Diabetic kidney disease (DKD) is one of the most significant microvascular complications of diabetes, characterized by high incidence and mortality; however, its pathogenesis remains unclear. Renal inflammation and macrophage infiltration play pivotal roles in driving DKD progression. The transcription factor forkhead box protein O1 (FOXO1) regulates the transcriptional expression of multiple pro-inflammatory molecules and modulates macrophage polarization. Nevertheless, its specific role in DKD macrophages remains unknown. In vivo, streptozotocin-induced DKD mice showed significantly higher FOXO1 expression in infiltrated kidney macrophages. Treatment with the FOXO1-selective inhibitor AS1842856 for 4 or 12 weeks reduced serum creatinine, blood urea nitrogen, renal matrix collagen deposition and the severity of macrophage infiltration in DKD mice. In vitro, using mouse bone marrow-derived macrophages and RAW264.7 cells cultured under high glucose, we found that high glucose promoted pro-inflammatory M1 macrophage polarization. This polarization process was effectively blocked by either AS1842856 treatment or FOXO1 small interfering RNA-mediated gene silencing. In summary, FOXO1 critically regulates macrophage infiltration and functional phenotype in DKD-affected renal tissue. Targeting FOXO1 therefore holds promise as a potential therapeutic strategy to delay DKD progression.
Fluoride is widely used for caries prevention due to its effects on mineralized tissues, yet its potential role as a modifier of systemic metal homeostasis remains insufficiently explored. This systematic review synthesizes preclinical evidence on the association between fluoride exposure and changes in metal and semi-metal concentrations across biological matrices. A comprehensive search strategy was conducted across major databases without language or date restrictions, following SyRF, CAMARADES and PRISMA 2020 guidelines. Thirty-one animal studies were included, encompassing multiple species, exposure conditions and analytical approaches. Despite substantial methodological heterogeneity, consistent patterns emerged. Fluoride exposure was associated with element-specific redistribution of the metallome rather than uniform change. Essential elements were predominantly depleted, most consistently zinc, copper and manganese, whereas the toxic metals lead and cadmium tended to be retained. This contrast between homeostatically regulated essential elements that are lost and non-regulated toxic metals that accumulate supports the hypothesis that fluoride differentially modifies the distribution and retention of co-existing elements. The novelty of this review lies in integrating metallomic outcomes across experimental models, highlighting fluoride as a potential systemic modulator rather than a tissue-specific agent. Although variability in study design and risk of bias limits causal inference, the consistent directionality of findings across models reinforces their biological plausibility and translational relevance.
Trazodone is an antidepressant approved for the treatment of major depressive disorder and is associated with a low incidence of sexual dysfunction. However, its effects on male reproductive health are not yet fully understood. Therefore, this study aimed to evaluate the effects of repeated trazodone administration on reproductive parameters and the distal cauda epididymal duct contractions in rats. Adult male Wistar rats were orally treated by gavage for 21 days with saline (control) or trazodone at 10 and 20 mg/kg. After treatment, the blood and reproductive organs were collected for the experimental analysis. Trazodone induced adverse reproductive effects in rats, evidenced by testicular tissue damage, increased intratesticular lipid peroxidation and reduced sperm production and sperm count in different epididymal regions. Additionally, trazodone treatment reduced progressive sperm motility, the number of viable and morphologically normal sperm, indicating decreased sperm quality. The contraction of the isolated distal cauda epididymal duct was also impaired by trazodone treatment, suggesting possible alterations during the emission phase of ejaculation. In conclusion, trazodone exhibited significant reproductive effects that may impair male fertility. These findings provide, to our knowledge, the first integrated assessment of trazodone-induced changes in testicular morphology, sperm parameters and epididymal duct contractility.
