Search Results (331)

Ovarian endometriosis (OE) is a chronic, inflammatory gynecological disorder associated with sterility and an elevated risk of ovarian cancer. Despite its high prevalence, the complex molecular mechanisms governing OE pathogenesis remain poorly investigated. We conducted a comprehensive histopathological and molecular investigation of OE in a cohort of 188 Saudi women (88 patients with OE and 100 healthy controls) using histopathological, qRT-PCR, immunostaining, and Western blot techniques. Histopathological analysis confirmed significant stromal fibrosis and chronic inflammation in endometriotic lesions. Gene expression profiling revealed a pro-proliferative, anti-apoptotic signature, marked by the upregulation of PTTG1 and the downregulation of TNFRSF10D, CDK4, and CDKN1A. Interestingly, we identified a post-transcriptional regulatory paradox in the inflammatory response: while IL-6 mRNA was significantly upregulated, its corresponding protein level was downregulated, suggesting a novel, tightly controlled mechanism to limit excessive local inflammation. Besides the increased autophagic activity and decreased Ubiquitin mRNA levels, epigenetic dysregulation was prominent, characterized by the upregulation of DNA methyltransferase DNMT3B and the downregulation of the histone variant H3.1. These findings elucidate novel molecular pathways underlying OE pathogenesis as evidenced by a post-transcriptional paradox in IL-6 expression, and uncover key dysregulations spanning cell proliferation, apoptosis, inflammation, autophagy, and epigenetic regulation. Full article

Background: Heart failure (HF) has traditionally been interpreted through hemodynamic, neurohormonal, and cardiorenal frameworks. Although these models explain many aspects of clinical decompensation, they do not fully account for persistent tissue congestion, unresolved myocardial edema, chronic sterile inflammation, and progressive fibrosis despite optimized therapy. Objectives: To review the anatomy, physiology, and pathobiological relevance of the cardiac lymphatic system in HF and to evaluate whether cardiac lymphatic dysfunction constitutes a mechanistic bridge linking congestion, inflammation, and adverse remodeling. Methods: This narrative review was based on a structured literature search of PubMed/MEDLINE, supplemented by manual backward reference screening and bibliographic verification through journal webpages. The search covered January 2000 to 15 April 2026, with emphasis on 2018 onward and on seminal mechanistic studies. Search domains included cardiac lymphatics, heart failure, lymphangiogenesis, myocardial edema, congestion, inflammation, myocardial infarction, pressure overload, and HFpEF. Results: Cardiac lymphatics regulate myocardial clearance of interstitial fluid, proteins, cytokines, lipids, and immune cells. Preclinical experimental evidence, mainly derived from myocardial infarction, pressure-overload, and lymphatic-insufficiency models, indicates that impaired lymphatic transport or insufficient lymphangiogenic adaptation promotes myocardial edema, inflammatory persistence, fibroblast activation, collagen deposition, and ventricular dysfunction. Human observational and early translational studies suggest that lymphatic dysregulation may also be relevant in selected HF phenotypes, although direct clinical evidence remains limited. Conversely, lymphangiogenic and lymphatic-restorative strategies, especially through the VEGF-C/VEGFR-3 axis, reduce edema, enhance inflammatory resolution, attenuate fibrosis, and improve ventricular performance in preclinical models. Conclusions: Cardiac lymphatic dysfunction provides a compelling conceptual framework that links congestion and inflammation in HF. Rather than acting as a passive bystander, the cardiac lymphatic circulation appears to be an active determinant of myocardial homeostasis and disease progression. Recognition of lymphatic insufficiency as a pathogenic component of HF may open new diagnostic and therapeutic avenues, including tissue-focused decongestion, lymphatic phenotyping, and targeted lymphatic repair. Full article

Infertility and ovarian ageing are increasingly acknowledged as illnesses affected not just by endocrine decline but also by chronic inflammatory stress and mitochondrial dysfunction in the reproductive milieu. The cGAS-STING signalling pathway has emerged as a significant possibility linking these activities. The cGAS-STING pathway, originally defined as a cytosolic DNA-sensing mechanism essential for innate immune defence, is now recognised as a broader modulator of sterile inflammation, cellular senescence, and tissue failure. Experimental reproductive models suggest that the activation of this system may operate as a crucial link between mitochondrial dysfunction, cytosolic DNA accumulation, inflammatory cytokine production, and the progressive decline of ovarian and endometrial function. The activation of cGAS-STING in granulosa cells has been associated with inflammatory signalling and impaired steroidogenic activity. Full article

