Search Results (261)

Breast cancer (BC) is a malignant tumor that develops in the mammary gland due to uncontrolled cell proliferation. Estrogen receptor (ER) signaling, mediated by 17β-estradiol (E2), plays a crucial role in regulating cell proliferation, differentiation, and survival. Specifically, the binding of E2 to the estrogen receptor alpha (ERα) increases cell proliferation. Conversely, selective estrogen receptor beta (ERβ) agonists inhibit cancer cell proliferation by suppressing the expression of oncogenes, making ERβ an important therapeutic target. Given the urgent need for targeted and effective therapies for BC, we implemented a strategy based on multicomplex pharmacophores modeling of ERβ (MPMERβ) and ERα (MPMERα), performing a virtual cross-screening of databases of clinically approved and experimental drugs to identify those with high affinity and stereoelectronic complementarity with the ERβ agonist pharmacophore hypothesis. The implementation of a chemoinformatic strategy enabled the identification of Sobetirome, Labetalol, and Procaterol as molecular hits on the ERβ pharmacophore map. Procaterol showed the most significant antiproliferative activity in vitro assays, with IC₅₀ values of 21.26 and 36.10 µM in MCF-7 and MDA-MB-231, respectively. It is imperative to note that these findings require experimental validation of the ERβ activation pathways to strengthen the possible therapeutic repurposing of the drugs selected through our in silico approach. Finally, this strategy not only facilitates drug repurposing under in silico simulation but also provides valuable information for the rational design of new drugs against BC. Full article

Chronic HBV infection remains a global health challenge, driving liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Liver injury is primarily mediated by host immune responses rather than direct viral cytotoxicity. Macrophages, including Kupffer cells, play dual roles in antiviral defense and disease progression. HBV skews macrophages toward an M2-like, immunosuppressive phenotype, promoting viral persistence and fibrogenesis via cytokines such as Interleukin (IL)-10 and Transforming growth factor-beta (TGF-β). Therapeutic strategies targeting macrophage polarization, including Toll-like receptor (TLR) agonists, immune checkpoint inhibitors, and nanoparticle-based systems, are under investigation. Addressing macrophage heterogeneity and the immunosuppressive hepatic microenvironment using advanced models is essential. Modulating macrophages offers a promising avenue to control HBV, restore immune balance, and mitigate liver injury. This review highlights the central role of macrophages in chronic HBV infection and explores emerging therapeutic strategies. Full article

Estrogen-related receptor beta (ESRRB) is thought to be an orphan receptor that functions as a transcription factor, pioneer factor, and mitotic bookmarker to regulate cell stemness, pluripotency, and differentiation. This study (1) investigates whether calcium and cadmium activation of ESRRB regulates signaling pathways of stemness and pluripotency, (2) explores the transcriptomic and biological alterations of metal activation of ESRRB, and (3) reveals the underlying mechanisms by which metals activate ESRRB. In HEK293T cells, treatment with calcium and cadmium increased the expression of ESRRB-regulated genes that was blocked by an ESRRB antagonist. In the breast cancer cell line MDA-MB-453, treatment with calcium, cadmium, or a synthetic agonist also increased the expression of ESRRB-regulated genes that was blocked by the antagonist, enhanced ESRRB nuclear localization, increased the recruitment of RNA polymerase 2 to estrogen-related receptor response elements (ERRE), enhanced cell stemness and proliferation pathways, and induced the expression of estrogen receptor alpha (ESR1 or Erα). Mutational analysis and molecular docking identified potential metal interaction sites within ESRRB’s ligand-binding domain. Together, these results suggest calcium acts as a natural ligand for ESRRB and cadmium, which mimics calcium, activate ESRRB to mediate cell stemness and pluripotency. Full article