The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is increasing significantly in an age-dependent manner. Growing evidence supports the conceptualization of AD as 'type 3 diabetes,' a term proposed to describe a metabolic disease primarily driven by impaired insulin signalling and insulin resistance within the brain. This review explores the shared molecular mechanisms underlying both T2DM and AD, including chronic neuroinflammation, oxidative stress, mitochondrial dysfunction and impaired glucose metabolism. Specifically, the crosstalk involves the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, where insulin resistance leads to increased glycogen synthase kinase 3β (GSK-3β) activity, promoting tau hyperphosphorylation and amyloid-β (Aβ) accumulation. Furthermore, the article examines the roles of the NOD-like receptor protein 3 (NLRP3) inflammasome, O-linked β-N-acetylglucosamine modification (O-GlcNAcylation), and the gut-brain axis as critical mediators linking metabolic dysfunction to neurodegeneration. Unlike previous reviews that predominantly address individual pathways in isolation, this review provides an integrated molecular framework that connects insulin resistance to neurodegeneration through converging signalling cascades and highlights emerging therapeutic targets including the NLRP3 inflammasome and O-GlcNAcylation as potential mechanistic bridges between T2DM and AD. Finally, the therapeutic potential of various antidiabetic agents such as glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and thiazolidinediones is discussed, as these drugs offer promising opportunities for the treatment and prevention of AD by targeting these common molecular pathways.
Vascular smooth muscle cells (VSMCs) are essential for maintaining arterial wall integrity, with their associated apoptosis critically involved in cardiovascular diseases. Intracellular chloride anion (Cl-) dysregulation is closely linked to apoptosis. However, the underlying mechanism via chloride-sensitive kinases remains unclear. Here, we show that hypotonic stimulation activates volume-regulated chloride channels (VRCCs) and induces the phosphorylation of the chloride-sensitive kinase WNK1. Activated WNK1 protects VSMCs against H2O2-induced apoptosis by maintaining the Bcl-2/Bax balance, preserving mitochondrial membrane potential and inhibiting caspase-9/3 activation. These findings uncover a novel protective role of WNK1 in VRCC-mediated Cl- signalling and provide new perspectives for targeting chloride-sensitive kinases in the treatment of hypertension and related cardiovascular diseases.
Geographic variation in ADHD treatment and diagnosis among children and adolescents is well documented, yet the system-level factors driving such differences remain poorly understood. We examined nationwide patterns of ADHD medication use and diagnoses in Denmark in 2024 and assessed whether municipal socioeconomy, regional hospital waiting times or private child psychiatrist capacity contributed to geographic variation. In this register-based cross-sectional study, we included all Danish residents aged 4-17 years using data from national registers. Pharmacological treatment was defined as at least one redeemed prescription for ADHD drugs, and diagnosis was defined as at least one hospital contact with ICD-10 codes F90.x/F98.8. Prevalence was calculated overall and stratified by sex and age, with associations explored using Spearman's rank correlations and regression analyses. ADHD medication prevalence varied sixfold across municipalities (9.6-58 per 1000), with parallel variation in diagnoses (15-74 per 1000) and the largest differences observed among adolescents. Municipal socioeconomic status was weakly and inversely correlated with medication use (ρ = -0.20, p = 0.049), but not diagnoses. Neither waiting times nor specialist capacity was significantly associated with either outcome. Marked geographic variation in ADHD medication use and diagnoses persists in Denmark despite a uniform healthcare framework, and appears largely unexplained by the system-level factors examined.
Genetic hypertrophic and dilated cardiomyopathies (HCM and DCM, respectively) are characterised by structural and functional abnormalities that can lead to heart failure. However, current therapies mainly reduce symptoms. Patient-derived human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes provide a valuable platform to study genotype-specific pathophysiology and pharmacology. We subjected hiPSC-cardiomyocytes from healthy individuals and from patients carrying pathogenic MYBPC3 (HCM) or LMNA (DCM) mutations to cyclic mechanical stretch, with or without the GATA4-targeted anti-hypertrophic compound 3i-1262, and assessed hypertrophy-associated, mechanosensitive and metabolism-related genes by qPCR, and hypertrophy-related proteins by Western blotting. Compared to control, HCM cardiomyocytes displayed higher basal expression of NPPB and MYH7, whereas DCM cardiomyocytes exhibited lower basal expression of NPPB and NPPA. Mechanical stretching induced NPPB and MYH7 upregulation in control cardiomyocytes, delayed MYH7 upregulation in HCM cardiomyocytes and NPPA downregulation in DCM cardiomyocytes. Other mechanosensitive genes, such as GAL, CSRP3 and SLC16A9, also exhibited genotype- and time-dependent regulation. In control cardiomyocytes, 3i-1262 produced limited modulation of stretch-induced gene expression but showed little or no effect in patient-derived cardiomyocytes. These findings demonstrate that cardiomyopathy mutations influence gene and protein expression, responses to mechanical stretch and 3i-1262, underscoring the value of patient-derived hiPSC-cardiomyocytes in disease modelling and drug discovery.
