Search Results (24,461)

Streptococcus canis is an opportunistic pathogen that colonises the mucosal surfaces and skin of its host. Though predominantly a veterinary pathogen affecting cats and dogs, S. canis has also been identified as the causative agent in severe human disease. IdeC is a secreted cysteine protease of S. canis that has a high specificity for IgG, cleaving at the hinge region. We show here that the protein binds back to the surface of the bacteria. Additionally, the protein contains a conserved Arg-Gly-Asp (RGD) motif, the minimal peptide sequence required for integrin binding. Several bacterial proteins containing RGD motifs have been implicated in adhesion and invasion of host cells. This RGD motif along with the ability of IdeC to bind back to the bacterial surface after secretion is the basis for this study into a potential secondary function of IdeC in adhesion and/or invasion. We used protein-coated latex beads to investigate the interaction of IdeC with epithelial and endothelial cells and, further, the extent to which the RGD motif is involved in this interaction by utilising an RGD->RGE recombinant protein. We also report here that the deletion of IdeC in S. canis results in a significant reduction in invasion into epithelial cells. Full article

Glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists, originally introduced for the management of type 2 diabetes mellitus and obesity, are increasingly recognized for their broader actions within the central nervous system, with emerging implications in neuropsychiatry and neurodegeneration. This review integrates current preclinical and clinical evidence, emphasizing their pharmacodynamic profile, central receptor distribution, and the molecular pathways linking metabolic signaling to neural function. Evidence suggests that GLP-1 receptor activation across key brain regions involved in energy balance and reward modulates multiple neurotransmitter systems, including dopamine and serotonin, as well as glutamatergic and GABAergic transmission, thereby influencing behavior, affective processes, and cognitive function. In parallel, these agents exhibit neuroprotective properties through improved neuronal insulin sensitivity, attenuation of neuroinflammatory pathways, and support of neuroplasticity, alongside effects on limiting pathological protein aggregation. Dual GIP/GLP-1 agonism may further potentiate these central actions through complementary metabolic and synaptic mechanisms. Although pharmacovigilance data have identified isolated neuropsychiatric adverse events, current clinical evidence does not support a consistent causal association. Collectively, incretin-based therapies represent a promising translational approach at the interface of metabolic and neuropsychiatric disorders, warranting further investigation into their long-term central safety, therapeutic efficacy, and clinical relevance. Full article

Autoimmune diseases arise from the failure of self-tolerance. The recognition of self-antigen peptide–MHC (pMHC) complexes by the T-cell receptor (TCR) is the fundamental event triggering autoimmune pathogenesis. While traditional immunosuppressants provide broad systemic effects, they often compromise global immunity. Emerging molecular strategies aim to selectively disrupt the trimolecular complex—comprising the TCR, the antigenic peptide, and the MHC molecule—to induce antigen-specific tolerance. This review highlights the pMHC–TCR interaction as the primary molecular checkpoint for antigen-specific intervention. We discuss the structural basis of these interactions and their potential to redefine the therapeutic landscape for autoimmune diseases (ADs). We examine the molecular drivers of tolerance breakdown—including genetic susceptibility, molecular mimicry, post-translational modifications (PTMs), and ectopic MHC II expression—that shape the autoreactive T-cell landscape. This review examines current advancements in biological and pharmacological interventions, such as pMHC-decorated nanoparticles and soluble pMHC, to reprogram pathogenic T-cell response. We also explored CAR-T therapy strategies for autoimmune diseases, such as CAR-Treg, designed to precisely modulate pMHC-TCR signaling. Collectively, these precision interventions in immunological synapse assembly during autoimmune response are considered the basis for safer, antigen-specific immunotherapy capable of restoring self-tolerance without global immunosuppression. Full article

