc⁻ and GPX4 inhibitors) and inhibitors (liproxstatin/ferrostatin derivatives, FSP1-CoQ10 activators) with promising therapeutic potential. However, clinical translation remains limited. Since dedicated therapeutics targeting ferroptosis are still in early development, current clinical evidence mainly comes from drug repurposing, approved drugs whose ferroptosis-modulating properties were discovered retrospectively after their initial approval. None of these completed trials used ferroptosis-specific pharmacodynamic data or prospectively tested ferroptosis as the primary therapeutic mechanism. Instead of just reclassifying these trials, this review introduces a four-category failure-mode framework, mechanism mismatch, biomarker absence, model-to-trial prediction, and target non-selective compound, to explain why preclinical signals of ferroptosis have yet to translate successfully. We conclude that progress depends on three developments: targeted modulators (purpose-developed or repurposed with confirmed engagement), proof-of-mechanism trials using ferroptosis-related endpoints, and patient selection aligned with precision medicine.
Serotonin 2A receptor binding, functional activity, and in vitro metabolism of two trideuteromethoxy 2C-B isotopologues.
Cozzi NV
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42313138 · Publisher ↗
The aim of this study was to investigate the effects of deuterium substitution on the in vitro pharmacology of the psychedelic drug 2-(4-bromo-2,5-dimethoxyphenyl)ethan-1-amine (2C-B). Two deuterated isotopologues of 2C-...
The aim of this study was to investigate the effects of deuterium substitution on the in vitro pharmacology of the psychedelic drug 2-(4-bromo-2,5-dimethoxyphenyl)ethan-1-amine (2C-B). Two deuterated isotopologues of 2C-B, namely 2-(4-bromo-5-methoxy-2-(methoxy-d3)phenyl)ethan-1-amine (2CB-2OCD) and 2-(4-bromo-2-methoxy-5-(methoxy-d3)phenyl)ethan-1-amine (2CB-5OCD), were synthesized and tested in cell lines expressing human 5-HT receptors for potential isotope effects on 5-HT receptor binding and functional activity, and for metabolism by human liver microsomes (HLM). The 2C-B isotopologues and 2C-B exhibited picomolar-to-nanomolar potency in binding to [I]DOI-labelled 5-HT receptors and were equally efficacious to 2C-B in stimulating 5-HT-mediated intracellular Ca release and β-arrestin 2 engagement. No appreciable metabolism was observed for 2C-B or the deuterated analogues by HLM over the time course of the experiment. Deuteration of the ring methoxys of 2C-B appeared to increase affinity at [I]DOI-labelled 5-HT receptors, likely due to dampened internal vibrational frequencies and rotational motions arising from primary and secondary kinetic isotope effects. Deuteration did not affect the ability of the drugs to stimulate intracellular calcium release or to recruit β-arrestin 2, with all compounds displaying similar low nanomolar potency and efficacy in these assays.
Pediatric hepatic laboratory reporting with CFTR modulators: a FAERS pharmacovigilance study.
Zhang X, Wang J, Wei D … +1 more , Wang X
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42313137 · Publisher ↗
Children receiving CFTR modulators undergo liver testing because labels warn about liver injury and liver failure. In FAERS, aminotransferase or bilirubin reports may reflect monitoring rather than confirmed injury. This...
Children receiving CFTR modulators undergo liver testing because labels warn about liver injury and liver failure. In FAERS, aminotransferase or bilirubin reports may reflect monitoring rather than confirmed injury. This study examined whether pediatric hepatic reporting was driven mainly by laboratory terms or by narrower injury/failure terms. FAERS/openFDA reports were analyzed using the 2026-01-27 update, retrieved on 30 April 2026. Pediatric reports required age < 18 years with age unit coded as years. Broad hepatic terms combined injury/failure terms and liver test abnormalities; narrow terms retained explicit injury/failure terms and excluded laboratory-only reports. RORs with 95% CIs used all other openFDA reports as comparator. A descriptive CF care context check summarized co-reported pancreatic enzyme replacement therapy and ursodeoxycholic acid/ursodiol terms. FAERS contained 34,731 CFTR modulator reports. The broad hepatic definition identified 935 CFTR hepatic reports, including 237 pediatric reports. Pediatric broad hepatic reporting was increased (ROR 1.67, 95% CI 1.46-1.90), whereas pediatric serious broad hepatic reporting was not (ROR 1.08, 95% CI 0.92-1.28). Pediatric narrow hepatic reporting was below background (ROR 0.65, 95% CI 0.50-0.84). Frequent terms were alanine aminotransferase increased, aspartate aminotransferase increased, and blood bilirubin increased. Pediatric FAERS data show a hepatic laboratory reporting pattern rather than a parallel increase in coded clinical liver injury. The findings support label-based monitoring and better case documentation. Incidence and treatment comparisons require multicenter pediatric cohort studies with exposed patient denominators.
