Search Results (1,465)

Acute inflammatory disorders, including acute lung injury, acute pancreatitis, ischaemia–reperfusion injury, and sepsis, are major clinical challenges characterised by rapid progression, a characteristic cytokine storm, and high mortality rates. The receptor for advanced glycation end-products (RAGE) serves as a pivotal multi-ligand pattern recognition receptor that integrates PAMPs and DAMPs. Excessive RAGE engagement triggers detrimental signalling cascades, notably NF-κB and MAPKs, which exacerbate hyperinflammation and lead to progressive organ dysfunction. Consequently, the RAGE axis represents a potent therapeutic target for mitigating hyperinflammation and improving clinical outcomes in acute inflammatory disorders. While initial pharmacological efforts focused on synthetic inhibitors and biologics, there is a shifting focus toward bioactive alternatives with high safety profiles. Here, we present recent molecular insights into RAGE-mediated pathogenesis in acute inflammatory disorders and evaluate current therapeutic strategies. Furthermore, we emphatically summarise the bioactive natural products, including terpenoids, flavonoids, alkaloids, and a xanthone, that prevent and treat acute inflammatory disorders by disrupting RAGE–ligand interactions and suppressing downstream oxidative stress and cytokine release. Integrating these molecular mechanisms with the pharmacological profiling of natural RAGE modulators provides a robust foundation for the development of next-generation therapeutic strategies to improve clinical outcomes in acute inflammatory disorders. Full article

Mechanical circulatory support (MCS) has transformed the management of advanced heart failure; however, device-related morbidity remains substantially driven by adverse interactions occurring at the blood–material and tissue–device interfaces. Despite progressive miniaturization and the evolution from first-generation pulsatile systems to contemporary continuous-flow devices, thrombotic, hemorrhagic, infectious, and inflammatory complications continue to limit long-term outcomes. This review examines the mechanistic contribution of material properties, surface architecture, and hemodynamic conditions to the pathogenesis of major MCS-associated complications, with particular emphasis on thrombogenicity, biomaterial-induced inflammatory activation, driveline and cannulation-associated infections, hemocompatibility disturbances, and device-related structural failure. The interplay between protein adsorption, platelet activation, complement cascade dysregulation, disturbed shear profiles, and biofilm formation is analyzed as a central determinant of adverse clinical events. Special attention is given to pediatric MCS, in which the continued reliance on extracorporeal pulsatile systems, unique anatomical constraints, and narrow therapeutic margins intensify susceptibility to both thromboembolic and infectious sequelae. Furthermore, the review addresses how material and surface modifications, and emerging biomimetic and anti-thrombogenic coatings may influence complication mitigation. By integrating clinical, engineering, and biomaterials perspectives, this work highlights that many complications traditionally regarded as secondary clinical phenomena are fundamentally rooted in device–material interactions and flow-mediated biological responses. Improved understanding of these mechanisms is essential for optimizing device design, enhancing hemocompatibility, and reducing complication burden in both adult and pediatric MCS populations. Full article

Cardiomyopathies are traditionally classified by structural and genetic phenotypes, but emerging evidence highlights chronic myocardial inflammation as a pivotal driver of disease progression across different etiologies. This review synthesizes the current literature on the cellular and molecular inflammatory mechanisms underlying hypertrophic cardiomyopathy, Anderson–Fabry disease, cardiac amyloidosis, arrhythmogenic cardiomyopathy, and dilated cardiomyopathy. Across these distinct conditions, endogenous triggers such as metabolic substrates, misfolded amyloid fibrils, mechanical stress, or viral genomes act as damage-associated molecular patterns. These stimuli activate innate and adaptive immune cascades, notably the Toll-like receptors, the NF-κB pathway, and the NLRP3 inflammasome. This immune activation establishes a pro-inflammatory microenvironment that promotes fibroblast reprogramming, myocardial edema, and progressive fibrotic or fibro-fatty remodeling. Inflammation is an active, core pathophysiological mechanism rather than a passive secondary bystander in cardiomyopathies. Recognizing these shared immune pathways provides a framework for improved risk stratification and highlights the potential for targeted immunomodulatory therapies to alter disease trajectories. Full article