To better address the challenge of corneal ulcer healing, with already available standard agents, and those recently introduced, such as stable gastric pentadecapeptide BPC 157, we introduced a novel conceptual framework—the “triad” of corneal ulcer healing↔corneal neovascularization↔intraocular pressure—and extended it to avascular tissues such as tendon. Within this framework, cytoprotection serves as the unifying principle, underscoring that therapeutic effects are not isolated but interconnected. Preclinical studies with BPC 157 therapy, as a cytoprotection agent, illustrate this integration. BPC 157 rapidly normalizes elevated intraocular pressure in glaucomatous rats, preserves retinal integrity, restores pupil function, maintains corneal transparency during ulcer or abrasion healing, and counteracts both corneal neovascularization and dry eye. In parallel, its consistent efficacy in tendon injury models highlights a cytoprotective specificity across avascular tissues. The cornea’s “angiogenic privilege,” preserved during healing and tendon recovery together, provides strong proof of concept. Furthermore, mapping standard therapeutic agents used for corneal ulcers, neovascularization, or glaucoma onto this triad, and linking them with tendon healing, reveals both shared pathways and inconsistencies across existing drug classes. Analyzed were the ascorbate, fibronectin, hyaluronic acid, metalloproteinase inhibitors, EGF, FGF, NGF, insulin, and IGF-1 (corneal ulcer healing), the antiangiogenic agents (endostatin, PAI-1, PEDF, angiostatin, TSP-1, TSP-2, IFN-α), corticosteroids, NSAIDs, cyclosporine A, anti-VEGF drops (treatment of corneal neovascularization), and alpha 2-agonists, beta-blockers, carboanhydrase inhibitors, muscarinic agonists, Rho-kinase inhibitors, and prostaglandin analogs (glaucoma). Taken together, these findings advance cytoprotection as a unifying therapeutic paradigm, with BPC 157 emerging as its first exemplar, and encourage further translational research toward clinical application. Full article

This review addresses the growing concern of oral side effects, particularly dry mouth, associated with semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) widely used for diabetes and obesity. A literature search of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar (March–September 2025) identified studies on GLP-1 receptor signaling, semaglutide pharmacology, salivary gland biology, biased agonism, β-arrestin, and cAMP pathways, and reported oral adverse effects. Of 183 records screened, 78 met inclusion criteria and were narratively synthesized across 5 mechanistic domains linking the molecular mechanisms that may underly semaglutide-induced alteration in salivary function by exploring GLP-1 receptor (GLP-1R) expression and signaling in salivary glands. The available literature data shows that different GLP-1 receptor agonists exhibit distinct patterns of GLP-1R activation, engaging the cAMP- and β-arrestin–dependent pathways to varying extents, which may thus differentially regulate exocytosis and cellular protection. Furthermore, semaglutide’s strong albumin binding leads to prolonged receptor activation, and may disturb the rhythmic calcium and cAMP cross-talk essential for normal salivary secretion. Persistent stimulation may cause receptor desensitization, β-arrestin–mediated internalization, and reduced gland responsiveness. Clinical pharmacovigilance data indicate disproportionality signals, suggesting that semaglutide may be reported more frequently with oral side effects compared with other GLP-1 receptor agonists, although spontaneous-report databases cannot confirm causality. These insights underscore the need for patient counseling, preventive oral care, and further studies on receptor signaling bias, contributing to personalized approach when using GLP-1RAs. Full article

Beta-agonists are growth promoters sparking considerable interest in animal husbandry. However, their numerous negative effects on health have led to a number of restrictions on their presence in agricultural products, which differ depending on the type of preparation and food. In this regard, there is a demand for methods of their mass, rapid, and easy control with strict, focused selectivity. In this paper, a lateral flow immunoassay (LFIA) with clenbuterol (CLE), a priority β2-agonist for food safety, as the main target compound is proposed. The LFIA is based on indirect labeling of specific antibodies by gold nanoparticles via anti-species antibodies. The development of the LFIA involved optimizing the concentrations of immunoreagents and the composition of the reaction mixture (buffer type and pH, ionic strength, detergents, and additional components). In qualitative (visual) mode, the LFIA detects up to 1.0 ng/mL of CLE. In quantitative mode, the detection limit reaches 0.02 ng/mL, surpassing previously described colorimetric LFIAs. The selectivity of the obtained and used monoclonal antibodies allows for the group-specific detection of CLE and structurally close (the presence of a trimethyl residue, similar charge distribution in the benzene ring) common β2-agonists—salbutamol and mabuterol—distinguishing them from other β-agonists, including the widely used β1-agonist ractopamine, which differs in application and biological activity. The assay time is 15 min. The application of the LFIA for meat samples demonstrated that the CLE recovery ranged between 86% and 104%. The obtained results confirm the effectiveness and competitive potential of the developed assay for screening meat products outside of laboratories. Full article