Safety profile and resource utilisation associated with systemic alteplase versus unfractionated heparin in intermediate-high risk pulmonary embolism: a prospective ICU cohort study.
Marić N, Milošević M, Likić R
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42313136 · Publisher ↗
Full-dose systemic thrombolysis reduces haemodynamic decompensation in intermediate-high risk pulmonary embolism (PE) but increases bleeding risk, and its real-world safety profile in ICU settings remains incompletely ch...
Full-dose systemic thrombolysis reduces haemodynamic decompensation in intermediate-high risk pulmonary embolism (PE) but increases bleeding risk, and its real-world safety profile in ICU settings remains incompletely characterised. We describe treatment selection patterns, safety outcomes, and resource utilisation associated with systemic alteplase versus unfractionated heparin (UFH) in ICU-managed intermediate-high risk PE. Prospective single-centre cohort; 80 adults with CTPA-confirmed intermediate-high risk PE (2020-2024), 40 per arm. Outcomes included mortality, bleeding, clinical deterioration, and ICU and hospital length of stay (LOS). Firth penalised logistic regression was used for binary outcomes with complete separation; negative binomial regression with covariate adjustment (age, APACHE II, Charlson Comorbidity Index, PESI class) for LOS. Clinicians preferentially selected alteplase for younger patients with greater PE-specific severity markers, and UFH for older, more comorbid patients with higher physiological derangement. Major bleeding was rare in both groups (UFH 2/40; alteplase 1/40; P = 0.781), with no intracranial or fatal events. Clinical deterioration occurred exclusively in the UFH group (17.5% vs 0%; P = 0.012), though most events represented rescue thrombolysis, structurally unobservable in the alteplase arm; no residual signal persisted after its exclusion (adjusted OR 0.77; P = 0.89). ICU LOS (rate ratio 0.70; P = 0.007) and hospital LOS (rate ratio 0.73; P = 0.019) were shorter with alteplase after covariate adjustment. In this prospective ICU cohort of carefully selected intermediate-high risk PE patients, systemic alteplase was associated with a favourable safety profile and shorter hospitalisation. These hypothesis-generating findings support prospective studies targeting ICU-managed intermediate-high risk PE.
Naringenin protects against L-NAME-induced preeclampsia and fetal developmental abnormalities via modulation of inflammation, eNOS/NO signaling, AKT/mTOR pathway, and restoring endothelial function.
Yahia R, Abd El-Rhman RH, Gad AM … +2 more , Gadelmawla MHA, Elhemiely AA
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42307641 · Publisher ↗
Preeclampsia considered as multi-organ disorder involving systemic inflammation and endothelial dysfunction. Our work was designed to investigate the protective role of Naringenin (NGN) against Nω-nitro-l-arginine methyl...
Preeclampsia considered as multi-organ disorder involving systemic inflammation and endothelial dysfunction. Our work was designed to investigate the protective role of Naringenin (NGN) against Nω-nitro-l-arginine methyl ester (L-NAME)-induced placental damage and congenital abnormalities in a rat model of preeclampsia. Forty-five adult female albino rats (weighing 160-180 g) were randomly allocated into nine groups (n = 6 per group) and treated for a duration of 18 days. Group 1 served as the untreated control, while Group 2 received 10% DMSO as a vehicle control. Group 3 was administered L-NAME (50 mg/kg, i.p.) from 13 to 18th day of gestation to induce preeclampsia and served as the positive control. Groups 4-6 received NGN alone at doses of 10, 25, and 50 mg/kg, p.o, respectively from 10 to 18th day of gestation. Groups 7-9 received NGN at the same doses, followed one hour later by L-NAME from day 13 to 18. Fetal developmental parameters and skeletal abnormalities were evaluated on gestational day 20. Placental inflammatory markers (TNF-α, IL-1β, TGF-β), signaling proteins (AKT and mTOR), and nitric oxide metabolites (NOx) were quantified using ELISA. Endothelial nitric oxide synthase (eNOS) expression was assessed by immunohistochemistry. Pre-treatment of L-NAME-administered dams with NGN reduced fetal death and resorption rates, elevated NO levels and eNOS expression, and significantly suppressed placental inflammatory markers (TNF-α, IL-1β, TGF-β). These effects were linked to the activation of the AKT/mTOR signaling cascade. Histopathological analysis of the placenta, liver, and kidney confirmed the biochemical findings. Furthermore, NGN alleviated intrauterine growth restriction by increasing fetal weight and length, and provided protection against L-NAME-induced morphological and skeletal deformities. The protective effects of NGN against L-NAME-induced preeclampsia appear to be dose-dependent and primarily mediated through the modulation of inflammation and endothelial dysfunction, suggesting a promising approach for combating preeclampsia.
