Search Results (3,170)

Advances in mass spectrometry-based metabolomics have enabled the detection of numerous small molecules in biological systems, revealing complex metabolic alterations associated with cancer. Among these, dipeptides are consistently detected in plasma, serum, and tumor tissue metabolomic profiles, yet their biological significance is not fully understood. In most studies, circulating dipeptides are interpreted as nonspecific byproducts of protein degradation generated during increased proteolysis. However, accumulating evidence suggests that at least some endogenous dipeptides may have biological activities, including antioxidant effects, metabolic modulation, and potential signaling functions. In this review, we examine the possible origins, transport mechanisms, and biological implications of circulating dipeptides in cancer metabolomics. We discuss multiple sources of dipeptide generation, including intracellular proteolysis, autophagy, extracellular matrix remodeling, tumor cell death, host tissue catabolism, and microbiome metabolism. We also summarize current knowledge regarding peptide transport systems and intracellular dipeptide metabolism that may regulate the fate of these molecules within mammalian systems. In addition, evidence supporting the biological activities of certain endogenous dipeptides is reviewed to evaluate the possibility that some circulating dipeptides may function as bioactive metabolites. Finally, we propose conceptual frameworks for interpreting circulating dipeptides in cancer, including their potential roles as indicators of protein turnover, intermediates in amino acid recycling, stress-buffering molecules, metabolic signals, or components of tumor–host metabolic communication. A better understanding of circulating dipeptides may provide new insights into cancer metabolism and reveal previously overlooked metabolite classes with potential biomarker or functional significance. Full article

Chronic inflammatory skin diseases, including psoriasis, hidradenitis suppurativa (HS), and atopic dermatitis (AD), are increasingly recognized as systemic disorders associated with chronic immune dysregulation. Growing evidence supports their links with metabolic disorders, reflected in heightened interest in therapeutic strategies targeting the immunometabolic axis. This review summarizes current knowledge on the role of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the regulation of immune and metabolic processes in chronic inflammatory skin diseases, with particular emphasis on molecular mechanisms and available experimental and clinical data. GLP-1RAs, widely used in the treatment of type 2 diabetes and obesity, may also exhibit anti-inflammatory and immunomodulatory properties beyond their classical metabolic effects. GLP-1 signalling can influence keratinocyte function, immune cell activity, and wound healing. Furthermore, it modulates multiple intracellular signalling pathways, including cAMP/PKA, AMPK, PI3K/Akt, and NF-κB, as well as immune axes such as IL-23/Th17/IL-17 and inflammasome-related signalling. Available evidence suggests that GLP-1RAs may reduce inflammation and disease activity in selected inflammatory dermatoses. However, current evidence remains limited and is based primarily on experimental studies, case reports, and small-scale observational studies. Further well-designed clinical trials are needed to better define the therapeutic potential of GLP-1RAs and their role in dermatological practice. Full article

Bacillus velezensis-based probiotics are increasingly recognized for their potential to enhance intestinal health in companion animals, yet their mechanisms of action in canine epithelial systems remain incompletely defined. This study aimed to evaluate whether a live Bacillus velezensis probiotic consortia (BC) modulates epithelial barrier integrity, immune signaling, apoptosis-renewal pathways, and metabolic activity in canine-relevant intestinal and macrophage cell models. MCA-B1 proximal gastrointestinal epithelial cells and DH82 macrophage-like cells were exposed to BC cultures, followed by quantification of tight-junction expression, permeability (FITC-Dextran), cytokine responses, phagocytic activity, apoptosis-related markers, and metabolomic profiles. BC treatment significantly strengthened the epithelial barrier, inducing a marked upregulation of Claudin 1 (CLDN1) (11.3 fold), CLDN4 (2.4 fold), Occludin (OCLN, 1.7 fold), and increasing key proteins including ZO-2 and cingulin while reducing LPS-induced FITC-Dextran permeability to 94.5%. BC concurrently modulated innate immune signaling, increasing MyD88 (33.2%), IL-8 (14.6 fold), IL-18 (2.6 fold), and IFNB1 protein levels, while enhancing anti-inflammatory regulation, including a robust rise in DH82-derived IL-10. Apoptosis-renewal markers shifted toward physiological turnover, with increased BCL2 (1.9 fold) and reduced BAK1. Metabolomic profiling of BC activity revealed elevated AMP, abundant Peptide Transporter 1 (PEPT1)-transportable peptides, increased γ-glutamyl metabolites, and lower Glutathione disulfide (GSSG), consistent with AMPK-linked tight-junction assembly and glutathione-supported redox buffering. Together, these data indicate that Bacillus velezensis-derived metabolites positively influence barrier-related, immunological, and metabolic responses in a canine proximal intestinal epithelial system and modulate functional responses in macrophage-like cells. These in vitro findings contribute to the mechanistic understanding of host cellular responses to Bacillus-associated metabolites. Full article