Background/Objectives: Asthma exacerbations are among the most frequent causes of pediatric emergency department (ED) visits, with over 700,000 annual cases in the United States and a significant number in Europe. Children under five years of age are particularly vulnerable to hospitalization. Methods: As timely assessment of exacerbation severity in the ED is critical, this review synthetizes data about tools such as the Pediatric Respiratory Assessment Measure (PRAM) and the Asthma Severity Score (ASS) aid in evaluating clinical status based on respiratory rate, oxygen saturation, accessory muscle use, and response to treatment. We also analyzed the proper management following established guidelines from GINA, NAEPP and other articles. Results: First-line therapy includes oxygen supplementation, short-acting beta-agonists (SABAs) administered frequently during the first hour, and early systemic corticosteroids. In moderate to severe cases, ipratropium bromide is added. For refractory or life-threatening presentations, intravenous magnesium sulfate, epinephrine, or ventilatory support may be required. Discharge is appropriate when symptoms resolve, oxygen saturation remains >94% on room air, and the child demonstrates adequate inhaler use. Hospitalization is indicated in cases of persistent hypoxemia, poor response, feeding difficulties, or social concerns. Post-discharge care includes thorough caregiver education, medication access, and a personalized asthma action plan to reduce recurrence risk. Conclusions: The effective diagnosis, appropriate exacerbation treatment, monitoring of patients in the post-attack period, as well as successful preventive medication play a key role in the management of pediatric patients with asthma. Full article

Alzheimer’s (AD) and Parkinson’s (PD) diseases are the most prevalent neurodegenerative disorders (NDs), posing a growing global health burden due to the lack of effective therapies. Current treatments offer only limited symptomatic relief without preventing the progression of NDs. In the search for novel therapeutic strategies, peroxisome proliferator-activated receptor alpha (PPARα) has emerged as a promising therapeutic target because mounting evidence suggests that PPARα activation can effectively modify key pathological mechanisms related to NDs, including neuroinflammation, mitochondrial dysfunction, oxidative stress, and impaired transcriptional regulation, processes leading to protein misfolding and aggregation. This review focuses on the potential therapeutic relevance of PPARα activation in AD and PD, discussing mainly insights from preclinical studies. Indicatively, gemfibrozil (PPARα agonist) markedly reduced the beta-amyloid burden, microgliosis, and astrogliosis in the hippocampus of 5xFAD mice and ameliorated their spatial learning and memory. Fenofibrate (PPARα agonist) reduced the depressive-like behavior and memory deficits in rotenone-lesioned rats developing Parkinsonism. It also restricted the depletion of striatal dopamine and protected their substantia nigra pars compacta from dopaminergic neuronal death and α-synuclein aggregation. Clinical trials gave disparate results, indicating either a benefit of fenofibrate in cognitive decline of AD patients or limited efficacy. The role of PPARα agonists in PD is less well established in human trials, which provided limited evidence of neuroprotection and reduced neuroinflammation. Although current findings are promising, they underscore the necessity of further rigorous clinical validation of the efficacy of various PPARα agonists in the retardation or even prevention of AD and PD symptomatology in both genders and the development of reliable biomarkers for the early assessment of the impact of PPARα agonists on NDs. The safety of these drugs in the elderly and their longitudinal effectiveness should also be evaluated. Full article

Diurnal enuresis can significantly affect a child’s biopsychosocial well-being; however, there is a lack of diagnostic and management algorithms on the diagnosis. The purpose of this literature review is to dissect the development of the evaluation and management of diurnal enuresis. A total of 44 articles published from January 1900 to December 2024 were chosen through literature searches in PubMed, Science Direct, Embase, and Google scholar. Search terms were “Diurnal Enuresis” or “Daytime Incontinence” as Mesh terms, and subsequent terms included “pediatrics”, “urinary bladder, overactive”, and “therapeutics”. Inclusion criteria included studies involving pediatric study subjects aged 5–18 years old with a specific diagnosis of diurnal enuresis, exclusion criteria were studies before 1900 and involving night-time wetting diagnoses. A consensus among the literature and the American Academy of Family Physicians recommends a stepwise diagnostic evaluation, including history taking followed by a focused physical exam, for diurnal enuresis has proven to be the most effective. Regarding treatment, biofeedback was shown to improve symptoms in 74% of cases in one study by Wiener, while pharmacological treatment via Mirabegron (beta 3 agonist) showed a 70% improvement in one study by Fryer, but older drugs such as oxybutynin (anticholinergics) are still preferred. A multidisciplinary approach with TENS therapy, behavioral modification, biofeedback, and pharmacology can enhance effectiveness, improve reliability, and provide more successful results while minimizing the impact of diurnal enuresis on a child’s well-being. Further research is needed to optimize pharmacologic management strategies and improve adherence to increase the likelihood of reaching treatment goals. Full article