Generalized pustular psoriasis (GPP) is a rare, severe, and potentially life-threatening inflammatory dermatosis increasingly recognized as a distinct disease entity rather than a variant of plaque psoriasis. Emerging evidence indicates that GPP is primarily driven by dysregulation of the interleukin-36 (IL-36) signaling axis, leading to amplification of proinflammatory cascades in keratinocytes and a predominantly innate, neutrophil-driven immune response. This promotes rapid neutrophil recruitment, sterile pustule formation, and abrupt cutaneous and systemic inflammation. Consistent with this, GPP demonstrates a greater predominance of innate immune and neutrophil-driven inflammation, whereas plaque psoriasis is more strongly associated with IL-23/Th17-mediated adaptive immune responses. Transcriptomic and genetic studies further support this distinction, demonstrating enrichment of IL-36-associated and neutrophil-related signatures, activation of MyD88-dependent pathways, and mutations in genes regulating the IL-36 axis, including IL36RN, AP1S3, and CARD14. Consequently, conventional systemic therapies and biologics targeting TNF-α, IL-17, and IL-23 pathways show variable efficacy and may act more slowly in GPP. In contrast, IL-36 receptor inhibitors represent a more mechanism-aligned approach and have demonstrated rapid and clinically meaningful responses in acute flares. However, important gaps remain, including the lack of validated biomarkers and limited data on long-term treatment outcomes. This review provides an integrated perspective on IL-36-driven inflammation in GPP, including comparison with plaque psoriasis, and outlines its implications for mechanism-based therapeutic approaches. Full article

The transition to a post-antibiotic era necessitates novel interventions to mitigate gastrointestinal inflammation and optimize metabolic efficiency in monogastric animals. This review evaluates the Hermetia illucens (BSF) lipid matrix as an evolutionary signal sensor rather than merely a caloric substrate. The BSF lipid fingerprint—rich in lauric acid and bioactive co-factors—exerts a synergistic “entourage effect,” which is proposed to thermodynamically disrupt pathogenic membranes and engage GPR84/PPARγ crosstalk to silence sterile inflammation. Metabolically, medium-chain fatty acids bypass the CPT-1 bottleneck, enabling rapid mitochondrial ATP rescue that supports intestinal tight junction restoration. This targeted immunomodulation is hypothesized to underpin an “immune-energy sparing” effect—redirecting bioenergetic fluxes from inflammatory antagonism toward muscle protein deposition—a phenomenon that correlates with improved feed conversion ratios in vivo. Full article

The concept of “fever burden” represents a quantitative and dynamic expression of the host immunometabolic response, integrating the duration, intensity, and temporal characteristics of postoperative temperature alterations. This review discusses the biological rationale underlying postoperative fever and explores its potential clinical relevance in the context of liver surgery, particularly in distinguishing infectious complications from sterile postoperative inflammation. This narrative review was based on a structured literature search of PubMed and Embase (2000–2025) to identify clinical and translational studies addressing postoperative fever after hepatic resection and liver transplantation. The retrieved literature was narratively synthesized with emphasis on fever burden, temperature trajectories, and biologically plausible mechanisms potentially associated with postoperative recovery and infectious complications. Current evidence suggests that postoperative fever may reflect dynamic activation of innate immune and inflammatory pathways rather than representing a purely binary sign of infection. In liver surgery, clinically relevant information may be better captured by temporal fever characteristics, including timing of fever onset, peak temperature, and recurrent febrile episodes, than by isolated temperature measurements alone. However, direct liver-surgery-specific evidence remains limited, and broader concepts related to temperature trajectories and immunometabolic phenotyping should currently be regarded as hypothesis-generating. Fever burden and temperature trajectory analysis may therefore represent promising conceptual approaches for interpreting postoperative host-response patterns after liver surgery, although their diagnostic and prognostic value requires prospective validation in liver-specific clinical cohorts. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as key drivers of hepatocellular carcinoma (HCC). Unlike HCC caused by viral infections or alcohol, MASLD/MASH-related liver cancer develops within a chronic immunometabolic environment characterized by lipotoxicity, sterile inflammation, fibrogenesis, and remodeling of the microenvironment. In this setting, interleukin-10 (IL-10) has attracted growing attention due to its complex, context-dependent roles in immune regulation and tumor immune tolerance. This review explores IL-10 biology and its connection to MASLD/MASH-associated HCC, emphasizing the paradox that IL-10 may diminish harmful inflammation in early stages while promoting immunosuppressive conditions in advanced disease. To supplement existing research, we performed an exploratory reanalysis of publicly available bulk liver RNA-seq data from a mouse model that progresses from MASLD/MASH to HCC. The reanalysis revealed a receptor- and effector-specific rewiring of the IL-10 pathway: while the expression of canonical signaling genes (Stat3, Jak1, Jak2, Tyk2, Socs3) showed minimal changes across stages, receptor subunits (Il10ra, Il10rb) and IL-10-responsive effectors (such as Scd2, related to lipid metabolism, and Ddit4, involved in mTOR and glycolysis regulation) displayed strong stage-dependent induction. This was accompanied by a decrease in hepatocyte signature profiles and an increase in stromal and immune signatures. These results generate new hypotheses and raise key questions—particularly whether a large portion of IL-10 modulation originates from peripheral or non-parenchymal sources, and whether the transcriptional patterns observed reflect protein-level changes—that will require stage-specific, cell-focused human studies incorporating proteomic and cytokine measurements. Full article