Global research hotspots and evolving themes in chemoresistance of hepatocellular carcinoma: a bibliometric analysis from a pharmacological perspective.
Chen L, Lin S, Huang Z … +1 more , Yin Y
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42307640 · Publisher ↗
Chemoresistance in hepatocellular carcinoma (HCC) complicates treatment and poses a substantial and growing burden to healthcare systems worldwide. Despite remarkable advances in recent years, the massive volume of publi...
Chemoresistance in hepatocellular carcinoma (HCC) complicates treatment and poses a substantial and growing burden to healthcare systems worldwide. Despite remarkable advances in recent years, the massive volume of publications has made it hard to identify overarching trends, critical turning points, and emerging frontiers. The present study aimed to conduct a comprehensive analysis of the global research landscape and summarize future hotspots. Articles on chemoresistance in HCC published in the Science Citation Index Expanded, Web of Science Core Collection, from 1991 to 2025 were searched. Bibliometrix (R package) was used for data analysis and visualization. CiteSpace was employed for keywords bursts detection. A total of 2571 publications by 12243 authors from 643 sources were included. An increase in the annual growth in the number of publications and citations was observed. Cancers had the most publications, and Cancer Research was the most cited. China and the USA are the dominant countries in this field. Sun Yat Sen University is the most productive affiliation. Wang Y is the most productive author. Besides topic-relevant keywords, terms like "expression," "apoptosis, " and "metastasis," etc. had high occurrence. Thematic shifts were also identified, transitioning from single-agent and single-target approaches to complex combination therapies and novel technological interventions. Conclusively, through a bibliometric analysis of publications, the present work shows key developments in the field of chemoresistance in HCC. Potential research hotspots include advanced combinatorial nano-immunotherapy, ferroptosis inducers, combined immunotherapy, and metabolic plasticity and stemness pathway regulators of cancer stem cells.
Xylazine-induced diuresis in rats is attenuated by κ-opioid receptor and α2-adrenoceptor antagonists.
Inan S, Rawls SM
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42307639 · Publisher ↗
Xylazine is an α2 adrenoceptor agonist approved for use in veterinary medicine as an analgesic and sedative. However, the recent use of xylazine as adulterant with opioids has created a public health emergency due to an...
Xylazine is an α2 adrenoceptor agonist approved for use in veterinary medicine as an analgesic and sedative. However, the recent use of xylazine as adulterant with opioids has created a public health emergency due to an increased number of addiction-related deaths and adverse effects. As a result, xylazine's pharmacological profile has been revisited, and it has been found to act as a full agonist at κ-opioid receptors. Because increased urine output is a well-established effect of κ-opioid receptor agonists, we determined if κ-opioid receptors are involved in xylazine-induced diuresis. Adult male Sprague-Dawley rats were used. A dose-response curve was first established through systemic administration of xylazine. Rats were injected with xylazine (1.25, 2.5, or 5 mg/kg) or saline and then placed into metabolic cages for 2 h for urine collection. Xylazine doses of 2.5 and 5 mg/kg significantly increased urine output compared to saline-injected rats, indicating that xylazine caused diuresis. Next, rats were pretreated with saline; a κ-opioid receptor antagonist, 5'-guanidinonaltrindole (5'-GNTI) (0.01-0.1 mg/kg); or an α2-adrenoceptor antagonist, yohimbine (0.3-1 mg/kg). Thirty minutes later, rats were injected with saline or a fixed dose of xylazine (2.5 mg/kg) and urine was collected for 2 h. Pretreatment with either 5'-GNTI or yohimbine significantly decreased xylazine-induced diuresis. Our findings suggest that xylazine-induced diuresis is mediated by both κ-opioid receptors and α2-adrenoceptors, highlighting the importance of considering κ-opioid receptor activation when evaluating in vivo pharmacological effects of xylazine.
Pharmacological assessment of drugs retained in the 1 and 24 WHO Essential Medicines List (1977-2025).
Bindel LJ, Seifert R
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42307638 · Publisher ↗
The Essential Medicines List (EML) provides international guidance for the selection of effective, safe, and essential drugs. Retained drugs were identified as medicines listed in both the 1 and 24 EML editions. The stud...
