Search Results (123)

A naive Bayesian classifier (NBC) combined with principal component analysis (PCA) effectively differentiates the dose-dependent effects of certain groups of psychoactive drugs based on their impact on the amplitude–spectral characteristics of electrocorticograms (ECoG) in rats. This approach has been shown to be useful for pharmacological screening of agents with unknown or poorly understood activity. Despite previously obtained optimistic results, classification determination for some drugs was inaccurate, necessitating the search for possible ways to improve the predictive effectiveness of the proposed algorithm. One possible approach would be to use as input quantitative data not only the impact of the psychoactive drugs studied on the amplitude–spectral characteristics of ECoG but also connectivity changes, including the average coherence power of different pairs of leads. The aim of this study was to compare the accuracy of NBC in classifying the pharmacological mechanism of action of agents with well-known mechanisms (test set) using pharmaco-EEG data on changes in the amplitude–spectral characteristics of ECoG, coherence, and the combined use of two data sets. Materials and methods. Experiments were performed on Wistar rats with chronically implanted ECoG electrodes. The training set, relative to which the effects of the pharmacological agents from the test set were classified, were the matrices of effects of 12 pharmacological agents: the NMDA antagonist dizocilpine, the D2/D3 antagonists haloperidol and sulpiride, the M-anticholinergic tropicamide, the H1/5HT2A receptor blocker hydroxyzine, the acetylcholinesterase inhibitor galantamine, the alpha-2 adrenergic agonist dexmedetomidine, the alpha-2 adrenergic antagonist atipamezole, the adenosine receptor blocker caffeine and the GABA-mimetics aminophenylbutyric acid (phenibut), bromdihydrochlorophenylbenzodiazepine (phenazepam) and 5-ethyl-5-phenyl-2,4,6(1H,3H,5H)-pyrimidinetrione. The test set included various drugs with tropism for the targets of the training set drugs: dopamine receptor antagonists chlorpromazine, droperidol, tiapride and raclopride, H1-histamine blockers diphenhydramine and promethazine, 5-HT2-receptor blockers ritanserin and glemenserin, acetylcholinesterase inhibitor ipidacrine, alpha2-adrenergic receptor antagonist yohimbine, alpha2-adrenergic agonists medetomidine and xylazine, GABA-mimetics 5-ethyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione and chloral hydrate. The analysis of the ECoG signal included the calculation of 132 amplitude–spectral characteristics and 75 coherence indicators, which, using the PCA, led to new integrative indicators used for further classification of the NBC. Results and discussion. For each drug in the test set, the median similarity probability with a particular group from the training set was calculated, which was used to assess the classification quality. It was found that, when using the amplitude–spectral characteristics of ECoG, the proposed methodological approach allows for the identification of the ECoG effects of several groups of psychoactive drugs, including D2/D3-dopamine, M-cholinergic, H1-histamine, and 5-HT2-serotonin receptor blockers, AChE inhibitors, GABA-mimetics, and alpha-2-adrenergic receptor agonists and antagonists. This approach enabled the correct classification of 18 of 24 groups in the test set. When using changes in coherence indices as the initial data, the classification accuracy also amounted to 18 of 24 groups. When combining the two data sets, the number of correctly identified NBC groups was 20 of 24 groups. When comparing the classification during training (confusion matrix), it was found that coherence data or adding coherence data to the data based on changes in amplitude–spectral characteristics leads to a statistically significant (p < 0.01 in both cases) increase in accuracy. Conclusions. The obtained data demonstrated high accuracy in classifying the pharmacological activity of the test sample drugs using any of the three compared approaches. Despite the lack of statistically significant differences between them, classification based on the combined dataset demonstrated a higher number of “correct” similarities. This allows us to recommend the approach based on combined data of drug effects on amplitude–spectral characteristics and coherence as the most promising for further studies using pharmaco-EEG screening. Full article