Multiple myeloma profoundly remodels the bone marrow microenvironment, causing osteolytic bone disease through a persistent uncoupling of bone resorption and formation. Beyond the canonical roles of the receptor activator of nuclear factor kappa-B ligand/receptor activator of nuclear factor kappa-B/osteoprotegerin triad and Wnt antagonism, three interdependent stress programs orchestrate the osteolytic niche. These include oxidative stress driven by mitochondrial and nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species; sterile inflammation sustained by damage-associated molecular patterns, pattern-recognition receptors, and pro-inflammatory cytokines; and autophagy–lysosomal remodeling governed by transcription factor EB and the coordinated lysosomal expression and regulation network. These axes intersect with iron handling and lipid peroxidation to regulate sensitivity to ferroptotic cell death, thereby shaping osteoclast priming, osteoblast suppression, and matrix turnover. Building on these mechanistic insights, we outline a translational framework that aligns standardized bone turnover markers of formation and resorption with composite panels of oxidative and nitrosative stress. This framework also integrates modern imaging to capture structural injury and metabolically active marrow disease. We further propose a therapeutic roadmap layered on antiresorptive foundations that targets selective inhibition of nicotinamide adenine dinucleotide phosphate oxidase 4 and calibrated modulation of nuclear factor erythroid 2–related factor 2, disrupts damage-associated molecular pattern and cytokine circuits, and applies lineage- and timing-specific tuning of autophagy together with restoration of ferroportin-1 or iron chelation. This integrated strategy is designed to recouple bone remodeling and improve clinically meaningful skeletal outcomes in multiple myeloma. Full article

Chronic wounds remain a persistent clinical challenge, trapped in a cycle of inflammation, infection, and impaired healing. While traditional dressings offer basic protection, they fail to address the complex pathophysiology of non-healing wounds. This review critically examines cellulose-based hydrogels as next-generation therapeutic platforms, analyzing their structure–property relationships, biofunctionalization strategies, and stimuli-responsive capabilities. We synthesize recent advances in antimicrobial, anti-inflammatory, and pro-regenerative hydrogels, highlighting how cellulose’s inherent tunability enables precision wound management. Finally, we confront the translational barriers—including scalability, sterilization, and regulatory hurdles—that must be overcome to bridge the gap between promising biomaterial research and clinical reality. By integrating materials science with wound pathophysiology, this review provides a roadmap for developing clinically viable cellulose-based hydrogels. Full article

Endothelial cell activation is one of the major pathophysiological aspects of sickle cell disease (SCD). In this review, we discuss the interaction of endothelial cells of various tissue beds, highlighting the specific biomarkers linked to endothelial cell activation and damage, and elaborate on endothelial cells’ role in the development of acute and chronic organ damage in SCD using existing clinical and preclinical data. Finally, we focus on liver sinusoidal endothelial cells (LSECs) and their role in hemoglobin scavenging, sterile inflammation, and organ damage in SCD, as well as potential therapeutic strategies to reverse organ damage induced by LSEC dysfunction in SCD. Full article