Heterologous protein secretion in filamentous fungi is often constrained by limitations in signal peptide recognition and intracellular trafficking. Aspergillus oryzae, a food-grade industrial fungus, has a robust native secretory system. However, its capacity for recombinant protein secretion remains suboptimal. Here, we developed a two-step, carrier-free engineering strategy to enhance protein secretion in A. oryzae. We identified endogenous signal peptides among highly secreted proteins using a green fluorescent protein (GFP) reporter. The oryzin signal peptide SPAoalp1 increased GFP secretion 5.50-fold compared with a no-signal-peptide control. We co-overexpressed Aosly1, a Sec1/Munc18 family protein that regulates soluble N-ethylmaleimide-sensitive factor attachment protein receptor–mediated vesicle trafficking, which, in combination with SPAoalp1, increased secretion approximately two-fold compared with SPAlp1 control and ten-fold with no-SP control. Applying the engineered platform for genetic improvement of heterologous bovine κ-casein increased secretion from 0.11 to 0.24 mg/L. Physiological optimization further increased secretion. The developed system provided initial evidence for secretion of a ~12 kDa band consistent with Aopafb transcription, with MIC₉₀ values of 4.56–8.24% (v/v) against two Candida albicans strains and 4.68% (v/v) against Aspergillus niger. The system offers a modular framework for engineering fungal secretion and expands the utility of A. oryzae for recombinant protein production. Full article

Background/Objectives: Developing novel strategies to combat respiratory infections caused by multidrug-resistant “priority pathogens” like the ESKAPEE Pseudomonas aeruginosa and Staphylococcus aureus is an urgent priority. Methods: We investigated two shortened variants of the proline-rich antimicrobial peptide (PrAMP) B7-005, B7-006 (15-mer) and B7-007 (13-mer). Evaluation included MIC assays against laboratory and clinical multidrug-resistant isolates, mechanistic studies of membrane permeabilization, cytotoxicity testing on BEAS-2B bronchial epithelial cells, and proteolytic stability assays in human elastase and sputum. Results: Despite their reduced size, lower positive charge, and decreased proline content, both variants retained full antimicrobial activity against clinical pathogens with consistent MIC values ≤ 25 µM. These variants exhibit membrane permeabilization in P. aeruginosa but may also relay on a hybrid mode of action involving also intracellular targets. Notably, B7-006 and B7-007 displayed low cytotoxicity compared to the lytic peptide BMAP-18. While B7-007 showed greater susceptibility to proteolytic degradation than its parent B7-005, it preserved partial integrity during the initial hours of exposure. Conclusions: Overall, these findings demonstrate that the B7 scaffold tolerates substantial truncation while preserving potency and selectivity, identifying a minimal 13-amino-acid active core. This work provides critical insights into structure–activity relationships and supports the development of compact, mechanistically versatile antimicrobial peptides to address the growing threat of multidrug-resistant respiratory pathogens. Full article

Background/Objective: In lung cancer treatment, increasing the concentration of antitumor drugs at the tumor site, enhancing efficacy, and reducing systemic toxicity are significant challenges. This study aims to develop an intelligent responsive polymer micelle system (GPDD) that achieves efficient accumulation and controlled release of drugs at lung tumor sites through targeted and pH-responsive design. Methods: The GPDD system is formed by the self-assembly of GE11-PEG-hyd-DOX conjugates and co-loads free DOX. This system utilizes the targeting effect of the GE11 peptide with the epidermal growth factor receptor (EGFR) to accumulate at the tumor site, while the hydrazone bond serves as a pH-responsive linker that breaks in the acidic tumor microenvironment, triggering drug release. Experiments employed CCK-8 cytotoxicity assays and tumor-bearing nude mouse models (strain not specified) for in vitro and in vivo evaluations. Results: In vitro experiments showed that GE11-modified GPDD effectively inhibited tumor cell growth. In tumor-bearing nude mouse experiments, GPDD demonstrated more significant tumor suppression effects and lower systemic toxicity compared to free DOX and unmodified PDD. Conclusions: The GPDD nanocarrier integrates targeting and pH responsiveness, improving antitumor efficacy and reducing side effects, with translational potential. The novelty of the study lies in its dual-functional design and co-loading strategy, providing new insights for tumor-targeted delivery systems. Full article

Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal aggregation of β-amyloid (Aβ) peptides, tau proteins, and neuroinflammation in the central nervous system (CNS). While most AD research has focused on the brain, the molecular pathology of the spinal cord remains poorly understood. In this study, we investigated amyloid pathology, neurodegeneration, neuroinflammation, and cholesterol metabolism across distinct regions of the spinal cord and examined sex-specific differences using a model of AD, 5xFAD mice. Our data reveal that Aβ accumulation was restricted to the cervical spinal cord at 3 months but was evident in all areas of the spinal cord by 9 months, with similar patterns in both female and male animals. Despite this early and progressive Aβ deposition, no significant neuronal loss was observed in the ventral horn of the cervical spinal cord in either sex at 3 or 9 months of age. In contrast, there was a significant positive correlation between Aβ deposition and Iba1+ cell density in the spinal cord of 5xFAD mice. The number of Iba1+ cells in both the grey and white matter was significantly increased in female and male 5xFAD mice compared with age-matched wild-type (WT) littermates at 9 months of age. Astrocytic responses, however, were sex-specific: female, but not male, 5xFAD mice exhibited a significant increase in GFAP+ astrocytes in the grey matter of the thoracic and lumber spinal cord at 9 months compared with 3 months and relative to age-matched WT controls in the cervical and thoracic spinal cord. Furthermore, GFAP+ area in the thoracic spinal cord was significantly higher in female 9-month-old 5xFAD mice compared with their male counterparts, indicating a female-specific astrocytic response in AD spinal cord pathology. Our data also show an increase in free cholesterol (Filipin+ area) in 5xFAD mice at 9 months relative to WT controls, accompanied by altered expression of cholesterol metabolism genes, including downregulation of Abca1, Cyp46a1 and Cyp27a1. Collectively, these findings provide new insights into AD progression in the spinal cord, highlighting molecular pathology of AD extending beyond the brain. Full article

The global burden of hypertension continues to rise, highlighting an urgent need for effective therapeutic strategies. Angiotensin-converting enzyme (ACE) is central to blood pressure regulation, but commonly used synthetic ACE inhibitors often have adverse side effects, spurring the search for safer natural alternatives. The aim of this study was to investigate Yanbian cattle hemoglobin as a novel precursor for ACE inhibitory peptides. The <1 kDa fraction was identified as exhibiting the highest inhibitory activity through the systematic screening of hydrolysates across multiple molecular weight ranges. LC-MS/MS analysis identified 1980 peptides, of which four were selected for further experiments. Solid-phase synthesis confirmed that NFGYDL exhibited the strongest ACE inhibition (IC₅₀ = 54.95 μM). Inhibition kinetics showed FHDYL acted as a mixed-type inhibitor, DLGHF and NFGYDL as competitive inhibitors and GFHLD as a non-competitive inhibitor. Molecular dynamics simulations validated the stable binding of these bovine blood-derived peptides to the ACE complex. HUVEC functional assays demonstrated that four peptides significantly increased angiotensin II-induced nitric oxide production and endothelin-1 levels, suggesting their potential antihypertensive activity. These findings suggested that bovine blood is a promising natural source of ACE-inhibitory peptides and holds potential for application as a functional component in functional foods targeting hypertension management. Full article

Antimicrobial resistance is a serious global public health concern, with Acinetobacter baumannii recognized as one of the most problematic multidrug-resistant (MDR) pathogens. This Gram-negative bacterium is highly persistent in the environment, possesses a remarkably adaptable cell envelope, and forms biofilms. As the effectiveness of conventional antibiotics declines, alternative strategies are being actively explored, particularly membrane-targeting approaches based on synthetic copolymers. These compounds mimic antimicrobial peptides, offer enhanced stability and structural tunability, and have a lower propensity to develop resistance. Recent advances in polymer chemistry have led to the design of antibacterial polymers with activity against MDR A. baumannii. Some of these act synergistically with existing antibiotics, restoring bacterial susceptibility or disrupting biofilms. However, their non-degradability remains a concern due to its potential implications for body/environment accumulation and related toxicity and/or selection of resistant strains. This review examines the biology of the A. baumannii cell envelope, its resistance mechanisms, and treatment limitations, while emphasizing the promise of membrane-active copolymers. By bridging materials science and microbiology, these approaches offer promising strategies for combating World Health Organization priority pathogens. Full article