Histamine is a biologically active monoamine acting through four G protein-coupled receptors (H₁R–H₄R), which represent attractive therapeutic targets for a range of diseases. Nowadays, H₄R is recognized as a key player in inflammation and cancer. Here, we describe the design, syntheses and characterization of new H₄R ligands containing pyrido[2,3-d]pyrimidine or pyrimidine scaffold. Candidate structures were scored in silico by docking to the structure of the human inactive H₄R. Favorable structures were synthesized and, after confirmation of identity, their affinities were verified in in vitro screenings. Tested compounds did not exhibit any relevant cytotoxic (PrestoBlue) or antiproliferative (BrdU incorporation) effects at concentrations used in the functional assays. In a radioligand displacement assay (H₄R affinity) the pyrimidine series showed lower binding, whereas several pyrido[2,3-d]pyrimidine derivatives and one pyrimidine analog produced >60% inhibition at 1 µM. Two similar compounds with the highest and moderate affinities were selected for further studies. In the G_i–cAMP pathway, both compounds behaved as moderate H₄R antagonists, but in contrast, their profiles diverged in the β-arrestin pathway. These findings suggest ligand-dependent biased differences in signaling across G-protein and β-arrestin pathways at H₄R. Overall, YAN-153 emerges as a promising lead structure for further optimization and for more detailed in vitro (e.g., metabolic stability, selectivity) and in vivo studies. Full article

Background/Objectives: Colitis involves both local intestinal damage and systemic dysfunction, driven by oxidative stress and immune imbalance. Histamine, acting through its receptors, influences these processes, yet its therapeutic relevance in colitis remains unclear. This review systematically examines histamine-mediated signaling in colitic inflammation and evaluates preclinical and clinical data on antihistamines to assess their potential as a mechanism-based treatment. Methods: A structured literature search was conducted using PubMed and Google Scholar to identify studies addressing histamine signaling and the use of antihistamines in colitis, using keywords such as “colitis,” “histamine,” “histamine receptors,” and “antihistamines.” Relevant experimental and clinical studies were screened and critically analyzed to provide an integrated overview of mechanistic and therapeutic insights. This review was designed as a mechanistic narrative synthesis based on a structured search and qualitative appraisal rather than a formal systematic review with quantitative risk-of-bias grading. Results: Findings from preclinical investigations consistently indicate that pharmacological manipulation of histamine signaling—especially through H3 and H4 receptor subtypes—reduces inflammatory activity and modulates oxidative balance in animal models of colitis. Conversely, clinical evidence concerning H1 and H2 receptor antagonists remains scarce and discordant, lacking sufficient support for a definitive causal relationship or unambiguous therapeutic efficacy. Importantly, no clinical studies to date have assessed the effects of selective H3 or H4 receptor blockers in individuals with colitis, revealing a substantial disconnect between bench research and bedside application. Existing human trials have mainly concentrated on mucosal endpoints, with little attention paid to systemic manifestations or oxidative stress-related parameters. Conclusions: Histamine-dependent signaling constitutes a mechanistically credible target in colitis, connecting immune activation, impairment of the epithelial barrier, and oxidative injury. Although experimental data are encouraging, clinical corroboration remains absent. Antihistamines may hold greater promise for alleviating systemic oxidative stress than for directly ameliorating intestinal inflammation. Rigorously designed clinical trials that incorporate both gastrointestinal and systemic outcome measures are necessary to elucidate their therapeutic position. Full article

The tree shrew (Tupaia belangeri) is increasingly recognized as an important experimental model for studying human diseases due to its close phylogenetic relationship with humans. Because the basilar artery’s response to endogenous vasoactive mediators varies among species, we investigated the effects of vasoactive substances on isolated tupaia basilar arteries to determine whether this species is suitable as a human model. 5-Hydroxytryptamine (5-HT) and histamine (His) induced contraction, while bradykinin (BK) and acetylcholine (ACh) produced concentration-dependent relaxation. Pharmacological analysis revealed that contractions triggered by 5-HT were regulated through 5-H₁ and 5-HT₂ receptors, while His-induced responses were mediated by H₁ receptors. BK-induced relaxation was inhibited by the B₂ antagonist HOE140 and N^ω-nitro-L-arginine (L-NA), but not by B₁ antagonists or indomethacin, suggesting a B₂ receptor-mediated nitric oxide (NO) pathway. ACh-induced relaxation was markedly reduced in the presence of L-NA and the M₃ antagonist pFHHSiD, indicating M₃ receptor-mediated NO release. At basal tone, L-NA evoked a contractile response, while indomethacin led to relaxation, suggesting basal regulation by NO and prostanoids. These findings demonstrate that 5-HT₁/5-HT₂ and H₁ receptors mediate contraction, while B₂ and M₃ receptors mediate relaxation in the tupaia basilar artery. This study highlights species-specific cerebrovascular regulation and supports the tupaia as a relevant model for investigating human cerebrovascular physiology and pathophysiology. Full article