Background/Objectives: Chronic wounds remain a formidable clinical challenge due to the suboptimal efficacy of conventional delivery systems and therapeutics. Textilinin-1, a venom-derived Kunitz-type serine protease inhibitor, has previously established its profile as a potent hemostatic agent. However, its potential as a multifunctional biopharmaceutical for wound management remains largely untapped. This study evaluates the pharmacological effects of Textilinin-1 in preclinical models of cutaneous wound repair. Methods: We employed an integrated platform comprising bioinformatics, in vitro cellular assays, and in vivo murine excisional wounds and a pilot porcine proof-of-concept model to assess the wound healing-promoting effects of Textilinin-1 and explore associated cellular responses associated with key stages of the wound healing cascade. Results: Textilinin-1 was associated with multiple cellular responses relevant to tissue repair. It attenuated M1-like inflammatory activation and showed preliminary growth-inhibitory activity against Staphylococcus aureus under the tested conditions. Concurrently, it enhanced the proliferative and migratory capacity of fibroblasts, endothelial cells, and keratinocytes, which are key cellular targets for wound closure. In pre-clinical pilot porcine and rodent models, Textilinin-1 treatment was associated with accelerated wound contraction and improved structural tissue quality. Conclusions: Our findings provide preclinical evidence that Textilinin-1 may promote cutaneous wound repair and modulate cellular responses relevant to key stages of the wound healing cascade. These results support further investigation of Textilinin-1 as a candidate for wound repair applications. Future studies are required to define its precise molecular mechanisms, evaluate its efficacy in chronic or otherwise compromised wound models, and optimize its topical formulation or hydrogel-based delivery. Full article

Acute kidney injury, a broad term associated with diverse etiologies, is a common pathological condition that develops into chronic disease via mechanisms that have yet to be fully understood. Key processes that promote chronic disease transition include mitochondrial dysfunction and aberrant complement system activation, specifically inducing inflammation and accumulation of pro-fibrotic changes. Although emerging evidence strongly indicates that these two processes are closely intertwined, identification of appropriate therapeutic targets remains limited. Among complement proteins, terminal portions of the cascade, including complement 5 (C5), exert particularly robust effects on mitochondrial function across tissues, including the kidney. Moreover, C5 is the most terminal portion of the cascade to produce a highly pro-inflammatory anaphylatoxin, positioning C5 as an ideal clinical target during kidney injury/disease. In this review, we will hence summarize current knowledge regarding mitochondrial contributions to kidney pathophysiology through the lens of the close relationship between mitochondria and the complement system, particularly C5. Full article

Polymer coatings are integral to nearly every modern cardiovascular and endovascular device, including drug-eluting stents (DESs) and drug-coated balloons (DCBs), bioabsorbable vascular scaffolds (BVSs), occluders, grafts, and catheter and guidewire hydrophilic surfaces. Persistent complications, including late stent thrombosis, delayed endothelialization, hypersensitivity, and restenosis, show that coatings actively shape biological responses rather than acting as inert drug carriers. Their surface chemistry, drug release kinetics, and degradation behavior are upstream determinants of blood– and tissue–material responses that govern healing and failure. This review frames coating selection as a structure–property–biological response problem. It surveys the major classes of synthetic polymer coatings and the defining surface and bulk properties. This review also examines how composition and architecture control drug release, and traces the interfacial cascade of protein adsorption, coagulation and complement activation, platelet and leukocyte responses, and neutrophil extracellular trap (NET) formation. These mechanisms are linked to contemporary design strategies that improve hemocompatibility, limit thrombosis, promote endothelial recovery, and tune degradation, and to the standardization and translation gaps that remain. The central message is that polymer coatings are not biologically equivalent. Their surface chemistries and degradation profiles determine the thrombo-inflammatory outcomes. Therefore, coating design should be guided by intended biological response, not drug release alone. Full article