AIM:To estimate persistence with antihypertensive therapy (AHT) and describe treatment changes and associated factors among persistent patients over 5 years. METHODS:We conducted a longitudinal cohort study using the IADB.nl pharmacy database in the Netherlands, including adults who initiated AHT between 2014 and 2018 after a 2-year washout. Persistence was assessed annually using a ±45-day window around each treatment anniversary. Among patients persistent throughout follow-up, treatment changes were classified yearly as no change, switching, intensification or de-intensification. A Markov model estimated transitions between treatment states, and logistic regression evaluated baseline factors associated with treatment changes. RESULTS:Among 22 027 starters (mean age 58.1 years, 51.1% women), annual persistence declined from 88.8% in year 1 to 80.7% in year 5, with 52.7% remaining persistent over 5 years. Treatment changes were most frequent in the first year, when 53.5% of persistent patients underwent intensification, de-intensification, or switching, and declined thereafter. The probability of remaining in the same state was high, particularly for 'no change' state (0.86). Female sex, combination therapy initiation and initiating on beta-blockers or calcium-channel blockers were associated with treatment changes. CONCLUSION:Antihypertensive pharmacotherapy is frequently modified early after initiation, followed by increasing long-term treatment stability among persistent users.
Drugs that interact with brain nociceptin/orphanin FQ (NOP) receptors can decrease ethanol consumption in preclinical models of alcohol use disorder (AUD). Studies using positron emission tomography (PET imaging) in humans with AUD reported lower levels of NOP receptors compared to controls. Here, uptake of the NOP receptor-selective PET radiotracer [11C]NOP-1A was measured in monkeys (six males, five females) when ethanol-naïve and again after a 4-month induction procedure plus 6 months of ethanol drinking (22 h/day, 5 days/week). Although there were no sex differences in brain uptake of [11C]NOP-1A before ethanol self-administration, sex differences were observed in relationships between [11C]NOP-1A uptake and ethanol-related measures. Baseline [11C]NOP-1A uptake in the orbitofrontal cortex in males and caudate nucleus in females predicted future ethanol intakes. Moreover, chronic ethanol self-administration produced changes in [11C]NOP-1A uptake in AUD-related brain areas. Increases in uptake were observed in the putamen of both sexes and in the nucleus accumbens and amygdala of males; females showed a decrease in the insula. Changes in [11C]NOP-1A uptake in the orbitofrontal cortex, putamen and hypothalamus of males and caudate nucleus of females were related to ethanol intake. These results demonstrate bidirectional relationships between brain NOP receptors and ethanol self-administration and provide evidence of subtle sex differences in these interactions.
Vitamin K was discovered during the 1930s when a strange haemorrhagic disorder was observed in chickens fed a cholesterol-free diet. A fat-soluble agent, present in green leafy vegetables and hog liver, was able to restore haemostasis in the chickens. The chemical structure and the physiological role of vitamin K were uncovered resulting in the Nobel Prize being awarded to Henrik Dam and Edward Doisy in 1943. The discovery of vitamin K led to a breakthrough in our understanding of the human coagulation system, where vitamin K plays a pivotal role in activating prothrombin and other coagulation factors. The prevention of vitamin K-dependent bleeding in newborns by vitamin K prophylaxis was introduced in the 1940s and is today a strong recommendation by the World Health Organization. Vitamin K also became crucial to the management of diseases with high risk of vitamin K deficiency due to malabsorption of fat. Later a new type of drug was developed, vitamin K antagonists, counteracting the physiologic effects of vitamin K for the prevention of thrombotic events. Recent research has indicated that vitamin K may have important functions beyond coagulation in extra-hepatic tissues by promoting healthy bone mineralization and preventing vascular calcification.
