Hyaluronan (HA) has traditionally been viewed as a structural component of the extracellular matrix, valued primarily for its viscoelastic, lubricating, and hydrating properties. However, accumulating evidence suggests that ultra-high molecular weight hyaluronan (UHMW-HA) functions far beyond passive tissue support, acting as a dynamic regulator of inflammation, mechanotransduction, immune homeostasis, cellular senescence, and regeneration. In this narrative review, we examine HA and specifically focus upon UHMW-HA operating as a “living hydrogel”, an adaptive regenerative macromolecule that continuously interacts with its microenvironment to shape tissue function and resilience. We examine evidence spanning evolutionary biology, glycobiology, biomaterials science, and regenerative medicine to examine how polymer size encodes biological activity and how UHMW-HA influences stem cell behaviour, extracellular matrix remodelling, and responses to injury and ageing. Attention is given to unique biological models, including the naked mole-rat, whose exceptional longevity and cancer resistance have been linked to abundant UHMW-HA, offering insights into the relationship between extracellular matrix architecture and organismal health. We further discuss how advances in synthetic biology and biomaterials engineering are enabling the development of next-generation HA-based hydrogels that mimic these adaptive properties for therapeutic applications in tissue engineering, in addition to potential roles in dynamically optimising wound repair, and musculoskeletal rejuvenation, through precision medicine approaches. Finally, we argue that reclassifying UHMW-HA as a living regenerative material rather than an inert scaffold provides a new concept for designing bioinspired therapeutics and understanding extracellular matrix function. This review demonstrates HA-adaptive macromolecules as critical entities in future regenerative strategies and highlights the specific and unique potential of UHMW-HA to combine material science developments with enhancement of preferable biological outcome.

Since the introduction of combined antiretroviral therapy, acquired immune deficiency syndrome (AIDS)-related lymphomas account for a growing proportion of deaths among people living with human immunodeficiency virus (PLWHIV). In addition to the immune deficiency caused by AIDS and other cofactors, it has been shown that circulating HIV-1 proteins play a critical role in lymphoma development. The HIV-1 matrix protein p17 (refp17) is released from infected cells and accumulates in lymph nodes of PLWHIV, even during effective pharmacological control of viral replication. Circulating refp17 deregulates the biological activity of different immune cells. Moreover, p17 variants (vp17s) characterized by peculiar amino acid insertions occurring in the C-terminal region of the protein, differently from the refp17, also induce B-cell growth and clonogenicity. Notably, vp17s were found at a significantly higher prevalence in PLWHIV with than without lymphoma. HIV-1 mutants expressing clonogenic vp17s are actively spreading, and their prevalence is globally increasing worldwide. RNA viruses exist as a population of quasi-species, transmitted from one host to another, which ultimately leads to viral evolution by generating new master sequences. Here, we developed a next-generation sequence approach to evaluate the frequency of vp17 quasi-species in PLWHIV upon time and demonstrated that the incidence of vp17s also increases at quasi-species levels. Additionally, we established a regression model capable of predicting the insertions with higher probability to be fixed, further highlighting the evolutionary relevance of the C-terminal region in the adaptation of p17 to the human host.

Inflammaging is defined as chronic low-grade inflammation associated with aging and is increasingly recognized as a dynamic and mechanistically driven biological process rather than a state adequately described by circulating biomarkers alone. Traditional inflammatory markers alone, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive Protein (CRP), fail to capture the complexity, tissue specificity, and causal architecture of inflammaging. Recent experimental evidence has demonstrated that diverse upstream drivers, including immunosenescence, gut microbiome dysbiosis, metabolic dysfunction, and cellular senescence, converge on a limited number of central inflammatory hubs, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and p38 mitogen-activated protein kinase (p38 MAPK) signaling. These mechanistic nodes represent promising therapeutic targets, potentially modifiable biological processes, and support the emerging concept of 'druggable inflammaging', whereby senotherapeutics, inflammasome inhibitors, innate immune modulators, and metabolic interventions may actively modify aging-associated inflammatory biology rather than simply monitor it through biomarkers. This review highlights a paradigm shift from biomarker-based assessment toward mechanism-based intervention, where inflammaging can be characterized as a modifiable biological process and a central target for precision pharmacological strategies in aging-related diseases.

