Search Results (2,552)

Bone loss in the maxillofacial region arises from multiple causes, including periodontal disease, trauma, surgical procedures, infection, congenital anomalies, and cancer. Traditional treatment relies on bone grafting, either alone or in combination with biomaterials. Advances in tissue engineering have introduced synthetic or natural scaffolds to mimic the mineralized bone matrix. Natural scaffolds offer excellent biocompatibility and similarity to native tissue but often lack sufficient mechanical strength and exhibit poor degradation rates. Synthetic scaffolds provide tunable porosity and mechanical stability; however, their biological inertness makes them poor sources of osteogenic signaling. A key factor in the success of any scaffold is its interaction with the host immune system. Upon implantation, the innate immune response is initiated, with neutrophils and macrophages being the first cells to contact the scaffold. Macrophage polarization toward proinflammatory (M1) or anti-inflammatory (M2) phenotypes determines whether the microenvironment favors inflammation or remodeling. The adaptive immune response also plays a critical role: T and B lymphocytes may promote tolerance and integration through Th2/Treg pathways and antibody-mediated regulation, or they may trigger chronic inflammation and rejection through Th1/Th17 activation. This review examines the natural and synthetic materials used for bone remodeling and their biological properties. It then outlines the sequence of immune events occurring from the moment a scaffold is implanted to its potential integration or failure. Finally, this study highlights the relevance of cellular models and in vitro assays for the early evaluation of immunogenicity and biocompatibility, which are essential for optimizing scaffold design and improving outcomes in maxillofacial bone regeneration. Full article

Thrombopoietin receptor agonists (TPO-RAs) have become an important component of pediatric immune thrombocytopenia (ITP) management, with growing evidence supporting their use in other hematologic disorders. We conducted a retrospective single-center study evaluating TPO-RA use at a pediatric oncohematology center in Poland between 1 January 2016, and 31 March 2026. Clinical indications, treatment patterns, efficacy, and safety outcomes were analyzed. Treatment response was defined as initial response (IR, platelet count [PLT] > 50 × 10⁹/L), complete response (CR, PLT > 100 × 10⁹/L), and sustained response (SR, PLT > 50 × 10⁹/L maintained in ≥75% of visits over 6 months). Thirty-five patients were included in the analysis. The most common indication was ITP (27/35, 77%), followed by severe aplastic anemia (5/35, 14%), poor graft function (2/35, 6%), and inherited platelet disorders (1/35, 3%). TPO-RA use increased over time, with more than half of patients (20/35, 57%) initiating therapy between 2024 and 2026. Overall IR, CR, and SR rates were 77%, 63%, and 61%, respectively, with a median time to response of 7 days (interquartile range [IQR], 7–12.5). TPO-RAs were increasingly used earlier in the disease course, including in rescue and off-label settings. Treatment was well tolerated, with only grade 1–2 adverse events reported. Our real-world data confirm the high efficacy and favorable safety profile of TPO-RAs in pediatric patients and support their expanding role in pediatric hematology beyond disease-specific indications. Full article

Heat shock proteins (HSPs) are highly conserved molecular chaperones that play a key role in maintaining protein homeostasis and cellular survival under stress conditions. Clinically relevant human pathogenic fungi include opportunistic fungi, dimorphic fungi, dermatophytes, Mucorales, and other pathogenic groups. HSPs, including Hsp90, Hsp70, Hsp60, Hsp40, and Hsp110, are essential for the correct nascent protein folding, aggregation prevention, and degradation of misfolded polypeptides. Fungal pathogens frequently encounter environmental and host-imposed stresses, including oxidative stress, temperature fluctuations, and antifungal treatments. This review synthesizes and critically analyzes current evidence on the role of HSP families in essential processes linked to fungal virulence, including morphogenetic transitions, biofilm formation, maintenance of cell wall integrity, and interactions with host immune cells. Beyond their canonical chaperone functions, HSPs act as central mediators in pathogenic processes, such as morphogenesis transitions, biofilm formation, cell wall integrity, and interactions with host immune cells. Hsp90 stabilizes key signaling proteins involved in stress responses, morphogenesis, and antifungal resistance, while Hsp60 and Hsp70 contribute to mitochondrial function, cell wall integrity, and immune modulation. Disruption of these chaperones impairs growth, reduces virulence, and increases susceptibility to antifungal agents. The rise of antifungal resistance underscores the urgent need for new therapeutic strategies. Targeting fungal HSPs has emerged as a promising approach due to their essential roles in stress tolerance and pathogenesis. Hsp90 inhibitors, including geldanamycin derivatives and other small molecules, have demonstrated the ability to impair fungal growth, reduce virulence traits, and sensitize resistant strains to conventional antifungal drugs. Combining HSP inhibitors with existing antifungal drugs represents a potential strategy to overcome resistance and improve treatment outcomes. This review summarizes the current knowledge on HSPs in pathogenic fungi, focusing on their roles in stress adaptation, virulence, host-pathogen interaction, antifungal resistance, and their potential as targets for novel antifungal therapies. Full article