The Essential Medicines List (EML) provides international guidance for the selection of effective, safe, and essential drugs. Retained drugs were identified as medicines listed in both the 1 and 24 EML editions. The study aims to pharmacologically assess and to distinguish established therapeutic value from questionable or obsolete current relevance. Retained drugs were assessed by therapeutic value and indication-specific justification. Listed indications and the importance developments were compared between the 1 (1977) and 24 EML (2025). The justification of listing was assessed by guideline recommendations, efficacy and safety, scope of clinical usage, and availability of alternatives. A structured assessment algorithm was applied to assign drugs to therapeutic value categories. 129 retained drugs were assessed. Most EML indications did not change (n = 65), followed by specifications (n = 26), additions (n = 24), narrowing (n = 8), or change (n = 6). 71 drugs (55.0%) were classified as having constant importance, 20 (15.5%) as increasing, and 38 (29.5%) as declining. Drugs can be categorized in preserved and clearly justified value, niche value, requiring indication correction, and obsolescence. Nineteen drugs were identified where continued EML listing warrants discussion, mainly due to restricted or second-choice use, reduced efficacy, high pathogen resistance, and toxicity issues. Historical retention on the EML does not necessarily indicate unchanged therapeutic value. A structured pharmacological assessment can distinguish valuable from obsolete retained drugs. EML-listed drugs require regular reassessment to ensure that future EML editions remain clinically justified and relevant for public health.
Decoding polycystic ovary syndrome: an integrated review of epidemiology, molecular mechanisms, animal models, and the expanding therapeutic landscape.
Sharata EE, Abdel-Samea AS, Ibrahim LY … +6 more , Mamdouh M, Khalid N, Rabea M, Mohamed GH, Abdelnaser M, Mohyeldin RH
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42307637 · Publisher ↗
Few conditions in reproductive medicine rival polycystic ovary syndrome (PCOS) in terms of clinical breadth and global impact. Affecting roughly 6-21% of women of childbearing age depending on which diagnostic criteria a...
Few conditions in reproductive medicine rival polycystic ovary syndrome (PCOS) in terms of clinical breadth and global impact. Affecting roughly 6-21% of women of childbearing age depending on which diagnostic criteria are applied PCOS sits at the intersection of endocrinology, metabolism, and gynecology, making it difficult to capture within any single disciplinary lens. Its hallmarks are well rehearsed: excess androgens, disrupted ovulation, and the characteristic follicular architecture seen on pelvic ultrasound. Yet what makes PCOS genuinely challenging is the degree to which these reproductive features overlap with far-reaching metabolic consequences, including insulin resistance, type 2 diabetes, lipid abnormalities, and a meaningfully elevated cardiovascular risk profile that persists well beyond the fertile years. Despite several decades of sustained investigation, the origins of PCOS remain imperfectly understood. Genetic susceptibility, epigenetic programming, environmental chemical exposures, and modern dietary habits all appear to play contributory roles, though no single culprit has emerged. The molecular picture is equally layered: aberrant insulin signaling feeds androgen overproduction, gonadotropin secretion goes out of balance, inflammatory cytokines accumulate, oxidative injury mounts, and more recently the gut microbial community has been implicated as an additional participant in this cascade. Diagnosis is further complicated by the phenotypic variability of the syndrome, with different criteria yielding meaningfully different patient populations. Treatment, in turn, requires individualization; lifestyle change, hormonal therapies, insulin sensitizers, and an expanding repertoire of repurposed drugs and plant-based agents each address different facets of a fundamentally heterogeneous disorder. This review provides a comprehensive and integrated account of PCOS across its full biological and clinical spectrum. It covers epidemiology, clinical presentation, risk factors, and current diagnostic frameworks. Pathophysiological mechanisms are examined in depth. A central and distinctive focus of this review is the experimental preclinical landscape. Established animal induction models, letrozole, dehydroepiandrosterone (DHEA), testosterone/dihydrotestosterone propionate, and high-fat diet protocols are critically evaluated for their translational relevance. Drawing on these models, we comprehensively catalogue protective agents across four systematic tables, encompassing both repurposed pharmaceuticals (metformin, GLP-1 receptor agonists, SGLT-2 inhibitors, statins, melatonin) and bioactive natural compounds (curcumin, berberine, quercetin, fisetin, myricetin, apigenin, and others), detailing their induction models, mechanistic pathways, and therapeutic outcomes. Together, this review aims to serve as a single, authoritative reference bridging basic science, translational pharmacology, and clinical practice in PCOS, while identifying the most promising avenues for future research and personalized therapeutic development.