Many approved oral paediatric medicines continue to have poor taste acceptance, suggesting that the ingredient blends employed in these medicines are not adequately effective in taste-masking drugs with strongly aversive tastes. To address this inadequacy, this narrative review provides a comparative evaluation of taste-masking ingredients used by the pharmaceutical industry with those employed in the food industry, as well as food items used by caregivers to mask the unpalatable taste of medicines for young children. Information was sourced from academic databases, industry publications, and caregiver forums on informal social platforms. Ingredients were classified into sweeteners, salts, acids, fats, peptides/amino acids, flavourants, cyclodextrins and polymers, with their taste-masking mechanisms delineated into receptor-level interactions and the creation of physical barriers and alternative dominant taste. Their applications are compared across the regulated medicinal and consumer food products, and in home remedies. Sweeteners show the highest cross-domain convergence as they are used in medicinal and food products and are recommended by caregivers. Peptides, amino acids, salt and texture modifiers applied in food and home remedies may have translational potential in medicines. Challenges, including drug–food interactions, regulatory constraints, and the need for combination approaches, are addressed. A decision framework is also designed to guide the development of simple, acceptable, and effective ingredient-based taste-masking systems for drugs with aversive tastes. Full article

Background/Objectives: Ventilator weaning imposes profound hemodynamic stress, unmasking cardiopulmonary vulnerability. Since conventional predictors of post-tracheostomy weaning failure remain elusive, biomarker-driven risk stratification offers a translational approach. We evaluated the prognostic utility of admission N-terminal pro-B-type natriuretic peptide (NT-proBNP) as an early triaging tool for weaning failure and explored its therapeutic implications alongside optimal tracheostomy timing. Methods: In this large-scale retrospective cohort study, we analyzed 707 critically ill patients who underwent tracheostomy in a medical intensive care unit. We investigated the association between baseline NT-proBNP levels—measured as a molecular surrogate of cardiovascular stress at ICU admission; echocardiographic parameters; and weaning outcomes. Multivariable logistic regression analysis was utilized to identify independent pathophysiological predictors associated with weaning failure. Results: Patients experiencing weaning failure exhibited significantly elevated admission NT-proBNP levels compared to those successfully weaned (3077.0 vs. 1410.0 pg/mL, p < 0.001). High admission NT-proBNP (>3271 pg/mL) was independently associated with an increased risk of weaning failure (adjusted odds ratio [aOR] 2.86, 95% confidence interval [CI] 1.81–4.53, p < 0.001). Conversely, an early clinical intervention—tracheostomy performed within 10 days of mechanical ventilation initiation—was associated with a significantly lower risk of weaning failure (aOR 0.55, 95% CI 0.35–0.87, p = 0.010). Furthermore, elevated biomarker levels strongly correlated with prolonged intensive care unit stays and higher 90-day mortality. Conclusions: Admission NT-proBNP serves as a powerful biomarker associated with cardiopulmonary vulnerability from the earliest stages of critical illness. Integrating this diagnostic biomarker with interventional strategies like optimal tracheostomy timing has significant prognostic implications. This biomarker-guided approach facilitates personalized risk stratification from ICU admission, potentially optimizing weaning pathways for mechanically ventilated patients. Full article

While the detrimental effects of high temperature stress on fish growth and disease resistance have been widely reported, its impact on muscle quality has received limited attention. In this study, largemouth bass Micropterus salmoides with an initial body weight of 45.73 g were subjected to a 60-day growth trial (~25 °C), followed by a 5-day acute warming phase and a subsequent 30-day chronic high temperature exposure (32 °C). Through integrated analyses of morphological parameters, texture characteristics, TUNEL assay, gene expression analysis, and metabolomics in muscle, the effects of high temperature stress on the meat quality of largemouth bass were systematically examined. The results showed that high temperature stress significantly upregulated key genes in the ubiquitin-proteasome pathway (trim13, foxo1α) and key genes in the autophagy-lysosome pathways (lc3α, lc3β, bcl2l1, ctsl2), induced apoptosis in muscle cells, and led to significant reductions in myofiber diameter and density. In terms of textural properties, high temperature stress significantly decreased parameters such as springiness, adhesiveness, and cohesiveness, as well as water holding capacity. Metabolomic analysis further revealed that high temperature induced remodeling of energy metabolism and significant reprogramming of purine and amino acid metabolic pathways, resulting in decreased levels of key flavor compounds, including IMP, GMP, flavor amino acids (glutamic acid, alanine, methionine, arginine, proline), and peptides (glu-glu-lys and glu-cys-gly), thereby adversely affecting muscle flavor quality. The findings of this study provide a theoretical basis for understanding the impact of thermal stress on the eating quality of farmed fish. Full article