Lactobacilli species have emerged as a focal point in food microbiology due to their core probiotic properties, including the regulation of intestinal homeostasis and the enhancement of immunity. This study focuses on Lacticaseibacillus rhamnosus MG0718 (hereinafter referred to as MG0718), employing a combined approach of phenotypic evaluation and whole-genome sequencing to assess its probiotic potential and analyze the correlation between its phenotype and genotype. In vitro experiments demonstrated that MG0718 possesses broad-spectrum antibacterial activity against pathogenic bacteria. In vitro experiments showed that MG0718 had broad-spectrum antibacterial activity against pathogenic bacteria such as Escherichia coli (E. coli), with an inhibition zone diameter of up to 13.67 ± 1.56 mm. It survived pH 2.5 for 6 h with only a 1.72 log10 reduction, and showed 0.78 and 1.11 log10 CFU/mL reductions in artificial gastric and intestinal fluids after 2 h. DPPH scavenging was 56.7% and total reducing power was 91.1%. In vivo, 7-day preventive administration maintained 100% survival against S. Typhimurium infection and alleviated weight loss. Bacterial loads in spleen, liver, and cecum dropped from 4.5, 4.5, and 4.2 to 3.6, 1.8, and 2.5 lg CFU/g, respectively. Whole-genome sequencing analysis indicated that the complete genome of MG0718 is 2,574,565 bp in length, containing 2813 CDS. Among these genomic components, 203 stress-related protein genes elucidate its superior environmental tolerance; one bacteriocin gene cluster, one EPS gene cluster and two secondary metabolite gene clusters provide the genetic basis for its antibacterial activity. Notably, no virulence factors were detected, ensuring the safety of the strain for application. In summary, the functional phenotypes of MG0718 are highly consistent with its genetic characteristics, identifying it as a probiotic candidate of significant developmental value. Future research should focus on clinical trials to further verify its practical benefits for human intestinal health and immunomodulation, thereby providing a robust scientific basis for its application in functional foods. Full article

Therapeutic vaccines are a key strategy to achieve the goal of “functional cure” of chronic viral infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human papillomavirus (HPV), and Epstein–Barr virus (EBV). Various platforms (such as viral vectors, nucleic acid vaccines, recombinant proteins, etc.) have successfully induced strong virus-specific T-cell responses in early trials, but their clinical efficacy is still limited by the immunosuppressive environment formed by the host. The core bottlenecks are severe T-cell exhaustion, viral immune escape, and various forms of local immune tolerance. Therefore, the field is moving toward combination therapies, including reduction of viral load, targeting of immune activation, and inhibition of inhibitory signaling pathways. This article summarizes the preclinical and clinical progress of therapeutic vaccines in the past decade, analyzes the major challenges in vaccine development, and discusses the future development directions in this field. Full article