The effects of chemotherapy on brain regions: implications for chemobrain revealed through metabolomic profiling.
Ahmed M, Zenati RA, Alkhoujah SM … +10 more , Abuhelwa AY, Alqudah MAY, Aleidi SM, Al-Hroub HM, Alhusban AY, Albohy A, Abu-Gharbieh E, Bustanji Y, Alzoubi KH, Semreen MH
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42307636 · Publisher ↗
Chemobrain (CMB) is a common complication that affects the majority of cancer patients and can persist for years following chemotherapy. Common symptoms are deficits in memory, attention, and affective regulation, yet th...
Chemobrain (CMB) is a common complication that affects the majority of cancer patients and can persist for years following chemotherapy. Common symptoms are deficits in memory, attention, and affective regulation, yet they are mainly diagnosed through patient-reported symptoms. Additionally, the molecular mechanisms underlying CMB remain poorly understood, limiting the development of effective neuroprotective strategies for cancer patients. Using a rat model of CMB, this study investigates the molecular impact of doxorubicin (DOX) and temozolomide (TMZ), administered individually and in combination in comparison with a control group (n = 10/group). Untargeted metabolomic profiling was performed on the cortex, cerebellum, and hippocampus tissues after performing the neurobehavioural tests. Behavioural assessments revealed impaired spatial learning and memory, particularly in the combination-treated group, together with alterations in anxiety-related behaviour. The metabolites were extracted from their respective tissues using a two-in-one extraction protocol and were analysed by TIMS-QTOF-MS/MS. DOX treatment was associated with relatively modest region-specific metabolic alterations, with patterns consistent with possible oxidative stress-related and membrane-associated responses. TMZ treatment was associated with metabolic changes involving nucleotide metabolism and energy-related pathways, particularly in the hippocampus. The combination treatment showed a distinct metabolic profile with partial qualitative overlap with TMZ-associated alterations. Overall, these findings suggest that chemotherapy exposure is associated with region-specific metabolic alterations that co-occur with behavioural changes relevant to a CMB-like phenotype. The present results should be interpreted as exploratory and hypothesis-generating, pending targeted metabolite validation and orthogonal mechanistic confirmation. Ultimately, understanding these responses can provide critical insights into CMB pathophysiology and may lay the groundwork for the development of targeted diagnostic, monitoring, and neuroprotective strategies.
Correction to: FOXK2/SH2D3A axis recruits EGFR to drive papillary thyroid cancer progression and confers sensitivity to EGFR inhibition.
Cui Q, Hong X, Gan L … +1 more , Shi B
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42301353 · Publisher ↗
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The activity of niosomal serratiopeptidase enzyme in combination with palmitoleic acid in rats with insulin-resistant polycystic ovarian syndrome.
Aljabali AAA, Hayjneh Y, Obeid MA … +5 more , Albokhadaim I, Alhojaily S, Afzal S, Haija YA, Al-Trad B
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42301352 · Publisher ↗
This study investigates the therapeutic potential of combining palmitoleic acid with niosomal serratiopeptidase in a rat model of insulin-resistant polycystic ovarian syndrome (PCOS). Niosomal serratiopeptidase was formu...
This study investigates the therapeutic potential of combining palmitoleic acid with niosomal serratiopeptidase in a rat model of insulin-resistant polycystic ovarian syndrome (PCOS). Niosomal serratiopeptidase was formulated by thin-film hydration and characterized for particle size, polydispersity index, zeta potential, and encapsulation efficiency. Thirty prepubertal female rats were divided into six groups (n = 5). A negative control (Group 1); PCOS rats (Group 2); PCOS rats treated with free niosomes (0.7 mg/kg, i.p.; Group 3); serratiopeptidase-loaded niosomes (1 mg/kg, i.p.; Group 4); palmitoleic acid (300 mg/kg, p.o.; Group 5); and a combination of serratiopeptidase-loaded niosomes plus palmitoleic acid (Group 6). PCOS was induced in groups 2-6 using letrozole plus a high-fat diet for 30 days, followed by 30 days of the respective treatments, after which body and ovarian weights, ovarian cysts, and histological and biochemical parameters were assessed. The niosomes prepared exhibited a size of 746.6 ± 54.1 nm and a PDI of 0.389 ± 0.03. Serratiopeptidase encapsulation efficiency was found to be around 74%. Compared with controls, the PCOS group exhibited estrous cycle irregularities and significant increases in ovarian volume (p < 0.01), ovarian index (ovarian weight/body weight × 100%; p < 0.01), cyst number (p < 0.01), fasting plasma glucose (p < 0.01-0.001), fasting insulin (p < 0.001), HOMA-IR (p < 0.001), luteinizing hormone (P < 0.001), and testosterone (p < 0.001), along with decreased follicle-stimulating hormone (p < 0.0001). While serratiopeptidase niosomes or palmitoleic acid alone partially improved PCOS parameters, including reductions in ovarian volume (p < 0.05) and metabolic and hormonal markers (p < 0.01-0.001), some effects did not reach statistical significance. In contrast, the combination of niosomal serratiopeptidase and palmitoleic acid produced the greatest effects, significantly improving metabolic, hormonal, and ovarian parameters toward near-normal levels (p < 0.05-0.0001). These preclinical findings suggest that niosomal serratiopeptidase combined with palmitoleic acid may represent a potential supportive therapeutic approach for PCOS; however, further clinical validation is warranted before any translational conclusions can be drawn.