Background: Hexavalent chromium (Cr(VI)) is a widespread environmental toxic heavy metal with strong oxidative properties; however, its immunotoxicity and metabolic mechanisms in rabbit spleen remain largely unclear. Methods: In this study, New Zealand rabbits were exposed to 0, 12.5, 25, and 50 mg/L Cr(VI) (as potassium dichromate, K₂Cr₂O₇) via drinking water for four weeks to investigate splenic damage and the underlying molecular pathways. Spleen pathological injury was evaluated by hematoxylin and eosin (H&E) staining, and the distribution of T cells, B cells, and macrophages was assessed by immunohistochemistry. Antioxidant enzyme activities and antioxidant substance levels were determined using ELISA, and the relative mRNA expression of immune factor genes, antioxidant-related genes, and ferroptosis-related genes was quantified by quantitative real-time PCR (qRT-PCR). In addition, the distribution of iron in splenic tissue was detected by enhanced Prussian blue staining. Results: Our results demonstrate that high-dose Cr(VI) significantly inhibited body weight gain, induced lymphocyte atrophy, vacuolization, and widening of intercellular spaces in the splenic white pulp. Furthermore, Cr(VI) reduced T and B lymphocyte populations, promoted macrophage infiltration and inflammatory cytokine gene expression in a concentration-dependent manner, impaired total antioxidant capacity, and led to a decrease in glutathione (GSH) levels in the spleen. Additionally, Cr(VI) exposure increased iron accumulation, activated the ACSL4–NOX lipid peroxidation cascade, and downregulated GPX4 expression, ultimately triggering ferroptosis. Conclusions: These findings reveal that Cr(VI) causes splenic immune injury by disrupting oxidative homeostasis and inducing ferroptosis, providing novel insights for evaluating immunotoxicity and identifying metabolic targets under Cr(VI) pollution. Full article

Vein graft restenosis is a leading cause of long-term failure after coronary artery bypass grafting (CABG), driven by maladaptive vascular smooth muscle cell (VSMC) responses to arterialization-induced inflammation. The key molecular mediators of this pathological remodeling, however, remain incompletely defined. Here, we integrated multi-omics analyses of human and canine vein graft specimens with in vitro functional assays to identify tenascin-C (TNC)—a matricellular extracellular matrix protein—as a critical regulator of VSMC dysfunction. TNC was specifically enriched in a synthetic, pro-inflammatory VSMC subpopulation. Pro-inflammatory stimuli potently induced TNC expression, which was functionally linked to VSMC phenotypic modulation, hyperproliferation, and enhanced migration. Mechanistically, TNC acts upstream of NF-κB signaling; siRNA-mediated TNC knockdown significantly reduced nuclear p65 protein levels and attenuated inflammatory responses. Our integrated computational and experimental data suggest that TNC, NF-κB, and TNF-α function within a sequential pro-inflammatory signaling cascade that sustains vascular inflammation and promotes neointimal hyperplasia. These findings reposition TNC from a passive structural component to an active driver of vascular pathology and highlight the TNC–NF-κB axis as a candidate target for therapeutic intervention to improve vein graft patency. Full article

Multiple sclerosis (MS) is a neuro-inflammatory disease characterized by demyelination in the central nervous system (CNS). Although a substantial endogenous capacity for remyelination has been demonstrated, this process is frequently incomplete and exhibits marked intra- and inter-individual heterogeneity. Several factors influence the extent of spontaneous myelin regeneration, including age, sex, disease course, and lesion localization. Oligodendrocytes (OL), derived from oligodendrocyte progenitor cells (OPCs), are the principal myelinating cells of the CNS. The regenerative cascade involves several key stages, including OPC activation, recruitment, differentiation into oligodendrocytes (OL), and myelin deposition. This process is orchestrated in a spatiotemporal manner by a complex interplay of intracellular signaling pathways, genetic determinants, and dynamic microenvironmental cues, which together balance inhibitory and pro-remyelinating influences. Several lines of evidence indicate that chronically demyelinated axons are vulnerable to degeneration, whereas successful remyelination may confer neuroprotection. These observations underscore remyelination as a promising neuroprotective therapeutic target for preventing or slowing disability progression in MS, a condition in which gradual neuroaxonal degeneration is believed to underlie irreversible disability progression. In this review, we aim to bridge the gap between fundamental biological mechanisms of remyelination and their clinical relevance. We examine recent advances in in vivo techniques for assessing remyelination and discuss how these measures correlate with clinical and disability outcomes. In addition, we review recent clinical trials of remyelination-promoting therapies and analyze the challenges that have limited their advancement beyond phase II. Overall, we seek to provide a comprehensive overview of the remyelination process from bench to bedside, highlighting both the obstacles and the therapeutic potential of remyelination strategies in MS. Full article