High-altitude environments, characterized by hypoxia, low temperature, and intense ultraviolet radiation, profoundly disrupt host intestinal homeostasis and reshape the gut microbiota, thereby influencing immune regulation and acclimatization. This review systematically summarizes the dynamic compositional and functional changes in the gut microbiota in high-altitude natives, immigrant populations, short-term visitors, and relevant animal models. Current evidence indicates that long-term high-altitude adaptation is associated with directional microbial remodeling, including the enrichment of anaerobic and short-chain fatty acid (SCFA)-associated taxa, which may support energy metabolism and immune homeostasis. In contrast, acute high-altitude exposure more readily induces dysbiosis, impairs intestinal barrier integrity, and promotes the translocation of endotoxins and bioactive metabolites. Mechanistically, the gut microbiota and its metabolites participate in high-altitude adaptation and high-altitude-related disease pathogenesis by modulating barrier function, inflammatory responses, oxidative stress, and immune signaling, and by mediating interorgan communication—characterized by metabolite-driven systemic inflammation or tolerance—through the gut–lung, gut–heart, gut–brain, gut–kidney, and gut–testis axes. SCFAs, bile acids, amino acid-derived metabolites, and succinic acid may control immune homeostasis and inflammatory responses through pathways including TLR4/NF-κB and NLRP3. Although the causal relationships, core microbial effectors, and population-specific heterogeneity remain incompletely defined, microbiota-targeted interventions, including probiotics, prebiotics, and fecal microbiota transplantation, have shown promise for promoting acclimatization and preventing high-altitude-related disorders. Overall, this review provides an integrated framework linking environmental stress, gut microbial ecology, and host immune–metabolic adaptation at high altitude, and highlights future directions for mechanistic and translational research in high-altitude medicine. Full article

Acne vulgaris is a prevalent inflammatory disorder of the pilosebaceous unit involving follicular hyperkeratinization, altered sebum production, Cutibacterium acnes proliferation, microbiome imbalance, and immune activation. Although antibiotics, retinoids, benzoyl peroxide, and keratolytic agents remain central to clinical management, their long-term use may be limited by irritation, recurrence, adherence issues, and increasing antimicrobial resistance. This narrative review critically evaluates the dermatological relevance of Melaleuca alternifolia tea tree essential oil (TTEO), Mentha piperita peppermint essential oil (PPEO), and polyhydroxy acids (PHAs), as well as their incorporation into biopolymeric delivery systems for acne-oriented topical applications. Following SANRA principles, evidence from clinical, preclinical, ex vivo, and in vitro studies was synthesized, with emphasis on antimicrobial activity, inflammatory modulation, keratolytic and barrier-supportive effects, formulation stability, and release behavior. TTEO shows the strongest clinical support among the reviewed natural bioactives, including reductions in lesion counts and acne severity when applied as conventional or nanoemulsion-based formulations. PPEO is mainly supported by experimental evidence, particularly antimicrobial activity against acne-associated microorganisms, anti-inflammatory potential, and menthol-related neurocutaneous effects, whereas acne-specific clinical validation remains limited. PHAs, particularly gluconolactone, are better supported for barrier improvement, hydration, tolerability, and seboregulation than for direct acne lesion reduction. Hydrogels, electrospun nanofibers, polymeric films, nanoencapsulation systems, and controlled-release platforms may improve local retention, protect volatile or irritation-prone compounds, and modulate active release at the skin surface. However, most biopolymeric platforms still rely on early-stage or indirect dermatological evidence. Overall, biopolymeric delivery systems offer a rational formulation strategy to improve the stability, tolerability, and localized action of selected acne-relevant bioactives, but their clinical translation requires standardized composition, reproducible fabrication, skin-relevant release assays, safety assessment, and controlled human studies. Full article