Exploring the material basis and potential mechanism of spleen-strengthening and damp-resolving prescriptions in the treatment of diabetes mellitus complicated with obesity based on data mining, UPLC-Q-TOF-MS/MS and network pharmacology.
Yang R, Li H, Qiu J … +3 more , Luo M, Liu Y, Gu W
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42301351 · Publisher ↗
Diabetes combined with obesity is a global public health problem, with insulin resistance and chronic low-grade inflammation as key mechanisms. TCM regards spleen deficiency and phlegm-dampness as its core pathogenesis....
Diabetes combined with obesity is a global public health problem, with insulin resistance and chronic low-grade inflammation as key mechanisms. TCM regards spleen deficiency and phlegm-dampness as its core pathogenesis. This study constructs a research paradigm integrating clinical RCT data mining, UPLC-Q-TOF-MS/MS experimental component identification and network pharmacology-based prediction.This study predicted the multi-component, multi-target and multi-pathway mechanisms of core spleen-strengthening and damp-resolving prescriptions for this comorbidity. High-frequency herbs were screened via data mining from RCTs; chemical components were experimentally identified by UPLC-Q-TOF-MS/MS; intersecting targets and pathways were predicted by network pharmacology and preliminarily verified by semi-flexible molecular docking and molecular dynamics simulation. A 7-herb core prescription and 30 active components (nobiletin, puerarin, etc.) were determined. 350 common targets and hub genes (AKT1, MTOR, MMP9, PTGS2) were screened, with PI3K-Akt, lipid-atherosclerosis and diabetic AGE-RAGE as main pathways. Molecular docking showed strong component-target binding, which was further validated by dynamics simulation. The prescription improves diabetes with obesity through synergistic networks, regulating glycolipid metabolism and inflammation via the above pathways, supporting its modern clinical application.
Enhanced antitumor efficacy of sulfasalazine and mesalazine in colorectal cancer through modulatory action of Lacticaseibacillus rhamnosus GG.
Elmahdy RK, Abdel-Raheem IT, Abd-Alhaseeb MM … +2 more , Ghoneim AI, Helmy MW
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42301350 · Publisher ↗
Colorectal cancer (CRC) ranks as the second most lethal cancer worldwide. Probiotics have long been utilized to treat gastrointestinal diseases. Probiotics may play a role in the prevention and treatment of CRC. Addition...