Anticontractile factors secreted by perivascular adipose tissue (PVAT) play an important role in regulating vascular tone. This process is driven by the neurotransmitter norepinephrine (NE), but recent data show that adrenergic innervation in PVAT is sparse. How limited innervation might initiate broad responses through PVAT depots remains unknown. Here, we used Ca²⁺ imaging with genetically encoded sensors, selective drugs, immunolabeling and a conditional ablation model to test the hypothesis that gap junction coupling among PVAT adipocytes contributes to how signals initiated by NE are distributed through PVAT depots. Despite exhibiting differing sensitivities to NE, adipocytes in aortic and mesenteric PVAT and in white adipose tissue displayed robust expression of the gap junction protein connexin-43 (Cx43). Blocking gap junction coupling with the drug carbenoxolone (Cbx) limited NE-evoked Ca²⁺ responses among adipocytes, while blocking Cx43 hemichannels with the mimetic peptide 43Gap26 had no significant effect. Fluorescence recovery after photobleaching (FRAP) in mPVAT was decreased in the presence of Cbx, suggesting impaired gap junction communication. Wire myography recordings of mesenteric arteries showed that the EC₅₀ for NE was higher in samples with intact PVAT than those without; however, this effect was not significantly different in samples from mice that lacked Cx43 in adipocytes. Analysis of multiple connexins showed that adipocytes upregulate Cx26 gene expression when Cx43 is deleted. These observations support the conclusion that Cx43-mediated gap junction coupling among PVAT adipocytes contributes to distributing signals initiated by NE; however, how this mechanism contributes to regulating vessel constriction remains unclear. This, and how potential compensatory mechanisms are enacted in adipocytes lacking Cx43, should be addressed in future work. Full article

Background/Objectives: This study aimed to clarify the cardioprotective effects of combined empagliflozin and sacubitril/valsartan therapy in an experimental rat model of heart failure (HF). The main research question was whether dual treatment provides greater functional and molecular benefit than either monotherapy, with particular emphasis on oxidative stress, inflammation, apoptosis, and JAK2/STAT3 signaling. Methods: HF was induced in rats by 7-day isoproterenol administration and confirmed four weeks later by echocardiographic evidence of reduced ejection fraction (<55%). The animals were then assigned to healthy control, untreated HF, empagliflozin, sacubitril/valsartan, and combined empagliflozin/sacubitril/valsartan groups. Following four weeks of treatment, ex vivo cardiac function was evaluated using the Langendorff technique. Serum cardiospecific markers and natriuretic peptides were measured by ELISA. Oxidative stress parameters were determined in coronary venous effluent, while myocardial gene expression of selected (anti)oxidative, (anti)inflammatory, (anti)apoptotic, and signaling markers was assessed by RT-PCR. Myocardial collagen content was evaluated using Picrosirius red staining. Results: HF rats exhibited impaired ex vivo myocardial function, elevated cardiac injury markers, increased oxidative stress, upregulation of pro-inflammatory and pro-apoptotic genes, activation of JAK2/STAT3 signaling, and increased myocardial collagen content. Both monotherapies produced partial benefit. In contrast, combined treatment achieved the most pronounced improvement in contractile performance, attenuated oxidative stress more consistently, reduced expression of TNF-α, IL-1β, IL-6, IL-17, Bax, CASP-3, and CASP-9, favorably modulated JAK2, STAT3, mTOR, and PPARγ expression, and decreased myocardial collagen content. Conclusions: Dual empagliflozin and sacubitril/valsartan therapy exerted broader cardioprotective effects than either monotherapy, likely through coordinated antioxidant, anti-inflammatory, anti-apoptotic, and signaling-related mechanisms. Full article