Background: Modern oncology views immune system dysfunction as a key factor in carcinogenesis. The induction of immunogenic cell death (ICD), a form of regulated cell death capable of activating adaptive immunity, represents a promising therapeutic strategy. Damage-associated molecular patterns (DAMPs) play a central role in this process. This review aims to summarize current knowledge of DAMPs, their release mechanisms during ICD, their classification, and their prognostic and therapeutic significance in antitumor immunity. Methods: We systematically reviewed and synthesized literature published in Pubmed and Google Scholar on ICD and DAMPs, focusing on distinct forms of DAMPs which were categorized based on recognition mechanisms (five classes) and cellular origin (extracellular, mitochondrial, nuclear, and cytosolic). Key molecules, their receptors, downstream signaling pathways, and clinical associations were analyzed. Results: The spatiotemporally coordinated release of the pattern of DAMPs promotes dendritic cell maturation, antigen presentation, activation of cytotoxic T lymphocytes, and elimination of tumor cells. DAMPs can exhibit a dual role: they are able to induce sterile inflammation essential for antitumor immunity, but may also contribute to metastasis and chronic inflammation. Among all DAMPs, high-mobility group box 1 (HMGB1, a nuclear DAMP) and calreticulin (CRT, a cytosolic protein) demonstrate the greatest prognostic value. Other DAMPs (e.g., extracellular matrix components, uric acid) act as signal amplifiers during various forms of cell death. Conclusions: Understanding the spatiotemporal dynamics of DAMP release is critical for activating immune responses against malignant cells. Monitoring DAMPs may improve patient stratification, predict therapeutic responses, and enable personalized immunotherapeutic strategies. Further investigation of ICD mechanisms and DAMP release represents a fundamental basis for developing novel anticancer therapies. Full article

Sickle cell anemia (SCA) is a genetic disorder characterized by chronic hemolysis, primarily driven by red blood cell lysis. Its pathophysiology is centered, though not exclusively, on the increased release of intracellular components, such as hemoglobin degradation products, which are known to stimulate innate immune responses and promote prothrombotic states. Current therapies alleviate symptoms, yet patients remain exposed to a chronic inflammatory milieu punctuated by episodes of acute pain. The recurrence of these crises can be life-threatening due to ischemia–reperfusion injury, hypercoagulability, and respiratory complications. Central mechanisms are marked by elevated hemolysis, heightened inflammatory signaling, and increased procoagulant activity, largely driven by soluble molecules released into the plasma, such as hemoglobin, nuclear molecules and other products. These compounds are recognized from sensors on immune and endothelial cells, named Pattern Recognition Receptors (PRRs), and constitute canonical pathways for intracellular activation. Four main types have been extensively studied in the literature over recent years in both infectious and sterile inflammatory contexts; still, only a few have elucidated the mechanisms underlying acute and chronic inflammation in patients with SCA. Although Toll receptors were shown to be major in triggering immunity, other receptors were found to be important regarding this function, which suggested a multifactorial mechanism for this triggering. Therefore, here, we propose a comprehensive review of previously published findings regarding the expression, activation, and dynamics of Toll-like, NOD-like, and RIG-I–like receptors in the progression of SCA and its associated inflammatory features. Full article

Vascular diseases impose a heavy global burden, yet existing therapies have limitations, necessitating novel drug targets. Ferroptosis, an iron-dependent, lipid peroxidation-driven form of cell death, acts not only as an initiator of metabolic collapse but also as a sterile inflammatory trigger by releasing damage-associated molecular patterns (DAMPs) and activating pro-inflammatory pathways. In this paper, we propose the “ferroptosis–inflammation circuit” as a self-amplifying loop where ferroptosis fuels inflammation and the inflammatory microenvironment reciprocally promotes ferroptosis via cell type-specific mechanisms. Although ferroptosis in cardiovascular diseases has been reviewed, its immunopathological role in specific vascular diseases and how macrophages, neutrophils, T cells, and vascular cells collaboratively drive pathology through this circuit remains underexplored. The unique perspective of this review is a systematic focus on the dynamic interplay between ferroptosis and immune responses within the vascular wall, moving beyond static metabolic descriptions. We synthesize evidence linking ferroptosis to atherosclerosis, pulmonary hypertension, stroke, aneurysms, and aortic dissection, emphasizing its immunological dimension across cell types. By defining the ferroptosis–inflammation circuit and its cell type-specific patterns, we reposition ferroptosis as a core pathological hub that couples metabolic dysregulation, immune activation, and vascular remodeling. Understanding this circuit may open novel therapeutic avenues for targeting the ferroptosis–immune interface. Full article