Restless legs syndrome (RLS) is a sensorimotor disorder with evening-predominant symptoms; convergent models implicate brain iron dysregulation and alter dopaminergic/glutamatergic signaling. Because EEG provides millisecond-scale access to cortical dynamics, we synthesized waking EEG/ERP findings in RLS (sleep EEG excluded). A structured search across major databases (1980–July 2025) identified clinical EEG studies meeting prespecified criteria. Across small, mostly mid- to late-adult cohorts, four reproducible signatures emerged: (i) cortical hyperarousal at rest (fronto-central beta elevation with a dissociated vigilance profile); (ii) attentional/working memory ERPs with attenuated and delayed P300 (and reduced frontal P2), pointing to fronto-parietal dysfunction; (iii) network inefficiency (reduced theta/gamma synchrony and lower clustering/longer path length) that scales with symptom burden; and (iv) motor system abnormalities with exaggerated post-movement beta rebound and peri-movement cortical–autonomic co-activation, together with evening-vulnerable early visual processing during cognitive control. Dopamine agonist therapy partially normalizes behavior and ERP amplitudes. These converging EEG features provide candidate biomarkers for disease burden and treatment response and are consistent with models linking brain iron deficiency to thalamo-cortical timing failures. This mechanistic review did not adhere to PRISMA or PICO frameworks and did not include a formal risk-of-bias or quantitative meta-analysis; samples were small, heterogeneous, and English-only. Full article

Background: Triple therapy (long-acting muscarinic antagonists (LAMAs), long-acting beta agonists (LABAs) and inhaled corticosteroids (ICSs)) is a recommended treatment for moderate-to-severe asthma at GINA Steps 4 and 5. However, little is known about the acceptance and use of triple therapy in everyday practice. The EU-LAMA Survey assessed specialists’ knowledge and views on triple therapy in daily practice. Methods: A 19-question survey was administered to 630 pulmonologists, allergologists, general practitioners, and internal medicine specialists in Poland (58%), Greece (27%), Sweden (6.3%), Slovenia (5.4%), and Austria (3.7%) using a dedicated online platform and computer-assisted web interviews. Results: The majority of the physicians were pulmonologists (59%), followed by allergologists (15.7%). For uncontrolled asthma at GINA Step 4, 81% of the respondents preferred increasing the ICS dose to the maximum level, whereas 76% opted to add LAMAs to medium-dose ICSs. At GINA Step 5, 79% of the respondents chose LAMAs first, followed by biological therapy (51%). Oral corticosteroids were favored over increasing the ICS dose and adding LAMAs. Triple therapy was mostly administered in one inhaler (70% and 82% at GINA Steps 4 and 5, respectively). Barriers to the use of LAMAs included a lack of reimbursement (31%), unclear guidelines (24%), lack of experience (18%), insufficient evidence (13%), fear of step-up regimens (10%), and the ease of increasing ICS doses (9%). Conclusion: Many physicians continue to rely on oral corticosteroids at GINA Steps 4 and 5 and infrequently refer patients to triple therapy or biological treatments at GINA Step 5. Full article

Background/Objectives: We here describe the impact of navigated care on utilization patterns of pharmacologic and minimally invasive overactive bladder therapies. Methods: This retrospective observational cohort study used electronic medical record data from the Precision Point Specialty Analytics Portal in the United States. Eligible patients were adults (≥18 years) newly diagnosed and treated for non-neurogenic overactive bladder (1 January 2015 to 31 December 2019). Categorical endpoints were analyzed by chi-square test or Fisher exact test. Of 170,000 eligible patients, 8982 (≈5%) were randomly selected and stratified by navigation status (navigated: 1150 [12.8%]; non-navigated: 7832 [87.2%]). Results: Overall, 60.0% of patients were female, 69.9% were White, and 42.7% had Medicare coverage. Navigated care was more common among women, Black patients, and those covered by Medicaid/Medicare. Initial pharmacologic treatment rates were similar between navigated and non-navigated groups (anticholinergic: 57.0% vs. 57.4%; beta-3 agonist: 43.0% vs. 42.6%). Greater percentages of navigated versus non-navigated patients received minimally invasive therapy (23.8% vs. 10.8%, respectively; p < 0.0001). Discontinuation rates were lower for navigated versus non-navigated patients undergoing pharmacologic treatment (62.5% vs. 71.3%; p < 0.0001). Conclusions: Patient navigation for overactive bladder may help increase access to minimally invasive therapies and may be a tool to address treatment disparities. Full article