The literature collected from various search engines and high-quality scientific databases reveals that amino acid (AA)-functionalized nanoparticles have emerged as a promising field for selective detection and remediation of heavy metals (HMs). Among the various nanoparticles (NPs), gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs) have drawn considerable attention, attributed to their unique optical, catalytic, and surface plasmon resonance properties. Functionalization with amino acids significantly enhances nanoparticle stability, biocompatibility, and metal-binding affinity through diverse functional groups. AA-functionalized AuNPs, including glycine, cystine, leucine, methionine, tyrosine, aspartic acid, histidine, and lysine-capped systems, exhibit tunable selectivity toward heavy metal ions. Bifunctionalization strategies further enhance sensitivity by inducing nanoparticle aggregation or signal amplification. Beyond single amino acids, polypeptides and protein-functionalized AuNPs offer enhanced molecular recognition and multivalent binding, expanding their applicability in complex matrices. Similarly, amino acid-functionalized AgNPs, such as those capped with similar amino acids stated above, exhibit strong interactions with heavy metals, AA bifunctionalization, and bimetallic nanoparticles (BNPs), particularly amino acid-functionalized Au–Ag systems, which combine the advantages of both metals, leading to improved sensitivity, selectivity, and signal strength. Although these advances have been made, a major gap remains in the systematic comparison of different amino acids, peptides, and bimetallic systems under real-world conditions. This gap can be addressed by standardized testing methods, clearer structure–function relationships and combined experimentation to guide the rational design of more efficient AA-functionalized nanoparticles. Full article

Background: Metabolic syndrome is characterized by dysregulated glucose metabolism and is a major risk factor for type 2 diabetes mellitus and cardiovascular disease. Although glucose-lowering therapies such as glucagon-like peptide-1 receptor (GLP-1R) agonists are effective, their use may be limited by cost, administration route, side effects and tolerability. Bergamot (Citrus bergamia Risso et Poiteau) extract, rich in flavanones, has shown favorable metabolic effects in clinical studies, although its mechanisms of action remain insufficiently defined. This study aimed to investigate the potential glucose-modulating mechanisms of a standardized phospholipid-formulated bergamot extract (BP) (Vazguard™) in vitro. Methods: GLP-1R activation was assessed in a U2OS cell line expressing cyclic adenosine monophosphate (cAMP)-sensitive Nomad Biosensors™. Dipeptidyl peptidase-4 (DPP4) activity was evaluated using a cell-free enzymatic assay, while Glucose transporter type 4 (GLUT4)-mediated glucose uptake was assessed in CHO-K1 cells stably expressing human GLUT4 using an adenosine triphosphate (ATP)-based readout. Cytotoxicity was also using lactate dehydrogenase (LDH), MTT, and nuclei count assays. Results: BP exhibited a dose-dependent (0.31–5 mg/mL) increase in cAMP biosensor fluorescence, consistent with GLP-1R-associated signaling and a maximal response of approximately 60% relative to the positive control (GLP-1R agonist II). No cytotoxic effects were observed. In contrast, BP showed no inhibitory effect on DPP4 activity and did not alter GLUT4-mediated glucose uptake under the experimental conditions tested. Conclusions: These findings provide novel mechanistic evidence that phospholipid-formulated bergamot extract suggests a possible involvement in GLP-1R-associated signaling in vitro, without detectable effects on DPP4 or GLUT4 pathways under the conditions tested. This suggests a mechanism consistent with weak agonist or allosteric modulation of GLP-1R and supports further investigation of bergamot formulated with phospholipids as potential natural adjuncts in metabolic health management. Full article