Systemic inflammation plays a pivotal role in the progression of rheumatoid arthritis (RA) and its associated comorbidities, ranging from cardiovascular (CV) disease to neurodegenerative conditions such as Alzheimer’s disease (AD). This narrative review examines the molecular cross-talk linking these pathologies, with a specific focus on the distinction between pentameric C-reactive protein (pCRP) and its proinflammatory monomeric form (mCRP). We discuss evidence suggesting that mCRP is not merely a passive marker but also an active driver of endothelial dysfunction, atherosclerosis, and synovial inflammation. This review further explores the connections among inflammatory biomarkers, blood vessel integrity, and neurodegeneration, detailing how persistent cytokine elevation (IL-6, TNF-α) and vascular injury contribute to cerebral small vessel disease (cSVD) and cognitive decline, with neurofilament light chain (NfL) serving as a key biomarker of neuroaxonal injury. Additionally, we address the neurobiology of pain in RA, highlighting the mechanisms of central sensitization (CS) and neuroimmune signalling that sustain pain-independent joint swelling. This evidence indicates that understanding the dynamic connection between CRP isoforms and neuronal markers should offer new insights for risk stratification and suggests that targeting mCRP may provide a novel therapeutic avenue to mitigate both articular and extra-articular manifestations of RA.

Vascular ageing is a complex process marked by progressive endothelial dysfunction, chronic low-grade inflammation ("inflammageing"), and reduced regenerative capacity, driven in part by an imbalance between protective endothelial autophagy and cellular senescence characterized by a proinflammatory senescence-associated secretory phenotype (SASP). Disruption of this autophagy-senescence axis accelerates vascular inflammation, arterial stiffening, and atherogenesis. High-intensity interval training (HIIT), consisting of repeated bouts of near-maximal anaerobic effort with recovery periods, is widely used by both elite and recreational athletes and is increasingly recognized as an effective nonpharmacological strategy to enhance endothelial function, arterial elasticity, and mitochondrial biogenesis. However, excessively intense or poorly structured HIIT, particularly in the absence of adequate recovery or in individuals with underlying cardiometabolic or vascular vulnerability, may induce endothelial stress and promote maladaptive vascular remodelling, including calcification and plaque instability. These considerations underscore the need for refined individualized exercise prescription strategies that balance performance benefits with endothelial protection. Based on these observations, here, we introduce a novel conceptual framework, "shear dose-calibrated HIIT," designed to understand and define an optimal shear dose capable of maximizing autophagic flux while minimizing SASP activation. Experimental and clinical evidence of HIIT-induced effects on flow-mediated dilation (FMD), pulse wave velocity (PWV), and redox biomarkers is presented, followed by the proposal of a biomarker panel for assessing autophagic flux and cellular senescence in peripheral samples (peripheral blood mononuclear cells (PBMCs), extracellular vehicles (EVs), and plasma). This integrative approach, which combines vascular mechanotransduction, redox biology, and autophagic signalling, provides a novel translational perspective on how individually calibrated HIIT can promote vascular longevity and reduce cardiometabolic risk associated with aging and metabolic syndrome.

C-reactive protein (CRP) has emerged as a crucial link between systemic and neuroinflammatory processes, though its role across neurological autoimmune disorders remains incompletely understood. Pathologies such as multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), Guillain-Barré syndrome (GBS), and myasthenia gravis (MG) share chronic, dysregulated inflammation resulting from loss of immune tolerance. Their pathogenesis arises from interactions among genetic susceptibility, environmental factors, and gut microbiota alterations that trigger autoreactive immune cascades through molecular mimicry, ectopic antigen expression, or paraneoplastic cross-reactivity. These immune pathways sustain inflammation and promote neuroaxonal injury. CRP, synthesized mainly by hepatocytes in response to interleukin-6 (IL-6), functions as both an effector and reporter of inflammation, linking systemic immune activation to neuroinflammatory damage. Elevated CRP levels correlate with unfavorable outcomes, including accelerated disability in MS, IL-6-mediated astrocyte injury in NMOSD, respiratory failure in GBS, and crisis susceptibility in MG. Composite indices such as the CRP-to-albumin ratio are emerging as refined prognostic markers, though interpretation is limited by non-specificity and biological variability. This review integrates current evidence on CRP's mechanistic roles, clinical associations, and translational potential in neuroinflammatory disorders, combining molecular, clinical, and imaging perspectives to refine its role within inflammation-driven neurodegeneration.

