Search Results (861)

Neuroinflammation is a key feature of Alzheimer’s disease (AD), and stem cell therapies have emerged as promising candidates due to their immunomodulatory properties. Neuro-Cells (NC), a combination of unmodified mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), have demonstrated therapeutic potential in models of central nervous system (CNS) injury and neurodegeneration. Here, we studied the effects of NC in APPswe/PS1dE9 mice, an AD mouse model. Twelve-month-old APPswe/PS1dE9 mice or their wild-type littermates were injected with NC or vehicle into the cisterna magna. Five to six weeks post-injection, cognitive, locomotor, and emotional behaviors were assessed. The brain was stained for amyloid plaque density using Congo red, and for astrogliosis using DAPI and GFAP staining. Gene expression of immune activation markers (Il-1β, Il-6, Cd45, Tnf) and plasticity markers (Tubβ3, Bace1, Trem2, Stat3) was examined in the prefrontal cortex. IL-6 secretion was measured in cultured human monocytes following endotoxin challenge and NC treatment. Untreated APPswe/PS1dE9 mice displayed impaired learning in the conditioned taste aversion test, reduced object exploration, and anxiety-like behavior, which were improved in the NC-treated mutants. NC treatment normalized the expression of several immune and plasticity markers and reduced the density of GFAP-positive cells in the hippocampus and thalamus. NC treatment decreased amyloid plaque density in the hippocampus and thalamus, targeting plaques of <100 μm². Additionally, NC treatment suppressed IL-6 secretion by human monocytes. Thus, NC treatment alleviated behavioral deficits and reduced amyloid plaque formation in APPswe/PS1dE9 mice, likely via anti-inflammatory mechanisms. The reduction in IL-6 production in human monocytes further supports the potential of NC therapy for the treatment of AD. Full article

Preeclampsia (PE) is a multifactorial hypertensive disorder unique to pregnancy and a leading cause of maternal and fetal morbidity and mortality worldwide. Its pathogenesis involves placental dysfunction and an exaggerated maternal inflammatory response. Uric acid (UA), traditionally regarded as a marker of renal impairment, is increasingly recognized as an active contributor to the development of PE. Elevated UA levels are associated with oxidative stress, endothelial dysfunction, immune activation, and reduced renal clearance. Clinically, UA is measured in the second and third trimesters to assess disease severity and guide obstetric management, with higher levels correlating with early-onset PE and adverse perinatal outcomes. Its predictive accuracy improves when combined with other clinical and biochemical markers, particularly in low-resource settings. Mechanistically, UA and its monosodium urate crystals can activate the NLRP3 inflammasome, a cytosolic multiprotein complex of the innate immune system. This activation promotes the release of IL-1β and IL-18, exacerbating placental, vascular, and renal inflammation. NLRP3 inflammasome activation has been documented in placental tissues, immune cells, and kidneys of women with PE and is associated with hypertension, proteinuria, and endothelial injury. Experimental studies indicate that targeting UA metabolism or inhibiting NLRP3 activation, using agents such as allopurinol, metformin, or MCC950, can mitigate the clinical and histopathological features of PE. These findings support the dual role of UA as both a biomarker and a potential therapeutic target in the management of the disease. Full article

Background/Objective: Early-onset neonatal sepsis (EOS), defined as infection occurring within the first 72 h after birth, remains a major contributor to neonatal morbidity and mortality worldwide. Although advances in perinatal care have improved overall outcomes, the diagnosis of EOS continues to be challenging. Clinical presentations are often nonspecific, laboratory confirmation is often delayed, and immune responses vary considerably among neonates. Expanding our understanding of the molecular mechanisms underlying EOS is essential in enhancing early detection, refining risk stratification, and guiding therapeutic strategies. This systematic review aims to synthesize the available information on the molecular pathways involved in EOS, focusing on pathogen-induced inflammation, systemic immune responses, sterile inflammatory processes, interactions between infectious and non-infectious pathways, as well as emerging molecular diagnostic approaches. Methods: A comprehensive review of original research articles and reviews published between January 2015 and January 2025 was conducted; studies were included based on their focus on human neonates and their analysis of molecular or immunological mechanisms relevant to EOS pathogenesis, immune dysregulation, or novel diagnostic strategies. Results: Pathogen-driven inflammation typically involves the activation of Toll-like receptors (TLRs), the recruitment of neutrophils, and the release of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α, particularly in response to vertical transmission of organisms like Escherichia coli and Streptococcus agalactiae. Systemic inflammatory responses are marked by cytokine dysregulation, contributing to multi-organ dysfunction. Sterile inflammation, often initiated by hypoxia–reperfusion injury or intrauterine stress, amplifies susceptibility to sepsis. Interactions between immune, metabolic, and endothelial pathways further exacerbate tissue injury. Recent advances, including transcriptomic profiling, microRNA-based biomarkers, and immune checkpoint studies, offer promising strategies for earlier diagnosis and individualized therapeutic options. Conclusions: EOS arises from a complex interplay of infectious and sterile inflammatory mechanisms. A deeper molecular understanding holds promise for advancing correct diagnostics and targeted therapies, aiming to improve neonatal outcomes. Full article