Micro- and nanoplastic (MNP) pollution has emerged as a global environmental and health concern, driving the rapid development of sensor technologies for faster, more sensitive, and field-deployable detection. This review synthesizes recent advances in optical, electrochemical, and biosensor platforms for MNP analysis and compares their analytical performance and practical feasibility. Optical sensors, including plasmonic, spectroscopic, and colorimetric systems, enable label-free and often rapid detection with material discrimination capability, and are well-suited for screening applications, though they commonly exhibit higher detection limits and matrix interference. Electrochemical sensors demonstrate the highest analytical sensitivity overall, frequently reaching low µg L⁻¹ to ng mL⁻¹ levels, with strong potential for miniaturization and on-site deployment; performance is further enhanced by nanostructured electrodes, photoelectrochemical designs, and signal amplification strategies. Biosensors incorporating peptides, aptamers, enzymes, or engineered proteins provide improved polymer selectivity and enable targeted detection, but face challenges related to stability, cross-reactivity, and reproducibility in complex samples. Practically, portable electrochemical and simple optical colorimetric platforms are currently the most feasible for field use, while hybrid bio-electrochemical systems show the highest performance potential. Future research should prioritize robust selective recognition elements, antifouling interfaces, standardized validation protocols, mixed-polymer quantification models, and integration with machine learning to enable reliable, real-world MNP monitoring. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and newer dual-incretin therapies have become central to the treatment of diabetes mellitus and obesity, with benefits extending beyond glycemic control. Their expanding use has prompted growing interest in their potential ocular effects. Experimental data support plausible protective mechanisms, including reduction in oxidative stress and neuroprotective effects on retinal and optic nerve tissues. Clinical evidence, however, remains heterogeneous. In diabetic retinopathy, the main concern appears to be transient early worsening associated with rapid glycemic improvement rather than direct retinal toxicity. A potential semaglutide-associated signal for non-arteritic anterior ischemic optic neuropathy has raised concern, although the absolute risk appears low and causality remains unproven. Emerging studies also suggest possible beneficial associations with glaucoma, ocular surface diseases, and certain retinal vascular outcomes, whereas the evidence regarding age-related macular degeneration and cataract remains conflicting or preliminary. Overall, ocular outcomes associated with incretin-based therapies seem to reflect a complex interplay among drug-specific pharmacology, systemic metabolic changes, and individual patient susceptibility rather than a class effect. Baseline ophthalmic assessment and individualized follow-up may be advisable in selected high-risk patients. Further prospective ophthalmology-focused studies are needed to clarify long-term safety and identify the patients most likely to benefit or develop adverse events. Full article

Buffalo milk is a rich source of various nutritional components and bioactive peptides, offering significant health benefits. Endogenous peptides, which occur naturally in milk, represent a valuable source of bioactive peptides with potential nutraceutical applications. However, research on endogenous peptides in buffalo milk remains limited. This study employed a quantitative peptidomic approach to characterize endogenous peptides across different lactation stages. A total of 2099, 2946, and 4418 peptides were identified in colostrum, transitional milk, and mature milk, respectively. The majority of these peptides were derived from β-casein, followed by α_S1-casein, κ-casein, and other proteins. Notably, variations in precursor proteins contributing to peptide production were observed throughout lactation. Phosphorylation levels of endogenous peptides were highest in mature milk, with serine residues predominating. Enzymatic cleavage analysis identified cathepsin D as the key enzyme involved in endogenous peptide production, while proline endopeptidase and plasmin exhibited stage-specific activities. Bioinformatics analysis revealed differentially expressed precursor proteins linked to complement cascades and NF-κB signaling, emphasizing the immune protective role of colostrum. Furthermore, 54 potentially bioactive peptides with favorable water solubility were identified in colostrum, of which 17 were predicted to possess anti-inflammatory properties. These findings contribute to a deeper understanding of the molecular basis of buffalo milk’s functional properties, highlighting its potential as a source of bioactive peptides for both nutritional and pharmaceutical applications. Full article