Toll-like receptors (TLRs) are conserved pattern recognition receptors essential to insect innate immunity. However, the functions of TLRs in Loxostege sticticalis, a destructive agricultural pest, remain poorly characterized. In this study, the full-length coding sequence of the L. sticticalis Toll receptor (LsToll) was identified and characterized to analyze its molecular features. Structural analysis showed that LsToll possesses typical Toll family features, including an extracellular domain containing 19 leucine-rich repeats (LRRs), a transmembrane helix, and a highly conserved intracellular Toll/interleukin-1 receptor (TIR) domain. LsToll transcript levels were significantly upregulated after bacterial challenge. RNAi-mediated silencing of LsToll significantly reduced larval tolerance to bacterial infection and increased mortality. Notably, LsToll suppression also induced severe developmental abnormalities, including molting obstruction, pupation failure, and defects in wing expansion in newly emerged adults. Transcriptome analysis after RNAi identified 5230 differentially expressed genes (DEGs), which were significantly enriched in insect hormone biosynthesis and metabolic pathways. Biochemical assays further confirmed that LsToll knockdown decreased 20-hydroxyecdysone (20E) titers and increased juvenile hormone III (JH III) titers. These results suggest that LsToll contributes to antibacterial defense and normal development in L. sticticalis. Its involvement in both survival and development indicates that LsToll may serve as a promising molecular target for sustainable pest management strategies. Full article

Background/Objectives: Metastatic melanoma increasingly includes clinical scenarios in which metastasis-directed treatment may complement systemic immunotherapy, particularly in oligometastatic disease. We evaluated outcomes of stereotactic body radiotherapy (SBRT) combined with immunotherapy in patients with metastatic melanoma, focusing on local control, survival, treatment sequencing, and safety. Methods: In this retrospective single-center study, 63 patients underwent SBRT for 97 extracranial metastatic lesions while receiving immune checkpoint inhibitors. The primary endpoint was local control (LC), while secondary endpoints included progression-free survival (PFS), overall survival (OS), and treatment-related toxicity. Results: LC rates at 12, 24, and 36 months were 95.9%, 89.7%, and 89.7%, respectively, demonstrating durable long-term control of treated lesions. Median OS was 47 months, while median PFS was not reached. A numerical trend toward longer PFS was observed among patients receiving SBRT during immunotherapy, although the differences were not statistically significant. No significant differences in LC were identified across oligometastatic disease subcategories. Combined treatment was well tolerated, with predominantly low-grade toxicity and no signal of increased immune-related adverse events. Conclusions: SBRT combined with immunotherapy appears to be a feasible and effective metastasis-directed treatment strategy in selected patients with metastatic melanoma. Durable local control, encouraging survival outcomes, and favorable tolerability support further prospective studies to optimize treatment sequencing and the integration of local and systemic therapies. Full article

Cold stress poses a significant challenge to aquatic organisms, affecting their survival, growth, and metabolic processes. This review explores the molecular mechanisms by which fish, crustaceans, and mollusks respond to cold stress, highlighting the shared and species-specific pathways that facilitate adaptation. Common responses to cold stress include modulation of energy metabolism, regulation of oxidative stress, immune responses, and maintenance of proteostasis. In particular, the activation of the adenosine 5′-monophosphate-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) pathways plays a critical role in regulating energy balance and autophagy in response to low temperatures. Furthermore, we examine the specific adaptive mechanisms employed by different groups of aquatic organisms. Fish utilize pathways such as peroxisome proliferator-activated receptor alpha/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPAR/PGC-1α) and fatty acid oxidation to optimize energy utilization and improve cold tolerance. Crustaceans rely on crustacean hyperglycemic hormone (CHH) signaling and AMPK pathway activation, while mollusks employ metabolic suppression and glycogen storage to survive cold exposure. Moreover, the regulation of autophagy and apoptosis, mediated by p53 and cyclin-dependent kinase 1 (Cdk1), ensures the survival of healthy cells under prolonged cold stress, with autophagy maintaining energy homeostasis and apoptosis eliminating damaged cells. This review also discusses the role of molecular chaperones like heat shock protein 70 (HSP70) and the ubiquitin-proteasome system (UPS) in protein homeostasis, highlighting their importance to protect cells under cold stress. The combined action of these molecular pathways allows aquatic organisms to cope with and adapt to cold environments, ensuring cellular integrity and enhancing survival. Future research should focus on integrating molecular, physiological, and ecological approaches to better understand cold tolerance mechanisms and improve aquaculture practices under climate change scenarios. Full article