Background/Objectives: Proton pump inhibitors (PPIs) are known to alter gut microbiota composition; however, their association with disease courses and outcomes in patients with inflammatory bowel disease (IBD) remains uncertain. Our aims were to evaluate the association between PPI use and treatment escalation, Clostridioides difficile infection, and healthcare utilization in IBD. Methods: We conducted a retrospective cohort study on the TriNetX platform. IBD patients with PPIs or histamine-2 receptor antagonists (H2RAs) were matched one-to-one using propensity scores. Outcomes included initiation of corticosteroids, biologic therapy, Clostridioides difficile (C. difficile) infection, and healthcare utilization. Outcomes were assessed during the 0–12-month and 3–12-month follow-up windows. Associations were estimated using odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals. Results: After matching, 12,808 patients were included in each group. During 0–12 months of follow-up, PPI use was associated with higher odds of systemic corticosteroid exposure (OR 1.56, 1.35–1.79), biologic therapy initiation (OR 1.99, 1.72–2.29), C difficile infection (OR 1.42, 1.18–1.70), and healthcare utilization (OR 1.18, 1.03–1.36) compared with H2RA use. Time-to-event analyses showed persistent associations with systemic corticosteroid exposure (HR 1.50, 1.31–1.72) and biologic therapy initiation (HR 1.91, 1.66–2.19), with attenuation of associations for infection and healthcare utilization in 3–12-month lag-time analyses. Similar patterns were observed in ulcerative colitis and Crohn’s disease subgroups. Conclusions: PPI was associated with higher risks of treatment escalation and C. difficile compared with H2RA in IBD. These findings highlight the importance of individualized selection and periodic reassessment of acid suppression therapy as part of personalized management strategies in IBD. Full article

Post-inflammatory hyperpigmentation (PIH) is a common pigmentary disorder characterized by excessive melanin production following skin inflammation. Histamine, a key inflammatory mediator, is known to stimulate melanogenesis via H₂ receptors; however, the underlying calcium (Ca²⁺) signaling mechanisms remain largely unexplored. In this study, we investigated the role of the ORAI1-STIM1 complex in histamine-induced melanogenesis using B16F10 melanoma cells and normal human epidermal melanocytes (NHEMs). Histamine (10–30 μM) significantly increased melanin content (2.5–2.8-fold), an effect specifically abolished by the H₂ antagonist famotidine. Notably, while acute histamine application failed to trigger immediate Ca²⁺ influx, chronic exposure significantly enhanced store-operated Ca²⁺ entry (SOCE) capacity by approximately 2.8-fold, providing evidence for a functional remodeling of the Ca²⁺ signaling machinery. Histamine-induced melanogenesis was significantly suppressed by intracellular Ca²⁺ chelation, pharmacological inhibition of ORAI1 (BTP-2 or Synta-66), and siRNA-mediated silencing of ORAI1 or STIM1, but not ORAI2, ORAI3, or STIM2. Our findings demonstrate that chronic histamine exposure drives hyperpigmentation through ORAI1-STIM1-mediated SOCE remodeling, establishing this complex as a promising therapeutic target for the treatment of PIH and related inflammatory pigmentary disorders. Full article

