Search Results (1,416)

Aging and obesity accompanied with hormonal disequilibrium represent critical, inter-related risk factors for breast cancer, significantly influencing disease incidence, progression, and therapeutic outcomes. This review aims to elucidate the multifaceted biological mechanisms linking obesity and aging to breast carcinogenesis, with a particular focus on the emerging therapeutic and preventive potential of postbiotics as molecules targeting cellular events important for cancer growth and responsiveness. Despite continuous advancement, breast cancer therapy still poses several challenges, such as treatment-induced acquired resistance, which is boosted by the inflammatory phenotype of senescent cancerous cells, as well as undesired side effects resulting from the destruction of normal cells. Such a complex background of breast carcinogenesis and oncotherapy resistance opens avenues to search for new preventive approaches and adjunctive treatment regimens. Postbiotics demonstrate a variety of benefits due to their selective antineoplastic activity, as well as the cytoprotective potential associated with antioxidant, anti-inflammatory and anti-senescent properties. Pleiotropic effects of postbiotics make them a promising tool for counteracting cellular and physiological disturbances that favor breast cancer development, including age- and obesity-related factors. They are prospective adjunctive agents in oncotherapy, albeit their efficacy and safety need to be thoroughly evaluated in clinical studies prior to implementation in routine treatment modes. Full article

Endocrine disorders are increasingly recognized as major contributors to secondary cardiomyopathies, leading to profound alterations in cardiac structure and function. This comprehensive review synthesizes current evidence on the genetic basis of cardiomyopathies associated with endocrine conditions, including primary aldosteronism, Cushing’s syndrome, pheochromocytoma/paraganglioma, acromegaly, thyroid disorders, hyperparathyroidism, and diabetic cardiomyopathy. We examine the contribution of somatic and germline mutations, genetic polymorphisms, shared molecular pathways transforming growth factor-β (TGF-β)/SMAD (TGF-β/SMAD signaling, the renin–angiotensin–aldosterone system, oxidative stress, and calcium handling), sarcomeric gene modifiers, ion channel variants, and epigenetic mechanisms to disease pathogenesis. We propose a conceptual framework distinguishing three major categories of genetic involvement: (i) variants causing the primary endocrinopathy; (ii) genetic modifiers of myocardial susceptibility under conditions of hormonal excess; and (iii) direct pleiotropic effects, whereby single gene variants independently cause both endocrine and cardiac phenotypes. In addition, we discuss genotype–phenotype correlations, ethnic and population differences in genetic susceptibility, the emerging role of polygenic risk scores, and precision medicine approaches. Overall, this review provides an integrated perspective on the complex genetic architecture of endocrine-related cardiomyopathies and outlines practical considerations for genetic testing aimed at improving patient management and clinical outcomes. Full article

Background/Objectives: Modern diabetes therapy extends beyond glycemic control and increasingly focuses on comprehensive risk reduction to prevent long-term complications, improve quality of life, and reduce premature mortality. Accordingly, modern therapeutic approaches address not only glucose metabolism but also cardiovascular, renal, and metabolic consequences of diabetes. Within this context, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a significant therapeutic class. In addition to their well-known effects on glycemic control and the metabolic-cardiovascular-renal axis, increasing evidence suggests that these agents may exert a range of pleiotropic effects and opening new therapeutic venues, discussed in this review. Methods: A narrative review of the literature was conducted using the PubMed, Scopus, and Google Scholar databases. Publications from 2014 and 2026 were screened using predefined keywords related to GLP-1 RAs and their potential effects across multiple physiological systems and diseases. Notably, more than 80% of the included studies were published between 2020 and 2026, reflecting the recent growth of research in this field. Results: GLP-1 RAs have been associated with beneficial effects across a wide range of conditions, including substance use disorders, mental health disorders, neurodegenerative diseases, obesity-related complications, liver disease, genitourinary disorders, osteoarthritis, and sleep apnea. While they are currently the most effective pharmacological agents for the treatment of obesity, they also significantly reduce hepatic steatosis and are associated with a decreased risk of developing hepatocellular carcinoma. Furthermore, they have also demonstrated positive effects against prostate cancer, polycystic ovary syndrome (PCOS), improved libido and fertility. Conclusions: GLP-1 RAs should no longer be regarded solely as antihyperglycemic agents. Instead, they represent a versatile therapeutic class with expanding clinical relevance across multiple medical disciplines. While current evidence is promising, further large-scale, well-designed clinical trials are required to define their full therapeutic potential. Full article