Caspases orchestrate metazoan apoptosis, regulating processes such as embryogenesis, the death of old and infected cells and immune tolerance. Structural orthologs of caspases have been identified in bacteria, plants, protists and fungi and regulated cell death has been demonstrated in these organisms. This led some researchers to conclude that fungal metacaspases might perform a similar function to caspases. This review discusses regulated cell death, beginning with an account of RCD and the central role of caspases in mammalian RCD. It goes on to give examples of RCD in fungi, compares the structure and activity of caspase orthologs and outlines examples of metacaspase-dependent and metacaspase-independent cell death in fungi, focusing on S. cerevisiae. Finally, it addresses the question “are metacaspases caspases?”, identifies alternative cell death proteases and recommends future research objectives. Full article

Ductal carcinoma in situ (DCIS) is a non-invasive precursor to invasive breast cancer. DCIS incidence continues to rise, yet its clinical management remains constrained by the absence of reliable biomarkers that can adequately distinguish indolent lesions from those with high invasive potential, to circumvent over- or under-treatment. Black women with DCIS are significantly more likely to progress to invasive breast cancer, are disproportionately diagnosed with high-grade, hormone receptor-negative lesions, and experience elevated risk of recurrence and mortality relative to White women with DCIS. These disparities persist despite comparable access to screening and treatment, suggesting underlying biological and tissue microenvironmental factors. This review synthesizes emerging evidence implicating early molecular and systemic changes that may be driving the disparity in DCIS progression. We highlight racial distinctions in interconnected pathways involving Wnt/β-catenin signaling, metabolic and nutritional dysregulation, immune microenvironment remodeling, and cellular tolerance of genomic instability. We further discuss how epigenetic alterations, obesity-associated inflammation, and immune dysregulation may arise during the pre-invasive stage that intersect with social and environmental exposures to influence racial differences in lesion fate. We spotlight candidate biomarkers disproportionately associated with aggressive disease in Black women—including KIFC1, a mediator of centrosome clustering and genomic instability tolerance, and ACKR1/DARC, a regulator of chemokine gradients and immune trafficking—as potential drivers of progression-permissive states. This review advances an integrated, equity-informed framework for DCIS progression that links early tumor evolution to coordinated alterations in genomic instability, immune regulation, metabolic signaling, and stress-adaptive pathways. Importantly, we propose that DCIS progression is governed not by isolated molecular alterations but by coordinated programs that enable survival under genomic and immunologic stress. Current clinical risk assays, which primarily capture tumor-intrinsic proliferation and hormone signaling, do not fully resolve these pathways and may therefore incompletely reflect biologically meaningful racial disparities. This synthesis underscores the need for pathway-level, microenvironment-informed, and population-representative approaches to DCIS risk stratification. Advancing such frameworks will be essential for identifying actionable biomarkers, refining early intervention strategies, and ultimately reducing racial disparities in breast cancer outcomes. Full article

Glioblastoma (GBM) is an aggressive primary brain tumor associated with poor prognosis and resistance to therapy, underscoring the need for reliable preclinical models to evaluate emerging treatments. The orthotopic implantation of GBM stem-like cells (GSCs), combined with the intratumoral delivery of therapeutic agents, represents a widely used approach for modeling GBM tumor growth and studying treatment response. In particular, oncolytic herpes simplex viruses (oHSVs) have emerged as a promising strategy to selectively target malignant cells while inducing antitumor immune responses with minimal systemic toxicity. However, performing repeated survival stereotactic neurosurgeries in the same animal poses significant technical challenges. Here, we describe a comprehensive and reproducible protocol for triple survival stereotactic neurosurgery in mice. This approach involves (i) the intracranial implantation of GSCs to establish orthotopic tumors, (ii) the intratumoral delivery of oHSV using the same stereotactic coordinates, and (iii) contralateral intracranial rechallenge with GSCs to evaluate therapeutic efficacy and resistance to tumor rechallenge as a measure of immune memory. Using this protocol, consistent tumor establishment was achieved, and mice tolerated repeated neurosurgical procedures with stable postoperative recovery. Successful intracranial rechallenge in the same animal demonstrates the technical feasibility of multiple survival surgeries while minimizing procedure-related variability and complications. This method enables longitudinal assessment of tumor progression, therapeutic response, and durable memory protection within a single subject. Furthermore, this protocol provides a versatile platform for evaluating oncolytic virotherapy and other localized treatment strategies for GBM. Full article