Skin wound healing is a complex and highly coordinated biological process involving inflammation, cell migration and proliferation, angiogenesis, extracellular matrix remodeling and tissue regeneration. While the zebrafish-derived antimicrobial peptide AP10W exhibits broad-spectrum antimicrobial properties, its potential in tissue repair remains unexplored. Herein, we demonstrate that AP10W possesses intrinsic wound-healing capabilities, providing a preliminary investigation into its underlying mechanisms. In this study, using a full-thickness murine wound model and in vitro cell-based assays to evaluate the effects of AP10W on fibroblasts, keratinocytes, endothelial cells, and macrophages, we found that AP10W significantly promoted fibroblast and keratinocyte migration and proliferation. Furthermore, it enhanced endothelial cell motility, survival, and tube formation, while upregulating key pro-angiogenic factors, including Vascular endothelial growth factor A (VEGFA), Platelet-derived growth factor (PDGF), and Fibroblast growth factor 2 (FGF2). Concurrently, AP10W drove macrophage reprogramming from a pro-inflammatory M1 phenotype toward a pro-healing M2 state, as evidenced by upregulated Arginase-1 (Arg-1) and Interleukin-10 (Il-10) expression, alongside attenuated Tumor necrosis factor-alpha (Tnf-α), Interleukin-1 beta (Il-1β), Interleukin-6 (Il-6), and Inducible nitric oxide synthase (iNOS) levels. In vivo, the topical application of AP10W accelerated wound closure, markedly improving re-epithelialization, collagen deposition, vascularization, tissue perfusion, and skin appendage regeneration. Preliminary mechanistic studies revealed that AP10W increased YAP expression and nuclear translocation; conversely, the pharmacological inhibition of YAP significantly abrogated these pro-healing effects. Collectively, our findings identify AP10W as a multifunctional peptide with potent wound-healing properties, positioning it as a promising candidate for wound therapy. Full article

Background: Myocardial fibrosis (MF) is a dynamic remodeling process characterized by excessive extracellular matrix (ECM) deposition, fibroblast activation, and dysregulated matrix turnover. Although initially reparative, persistent fibrotic remodeling promotes myocardial stiffening, electrical instability, and progressive cardiac dysfunction across diverse cardiovascular diseases. Circulating biomarkers reflecting collagen synthesis, degradation, proteolytic regulation, and inflammatory activation have emerged as potential tools for assessing fibrotic activity and risk stratification. Methods: This targeted narrative review was based on manually guided searches of PubMed and Scopus, supplemented by citation chaining and inclusion of landmark mechanistic and translational studies. Publications addressing myocardial extracellular matrix remodeling, circulating fibrosis-related biomarkers and imaging-derived fibrosis phenotypes were selected for qualitative synthesis. Results: Myocardial fibrosis reflects interconnected inflammatory, neurohormonal, oxidative, and extracellular matrix remodeling pathways. Among circulating biomarkers, C-terminal propeptide of procollagen type I (PICP) showed the most consistent association with myocardial collagen burden and adverse outcomes, whereas carboxy-terminal telopeptide of type I collagen (CITP), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), galectin-3, osteopontin, soluble suppression of tumorigenicity 2 (sST2), and natriuretic peptides provided more context-dependent signals. Standalone interpretation remains limited by restricted cardiac specificity, renal dysfunction, systemic inflammation, assay heterogeneity, and lack of standardized thresholds. Integration with cardiac magnetic resonance (CMR)-derived late gadolinium enhancement (LGE), T1 mapping, and extracellular volume (ECV) may improve biological and structural phenotyping. Conclusions: Circulating biomarkers capture complementary dimensions of myocardial remodeling but cannot replace structural imaging. We propose an updated, hypothesis-generating biomarker–imaging framework integrating inflammatory activation, collagen turnover, matrix quality, hemodynamic stress, and structural imaging to support phenotypic stratification and future validation of antifibrotic strategies. Full article