Cirrhosis remains a significant global health burden, responsible for nearly 4% of annual deaths worldwide. Despite progress in antiviral therapies and public health measures, its prevalence has plateaued, particularly in regions affected by viral hepatitis, alcohol misuse, and metabolic syndrome. This review presents a comprehensive synthesis of the multifactorial drivers of cirrhosis, including hepatocyte injury, liver stellate cell activation, and immune-mediated inflammation. The emphasis is on the central role of metabolic dysfunction, characterized by mitochondrial impairment, altered lipid and glucose metabolism, hormonal imbalance, and systemic inflammation, in exacerbating disease progression. While current therapies may slow the progression of early-stage disease, they are very often ineffective in reversing established fibrosis. Emerging molecular strategies offer promising alternatives by targeting key pathogenic pathways. These include AMPK activators (e.g., metformin, AICAR), FGF21 analogs, and mitochondria-targeted agents (e.g., MitoQ, urolithin A, NAD+ precursors) to restore bioenergetic balance and reduce oxidative stress. Other approaches, such as mesenchymal stem cell therapy, inflammasome inhibition, and hormonal modulation, aim to suppress fibrogenesis and restore liver homeostasis. The integration of systems biology and multi-omics profiling supports patient stratification and precision medicine. This review highlights a shift toward mechanism-based interventions that have the potential to alter cirrhosis outcomes and improve patient survival. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease characterized by chronic inflammation, vascular remodeling, and immune dysregulation. COVID-19, caused by SARS-CoV-2, shares several systemic immunohematologic disturbances with IPF, including cytokine storms, endothelial injury, and prothrombotic states. Unlike general comparisons of viral infections and chronic lung disease, this review offers a focused analysis of the shared hematologic and immunologic mechanisms between COVID-19 and IPF. Our aim is to better understand how SARS-CoV-2 infection may worsen disease progression in IPF and identify converging pathophysiological pathways that may inform clinical management. We conducted a narrative synthesis of the peer-reviewed literature from PubMed, Scopus, and Web of Science, focusing on clinical, experimental, and pathological studies addressing immune and coagulation abnormalities in both COVID-19 and IPF. Both diseases exhibit significant overlap in inflammatory and fibrotic signaling, particularly via the TGF-β, IL-6, and TNF-α pathways. COVID-19 amplifies coagulation disturbances and endothelial dysfunction already present in IPF, promoting microvascular thrombosis and acute exacerbations. Myeloid cell overactivation, impaired lymphocyte responses, and fibroblast proliferation are central to this shared pathophysiology. These synergistic mechanisms may accelerate fibrosis and increase mortality risk in IPF patients infected with SARS-CoV-2. This review proposes an integrative framework for understanding the hematologic and immunologic convergence of COVID-19 and IPF. Such insights are essential for refining therapeutic targets, improving prognostic stratification, and guiding early interventions in this high-risk population. Full article