Neurological disorders, including stroke, traumatic brain injury, and spinal cord injury, constitute one of the most important causes of mortality and morbidity worldwide for which current treatment options focus on resolving neuroinflammation rather than on tissue and neuronal regeneration. Mesenchymal stem cells (MSCs) could be a potential therapeutic option due to their immunomodulatory, neuroprotective, and paracrine secretion of extracellular vesicles and trophic factors which modulate microglial activation, preserve blood-brain barrier (BBB) integrity, and neuroplasticity, but with limitations due by poor survival, retention, and phenotypic instability following direct transplantation. The purpose of this narrative review is to present mechanotransduction signaling pathways (integrin-FAK, PI3K/Akt, Rho/ROCK, and YAP/TAZ) through which MSC-based biomaterial scaffolds, especialy hyaluronic acid (HA) hydrogels, make the transition from reparative to regenerative medicine in central nervous system (CNS) injury. Even if most of the evidence from preclinical studies suggests that dynamically tunable MSC-scaffold systems represent promising platforms for neural tissue engineering and regenerative medicine, further translational studies and well-designed clinical investigations are required to establish their therapeutic efficacy and clinical applicability.

Regular physical activity induces a dynamic crosstalk between skeletal muscle and adipose tissue, modulating the key molecular pathways that underlie metabolic flexibility, mitochondrial function, and inflammation. This review highlights the role of myokines and adipokines—particularly IL-6, irisin, leptin, and adiponectin—in orchestrating muscle–adipose tissue communication during exercise. Exercise stimulates AMPK, PGC-1α, and SIRT1 signaling, promoting mitochondrial biogenesis, fatty acid oxidation, and autophagy, while also regulating muscle hypertrophy through the PI3K/Akt/mTOR and Wnt/β-catenin pathways. Simultaneously, adipose-derived factors like leptin and adiponectin modulate skeletal muscle metabolism via JAK/STAT3 and AdipoR1-mediated AMPK activation. Additionally, emerging exercise mimetics such as the mitochondrial-derived peptide MOTS-c and myostatin inhibitors are highlighted for their roles in increasing muscle mass, the browning of white adipose tissue, and improving systemic metabolic function. The review also addresses the role of anti-inflammatory compounds, including omega-3 polyunsaturated fatty acids and low-dose aspirin, in mitigating NF-κB and IL-6 signaling to protect mitochondrial health. The resulting metabolic flexibility, defined as the ability to efficiently switch between lipid and glucose oxidation, is enhanced through repeated exercise, counteracting age- and disease-related mitochondrial and functional decline. Together, these adaptations demonstrate the importance of inter-tissue signaling in maintaining energy homeostasis and preventing sarcopenia, obesity, and insulin resistance. Finally, here we propose a stratified treatment algorithm based on common age-related comorbidities, offering a framework for precision-based interventions that may offer a promising strategy to preserve metabolic plasticity and delay the age-associated decline in cardiometabolic health.

HA (hyaluronan) has been considered in recent years as a naturally occurring modifiable gel-like scaffold that has the capability to absorb and release drugs over an extended period of time making it suitable as a potential chemotherapeutic delivery agent. Considering the limited treatment options available in the treatment of glioblastoma, in this review, we discuss the novel utilisation of ultra-high molecular weight HA—originally identified as a mechanism for maintaining longevity in the naked mole-rat—as both a protective and extracellular matrix-optimizing colloidal scaffold, and a means to deliver therapy in resected brain tumours. The unique properties of this unique form of HA cross-linked gel indicate potential future use in the prevention and treatment of both proliferative-based and inflammation-driven disease.