Introduction: Periprosthetic joint infections (PJI) are among the most serious and costly complications in orthopedic surgery, significantly affecting patient prognosis and healthcare systems. Despite rigorous aseptic measures, intraoperative contamination of sterile fields, instruments, and air remains a persistent source of potential infection. This study investigates the relationship between the microbial contamination of sterile fields during arthroplasty and postoperative inflammatory markers, with the objective of determining whether the contamination of sterile fields correlates with the presence of periprosthetic joint infection (PJI). Material and Methods: This prospective observational study included 33 patients undergoing total hip or knee arthroplasty in a university-affiliated orthopedic center. Intraoperative samples were collected from sterile fields and equipment to detect microbial contamination, while postoperative monitoring involved the C-reactive protein (CRP); erythrocyte sedimentation rate (ESR); leukocyte count; temperature; and wound assessment on days 1, 3 and 7. All patients received 48 h of prophylactic cefuroxime. Statistical analysis was conducted using the International Business Machines (IBM) Statistical Product and Service Solutions (SPSS) software for Windows, version 30.0 (IBM Corporation, Armonk, New York, United States of America) with significance set at p ≤ 0.05. Results: Postoperative inflammatory markers showed distinct patterns depending on the isolated microorganism, with Proteus vulgaris and Staphylococcus hominis ssp. consistently associated with higher CRP and leukocyte values, indicating a more intense systemic response. Staphylococcus epidermidis was the most frequently isolated species but showed moderate inflammatory profiles, suggesting its potential role in subclinical colonization. A strong correlation between CRP on day 3 and leukocyte count (r = 0.81) confirms their combined utility in the early detection of infectious complications, while ESR appeared less dynamic and more complementary in nature. Discussion: This study highlights the significant role of intraoperative contamination and microbial virulence in shaping the postoperative inflammatory response after arthroplasty. Elevated CRP and leukocyte levels, particularly on day 3, were closely associated with pathogens known for biofilm formation and chronic infections. Despite prophylactic antibiotic use, confirmed infections still occurred, suggesting the need to reassess current protocols and enhance intraoperative contamination control. Conclusions: Pathogen presence in sterile fields during arthroplasty increases the risk of periprosthetic joint infections, often without early clinical symptoms. CRP on day 3 and leukocyte count were the most reliable early indicators of persistent inflammation. Full article

Bladder cancer (BCa) arises from the interaction between environmental exposures and the host’s immunity and microbiome. Once considered sterile, the urinary tract is now known to harbor a resident urinary microbiome (UM) that dynamically interacts with the immune system and is influenced by systemic immunomodulatory effects of the gut microbiome (GM) brought on by the emerging gut–bladder axis. Accumulating evidence links alterations in UM and GM leading to BCa development, progression, and recurrence. Loss of protective taxa (e.g., Lactobacillus, Bifidobacterium and Ruminococcus) and enrichment of pro-inflammatory or genotoxic bacteria (e.g., Fusobacterium, Acinetobacter, Prevotella and Enterobacteriaceae) are associated with immune evasion and systemic inflammation. Microbial metabolites, especially short-chain fatty acids (SCFAs), play a key role in shaping tumor immunity and show diagnostic and prognostic potential, with specific microbial signatures correlating with recurrence risk, survival, and treatment response. Therapeutically, growing evidence suggests that microbiome composition influences immunotherapy response, highlighting opportunities for microbiome-based interventions. This review aims to summarize the rationale to implement microbial modulation strategies (e.g., dietary modulation, probiotics, fecal microbiota transplantation (FMT), and emerging synbiotic or postbiotic approaches) while addressing their current limitations and future requirements in order to develop microbiome-guided therapies, diagnostics and prognostic tools for BCa. Full article