Inflammatory Bowel Disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), results from dysregulated immune responses that drive chronic intestinal inflammation. Neutrophils, as key effectors of the innate immune system, contribute to IBD through multiple mechanisms, including the release of reactive oxygen species (ROS), pro-inflammatory cytokines, and neutrophil extracellular traps (NETs). NETs are web-like structures composed of DNA, histones, and associated proteins including proteolytic enzymes and antimicrobial peptides. NET formation is increased in IBD and has a context-dependent role; under controlled conditions, NETs support antimicrobial defense and tissue repair, whereas excessive or dysregulated NETosis contributes to epithelial injury, barrier disruption, microbial imbalance, and thrombotic risk. This review examines the roles of neutrophils and NETs in IBD. We summarize recent single-cell and spatial-omics studies that reveal extensive neutrophil heterogeneity in the inflamed gut. We then address the dual role of neutrophils in promoting tissue damage—through cytokine release, immune cell recruitment, ROS production, and NET formation—and in supporting microbial clearance and mucosal healing. We also analyze the molecular mechanisms regulating NETosis, as well as the pathways involved in NET degradation and clearance. Focus is given to the ways in which NETs disrupt the epithelial barrier, remodel the extracellular matrix, contribute to thrombosis, and influence the gut microbiota. Finally, we discuss emerging therapeutic strategies aimed at restoring NET homeostasis—such as PAD4 inhibitors, NADPH oxidase and ROS pathway modulators, and DNase I—while emphasizing the need to preserve antimicrobial host defenses. Understanding neutrophil heterogeneity and NET-related functions may facilitate the development of new therapies and biomarkers for IBD, requiring improved detection tools and integrated multi-omics and clinical data. Full article

In recent years, a long list of relevant studies has highlighted the engagement of the nervous system in the fine-tuning of tumor development and progression. Several authors have shown that different types of nerve fibres (sympathetic, parasympathetic/vagal or somatosensory fibres) may contribute to tumor innervation affecting cancer initiation, progression and metastasis. A large presence of nerve fibres is frequently observed in tumors with respect to the corresponding healthy tissues. In this regard, it is worth noting that in some cases a reduced innervation may associate with slow tumor growth in a tissue-specific manner. Current studies have begun to shed light over the role played in this specific process by Schwann cells (SCs), the most abundant glial cells of the peripheral nervous system. SCs observed in cancer tissues share strong similarities with repair SCs that appear after nerve injury. A large body of research indicates that SCs may have a role in shaping the microenvironment of tumors by regulating the immune response and influencing their invasiveness. In this review, we summarize data relevant to the role of peripheral innervation in general, and of SCs in particular, in defining the progression of different tumors: melanoma that originate in the skin with mainly sensory innervation; pancreatic and liver-derived tumors (e.g., pancreatic adenocarcinoma and cholangiocarcinoma) with mainly autonomous innervation. We conclude by summarizing data regarding hepatocarcinoma (with anatomical predominance of small autonomic nerve fibres) in which the potential relationship between innervation and tumor progression has been little explored, and largely remains to be defined. Full article

Increased epithelial and endothelial permeability, along with dysregulated inflammatory responses, are key aspects of acute respiratory distress syndrome (ARDS) pathophysiology, which not only impact the lungs but also contribute to detrimental organ crosstalk with distant organs, ultimately leading to multiple organ dysfunction syndrome (MODS)—the primary cause of morbidity and mortality in patients with lung injury (LI) and ARDS. It is predominantly manifested by hypoxemic respiratory failure and bilateral pulmonary infiltrates, which cannot be fully attributed to cardiac failure or hypervolemia, but rather to alveolo-capillary barrier dysfunction, dysregulated systemic and pulmonary inflammation, immune system abnormalities, and mechanical stimuli-related responses. However, these pathological features are not uniform among patients with ARDS, as distinct subphenotypes with unique biological, clinical, physiological, and radiographic characteristics have been increasingly recognized in recent decades. The severity of ARDS, clinical outcomes, mortality, and efficacy of applied therapeutic measures appear significant depending on the respective phenotype. Acknowledging the heterogeneity of ARDS and defining distinct subphenotypes could significantly modify therapeutic strategies, enabling more precise and targeted treatments. To address these issues, a comprehensive literature search was conducted in PubMed using predefined keywords related to ARDS pathophysiology, subphenotypes, and personalized therapeutic approaches. Optimizing the identification and characterization of discrete ARDS subphenotypes—based on clinical, biological, physiological, and radiographic criteria—will deepen our understanding of ARDS pathophysiology, promote targeted recruitment in prospective clinical studies to define patient clusters with heterogeneous therapeutic responses, and support the shift toward individualized treatment strategies. Full article

Systemic sclerosis (SSc) is a heterogeneous disease characterized by vascular alterations, immune dysregulation, and fibrosis. Solid evidence supports the hypothesis that endothelial dysfunction is the key player in SSc vascular injury and a critical factor concurring to the initiation of SSc pathogenesis. This narrative review reports on persistent endothelial dysfunction, resulting from oxidative stress, autoimmunity, and impaired vascular repair, in the course of SSc, and how it can trigger and sustain fibrotic remodeling of various organs. In this paper, we also analyze the impact on SSc of impaired angiogenesis and vasculogenesis, diminished endothelial progenitor cell function, and endothelial-to-mesenchymal transition, which can collectively disrupt vascular homeostasis and promote myofibroblast activation. These pathologic events underlie the hallmark clinical manifestations, i.e., Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. The review highlights how recognizing SSc as a paradigm of systemic endothelial dysfunction may reframe our understanding of its physiopathology, modify current therapeutic strategies, and unveil new therapeutic targets. Full article