Introduction: Recent technological progress in optical imaging—such as adaptive optics, interferometry and tomography—has greatly improved the resolution of retinal imaging. The ability to capture sequential images over time is particularly valuable for continuous monitoring and assessment of retinal diseases. Methods: This cross-sectional study involved patients with type 2 diabetes mellitus and age-matched controls from the Diabetes and Ophthalmology Department of the Emergency Military Clinical Hospital “Dr. Constantin Papilian” Cluj-Napoca between October 2023 and October 2024. These patients were assessed for inclusion and exclusion criteria and then categorized into two groups: the diabetes group and control group. Each participant underwent a comprehensive ophthalmological examination and retinal evaluation using SS-OCT (Spectralis Heidelberg Engineering, Heidelberg, Germany). The parameters measured included the superficial and deep foveal avascular zones (FAZ) in only one eye for each patient, selected based on image quality. Additionally, each patient underwent quantitative analysis of serum C-reactive protein (CRP) levels. Results: A total of 33 patients (33 eyes) featured, 13 men and 20 women. The DM group showed statistically significant higher results for CRP value compared to healthy subjects (p < 0.001). Also, both superficial and deep FAZ areas were statistically significantly higher for diabetes patients compared to the healthy controls (p < 0.05). The correlation analysis revealed that there was no significant correlation between CRP and either superficial FAZ (p = 0.809) or deep FAZ (p = 0.659). However, a significant positive moderate correlation was found between superficial FAZ and deep FAZ (r = 0.577, p = 0.015). Conclusions: Our findings showed a significantly enlarged FAZ in diabetic patients compared to healthy individuals, highlighting its potential as an early indicator of microvascular alterations in diabetes. While CRP levels were notably elevated in the diabetic group, no significant association was found between CRP and FAZ measurements, suggesting that FAZ changes may occur independently of systemic inflammatory status.

Periodontitis is unanimously accepted to be the sixth complication of diabetes mellitus (DM), while the inverse relationship of causality is still to be deciphered. Among the proposed mechanisms is gut dysbiosis, which is responsible for the systemic release of proinflammatory mediators. In this process, Gram-negative bacteria from the oral cavity enter the general circulation, leading to the emergence of bi-hormonal beta-pancreatic cells that lack the ability to secrete insulin. Additionally, epigenetic and adaptive mechanisms in affected cells may play a role in reducing inflammation. The release of reactive oxygen species, proinflammatory cytokines, and adipokines, such as interleukins, tumor necrosis factor alpha, leptin, prostaglandin E2, C-reactive protein, or matrix metalloproteinases, determine epigenetic changes, such as the methylation of DNA nucleotides or changes in the activity of histone acetylases/deacetylases. The management of periodontitis involves targeting inflammation, and its potential connection to epigenetic modulation observed in other chronic conditions may help to explain its role in preventing DM in affected patients. This review focuses on the key epigenetic changes in periodontitis that might contribute to DM development, and explores the mechanisms and novel multi-drug therapies that could help to prevent these effects.

Non-Hodgkin lymphoma (NHL) remains the most common malignancy and cause of death among human immunodeficiency virus (HIV-1)-positive individuals, its prevalence remaining even after the introduction of combined antiretroviral therapy (cART). The mechanisms underlying B-cell tumorigenesis are still poorly understood; however, recently, a key role for p17 variants (vp17s) in lymphoma development has been clearly elucidated. Here, we describe findings on lymphomagenic vp17s and discuss their potential role as diagnostic and prognostic markers that could be used to predict the HIV-positive patients at higher risk of developing lymphoma. Specifically, vp17s endowed with amino acid (aa) insertions in their C-terminal region, at positions 114–115 (Glu-Lys), 117–118 (Ala–Ala) and 125–126 (Gly–Asp), were found to be significantly more prevalent in HIV-positive individuals with lymphoma as compared to those without. Alterations in the primary aa sequences destabilize the protein, exposing a previously hidden functional epitope which interacts with protease-activated receptor-1 (PAR-1) and stimulates the protein kinase B pathway, conferring oncogenic potential to vp17s and possibly contributing to lymphomagenesis. Therefore, ultradeep sequencing technologies, such as next-generation sequencing, could serve as a valuable screening tool for identifying and monitoring the HIV-positive patients at higher risk of developing lymphoma, paving the way for targeted preventive intervention strategies.