Background/Objectives: The global prevalence and incidence of inflammatory bowel diseases have risen in the past two decades. Among them, Crohn’s disease and ulcerative colitis are still challenging to treat due to vascular and proliferative alterations. Studies in rats suggest that blocking histamine receptors (H1–H4) can improve colitis progression. However, the specific histamine receptor responsible for this effect remains debated. The experiment aimed to assess the role of specific histamine receptor subtypes in colitis development, focusing on oxidative stress markers in the liver and skeletal muscle. Methods: The study involved 60 adult male Wistar rats, divided into control and colitis experimental groups. Colitis was induced through intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid. Animals in both experimental groups received intramuscular injections of NaCl (non-treated, NT) or H1, H2, H3, and H4 receptor antagonists (10 study subgroups in total). On day eight, the animals were re-anesthetized and euthanized via exsanguination. Then, liver and skeletal muscle (m. soleus) samples were collected for analysis of oxidative stress markers. Results: The analyses of skeletal muscle samples showed that using the H1 and H2 receptor antagonists increased superoxide dismutase (SOD) and catalase (CAT) activities, as well as parameters related to glutathione metabolism (reduced glutathione (GSH), glutathione S-transferase (GST)) in rats from the control groups, indicating enhanced antioxidant defense. In rats with chemically induced colitis, we observed that H1 receptor antagonists elevated CAT activity, whereas β-esterase (β-EST) activity remained elevated across all colitis subgroups. In the liver, histamine receptor antagonists produced receptor-specific redox effects: the H2 receptor antagonist reduced oxidative damage (malondialdehyde (MDA)); the H1 receptor antagonist attenuated SOD hyperactivity, but depleted GSH; and the H4 receptor antagonist increased GSH while elevating MDA. Chemically induced colitis increased α- and β-EST activities, whereas administration of the H1 or H3 antagonist reduced β-EST levels. Conclusions: Histamine receptor antagonists modulated oxidative stress responses in both liver and skeletal muscle tissues in a receptor-dependent manner. Among them, the H2 receptor antagonist most effectively mitigated hepatic oxidative injury, highlighting its potential as a therapeutic target in colitis-associated systemic oxidative stress. Full article

Background: Glioblastoma is the most common and malignant primary brain tumor in adults, with current treatment presenting limited effectiveness. Therapeutic resistance stems largely from its marked molecular and cellular heterogeneity. Multitarget small molecules (MSMs) have emerged as a promising strategy for treating complex diseases such as cancer. In the present work, we generated a novel family of indole-based MSMs engineered to inhibit histone deacetylases (HDACs), monoamine oxidases (MAOs) and cholinesterases (ChEs) while simultaneously acting as histamine H₃ receptor (H3R) antagonists and sigma-1 receptor (S1R) agonists. Methods: To accomplish this, we combined selected pharmacophoric moieties from the parent compounds Contilisant and the HDAC pan-inhibitor Belinostat. Nine MSMs were synthesized. Results: Most of them showed cytotoxic activity in glioma cells. Among them, three molecules (MTP142, MTP156 and MTP150) were prioritized based on potency; these compounds impaired glioma stem cell (GSC) activity and were predicted to cross the blood–brain barrier. In vivo and multi-omic analyses centered on MTP150 showed significant tumor growth inhibition, both as monotherapy and in combination with temozolomide (TMZ). Transcriptomic and proteomic profiling of patient-derived GSCs revealed MTP150-induced disruption of cell cycle regulation pathways. Conclusions: Our data reveal the efficacy of a novel family of MSMs in the pre-clinical setting of glioblastoma. Full article

Background/Objectives: Glioblastoma is the most common and aggressive primary brain tumor in adults, with patient prognosis remaining poor. Treatment resistance and tumor recurrence are frequent, primarily due to the high intra- and inter-tumoral heterogeneity and the existence of glioma stem cells. Thus, there is an urgent need for novel and more effective therapeutic strategies. Multitarget small molecules (MSMs) are emerging as a novel therapeutic strategy for the treatment of complex diseases such as cancer. Methods: In the present work, we have generated a novel family of indole-based MSMs with pharmacophoric moieties combining the parent compounds Contilisant and the HDAC inhibitor Tubastatin A. Thus, the MSMs were designed to inhibit monoamine oxidases (MAOs), cholinesterases (ChEs) and histone deacetylases (HDACs), while acting as histamine H3 receptor (H3R) antagonists and sigma 1 receptor (S1R) agonists. We generated four different molecules and evaluated in detail the activity of the two most efficient MSM compounds in vitro and in vivo. Results: These molecules induced potent cytotoxic effects in vitro in patient-derived glioma stem cells and glioblastoma cell lines and significantly impaired tumor growth in vivo. OMIC analyses further revealed that the compounds induce dysregulation of the cell cycle in glioma stem cells. Moreover, in silico analyses indicated that these compounds are theoretically capable of crossing the blood–brain barrier, while exhibiting low toxicity in healthy cells. Conclusions: In conclusion, our findings demonstrate the potential antitumor activity of a novel family of MSMs in preclinical models of glioblastoma. Full article