Postoperative inflammation is a necessary response to surgical injury that supports tissue repair and regeneration. However, successful healing depends not only on the initial inflammatory response but also on its timely resolution. Failure to resolve inflammation can impair wound healing, promote fibrosis, and increase the risk of postoperative complications. Increasing evidence suggests that effective recovery is driven by the transition from inflammation to repair and regenerative processes. Diet plays an important role in this transition, as nutrients not only provide metabolic support but also regulate key pathways involved in inflammation, tissue regeneration, redox balance, and immune function. Omega-3 polyunsaturated fatty acids could serve as precursors for specialized pro-resolving mediators that actively terminate inflammation and may promote macrophage-driven tissue repair. Polyphenols and antioxidant micronutrients modulate NF-κB and Nrf2-dependent signalling, attenuating oxidative amplification of inflammatory cascades. Micronutrients and amino acids further regulate enzymatic processes governing collagen synthesis, angiogenesis, and immune competence. Concurrently, diet-driven preservation of gut barrier integrity limits endotoxin-mediated amplification of systemic inflammatory responses. By targeting interconnected molecular networks, including inflammasome activation, mitochondrial redox signalling, and metabolic programming of immune cells, anti-inflammatory dietary patterns may promote immune resolution rather than immunosuppression. This distinction is particularly relevant in the postoperative setting, where balanced inflammation is required for both host defence and regenerative healing. This review synthesizes current molecular and translational evidence linking dietary modulation to postoperative inflammatory control and tissue regeneration. By integrating insights from immunology, metabolism, and nutritional science, it positions diet as an active, biologically grounded component of perioperative management and highlights future directions for precision nutrition strategies aimed at optimizing surgical recovery. Full article

[¹⁸F]-PSMA PET/CT is a high-impact modality for the staging and restaging of prostate cancer, but its wide anatomic coverage and tracer biology generate frequent incidental findings on both PET and the accompanying low-dose CT (LDCT). This narrative review is restricted in scope to fluorine-18 PSMA tracers because tracer-specific biodistribution and pitfall profiles shape what is perceived as incidentaloma: how confidently lesions can be categorized, and how often borderline findings trigger downstream testing, particularly for skeletal foci with [¹⁸F]-PSMA-1007. Specifically, [¹⁸F]-PSMA-1007 shows substantially higher rates of focal unspecific bone uptake than [⁶⁸Ga]-PSMA-11—reported in multicenter studies as affecting up to 40–50% of patients—which directly inflates the pool of potential incidentalomas and creates a tracer-specific false-positive problem with no parallel in gallium-68 practice. Additionally, [¹⁸F]-DCFPyL has different urinary clearance kinetics that affect bladder and ureteral uptake patterns, altering what qualifies as physiologic versus incidental in the pelvis. These differences mean that the threshold for Category B versus C classification—and the appropriate cascade-resistant language—must be tuned to the specific tracer in use. A framework built on [⁶⁸Ga]-PSMA-11 data would systematically underestimate bone pitfall frequency in [¹⁸F]-PSMA-1007 practice and could therefore paradoxically increase rather than reduce cascades if applied uncritically across tracers. These biodistribution differences have direct and concrete consequences for reporting behaviour and downstream management. In [¹⁸F]-PSMA-1007 practice, a focal bone uptake without a CT correlate in a mechanically plausible location—such as an anterior rib or vertebral endplate—should trigger Category B language in the report conclusion: the finding is documented in the body with explicit safety netting (“most consistent with unspecific uptake; no routine workup unless interval growth, new pain, or aggressive CT morphology”), and no referral to bone scintigraphy or MRI is generated. Without tracer-specific awareness, the same finding would typically prompt a reflex bone scan or whole-body MRI referral, delaying definitive prostate cancer management by weeks and adding imaging costs without diagnostic gain. By contrast, in [⁶⁸Ga]-PSMA-11 practice, an equivalent focal bone uptake without a CT correlate carries a higher prior probability of true metastatic disease given the lower background rate of unspecific uptake and should more often be reported at Category B with a lower threshold for escalation or more cautious language. For [¹⁸F]-DCFPyL, the higher urinary activity in the pelvis means that ureteral segments can mimic lymph node disease; recognizing this as a physiologic variant (Category C) rather than an equivocal nodal finding (Category B) avoids unnecessary pelvic MRI referrals that would otherwise be triggered by an uncontextualized report. In practical terms, the tracer-specific calibration of the overlay therefore changes not only the category assigned but also the specific safety-netting language and the escalation trigger, which directly modifies the downstream management pathway for each affected finding type. The scanned population—predominantly older men with a high prevalence of degenerative, inflammatory, and vascular abnormalities—creates substantial background noise that can drive low-value diagnostic cascades if incidental findings are communicated without actionability context. We integrate society-endorsed frameworks (EANM/SNMMI procedure guideline 2.0; E-PSMA; PSMA-RADS; and PROMISE/miTNM with miPSMA score) and propose a cascade-aware overlay for incidental findings that can be appended to existing PSMA reporting standards rather than replacing them. The A/B/C actionability overlay is a structured expert-consensus framework informed by existing evidence-based guidelines for specific finding types and by tracer-specific cohort data; it has not yet been prospectively validated as a standalone tool, and its current level of evidence is therefore analogous to a structured expert recommendation rather than an evidence-based clinical guideline. We operationalize a three-tier actionability scheme across PET- and CT-dominant findings, provide cascade-resistant language for conclusions, and clarify why SUVmax-only “probability scales” for lymph nodes are not recommended in routine reports. Three practical tables summarize PET incidental findings, lymph node reporting frameworks, and LDCT incidental findings, and two structured report templates are provided (concise and extended), with the extended version explicitly labelling actionability tiers and escalation triggers. Finally, we outline concrete AI use cases for standardization and triage while emphasizing governance to avoid the amplification of false positives and paradoxical growth of cascades. Full article