Background: Vitamin D has been increasingly investigated for its pleiotropic immunomodulatory and antimicrobial effects, which may influence periodontal inflammation and healing. This systematic review aimed to evaluate the impact of serum vitamin D levels and vitamin D supplementation as an adjunct to non-surgical periodontal therapy (NSPT) on clinical and microbiological outcomes in patients with periodontitis. Methods: An electronic search was conducted in MEDLINE and other major databases up to September 2025. Randomized controlled trials assessing the relationship between vitamin D status or supplementation and periodontal outcomes following NSPT were included. Data were synthesized qualitatively, focusing on changes in serum 25(OH)D levels and periodontal parameters, including probing pocket depth (PPD), clinical attachment level (CAL), plaque index (PI), and gingival inflammation. Results: Four studies met the inclusion criteria. In patients with sufficient baseline vitamin D levels, supplementation provided limited additional clinical benefits beyond NSPT alone. Conversely, in vitamin D-deficient patients, supplementation regimens capable of restoring serum 25(OH)D levels above 30 ng/mL were consistently associated with greater reductions in PPD, improved CAL, and decreased plaque and bleeding indices. Microbiological analyses also revealed a reduction in red complex periodontal pathogens in supplemented groups. Conclusions: Vitamin D supplementation enhances the clinical effectiveness of NSPT primarily in patients with documented vitamin D deficiency. Its adjunctive benefits appear to be mediated by immunomodulatory and antimicrobial mechanisms that complement mechanical debridement. While current evidence supports targeted supplementation in deficient individuals, long-term randomized trials are required to establish standardized protocols and confirm sustained clinical benefits. Full article

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has driven the global COVID-19 pandemic, imposing a tremendous burden on public health. As the virus continually evolves through rapid mutations, the pandemic has transitioned into a prolonged endemic phase. Despite the development of novel drugs and vaccines, clinical outcomes remain suboptimal for vulnerable populations, including the elderly and those with comorbidities or compromised immunity. Tea polyphenols, a class of structurally diverse and bioactive nutraceuticals, may modulate viral entry, replication, and host inflammatory pathways implicated in disease progression through pleiotropic effects on viral attachment, membrane fusion, intracellular replication, and proteolytic processing. Here, we provide an updated chemo-biological perspective on the antiviral and immunomodulatory mechanisms of tea polyphenols against SARS-CoV-2. Current evidence highlights their potential to serve as promising candidates for further mechanistic and translational investigation as adjunctive strategies and nutraceuticals for COVID-19 management. Importantly, no large-scale randomized controlled trials have yet demonstrated clinical benefit of tea polyphenols in COVID-19. Full article