Angiotensin-converting enzyme (ACE) inhibitors (ACEis) are one of the most successful drug classes for the treatment of hypertension and the prevention of its cardiovascular complications. ACE activates the pressor hormone angiotensin but also inactivates the vasodilator peptide bradykinin (BK). A rare side effect of ACEis, angioedema (AE), has been proposed to result from pro-inflammatory effects of BK. Novel considerations are offered in this debate: (1) the bradykinin B2 receptor antagonist icatibant has had an inconsistent effect on ACEi-associated AE, but its potency and duration of action are much inferior to those of a novel nonpeptide antagonist of this receptor, deucrictibant. (2) Tissue kallikrein (KLK-1) is an effective kininogenase, particularly abundant in the salivary glands, possibly related to orofacial presentation of ACEi-induced AE. (3) The strongly regulated human kinin B1 receptor, optimally responsive to Lys-des-Arg⁹-BK, is functionally compartmentalized with KLK-1 which produces Lys-BK from kininogens. Chronic treatment with ACEi drugs in laboratory animals induces the expression of vascular B1R that mediates vasodilation. Therefore, ACEi-AE may be largely or completely initiated by KLK-1. Inhibitors of this protease or combined antagonists of both kinin receptor subtypes may be useful for the management of this condition. Full article

The identification of novel natural sources of bioactive peptides with multifunctional health-promoting properties remains a major challenge for the development of nutraceutical and therapeutic agents. Prosopis laevigata (mesquite), a plant of economic, medicinal, and nutritional relevance in Mexico, has been poorly explored as a source of protein-derived bioactive molecules. Therefore, this study evaluated the antioxidant, antimicrobial, cytotoxic, and enzymatic inhibitory activities of peptides obtained from the enzymatic hydrolysis of P. laevigata cotyledon proteins. The resulting hydrolysates exhibited significant antioxidant activity, for peptide fractions smaller and larger than 5 kDa, in the ABTS and FRAP assays. Cytotoxic activity against HepG2 liver cancer cells was observed at high peptide concentrations (8 mg/mL). Additionally, the peptides inhibited the growth of Staphylococcus aureus but showed no activity against Escherichia coli. The peptides also displayed partial inhibition of α-amylase activity, with peptides <5 kDa exhibiting competitive inhibition and peptides >5 kDa showing a mixed inhibition pattern. Overall, these findings highlight P. laevigata seeds as a promising source of multifunctional bioactive peptides with potential applications in functional foods and health-related biotechnological developments. Full article

The rapid global spread of antimicrobial resistance among pathogenic microorganisms poses a serious challenge to both human and animal health, underscoring the urgent need for new strategies to combat resistance. Antimicrobial peptides (AMPs), key components of the innate immune system, are promising candidates because they disrupt the membranes of bacteria, fungi, and viruses, thereby reducing the risk of resistance development. Lactoferrin (LF), a multifunctional iron-binding glycoprotein abundant in mammalian milk, is a rich source of AMPs. Cationic peptide fragments such as lactoferricin and lactoferrampin exhibit more potent direct antimicrobial activity than the intact protein. Our previous studies have shown that peptides derived from Equine milk lactoferrin exhibit antihypertensive, anti-inflammatory, and anti-oncogenic activity in silico, highlighting their multifunctional bioactive potential. Building on these results, the present study aims to investigate the antimicrobial properties of these peptides. We used an integrated approach combining computer modeling and in vitro studies to identify and validate novel antimicrobial peptides from equine milk lactoferrin. Bioinformatics tools, including AMPScanner and CAMP, were used to predict antimicrobial domains, followed by experimental testing against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The results showed that equine milk lactoferrin peptides possess potent and selective antimicrobial activity, with efficacy varying across bacterial species. These data expand the functional profile of lactoferrin-derived peptides, demonstrating their multifunctionality, and suggest that equine milk lactoferrin represents a promising natural source of antimicrobial agents, supporting alternative strategies to reduce antibiotic use in human and veterinary medicine. Full article