Introduction: Patients with inflammatory bowel disease (IBD) have an increased risk of Clostridioides difficile infection (CDI). While antibiotic exposure has been considered the most prominent risk factor for CDI, proton pump inhibitor (PPI) use is another potential risk factor. Methods: From January 2017 to April 2021, we examined the University of Missouri’s IBD patients’ medical records. Laboratory-confirmed CDI diagnosis was the main outcome of interest. The usage of PPIs was the exposure of interest. The odds ratio between CDI risk in PPI users and non-users was estimated using logistic regression models. We investigated CDI risk with PPI use duration using stratified analysis. Results: Overall prevalence of CDI was 9%. 358 patients (42%) reported using PPI, with an average duration of ~30 months, with a range of 0.1 to 255. PPI use was associated with a higher risk of CDI in both the unadjusted (OR = 1.58 [0.98–2.53]; p = 0.06) and adjusted models (9.23 [2.11–40.34]; p = 0.003). Only those who used PPIs for less than 30 months had a greater risk of CDI in the stratified analysis (OR = 2.10 [1.16–3.38], p = 0.014). Long-term use (≥30 months) did not increase the incidence of CDI (OR = 0.74 [0.29, 1.83]; p = 0.510). Discussion: This is the single largest study of the US general IBD population to evaluate the association between PPI use and risk of developing CDI. PPI therapy was linked to a significant elevation in CDI risk, restricted to PPI use for up to 30 months. Histamine-2 receptor antagonists (H2RAs) did not increase the risk of CDI. Full article

Respiratory and food allergy conditions are increasing internationally and the most commonly used drugs in these conditions are antihistamines, products that can interfere as histamine receptor antagonists. In accordance with the need to test new principals capable of developing fewer side effects, we preliminarily studied the therapeutic antihistamine effect in vitro and in vivo of an innovative nutraceutical blend based on Quercetin, Perilla frutescens, Boswellia serrata, Blackcurrant, Parthenium, Helichrysum, Lactobacillus acidophilus and Bifidobacterium animalis. The in vitro test demonstrated the interaction between the examined mixture and a rat leukemia cell line (RBL-2H3) widely used as a model simulating mast cells in immunological and allergological studies; this pre-clinical test demonstrated a statistically significant reduction in cell histamine degranulation (about 30%). The in vivo test demonstrated instead that the mixture interferes up to 30% in the development of histamine wheal. In addition, during the in vitro test, we also tested the effect of the mixture on allergic inflammation, so we evaluated the interference of the mixture on TNF alpha levels, determining a reduction in tested concentrations of about 13%. Full article

Breast cancer remains a leading cause of mortality among women despite advances in early detection and targeted therapies, underscoring the need for safer and more effective treatment options. Drug repurposing offers a promising strategy by leveraging existing pharmacological agents with established safety profiles. Desloratadine, a second-generation H1-histamine receptor antagonist widely prescribed for allergic conditions, has attracted interest in oncology because histamine signaling influences proliferation, angiogenesis, and immune responses, yet its anticancer potential remains poorly understood. In this study, we investigated its effects in MCF-7 breast cancer cells, which harbor wild-type TP53. Desloratadine inhibited cell viability in a dose-dependent manner, with an IC₅₀ of 14.2 µg/mL. Mechanistic analyses revealed that growth inhibition was primarily mediated through apoptosis, confirmed by Hoechst 33342 staining, ROS generation, annexin V/PI staining, and caspase-dependent pathways. Gene expression profiling demonstrated upregulation of TP53, FAS, and BAX, alongside reduced PARP-1 and NF-κB expression, with no detectable STAT3 or BCL2 expression. Flow cytometry indicated accumulation of cells in the sub-G₁ phase and G₂/M arrest, consistent with apoptosis induction. Molecular docking further supported these findings, showing that Desloratadine binds with high affinity to p53 (−7.0 kcal/mol), FAS (−6.8 kcal/mol), and NF-κB (−6.5 kcal/mol), forming stabilizing hydrogen bonds and hydrophobic interactions aligned with the observed gene expression changes. To confirm the functional role of TP53, we generated CRISPR-Cas9 knockout MCF-7 cells. Compared with wild-type cells, these knockout cells displayed markedly reduced sensitivity to Desloratadine, with the IC₅₀ shifting from 14.2 µg/mL to 36.4 µg/mL, demonstrating that p53 is a key mediator of the drug’s cytotoxic effect. Collectively, these findings identify Desloratadine as a potential repurposed drug candidate for breast cancer therapy, acting at least in part through a p53-dependent apoptotic pathway. Full article