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by systemic inflammation, endothelial dysfunction, and placental insufficiency. While inadequate trophoblast invasion and impaired spiral artery remodeling have long been recognized as central to its pathogenesis, emerging evidence underscores the critical roles of dysregulated iron metabolism and its crosstalk with immune responses, particularly macrophage-mediated inflammation, in driving PE development. This review systematically explores the dynamic changes in iron metabolism during pregnancy, including increased maternal iron demand, placental iron transport mechanisms, and the molecular regulation of placental iron homeostasis. We further explore the contribution of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, to trophoblast dysfunction and pregnancy-related diseases, including PE. Macrophages, pivotal immune regulators at the maternal–fetal interface, exhibit distinct polarization states that shape tissue remodeling and immune tolerance. We outline their origin, distribution, and polarization in pregnancy, and emphasize their aberrant phenotype and function in PE. The bidirectional crosstalk between iron and macrophages is also dissected: iron shapes macrophage polarization and function, while macrophages reciprocally modulate iron homeostasis. Notably, excessive reactive oxygen species (ROS) and pro-inflammatory cytokines secreted by M1-polarized macrophages may exacerbate trophoblast ferroptosis, amplifying placental injury. Within the context of PE, we delineate how iron overload and macrophage dysfunction synergize to potentiate placental inflammation and oxidative stress. Key iron-responsive immune pathways, such as the HO-1/hepcidin axis and IL-6/TNF-α signaling, are discussed in relation to disease severity. Finally, we highlight promising therapeutic strategies targeting the iron–immune axis, encompassing three key modalities—iron chelation therapy, precision immunomodulation, and metabolic reprogramming interventions—which may offer novel avenues for PE prevention and treatment. Full article

REG3A, a prominent member of the human regenerating islet-derived (REG) lectin family, plays a pivotal and multifaceted role in immune defense, inflammation, and cancer biology. Primarily expressed in gastrointestinal epithelial cells, REG3A reinforces barrier integrity, orchestrates mucosal immune responses, and regulates host–microbiota interactions. It also functions as a potent non-enzymatic antioxidant, protecting tissues from oxidative stress. REG3A expression is tightly regulated by inflammatory stimuli and is robustly induced during immune activation, where it limits microbial invasion, dampens tissue injury, and promotes epithelial repair. Beyond its antimicrobial and immunomodulatory properties, REG3A contributes to the resolution of inflammation and the maintenance of tissue homeostasis. However, its role in cancer is highly context-dependent. In some tumor types, REG3A fosters malignant progression by enhancing cell survival, proliferation, and invasiveness. In others, it acts as a tumor suppressor, inhibiting growth and metastatic potential. These opposing effects are likely dictated by a combination of factors, including the tissue of origin, the composition and dynamics of the tumor microenvironment, and the stage of disease progression. Additionally, the secreted nature of REG3A implies both local and systemic effects, further modulated by organ-specific physiology. Experimental variability may also reflect differences in methodologies, analytical tools, and model systems used. This review synthesizes current knowledge on the pleiotropic functions of REG3A, emphasizing its roles in epithelial defense, immune regulation, redox homeostasis, and oncogenesis. A deeper understanding of REG3A’s pleiotropic effects could open up new therapeutic avenues in both inflammatory disorders and cancer. Full article