Background: Improving grain yield in wheat remains a top priority, requiring integrated breeding and genetic strategies. This complexity poses a major challenge, driven by quantitative polygenic inheritance, environmental influence, and intricate genetic interactions. We investigated genetic factors and their interactions for agronomic and yield traits in two high-yielding winter wheat cultivars adapted to the US Southern Great Plains. Methods: A bi-parental mapping population consisting of 221 F₇ recombinant inbred lines (RIL) derived from ‘TAM 204’ and ‘Iba’ was evaluated for three years in 11 Texas environments. Both parents and RIL population were genotyped on Illumina NovaSeq 6000 and sequences were aligned to IWGSC RefSeq v1.0 using Bowtie2 for SNP calling. For QTL analyses, each trait was analyzed by individual environment, across multiple environments and mega-environments. Results: A total of 86 QTL were mapped for five traits and among them 32 were consistent in more than one environment or analysis. Among consistent QTL, four were pleiotropic to more than one agronomic or yield traits mapped on chromosomes 2B (57.18, 59.47 Mb) and 2D (29.34, 40.64 Mb). The consistent QTL on chromosome 2D (29.34 Mb) was pleiotropic to GYLD, DTH, TW, TKW and explained maximum phenotypic variation for all traits, representing photoperiod gene (Ppd-D1). Another QTL on chromosome 2D (40.64 Mb) was pleiotropic to GYLD and TW and based on the physical position comparisons it likely reflects a unique locus in Iba. The pleiotropic consistent QTL Qgyld.tamu.2B.59 from TAM 204 represents Ppd-B1 gene. Moreover, it is more likely that Qdth.tamu.5B.575 represents the Vrn-B1 gene in Iba. A total of 23 digenic epistatic interactions involved consistent QTL for all traits. Amongst these, epistatic interactions between the consistent QTL on 2B (57.18 Mb) and 2D (29.34 Mb) were observed for GYLD, DTH and TKW. Conclusions: Our findings revealed key allelic diversity and interaction effects in elite wheat cultivars, paving the way for marker development for identified pleiotropic loci and implementation in marker-assisted selection and recombination breeding. Full article

Circadian disruption represents a global health issue associated with cardiometabolic diseases, sleep disturbances, and mood disorders, driven by a pathophysiological network including clock gene dysregulation and impaired melatonin synthesis. Vitamin D exerts pleiotropic effects on metabolic regulation, immune function, neurotransmission, and possibly circadian synchronization. Emerging evidence suggests that vitamin D and its hydroxyderivatives modulate clock gene expression, influence transcriptional regulators such as retinoic acid receptor-related orphan receptors and REV-ERBs, and interact with melatonin synthesis and signaling. Vitamin D deficiency has been associated with metabolic syndrome, impaired sleep quality, and depression. Although interventional studies yield heterogeneous results, higher vitamin D status may confer protective metabolic and neurobehavioral effects. This review summarizes current evidence on the role of vitamin D in circadian disruption and evaluates its potential therapeutic relevance in circadian–metabolic dysregulation. Full article

Novel pharmacological approaches advocate developing multitarget drugs, that is, molecules capable of simultaneously acting on two or more pharmacological targets to produce synergistic effects from a single compound in each disease. This strategy may help reduce required doses and prevent drug–drug interactions typically associated with polypharmacy. Coumarins are natural products with diverse pharmacological activities, including antioxidant, anti-inflammatory, anticancer, neuroprotective, cardioprotective, and antithrombotic effects. The pleiotropic actions of these molecules suggest that modifying the coumarin structure could yield new multi-target antiplatelet agents with greater efficacy and safety than those currently available in clinical practice. In this work, we began with a theoretical approach using molecular docking and designed three coumarins that simultaneously inhibited platelet aggregation induced by epinephrine, collagen, and ADP. Experimentally, we evaluated the structure activity relationship of three coumarins: (A) 6,7-dimethoxy-3-(1H-pyrrol-1-yl)-2H-chromen-2-one, (B) 7,8-dimethoxy-3-(1H-pyrrol-1-yl)-2H-chromen-2-one, and (C) 3-(1H-imidazol-1-yl)-6,7-dimethoxy-2H-chromen-2-one. In silico studies suggest that compounds B and C may exhibit antagonistic interactions at the α₂-adrenergic, GPVI collagen, and P₂Y₁₂ ADP receptors. Additionally, molecular docking indicates essential interactions between the compounds and the GPIIb/IIIa fibrinogen receptor. Full article

Hydra vulgaris, an ancient cnidarian, exhibits remarkable regenerative and neurogenic abilities, mediated by morphogenetic peptides, particularly the head activator peptide. This neuropeptide appears to regulate cell proliferation, differentiation, and nerve net maintenance in hydra and, surprisingly, exerts similar mitogenic and neurogenic effects in mammalian systems. Despite early enthusiasm, research on head activator has declined, due to controversies about its genetic origin, receptor identity, and artefacts generated during isolation. Nonetheless, a synthetic variant of head activator corresponding to the described sequence has consistently exhibited strong biological activity in a variety of mammalian cells. Experimental evidence implicates the sortilin-related receptor (SorLA) as a primary receptor in mammals, with potential modulatory roles for the G-protein-coupled receptor GPR37. This review consolidates current knowledge on the evolutionary context, molecular characteristics, and functional activities of head activator. Insights from mammalian systems highlight its pleiotropic effects across species. Given its neuroprotective, regenerative, and immunomodulatory properties, head activator may merit reconsideration as a therapeutic candidate for neurodegenerative disorders and regenerative medicine. Full article