Transient receptor potential ankyrin 1 (TRPA1) is a cation channel originally identified in lung fibroblasts and extensively studied in sensory neurons, where it is associated with pain and neurogenic inflammation. We and others have recently shown that TRPA1 is also expressed in lung epithelial cells and that its expression is regulated by the cytokine environment. In the present study, we used next-generation sequencing to analyse the role of TRPA1 and the effects of its inhibition on human A549 lung epithelial cell phenotype under inflammatory conditions. Two different TRPA1 inhibitors (HC-030031 and A-967079) were used and found to alter the expression of 968 genes: 576 genes were downregulated, and 392 upregulated. Ingenuity Pathway Analysis (IPA) predicted that TRPA1 inhibitors significantly suppress the activity of pulmonary fibrosis idiopathic signalling and wound healing pathways. In these pathways, altered genes included matrix metalloproteinases (MMPs), growth factors, collagens and transcription factors. The major profibrotic mediators MMP-12 and MMP-7 were among the most strongly inhibited genes by TRPA1 inhibitors. STRING network analysis suggests that TRPA1 regulates fibrosis-related genes through FOS gene and AP-1 transcription factor. These findings together with previous data propose TRPA1 as a factor and therapeutic target in fibrotic lung diseases, which are associated with poor survival and critical need for novel disease-modifying therapies.
BACKGROUND:Psychotropics are increasingly prescribed in paediatrics despite limited evidence regarding their benefits and effectiveness. Although deprescribing approaches are established in adults, structured paediatric strategies remain poorly defined. AIMS:To identify and evaluate clinical practice guidelines (CPGs) on psychotropic deprescribing in youth, to describe and discuss recommendations regarding when and how to deprescribe in practice. METHODS:We systematically searched PubMed, Embase, PsycInfo, Scopus, Web of Science and grey literature (2015-2025). Two reviewers independently screened and evaluated the quality of the guidelines (AGREE II). We derived from this a psychotropic deprescribing algorithm in youth, supplemented with clinical expertise. RESULTS:Among the 1390 records identified, none strictly met the methodological criteria for formal CPGs. Nevertheless, we assessed two papers that provided practical deprescribing recommendations and shared several characteristics with CPGs. One systematic review focused on antidepressant discontinuation, recommending tapering after remission with gradual dose reduction and monitoring to distinguish withdrawal from relapse. One narrative review provided child-specific guidance for stimulants, recommending reassessment and possible discontinuation after 1 year of stability. Both were rated as 'moderate' using the AGREE II tool and provided limited practical detail on stepwise deprescribing procedures. CONCLUSION:Critical gap and urgent need for paediatric-specific deprescribing guidelines. We propose an expert-informed stepwise deprescribing algorithm.
BACKGROUND:General practitioners manage most opioid tapering. This process requires time-consuming, individualised planning accounting for patient preferences, dose options and costs. Consequently, clinicians need tools to support tapering. This review explores existing international digital decision support systems for opioid tapering. METHODS:We conducted a scoping review following the JBI methodology. Five databases (PubMed, Embase, CINAHL, Cochrane and Web of Science) were searched in January 2026. Title/abstract and full-text screening were performed independently by two reviewers based on predefined eligibility criteria. Disagreements were resolved by a third reviewer. Data were extracted and summarised both descriptively and narratively. RESULTS:The search identified 2340 studies, of which four met the eligibility criteria. The studies included described four different technology-driven decision support tools for opioid tapering. The tools varied in format and clinical context (primary and secondary care), but they all aimed to support clinicians in planning and managing opioid tapering. Evidence on clinical effectiveness and real-world implementation was limited across the studies. CONCLUSION:Only few studies have investigated technology-driven decision support for opioid tapering, and only one is set within a European context. While tools exist in different formats and clinical settings, evidence on their effectiveness and real-world implementation remains limited, highlighting a need for further development and evaluation.
The 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor rosuvastatin is a substrate of breast cancer resistance protein (BCRP). BCRP inhibition increases rosuvastatin plasma concentrations and may result in concentration-dependent muscle toxicity, at worst rhabdomyolysis. We investigated if concomitant use of rosuvastatin and drugs identified as in vitro BCRP inhibitors shows an increased number of rhabdomyolysis events based on pharmacovigilance data. From reports in the US Food and Drug Administration Adverse Event Reporting System for patients using rosuvastatin, we formed interaction (rosuvastatin with inhibitor) and non-interaction (rosuvastatin without inhibitor) groups for 71 BCRP inhibitors. These groups were further divided into subgroups with or without rhabdomyolysis. For each inhibitor, we calculated reporting odds ratio (ROR) and 95% confidence intervals (CIs). We identified 9777 individual rosuvastatin-related reports during 2013-2023, including 815 rhabdomyolysis reports. Of the 71 inhibitors, 19 had enough reports for analysis. Significantly increased RORs were obtained for the clinical BCRP inhibitors febuxostat (ROR 2.47, 95% CI 1.38-4.43) and ticagrelor (ROR 4.15, 95% CI 3.32-5.20). Amiodarone, erlotinib and rifampicin showed significantly increased RORs. Our findings support known interactions involving febuxostat and ticagrelor and suggest that also other BCRP inhibitors may increase the risk of rosuvastatin-induced rhabdomyolysis.