The intricate interplay of direct and indirect mechanisms relating to immune dysfunction, chronic inflammation, and viral proteins represents a key factor of lymphomagenesis in HIV-infected patients. Indirect mechanisms based on cytokine dysregulation, HIV-induced immune dysfunction, and co-infections with oncogenic viruses induce chronic B-cell activation and generation of a prone environment for malignant transformation and tumor growth. Direct mechanisms arise from oncogenic influences of p17, Tat, and Nef HIV proteins, which generate genomic instability, alteration of cellular signaling, and activation of oncogenic pathways. Vp17’s implication in lymphomagenesis and angiogenesis, ensured by activation of PAR1/EGFR/PI3K/Akt and MEK/ERK1/2 pathways, emphasizes the critical need for developing therapeutic strategies that target their signaling mechanisms. This review shows an insight into the pathological mechanisms involved in lymphomagenesis in HIV-infected individuals, focusing on finding novel therapeutic approaches directed at immune rehabilitation and oncogenic signaling pathways.

Monomeric C-reactive protein (mCRP), derived from the dissociation of the native pentameric CRP (pCRP), has been implicated in the pathophysiology of various neurological conditions, particularly intracerebral hemorrhage (ICH) and neurodegenerative diseases. mCRP accumulates in the brain after hemorrhagic stroke, contributing to the formation of the metabolic penumbra and promoting inflammation. Recent studies have linked mCRP to the activation of microglia, endothelial cells, and complement pathways, which collectively intensify neuroinflammation and disrupt tissue repair mechanisms. Additionally, mCRP is associated with cognitive decline, particularly in ICH survivors, by promoting microvascular damage, neurodegeneration, and vascular instability. The presence of mCRP in distant regions of the brain, including the hypothalamus, suggests its potential role in spreading inflammation and exacerbating long-term neurological damage. This review synthesizes findings on the pathogenic role of mCRP in stroke and neurodegeneration, proposing that mCRP could serve as both a biomarker and a therapeutic target for improving outcomes in stroke patients. Emerging immunopharmacological strategies are being actively pursued to mitigate the pathogenic activity of mCRP, a potent pro-inflammatory effector implicated in a variety of immune-mediated and neuroinflammatory conditions. These approaches encompass the inhibition of native pentameric CRP dissociation into its monomeric isoform, the disruption of mCRP’s high-affinity interactions with lipid rafts and cell surface receptors involved in innate immune activation, and the enhancement of its clearance through mechanisms such as solubilization, opsonin-mediated tagging, and phagocytic engagement. Targeting these immunoregulatory pathways offers a compelling therapeutic framework for attenuating mCRP-driven inflammatory cascades in both systemic and CNS-specific pathologies.

Platelets play a pivotal role in coagulation, traditionally recognized for their involvement in thrombin generation via the prothrombinase complex and for regulating thrombopoietin (TPO) synthesis through platelet-mediated TPO uptake. However, recent studies suggest that TPO homeostasis involves more dynamic, feedback-driven mechanisms, though these interactions remain incompletely described and experimentally confirmed. The interplay between platelet activating factor (PAF) secretion, fibrinolysis, interleukin-6 (IL-6) signalling, hepatic TPO synthesis, as well as the complexity of platelet subpopulations, emphasises platelets’ multifaceted role in haemostasis and haematopoiesis. Our article investigates novel pathways by which fibrinogen degradation products (FgDPs) influence plasminogen and TPO synthesis, focusing on the interconnection between procoagulant platelets, platelet-derived messengers, and fibrinolytic processes. In this work several intermediary mechanisms are hypothesised, including the FgDP-IL-6-plasminogen pathway, the PAF-IL-6-TPO pathway, and the thrombin-FgDP-IL-6-TPO pathway, which may link FgDP and plasminogen biosynthesis with platelet activation, cytokine release, and thrombopoiesis regulation. The proposed mechanisms involve secretion of PAF by procoagulant platelets, inducing IL-6 synthesis in endothelial cells, fibroblasts, and vascular smooth muscle cells. Subsequently, IL-6 stimulates hepatocyte-driven TPO production, potentially serving as a feedback mechanism to restore platelet counts following coagulation. Furthermore, fibrinolysis-generated FgDPs may further enhance IL-6 release, implying alternative routes for TPO regulation. Our hypotheses challenge the prevailing view that platelet numbers alone dictate TPO homeostasis. Therefore, we propose that inflammatory and fibrinolytic signals actively regulate TPO homeostasis, challenging the platelet-count-centric paradigm. These insights provide a new perspective on haematopoiesis and suggest novel therapeutic targets for thrombocytopenia and coagulation disorders, highlighting the need for further experimental validation.