This review aims to comprehensively examine spent coffee grounds (SCGs) as a sustainable source of antioxidant and immunomodulatory bioactives, with a specific focus on their capacity to modulate membrane-level signaling through ion channels and G-protein-coupled receptors (GPCRs) in the context of lifestyle-related chronic diseases. SCGs, the major solid by-product of coffee brewing, represent an underutilized yet highly abundant source of bioactive compounds, including chlorogenic acids, phenolic acids, melanoidins, diterpenes, and residual alkaloids. Lifestyle-related chronic diseases, including type 2 diabetes, obesity, cardiovascular disease, and chronic inflammatory disorders, are increasingly recognized as immunometabolic conditions driven by persistent low-grade inflammation, redox imbalance, and dysregulated membrane signaling. This review synthesizes current evidence demonstrating that bioactives contained in SCG extracts exert antioxidant and immunomodulatory effects that extend beyond radical scavenging. Crucially, these compounds also act as modulators of membrane-level signaling, representing a mechanistic perspective that has not been previously integrated for SCGs in the context of chronic disease. The different extraction methodologies and the obtained results are evaluated with the aim to identify the most effective experimental approach and extraction conditions. The paper also discusses how SCG compounds regulate redox-sensitive ion channels (including calcium channels, TRP channels, and potassium channels), and key GPCR pathways (such as GPR120, GPR43, and adenosine receptors), thereby influencing immune cell activation, cytokine production, insulin signaling, and metabolic inflammation. Particular attention is given to the role of microbial fermentation and enzymatic processing in enhancing SCG bioavailability, generating postbiotic metabolites that further engage GPCR–ion channel crosstalk. By integrating extraction approaches, antioxidant chemistry, immunology, membrane signaling, and nutritional metabolism, this review positions SCG as a sustainable functional ingredient capable of restoring immune tolerance and metabolic homeostasis. These insights support the valorization of SCGs within the circular economy framework and highlight their potential application in next-generation immunonutrition strategies for chronic disease prevention and management. Full article

A novel Bacillus velezensis strain DY201, isolated from broiler feces, was characterized to assess its probiotic potential as an antibiotic alternative in poultry production. The strain demonstrated robust environmental tolerance with optimal growth at 42 °C and 51.32% survival following sequential exposure to simulated gastric and intestinal fluids. DY201 exhibited broad-spectrum antimicrobial activity against enterotoxigenic Escherichia coli K88, Staphylococcus aureus, Salmonella pullorum, and Clostridium perfringens, with activity remaining stable across pH 5.0–8.0 and retaining over 92.65% efficacy after 85 °C treatment. Scanning electron microscopy revealed metabolite-induced membrane perforation in target pathogens. Although whole-genome sequencing identified 14 biosynthetic gene clusters for lipopeptides including surfactin and fengycin, integrated proteomic and metabolomic analyses detected small-molecule metabolites—Withaferin A, 2′-hydroxy-2-methoxychalcone, and platycodigenin—as the primary antimicrobial effectors. In a preliminary broiler trial, dietary DY201 supplementation significantly increased the relative abundance of Bacillus in the ileum from 0.30% to 10.30% (p = 0.0434) and in the jejunum from 0.77% to 5.56% (p = 0.0453), enriched the generally beneficial genus Lactobacillus in the jejunum from 73.05% to 80.11% (p = 0.0323), and reduced Candidatus Arthromitus in the ileum from 13.38% to 0.59% (p = 0.0105). These findings support B. velezensis DY201 as a promising probiotic candidate for intestinal microbiota modulation in broilers, although functional intestinal health benefits require further validation through growth performance, barrier function, immune response, and pathogen challenge studies. Full article