Background: Saharan dust intrusions (SDIs) are associated with poor air quality and adverse respiratory outcomes. However, their impact on real-world inhaler utilization remains insufficiently characterized. We aimed to examine the association between SDI and the dispensing of short-acting beta-agonists (SABA) and inhaled corticosteroid–long-acting beta-agonist (ICS–LABA) combinations in the Canary Islands, Spain. Methods: Pharmaceutical sales data for SABA and ICS–LABA were collected from 60 pharmacies in Santa Cruz de Tenerife (TF) and Las Palmas de Gran Canaria (GC) between June 2017 and May 2022. SDI days were identified based on daily PM₁₀ concentrations > 40 µg/m³ from the regional air quality monitoring network. Linear regression models evaluated associations between drug dispensations and SDI presence, frequency, and intensity, adjusting for seasonality (winter vs. summer). Results: Over 60 months, SABA sales were 14.8% lower in TF compared with GC, while ICS–LABA sales were 10.9% higher. SDI presence was associated with significantly higher ICS–LABA dispensations in both provinces (+5.7% in TF, +10.2% in GC), whereas no association was found for SABA. ICS–LABA sales correlated weakly but significantly with both SDI frequency and PM₁₀ levels. Seasonal analysis revealed stronger effects in winter, with ICS–LABA dispensations increasing by 14.3% (TF) and 9.6% (GC) during SDI months. For SABA, seasonal differences were independent of SDI exposure. Conclusions: SDIs in the Canary Islands are independently associated with increased dispensing of ICS–LABA maintenance therapy, particularly during winter months. Dispensing data offer a valuable population-level indicator of respiratory impact from natural airborne pollution and support the integration of environmental alerts into preventive respiratory care strategies. Full article

Background: Cardiometabolic syndromes, including diabetes, obesity, and metabolic syndrome, significantly contribute to cardiovascular fibrosis, a major driver of heart failure. Non-coding RNAs (ncRNAs)—notably microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)—have emerged as critical epigenetic regulators of fibrotic remodeling. Recent studies indicate that widely used metabolic modulators can influence ncRNA expression, potentially impacting on cardiovascular fibrosis. This review synthesizes evidence on the interplay between metabolic therapies and ncRNA regulation, with emphasis on therapeutic and biomarker potential of miRNAs. Methods: A literature search was manually curated and conducted on PubMed for studies published mainly in the last decade and evaluating the effects of metformin, sodium-glucose cotransporter-2 (SGLT2) inhibitors, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, glucagon-like peptide 1 (GLP-1) receptor agonists, and fatty acid oxidation inhibitors on ncRNA expression in the context of cardiovascular fibrosis. Data from in vitro, in vivo, and clinical studies were extracted and categorized by drug class, ncRNA target, and functional outcomes. Results: Several metabolic modulators specifically downregulate pro-fibrotic (miR-21, miR-92, H19, and metastasis associated lung adenocarcinoma transcript 1 (MALAT1)) and upregulate anti-fibrotic ncRNAs (miR-29, miR-133a, miR-711, miR-133a, miR-30a and miR-200 family). This results in global attenuation of the transforming growth factor- beta (TGF-β) signaling, which limits extracellular matrix (ECM) accumulation thus improving myocardial compliance. Across drug classes, changes in ncRNA profiles paralleled improvements in fibrosis-related endpoints. Conclusions: Metabolic modulators exert anti-fibrotic effects partly through ncRNA regulation, offering novel therapeutic strategies and potential biomarkers for cardiovascular fibrosis in cardiometabolic disease. Targeting metabolic–ncRNA crosstalk may enable more precise and synergistic interventions for preventing or reversing pathological remodeling. Full article

Breast cancer (BC) is associated with multiple molecular factors such as overexpression of the beta-2 adrenergic receptor (ADRB2) and the overproduction of its agonists (norepinephrine and epinephrine). The role of adrenergic signaling in BC highlights the therapeutic potential of non-selective beta-blockers (nsBBs) as inhibitors of well-established protumor signaling pathways related to ADRB2 and their possible affinity for other important protumoral receptors. Our aim was to identify how nsBBs currently prescribed may also interact with receptors other than ADRB2, which are related to the pathophysiology of BC, using bioinformatic intracellular pathway analysis (BIPA). Subsequently, the affinity of nsBBs for both ADRB2 and the targets identified by BIPA was evaluated. We found that, beyond ADRB2, both receptor tyrosine kinase 2 (ERBB2) and neuropeptide Y receptor (NPYR) are promising targets for nsBBs in the adjuvant treatment of BC, according to BIPA. Docking studies showed that the nsBB with the highest binding affinity (ΔG) was carvedilol (−10.5 kcal/mol), followed by propranolol (−8.5 kcal/mol). These in silico findings suggest previously unrecognized pharmacological mechanisms for nsBBs in the possible treatment for BC. Notably, differences in receptor affinity were observed among the nsBBs, with carvedilol exhibiting the strongest binding affinity values on ADRB2, ERBB2, and NPYR as biological targets against BC cells. These promising results require future experimental validation. Full article