Microplastics and nanoplastics (MNPLs) are increasingly recognized as dynamic vectors capable of transporting a wide range of environmental contaminants, as well as acting as physical particulates. Their small size, high surface reactivity and strong sorption capacity allow them to carry metals, pesticides, pharmaceuticals and endocrine-active compounds into biological systems. This narrative review examines how these particle-contaminant complexes influence oxidative stress, inflammatory signaling and endocrine function during early development. Relevant literature was identified through structured searches of PubMed, Scopus, Web of Science and Google Scholar, with a focus on the physicochemical properties of plastics, sorption mechanisms, gut barrier physiology and developmental toxicology. Early developmental stages are particularly sensitive, as immature mucus layers, permeable epithelial junctions and underdeveloped detoxification pathways facilitate the uptake and systemic distribution of MNPLs. Once internalized, these particles and their chemical cargo promote the generation of reactive oxygen species through redox-active contaminants, surface-catalysed reactions and mitochondrial dysfunction. The resulting oxidative imbalance activates stress-responsive pathways, including Nrf2–Keap1 signaling, and promotes lipid peroxidation, DNA damage and cellular dysfunction. MNPLs also stimulate inflammatory cascades by activating pattern-recognition receptors, altering cytokine profiles and disrupting epithelial homeostasis. These responses are intensified in the presence of sorbed pollutants, leading to sustained inflammatory states that can be particularly detrimental during organogenesis and immune maturation. Endocrine function is likewise affected, as MNPLs transport hormonally active chemicals and can interfere with hormone-responsive pathways through oxidative and inflammatory mechanisms. These interactions may disrupt thyroid signaling, metabolic regulation and the development of the reproductive axis, with potential long-term physiological consequences. Integrating evidence from polymer chemistry, contaminant behavior and developmental physiology, this review shows that MNPLs act as biologically active vectors that may increase oxidative, inflammatory and endocrine disturbances during early development. These findings highlight the importance of considering particle–contaminant interactions as a critical component of early-life risk assessment. Full article