Triple-negative breast cancer represents one of the most aggressive and therapeutically challenging subtypes of breast malignancies, characterized by marked biological heterogeneity, rapid progression, and limited targeted treatment options. Conventional therapies are frequently constrained by drug resistance, systemic toxicity, and high rates of recurrence. In this context, natural products have gained increasing attention as multifunctional agents capable of modulating several hallmarks of triple-negative breast cancer. Bioactive compounds, including polyphenols, terpenoids, alkaloids, and marine-derived molecules, exhibit pleiotropic antitumor effects by interfering with key oncogenic pathways. Importantly, these compounds have demonstrated the ability to counteract major mechanisms of therapeutic resistance, modulate the tumor immune microenvironment, and enhance the efficacy of standard chemotherapy and immunotherapy. Advances in drug delivery strategies, such as nanoparticle-based systems and tumor-targeted formulations, together with patient-specific molecular profiling, further expand the potential of these agents within personalized treatment approaches. This narrative review critically examines the role of natural compounds in targeting the hallmarks of triple-negative breast cancer and their potential synergistic use to improve therapeutic efficacy while reducing treatment-related toxicity. Overall, the integration of natural product-based strategies into precision oncology frameworks may offer more effective, less toxic, and individualized therapeutic options for this aggressive breast cancer subtype. Full article

Background: Neuropathic pain remains a major unmet clinical challenge. Growing evidence identifies sigma receptors (σRs) as pivotal intracellular modulators of maladaptive stress signaling, positioning them as promising non-opioid targets for chronic pain management. Notably, despite the pleiotropic nature of σRs in regulating diverse cellular pathways—which might theoretically suggest a high risk of off-target effects—current selective antagonists have demonstrated remarkable safety and tolerability profiles. Sigma-1 and sigma-2 receptors (σ1R and σ2R) are molecularly and functionally distinct proteins that regulate neuronal excitability, proteostasis, and neuroimmune communication, all mechanisms that characterize neuronal excitability and cellular stress adaptation. σ1R acts as a ligand-operated molecular chaperone at the mitochondria-associated endoplasmic reticulum membrane. Extensive preclinical data demonstrate that σ1R antagonism attenuates peripheral and central sensitization, suppresses neuroinflammation, and restores opioid analgesic efficacy. These findings are supported by the advanced clinical candidate E-52862, which has shown efficacy and a favorable safety profile in neuropathic pain conditions. σ2R, identified as transmembrane protein 97 (σ2R/TMEM97), functions as a regulator of cholesterol trafficking, lysosomal integrity, and integrated stress response (ISR). σ2R modulation alleviates neuropathic pain by restoring proteostatic balance and reducing ISR-driven neuronal vulnerability rather than directly suppressing excitability. Emerging σ2R ligands such as FEM-1689, UKH-1114, and CM-398 provide compelling proof-of-concept for durable, disease-modifying analgesia. Methods: A structured literature search was conducted using PubMed, Scopus, and Web of Science to identify studies published within the last decade describing σ1R and σ2R/TMEM97 biology, ligand development, and their preclinical or clinical evaluation in neuropathic pain. Reference lists were manually screened to ensure comprehensive coverage. Conclusions: This review synthesizes pharmacology, ligand development, and translational evidence supporting σRs as next-generation targets for neuropathic pain therapy, highlighting convergent roles of σ1R and σ2R in pain chronification and outlining future directions for structure-guided therapeutic strategies. Full article