Background/Objectives: In a recent article we outlined how the vestibular efferent system connects the stereo/kinociliary complex at the apex of the macular vestibular hair cells of the inner ear and coordinates movement so that planned body movements are precisely timed to coordinate with the expected otoconial movement that the body movement induces. Methods: Our present article proposes an extension of this concept with details about how a sailor develops “sea legs.” The rocking motion of a boat in rough seas requires sailors to sway in order to remain vertical. This causes fluctuation in the gravity-referenced otoconial signal. Results: As a sailor develops sea legs, it is necessary that the routine vestibular efferent system activity (based on gravity-referenced orientation on land) is disrupted as the otoconia move with this rocking process in order to re-coordinate with the new otoconial movement. As a result, the cerebral cortex must reconfigure vestibular efferent activity so that the stereo/kinociliary complex moves in conjunction with the otoconial movement. This process is carried out via the striated organelle (STO) and is one that takes several days. Those who are unfortunate and have severe motion sickness, become extremely unwell with nausea, vomiting, severe unsteadiness, and anorexia during this time. Conclusions: The present article describes how “sea legs” develop and discusses why an unpleasant symptom set can accompany it. We will also outline how a new medication, a calcitonin gene-related peptide (CGRP) inhibitor, which is presently used for the treatment of vestibular dysfunction, has been shown to suppress vestibular efferent activity and may be an effective therapy for these overly symptomatic individuals. Full article

Background: The renin-angiotensin system (RAS), traditionally known for its role in cardiovascular regulation, has also emerged as a key regulator of tumor progression and metastasis. Dysregulation of the RAS components has been implicated in breast cancer due to the significant presence of the RAS-related proteins in the breast tissue. This study aims to identify the dysregulated RAS components and investigate their potential as candidate biomarkers. Methods: A pilot case–control study was carried out with 21 treatment-naïve breast cancer patients and 17 healthy controls. Plasma levels of Ang 1-7, Ang II, ACE2 and selected cytokines (IL-6, IL-8, IL-10 and IFN-γ) were measured using LC-MS/MS and ELISA. ROC curves were used to assess changes in biomarker levels across the RAS components. Results: This pilot cohort showed evidence of altered circulating RAS-related analytes and IL-10 in treatment-naïve breast cancer patients compared with controls. The ratio of Ang 1-7/Ang II was reduced by over two-fold in breast cancer patients (p = 0.0442). While plasma ACE2 was significantly elevated in breast cancer patients (p = 0.0005), IL-10 was significantly suppressed (p = 0.0420). In exploratory logistic regression analysis, ACE2 showed potential as a classifier with improved discrimination when combined with Ang 1-7 and Ang II (AUC = 0.9396 [95% bootstrap CI: 0.84–1.00], accuracy = 92.59% at the Youden-optimized threshold). However, due to the small sample size and methodological limitations, these findings require further validation. Conclusions: In this exploratory pilot study, plasma ACE2, the Ang 1-7/Ang II ratio, and IL-10 showed promising discriminatory performance. However, these findings are hypothesis-generating and require external validation in larger, prospectively enrolled cohorts before any clinical inference can be drawn. Full article

The environmental burden from cosmetic production has intensified interest in sustainable and scientifically robust raw materials. Among the emerging alternatives, agro-industrial residues are gaining attention as chemically rich sources of bioactive compounds with potential for dermocosmetic applications. However, research on their molecular activity, formulation performance, and industrial feasibility remains fragmented across the fields of sustainability, dermatology, and engineering. This narrative review synthesizes current knowledge on the phytochemical composition of extracts from agro-residues. It also critically examines their effects on key skin-related pathways, including oxidative stress modulation, extracellular matrix regulation, inflammation, senescence, and barrier function. Compounds such as polyphenols, carotenoids, peptides, and polysaccharides have been reported to influence signaling networks, including Nrf2/ARE, NF-κB, TGF-β/Smad, and PI3K/AKT/mTOR. Importantly, most of this evidence originates from in vitro and ex vivo studies on animal models, while controlled human and clinical studies remain limited; thus, mechanistic findings should not be equated with proven dermocosmetic efficacy. Nevertheless, challenges remain, such as compositional variability, safety-validation requirements, limited skin bioavailability and stability of bioactives in finished formulations, and limitations in scalable green extraction. Economic modeling and life-cycle assessment also highlight the need to verify both financial and environmental viability. Advancing agro-residue-derived bioactives toward mainstream cosmetic use will require strategies that integrate molecular characterization, regulatory alignment, rigorous claims substantiation and sustainable process optimization. Full article