Sepsis-associated encephalopathy (SAE) is a frequent neurological complication of sepsis, driven by six interconnected pathophysiological components: (1) systemic inflammation-triggered neuroinflammatory cascades, initiated by systemic recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and propagated by pro-inflammatory mediators; (2) central nervous system (CNS) immune cell-mediated neuroinflammation, wherein microglia, regulatory T cells, and neutrophils dynamically regulate inflammatory progression; (3) blood–brain barrier (BBB) disruption, progressing from functional disturbance to structural damage via tight junction degradation and immune infiltration; (4) multimodal programmed cell death, encompassing autophagy, apoptosis, pyroptosis, and ferroptosis driven by mitochondrial dysfunction; (5) neurotransmitter network imbalance, manifesting as cholinergic deficiency and glutamate excitotoxicity; and (6) gut–brain axis dysregulation, characterized by reduced microbiota-derived metabolites such as butyrate and indolepropionic acid. These components are organized along a core pathological axis comprising four sequential stages: neuroinflammatory storm (encompassing components 1 and 2) → BBB disruption and microcirculatory disturbances (component 3) → multimodal programmed cell death (component 4) → neurotransmitter imbalance (component 5), with the gut–brain axis (component 6) functioning as a bidirectional regulatory node that intersects and modulates all four stages. Mitochondrial dysfunction serves as the central converging node linking these pathological axes. Targeted interventions against neuroinflammation, immune cell modulation, BBB restoration, inhibition of aberrant cell death, neurotransmitter homeostasis, and gut microbiota remodeling hold therapeutic promise. Elucidating the crosstalk among these pathways will accelerate the clinical translation of precision therapies for SAE. Full article

Acute ischemic stroke is one of the leading causes of mortality and disability globally, characterized by a complex and temporally structured cascade of cellular and molecular events. Although reperfusion therapies have improved outcomes, their narrow therapeutic window and limited availability leave many patients without effective treatment, highlighting the need for effective neuroprotective strategies capable of targeting multiple interconnected pathways. Melatonin has been proposed as a potential adjunctive neuroprotective agent based on its pleiotropic properties, modulating cellular signaling networks including antioxidant, anti-inflammatory, mitochondrial stabilizing, and BBB-preserving effects. Melatonin regulates key signaling pathways, thereby coordinating cellular responses to injury in multiple stages of ischemic pathophysiology, positioning it as a potential adjunctive therapy. Preclinical studies consistently demonstrate reductions in infarct volume, preservation of neuronal architecture, and improvements in neurological outcomes. However, clinical evidence remains limited to a small number of clinical trials, which suggest safety and possible early neurological benefit but are underpowered to determine long-term efficacy. Importantly, translational gaps persist regarding optimal dosing, duration of administration, and alignment with the temporal dynamics of post-ischemic injury. This review integrates current knowledge on the cellular and molecular mechanisms underlying the potential neuroprotective actions and its role as a pleiotropic modulator of ischemic injury. Full article

Dandruff (DF) is a prevalent, recurrent inflammatory scalp disorder increasingly recognized as a complex state of functional dysbiosis rather than a simple Malassezia overcolonization. The scalp microbiome is predominantly shaped by Malassezia species (M. restricta and M. globosa), Cutibacterium, and Staphylococcus species. Recent multi-omics evidence indicates that DF pathogenesis is driven by the destabilization of microbial interaction networks and strain-level functional heterogeneity, characterized by the disruption of the C. acnes/S. epidermidis balance and the opportunistic expansion of Staphylococcus aureus. Mechanistically, Malassezia utilizes its lipolytic repertoire to hydrolyze host sebum into irritant free fatty acids and peroxides. Concurrently, oxidative metabolites like squalene peroxide (SQOOH) penetrate the stratum corneum to activate the NF-κB and aryl hydrocarbon receptor (AhR) pathways, triggering a pro-inflammatory cascade that overexpresses keratins (K6/16/17) and downregulates filaggrin. This molecular cascade drives abnormal keratinocyte turnover and lipidomic remodeling, establishing a self-perpetuating “metabolism–inflammation–barrier disruption” pathological cycle. This review systematically elucidates the molecular etiology of DF as an ecological disorder driven by a tripartite imbalance among the microbiome, host physiology, and the environmental niche. We propose that next-generation therapeutic paradigms must transcend traditional antifungal eradication, focusing instead on targeted molecular intervention and microecological restoration to recalibrate overall scalp homeostasis. Full article