Background/Objectives: Retinoblastoma represents the most common intraocular malignancy in childhood; however, the clinical applicability of mitomycin C (MMC) is restricted by dose-dependent ocular toxicity. Consequently, the development of pharmacological strategies that sensitize tumor cells to MMC while allowing dose reduction remains an unmet therapeutic objective. In this context, quercetin, a bioactive flavonoid with pleiotropic anticancer properties, has emerged as a potential chemosensitizing agent. Methods: Human retinoblastoma cell lines Y79 and WERI-Rb1 were exposed to MMC and quercetin, administered either individually or in fixed-ratio combinations. Cytotoxic responses were quantified through dose–response modeling and IC₅₀ determination following 24 and 48 h of treatment. Drug–drug interactions were quantitatively characterized using the Chou–Talalay combination index (CI) approach and isobologram analysis. Cell cycle distribution was assessed by propidium iodide (PI)-based flow cytometric analysis to evaluate treatment-associated alterations in cell cycle progression. Apoptotic cell death was assessed by Annexin V-FITC/PI flow cytometry, while transcriptional modulation of genes associated with apoptosis, cell cycle regulation, and oxidative stress (BAX, BCL-2, TP53, CASP3, CDKN1A, and HMOX1) was evaluated by qRT-PCR. Modulation of tumor-supportive signaling was examined by measuring VEGF and IL-6 secretion. Translational relevance was further investigated using a three-dimensional (3D) tumor spheroid model, and the functional contribution of reactive oxygen species (ROS) was interrogated through N-acetyl-L-cysteine (NAC) rescue experiments. Results: Quercetin significantly enhanced the cytotoxic activity of MMC in both retinoblastoma cell lines, with CI values below 1 across IC₅₀–IC₉₀ effect levels, indicating a synergistic pharmacological interaction. PI–FACS analysis revealed that combined MMC and quercetin treatment induced a pronounced accumulation of cells in the G2/M phase, consistent with cell cycle arrest, with a more marked effect observed in Y79 cells compared with WERI-Rb1 cells. Combination treatment resulted in a pronounced increase in apoptotic cell populations compared with single-agent exposure and triggered a coordinated pro-apoptotic transcriptional response, characterized by increased expression of BAX, TP53, CASP3, CDKN1A, and HMOX1, alongside suppression of BCL-2 and a marked shift in the BAX/BCL-2 ratio. Concurrently, VEGF and IL-6 secretion were significantly reduced, reflecting attenuation of pro-angiogenic and pro-inflammatory signaling. Notably, synergistic cytotoxicity was maintained in 3D tumor spheroids, where combined treatment induced spheroid shrinkage, architectural disruption, and reduced viability. NAC pretreatment diminished ROS accumulation and partially restored cell viability, indicating that oxidative stress contributes to, but does not solely account for, the observed synergistic cytotoxic effect. Conclusions: Collectively, these findings indicate that quercetin appears to function as an effective chemosensitizing adjuvant to MMC in retinoblastoma models, through transcriptional changes consistent with p53-associated apoptotic signaling at the transcriptional level, G2/M cell cycle arrest, and partial involvement of ROS-related cellular stress responses, along with suppression of tumor-supportive signaling pathways. The preservation of synergistic activity in 3D tumor spheroids supports the potential preclinical relevance of this combination. However, these findings are based on transcriptional and phenotypic analyses and should be interpreted as hypothesis-generating, requiring further validation through protein-level and in vivo studies before translational application. Full article