Colorectal cancer (CRC) ranks as the second most lethal cancer worldwide. Probiotics have long been utilized to treat gastrointestinal diseases. Probiotics may play a role in the prevention and treatment of CRC. Additionally, the anti-inflammatory drugs sulfasalazine (SSA) and mesalazine (MESA) have a preventive role in CRC. This study investigates the modulatory antitumor effects of combining the probiotic Lacticaseibacillus rhamnosus GG (LGG) with SSA or MESA and the associated molecular mechanisms in CRC. In vitro studies of LGG-CFS, both alone and in combination with SSA or MESA, were assessed in HCT-116 and HT-29 CRC cells. In vivo, 61 albino rats aged 8 weeks were used and CRC was induced using 1,2-dimethylhydrazine. The 1,2-dimethylhydrazine-induced rats were divided into six groups, each of eight-in addition to the negative control group (received phosphate buffer saline only)-as follows: (I) positive control group (received DMH only), (II) SSA-treated group, (III) MESA-treated group, (IV) LGG-treated group, (V) SSA + LGG-treated group, and (VI) MESA + LGG-treated group. Rats received daily oral doses of SSA (250 mg/kg), MESA (62.5 mg/kg), LGG (1 × 10 CFU lactobacilli/1 ml), SSA + LGG, and MESA + LGG for 4 weeks. In both cell lines, the control group (positive control, human cancerous cells without further treatment) exhibited a reduction in annexin V, whereas the specified treatments elevated annexin V levels in both cells, thereby inducing apoptosis. In vivo, positive control rats exhibited upregulation of TLR2/AKT/NF-κB, IL-6, IFN-γ/STAT-3/PD-L1, COX-2/HIF-1α/VEGF signaling, and Ki-67, resulting in the induction of proliferation, hypoxia, and angiogenesis and inhibition of apoptosis. All treatment regimens downregulated TLR2/AKT/NF-κB, IL-6, IFN-γ/STAT-3/PD-L1, COX-2/HIF-1α/VEGF crosstalk's, and Ki-67, hence inhibiting proliferation, hypoxia, angiogenesis, and inducing apoptosis. Surprisingly, the combination of LGG with either SSA or MESA demonstrated the greatest efficacy through the aforementioned pathways with the superiority to the LGG + SSA combination in both experimental models. The current findings revealed novel insights into the potential antitumor effects of combining LGG with either SSA or MESA compared to each drug individually in CRC management. Further preclinical and clinical trials are warranted to evaluate this promising regimen compared to standard therapy of CRC.
Emerging therapeutic strategies in multiple sclerosis: a focus on innovative and targeted approaches.
Thalib HI, Khan S, Sideeque S … +3 more , Sheriff TZ, Muzammil A, Hassan FE
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42295377 · Publisher ↗
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system marked by damage to myelin and nerve cells. Current treatments help control inflammation but have limited success in progressive stages...
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system marked by damage to myelin and nerve cells. Current treatments help control inflammation but have limited success in progressive stages and repairing nerve damage. This review aims to summarize new therapies for MS that target both inflammation and neurodegeneration beyond traditional immunosuppressive drugs. We conducted a thorough literature search to summarize key findings from original studies, including clinical trials investigating novel MS treatments such as Bruton's tyrosine kinase (BTK) inhibitors, CAR T-cell therapy, vaccines targeting Epstein-Barr virus (EBV) and specific antigens, drugs promoting remyelination, monoclonal antibodies, stem cell therapy, sphingosine-1-phosphate receptor modulators, cytokine blockers, gut microbiome interventions, and nanotechnology-based drug delivery. Emerging therapeutic strategies in MS increasingly target mechanisms beyond conventional immunosuppression, including B-cell and microglial modulation, immune tolerance induction, remyelination, cytokine signaling, microbiome regulation, and enhanced central nervous system drug delivery. BTK inhibitors and S1P receptor modulators demonstrated anti-inflammatory activity in clinical trials, although some agents failed to show superiority over established therapies. Cell-based therapies, including CAR T-cell therapy and stem cell transplantation, showed early promise in refractory disease but remain limited by safety concerns and insufficient long-term data. Remyelination-promoting agents and EBV-targeted immunotherapies demonstrated encouraging preliminary findings; however, many approaches remain in preclinical or early-phase clinical stages. Nanotechnology-based delivery systems and microbiome-directed therapies represent emerging areas with potential translational relevance. Emerging therapies in MS reflect a growing shift toward mechanism-based and potentially personalized therapeutic strategies. Although several approaches demonstrate promising preclinical and early clinical results, many remain investigational, and further large-scale studies are required to establish long-term efficacy, safety, and clinical applicability.
Vericiguat as an adjunct to temozolomide therapy improves behavioral and tumor outcomes in experimental glioblastoma.
Niya FR, Bashiri H, Emadi L … +2 more , Jonaidi H, Azizi S
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42295376 · Publisher ↗
Glioblastoma (GBM) is an aggressive brain tumor with limited effective therapies. The standard agent, Temozolomide (TMZ) though beneficial, often induces neurocognitive side effects that compromise quality of life. This...