Background: The spleen is the primary reservoir of immune cells in mammals. Diverse stimuli can disrupt spleen homeostasis, resulting in spleen injury and immune dysfunction. This study employed a porcine model to assess the therapeutic potential of salvianolic acid B (SAB) against lipopolysaccharide (LPS)-induced splenic injury. Methods: Seventy-two male weanling piglets were randomly assigned to one of four groups: CON-SS, SAB-SS, CON-LPS, and SAB-LPS. The CON-SS and CON-LPS groups received a basal diet, while SAB-SS and SAB-LPS groups received a SAB-supplemented diet. After 14 d, the CON-SS and SAB-SS groups received an intraperitoneal injection of sterile saline, whereas the CON-LPS and SAB-LPS groups were injected with LPS. Blood and spleen tissues were harvested 6 h post-injection for biochemical analysis. Results: LPS induced systemic immune disorders in piglets, as evidenced by increased immune organ indices and decreased white blood cell, lymphocyte, and basophil counts in blood (p < 0.05). LPS also caused histoarchitectural disruption, cell apoptosis, oxidative stress, and inflammation in the spleen (p < 0.05). Conversely, SAB improved splenic histopathology and reduced splenic apoptosis and pro-inflammatory mediators in piglets (p < 0.05). SAB significantly mitigated peroxidation accumulation by facilitating the nuclear translocation of nuclear factor erythroid 2-related factor 2 and strengthening the antioxidant system, and inhibited nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome activation (p < 0.05). Mechanistically, SAB attenuated LPS-induced splenic oxidative stress and NLRP3 inflammasome activation by restoring mitochondrial structure and function (p < 0.05). Conclusions: This research unveils that SAB alleviates LPS-induced spleen disorder by reinforcing antioxidant system and suppressing NLRP3 inflammasome, highlighting SAB’s potential as a prospective therapeutic agent for spleen disorders. Full article

Myocardial injury following polytrauma is a significant yet often underdiagnosed condition that contributes to acute cardiac dysfunction and long-term cardiovascular complications. This review examines the role of systemic inflammation, oxidative stress, neuro-hormonal activation, and immune dysregulation in trauma-induced myocardial damage. Key immunological markers, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and adhesion molecules (ICAM-1, VCAM-1), are implicated in endothelial dysfunction, myocardial apoptosis, and ventricular remodeling. The interplay between these factors potentially exacerbates cardiac injury, increasing the risk of heart failure. Biomarker-guided approaches for early detection, combined with advanced imaging techniques such as speckle-tracking echocardiography and cardiac MRI, offer promising avenues for risk stratification and targeted interventions. Anti-inflammatory and oxidative stress-modulating therapies may mitigate myocardial damage and improve outcomes. This article highlights the clinical relevance of integrating immunological markers into diagnostic and therapeutic strategies to enhance the management of trauma-related cardiac dysfunction and reduce long-term morbidity. Full article

This review summarizes the available evidence on hyaluronic acid’s (HA’s) role in immune response. HA is one of many components in the extracellular matrix that transmits signals from the extracellular microenvironment to cellular effector systems in immune cells. The final effect of these interactions depends on the type of cells and receptors used and the size of HA particles. HA’s activation of intracellular signaling pathways leads to an immune response involving the release of pro- or anti-inflammatory cytokines and chemokines. These play a crucial role in defense mechanisms, such as protecting against pathogens and tissue healing after injuries. HA, as a signaling particle, is also involved in the intensification of the cytokine storm during COVID-19. Multifold increases in HA content in the lungs and the strength of its impact on the immune system define an “HA storm”. The molecular mechanisms involved in inflammation and initiation, including the promotion of cancer, also begin in the microenvironment, and hyaluronic acid is a key element. In this paper, we focus on intra- and intercellular signaling pathways using HA participation rather than injection preparation based on HA use for esthetic treatment. Full article

Spinal cord injury (SCI) triggers both local and systemic pathological responses that evolve over time and differ with injury severity. Small extracellular vesicles (sEVs), known mediators of intercellular communication, may serve as biomarkers reflecting these complex dynamics. In this study, we investigated whether SCI severity modulates the composition and abundance of circulating plasma-derived sEVs across subacute and chronic phases. Using a graded thoracic contusion model in mice, plasma was collected at defined timepoints post-injury. sEVs were isolated via size-exclusion chromatography and characterized using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and MACSPlex surface marker profiling. We observed an SCI-dependent increase in sEVs during the subacute (7 days) phase, most notably in moderate injuries (50 kdyne), with overall vesicle counts lower chronically (3 months). CD9 emerged as the predominant tetraspanin sEV marker, while CD63 and CD81 were generally present at low levels across all injury severities and timepoints. Surface sEV analysis revealed dynamic regulation of CD41⁺, CD44⁺, and CD61⁺ in the CD9⁺ sEV subset, suggesting persistent systemic signaling activity. These markers, traditionally associated with platelet function, may also reflect immune or reparative responses following SCI. Our findings highlight the evolving nature of sEV profiles after SCI and support their potential as non-invasive biomarkers for monitoring injury progression. Full article