Introduction/Objective: Common hop (Humulus lupulus L.) is a multi-component plant material that has been extensively studied for its antioxidant, anti-inflammatory, cardioprotective, metabolic, neuroprotective, immunomodulatory and anti-cancer properties. This review summarises current data on the molecular mechanisms of action of hop compounds, their therapeutic potential, metabolic interactions and biological significance, with particular emphasis on bioavailability, signalling pathways and organ-specific effects. Methods: A comprehensive literature review was conducted, covering in vitro and in vivo studies and available clinical trials analysing the biochemical activity, molecular targets and physiological effects of bioactive compounds in hops. Particular attention was paid to the regulation of oxidative stress, inflammatory signalling, mitochondrial function, metabolic pathways, interactions with the gut microbiota and their impact on the development of chronic diseases. Results: Bioactive compounds in hops modulate numerous key signalling pathways, including NF-κB, Nrf2, AMPK, MAPK, PPAR and PI3K/AKT/mTOR. They have been shown to reduce oxidative stress, inhibit the production of pro-inflammatory cytokines, regulate apoptosis, improve mitochondrial function, and activate endogenous antioxidant systems. Hops have a protective effect in cardiovascular diseases, metabolic disorders, neurodegenerative diseases and selected cancers through anti-inflammatory, anti-proliferative and metabolic mechanisms. In addition, hop compounds modulate the composition and activity of the gut microbiota, which promotes improved metabolic homeostasis. Despite relatively good intestinal absorption, systemic bioavailability remains limited; however, modern delivery systems significantly increase the stability and plasma concentrations of these compounds. Conclusions: Common hops have broad therapeutic potential due to their ability to regulate oxidative, inflammatory, metabolic and apoptotic processes at multiple levels. Their pleiotropic activity makes them a promising candidate for the prevention and treatment of chronic diseases. The development of delivery systems and consideration of the role of the gut microbiota may further increase its clinical application. Full article

Exposure of healthy tissue to ionizing radiation (IR) occurs due to nuclear accidents and terrorism, as well as radiotherapy. The vascular endothelium is a key target of IR, and microvascular endothelial cells (ECs) are particularly vulnerable to radiation. IR induces EC activation leading to endothelial cell injury. Human ghrelin is a stomach-derived peptide with pleiotropic effects, including protection against inflammation. We hypothesize that human ghrelin improves survival in total body irradiation (TBI) and that ghrelin’s protective effect could be mediated by attenuating endothelial cell injury. To test this, mice were exposed to TBI and after 24 h were treated subcutaneously with human ghrelin once daily for 4 days and monitored for 30 days. The survival rate of the human ghrelin-treated group was significantly higher than that of the vehicle group. Subsequently, human ghrelin treatment showed an effective dose modification factor of 1.0681. On day 4 after TBI, human ghrelin significantly attenuated EC permeability in the lungs and improved tight junction protein ZO-1 expression. Human ghrelin also improved ZO-1 and Claudin5 expression in primary mouse lung vascular endothelial cells. Taken together, these results indicate that human ghrelin improves survival after TBI, and its survival benefit is in part due to the attenuation of EC permeability and microvascular barrier dysfunction. Full article

Background/Objectives: The study’s goal is to assess the association between long-term statin therapy and influenza incidence, influenza severity, and all-cause mortality. Methods: Two population-based dynamic cohorts (exposed and unexposed to statins) were followed from 2010 to 2019. Participants were 60 years or older; frail patients were excluded. The primary outcomes were influenza incidence, influenza-related intensive care unit (ICU) admission as a proxy for severity, and all-cause mortality. The exposed cohort comprised new statin users with a minimum of two pharmacy invoices within 90 days of enrollment. Adjusted risk ratios (aRRs) for influenza incidence, ICU admission, and mortality rate were calculated using Poisson regression. Results: The initial study population of 639,564 individuals was evenly split into exposed (319,782) and unexposed (319,782) cohorts; mean age was 71 years (standard deviation: 8 years), and 57% were women. Compared to non-users, new statin users showed a higher influenza incidence [9.39 (95% confidence interval: 9.36–9.42) vs. 7.64 (7.61–7.66) per 1000 person-years], ICU admission [1.65 (1.65–1.66) vs. 1.36 (1.35–1.36) per 1000 person-years], and overall mortality rate [97.09 (96.75–97.43) vs. 94.15 (93.82–94.47) per 1000 person-years]. Adjusted analysis revealed no significant association between statin use and influenza incidence [aRR: 1.04 (0.98–1.10)] or influenza-related ICU admission [aRR: 1.03 (0.89–1.19)] and shifted the effect on mortality from harmful to beneficial [aRR: 0.88 (0.87–0.89)]. Conclusions: Despite new users’ greater vulnerability at the start of treatment, our findings indicate that statins do not influence influenza incidence or severity but reduce all-cause mortality, warranting further exploration of their anti-inflammatory properties. Full article