Phα1β is a peptide toxin originally isolated from the venom of the Brazilian spider Phoneutria nigriventer, known for its potent analgesic effects in preclinical models of acute and chronic pain. However, clinical translation has been limited by production constraints. A recombinant analogue, CTK01512-2, was developed and has demonstrated antinociceptive efficacy comparable to the native toxin in diverse experimental models. In this study, we examined the effects of CTK01512-2 on N-type voltage-gated calcium channels (Cav2.2) expressed in transiently transfected HEK-293 cells and confirmed its antinociceptive action in a mouse model of neuropathic pain. CTK01512-2 induced a partial (~50%) and reversible inhibition of Cav2.2-mediated calcium currents, with a calculated half-maximal inhibitory concentration (IC50) of 3.94 nM. In contrast to ω-conotoxin MVIIA, a clinically approved irreversible Cav2.2 blocker, CTK01512-2 allowed current recovery after washout, indicating reversible binding. Notably, the toxin did not significantly alter the voltage dependence or kinetics of channel activation. These findings identify CTK01512-2 as a selective and reversible Cav2.2 channel modulator, underscoring its therapeutic potential as a novel analgesic agent for chronic pain management.
Medication burden in older patients with chronic kidney disease (CKD) is substantial, and simple medication counts are insufficient for identifying those at elevated risk of inappropriate prescribing. This study characterized medication burden by assessing the number of medications, potentially inappropriate medications (PIMs) and anticholinergic burden in dialysis and non-dialysis patients with CKD aged ≥ 65 years. This retrospective study included patients with a CKD diagnosis who had hospital contact at the Department of Nephrology, Aalborg University Hospital, Denmark, between January and December 2022. Patients were classified as receiving dialysis or not, and polypharmacy and hyper-polypharmacy were defined as ≥ 5 and ≥ 10 medications, respectively. PIMs were identified using the EU(7)-PIM list, and anticholinergic burden was evaluated using the ACB scale with a cut-off of ≥ 3 points. In total, 140 dialysis patients and 534 non-dialysis patients were included. Polypharmacy was present in all dialysis patients and in 83% of non-dialysis patients, whereas hyper-polypharmacy affected 89% and 56%, respectively. Dialysis patients had a higher median number of PIMs (3 vs. 2) and a greater proportion with an ACB score ≥ 3 (44% vs. 27%). Proton pump inhibitors (PPIs), opioids and non-benzodiazepine hypnotics (Z-drugs) were identified as common PIMs, whereas bladder antimuscarinics (tolterodine and solifenacin), sedating antihistamines (clemastine and promethazine) and antipsychotics with anticholinergic properties (quetiapine) were the most frequently used medications with strong anticholinergic properties. In conclusion, medication burden in patients with CKD is high, and incorporating PIMs and ACB scores may identify prescribing risks not captured by medication counts alone.
There are no bibliometrics analyses on articles published in clinical pharmacology journals. We aimed to determine the countries in which authors of original investigations or meta-analyses were based and their international collaboration. This is a cross-sectional study conducted in six journals linked to learned clinical pharmacology societies/associations. For each journal, we started with the June-2025 issue and searched backward for articles meeting the selection criteria until 100 were identified or the January-2024 issue was reached. To calculate the credit by country, we used the complete fractionalized counting (CFC) method for assessing authors' contribution considering only the country of the authors included in the byline. CFC awards 1 credit among all authors and countries. A total of 503 articles were included in the analysis: 100 from four journals and 79 and 24 from the other two. Investigators from 66 countries from all continents contributed as authors; 46 countries provided lead authors. All but one were multi-authored articles; 9% were authored by international teams (range among the six journals: 16%-41%). Of the 503 credits, top countries were the United States (99.14), China (76.14), Japan (31.65), Denmark (28.69) and the Netherlands (27.29). The 17 EU countries obtained 151.86 credits (30.2% of the total). Among the top 25 countries, only five were not high-income countries. This exploratory analysis showed that with limited international collaboration, the authors of these studies worked mainly in wealthy countries, except for China.