Glioblastoma (GBM) is an aggressive brain tumor with limited effective therapies. The standard agent, Temozolomide (TMZ) though beneficial, often induces neurocognitive side effects that compromise quality of life. This study examined whether combining Vericiguat; a soluble guanylate cyclase stimulator, with standard or reduced TMZ doses could enhance antitumor efficacy and behavioral outcomes while reducing adverse effects in a rat model of GBM. 80 male Wistar rats received intracerebral injections of C6 glioma cells and were assigned to eight groups: Sham, Tumor, Vehicle, TMZ 3.75 mg/kg, TMZ 7.5 mg/kg, Vericiguat 0.5 mg/kg, and their combinations. Behavioral assessments (open field, elevated plus maze, rotarod, passive avoidance, and social interaction) were performed on days 20-24. On day 25, brain tissues were analyzed histologically and immunohistochemically (Ki-67). Survival was monitored for three months. Combination therapy significantly improved anxiety-like behavior, motor coordination, learning, memory, and social interaction compared with untreated tumor-bearing rats. Co treatment also extended survival, reduced tumor proliferation (lower Ki-67 expression), and preserved brain tissue structure. Vericiguat combined with low-dose TMZ produced synergistic effects on tumor suppression and neurocognitive recovery in GBM rats. These findings suggest that Vericiguat may enhance TMZ efficacy, enabling dose reduction and minimizing TMZ induced neurotoxicity while maintaining therapeutic effectiveness.
Ellagic acid and montelukast mitigate arsenic trioxide-induced hepatotoxicity via modulation of oxidative stress, inflammatory pathways, and mitochondrial apoptosis.
Gharibi M, Oroojan AA, Behmanesh MA … +3 more , Amirgholami N, Etedali H, Alboghobeish S
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42295375 · Publisher ↗
Arsenic trioxide (AsO) is an effective therapeutic agent for acute promyelocytic leukemia. However, its clinical application is limited by hepatotoxicity, mainly linked to oxidative stress, inflammatory activation, and m...
Arsenic trioxide (AsO) is an effective therapeutic agent for acute promyelocytic leukemia. However, its clinical application is limited by hepatotoxicity, mainly linked to oxidative stress, inflammatory activation, and mitochondrial dysfunction. This study investigated whether ellagic acid (EA) and montelukast (MK), alone or together, protect against AsO-induced liver injury in mice. Male NMRI mice were treated with AsO in the presence or absence of EA and MK for 10 days. After treatment, we performed biochemical, molecular, mitochondrial, and histopathological evaluations. AsO exposure led to pronounced hepatic injury, which was evident from elevated liver enzyme levels, increased lipid peroxidation, raised pro-inflammatory cytokines, reduced mitochondrial membrane potential, and increased apoptosis indices. Administration of EA or MK alone partly reduced several of these parameters. In contrast, concurrent use of EA and MK produced more marked improvements, including normalization of liver enzymes, enhanced antioxidant enzyme activity, lower pro-inflammatory and apoptotic markers, and preserved mitochondrial function. These protective effects were supported by consistently improved liver histopathology. In conclusion, combined EA and MK administration reduces AsO-induced hepatotoxicity. This protection occurs by modulating oxidative stress, inflammation, and mitochondrial-dependent apoptosis. These findings indicate that targeting several processes could help reduce liver side effects from arsenic-based chemotherapy.
AMPK-mediated modulation of JAK2/STAT3 signaling in asthma: a promising target for controlling airway inflammation and remodeling.
Althagafi H, Al-Kuraishy HM, Badawy HK … +2 more , Mustafa AM, Batiha GE
Naunyn Schmiedebergs Arch Pharmacol · 2026 Jun · PMID 42287317 · Publisher ↗
To highlight the therapeutic potential of targeting the AMPK/JAK2/STAT3 signaling axis in severe asthma, particularly neutrophilic and steroid-resistant forms, where current therapies such as corticosteroids show limited...
To highlight the therapeutic potential of targeting the AMPK/JAK2/STAT3 signaling axis in severe asthma, particularly neutrophilic and steroid-resistant forms, where current therapies such as corticosteroids show limited long-term effectiveness. This review examines current evidence on the role of the AMPK/JAK2/STAT3 pathway in asthma pathogenesis, with emphasis on its involvement in airway inflammation, immune dysregulation, and airway remodeling. It also evaluates the potential of pharmacologic modulators, especially AMPK activators such as metformin and JAK inhibitors, as targeted therapeutic strategies. The JAK2/STAT3 axis promotes pro-inflammatory type 2 and type 17 immune responses, airway inflammation, and structural airway changes. In contrast, AMPK acts as an anti-inflammatory regulator that can suppress excessive STAT3 activation and help restore immune balance. Available evidence suggests that activation of AMPK, particularly by metformin, alone or in combination with JAK inhibitors, may reduce cytokine release, modulate immune cell differentiation, and limit pathologic cellular remodeling in asthma. Targeting the AMPK/JAK2/STAT3 axis may provide a unified and promising therapeutic approach for severe, treatment-resistant asthma. Although current findings support the clinical potential of this strategy, further studies are needed to clarify the underlying mechanisms in human asthma and to optimize its application within a precision medicine framework.
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