The antipsychotic drug haloperidol is found on the WHO list of essential drugs. In vitro, haloperidol demonstrates binding affinity for various receptors, including histamine H₂ receptors (H₂Rs). Several cardiac effects of haloperidol are known, but it remains unclear whether H₂Rs are involved. Here, the hypothesis was tested that haloperidol has the potential to act as either an agonist or an antagonist of human cardiac H₂Rs. The contractile effects of haloperidol were studied in isolated left and right atrial preparations from transgenic mice overexpressing human H₂Rs in the heart (H₂-TG), and compared to human atrial preparations from adult patients. Haloperidol reduced the histamine-stimulated force of contraction in the human atrial preparations as well as the histamine-stimulated force of contraction and beating rate in the left and right atrial preparations from the H₂-TG, respectively. Moreover, haloperidol reduced the isoprenaline-stimulated force of contraction in the human atrial preparations. In the wild-type mouse preparations, haloperidol only reduced the isoprenaline-stimulated beating rate in the right atria, but not the force in the left atria. Principally, haloperidol is capable of acting as an antagonist of both H₂Rs and β-adrenoceptors in the human heart. However, the effects are only relevant at very high doses of haloperidol, which are never or seldom achieved in practice. Full article

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder characterized by immune dysregulation and epidermal barrier dysfunction. Advances in understanding the interplay of genetic predisposition, cytokine signaling, and environmental triggers have led to the emergence of targeted therapies. Although biologic agents such as dupilumab, tralokinumab, and lebrikizumab have revolutionized AD management, their high costs, injectable administration, and limited global accessibility highlight the need for alternative options. Small molecule therapies are gaining momentum as they target intracellular pathways central to AD pathogenesis and offer oral or topical administration routes. This review provides a comprehensive analysis of key agents including Janus kinase (JAK) inhibitors (upadacitinib, abrocitinib, baricitinib, ruxolitinib, delgocitinib), phosphodiesterase 4 (PDE4) inhibitors (crisaborole, difamilast, roflumilast, apremilast), as well as STAT6 degraders (KT621, NX3911), aryl hydrocarbon receptor modulators, histamine H4 receptor antagonists (adriforant, izuforant), and sphingosine-1-phosphate receptor modulators (etrasimod, BMS-986166). We summarize their mechanisms of action, pharmacological profiles, and pivotal clinical trial data, emphasizing their potential to address unmet therapeutic needs. Finally, we discuss safety concerns, long-term tolerability, and future directions for integrating small molecule therapies into precision treatment strategies for moderate-to-severe AD. Full article

Influenza is still a chronic global health threat, inducing a sustained search for effective antiviral therapeutics. Computational methods have played a pivotal role in developing small molecule therapeutics. In this study, we applied a combined in silico and in vitro approach to explore the potential anti-influenza activity of cyproheptadine, a clinically used histamine H1 receptor antagonist. Virtual screening based on the average quasivalence number (AQVN) and electron–ion interaction potential (EIIP) descriptors suggests similarities between cyproheptadine and several established anti-influenza agents. The subsequent ligand-based pharmacophore screening of a focused H1 antagonist library was aligned with the bioinformatics prediction, and further experimental in vitro evaluation of cyproheptadine demonstrated its anti-influenza activity. These findings provide proof of concept for cyproheptadine’s in silico-predicted antiviral potential and underscore the value of integrating computational predictions with experimental validation. The results of the current study provide a preliminary proof of concept for the predicted anti-influenza potential based on computational analysis and emphasize the utility of integrating in silico screening with experimental validation in the early stages of drug repurposing efforts. Full article