p17, the human immunodeficiency virus type 1 (HIV-1) matrix protein traditionally associated with viral assembly, has been recently investigated for its extracellular functions linked to vascular damage. This review examines the molecular and pathogenic signatures by which p17 and its variants (vp17s) contribute to endothelial activation, aberrant angiogenesis, and vascular inflammation, highlighting their relevance even under effective antiretroviral therapy (ART). Specifically, p17 exerts chemokine-like activities by binding to chemokine (C-X-C motif) receptor-1 and 2 (CXCR-1/2) on endothelial cells (ECs). This interaction triggers key signaling cascades, including the protein kinase B (Akt)-dependent extracellular signal-regulated kinase (ERK) pathway and endothelin-1/endothelin receptor B axis, driving EC motility, capillary formation, and lymphangiogenesis. Variants such as S75X demonstrate enhanced lymphangiogenic potency, associating them with tumorigenic processes involved in non-Hodgkin lymphoma (NHL) pathogenesis. Importantly, p17 promotes endothelial von Willebrand factor (vWF) storage and secretion, implicating a pro-coagulant state that may trigger the increased thromboembolic risks observed in HIV-positive patients. Furthermore, p17 crosses the blood–brain barrier (BBB) via CXCR-2-mediated pathways, contributing to neuroinflammation by activating microglia and astrocytes and amplifying monocyte chemoattractant protein-1 (MCP-1) levels, therefore playing a critical role in the development of HIV-associated neurocognitive disorders. Hence, the elaboration of potential therapeutic strategies finalized at inhibiting p17/vp17s’ interaction with their receptors could complement ART by addressing HIV-related neurovascular morbidity.

Chronic low-grade systemic inflammation is increasingly recognized as a key mediator linking stress, pain sensitivity, and cognitive decline. Central to this process are the acute-phase reactants interleukin-6 (IL-6) and C-reactive protein (CRP), which serve as biomarkers of systemic inflammation while promoting neuroimmune dysregulation. Emerging evidence implicates the IL-6-CRP axis in the amplification of pain perception, central sensitization, and stress hypersensitivity, ultimately promoting neurodegenerative processes such as those observed in Alzheimer's disease (AD) and vascular dementia. Monomeric CRP (mCRP), a proinflammatory isoform generated under mechanical or oxidative stress, can trigger histone modifications (e.g., H3 citrullination), activate endothelial and immune cells, and exacerbate inflammatory pain pathways. These mechanisms are further modulated by genetic and epigenetic factors, including IL-6/CRP/NR3C1 gene variant expression; promoter methylation; and stress-responsive microRNAs, which intersect with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, impairing immune resolution and neurocognitive resilience. Psychosocial stressors, such as the burden of caregiving or perfectionistic cognitive patterns, amplify IL-6 and CRP levels, particularly when pain is present, suggesting a synergistic interaction between emotional distress and somatic inflammation. Specifically, elevated CRP is associated with increased pain sensitivity, lower pain thresholds, and cognitive decline even in subclinical populations, providing a feedforward model in which chronic stress and pain potentiate systemic inflammation, disrupt neuroendocrine feedback, and accelerate neurodegenerative pathology. However, in this model, the potentially critical mechanistic and pathological role of mCRP remains to be discovered. This review addresses the missing elements of these overlapping pathways and discusses the therapeutic potential of targeting IL-6-CRP signaling, stress regulation, and epigenetic modifiers as strategies to ameliorate inflammation-driven cognitive decline and enhance stress resistance in chronic disease contexts. We propose that plasma mCRP or more likely the isoform-aware metric, the mCRP/CRP ratio, will provide a biologically anchored, potentially more discriminative approach to vascular-neuroimmune risk and capture the propensity for local effector signaling, likely outperforming hs-CRP or IL-6 alone for risk stratification across neurovascular and stress-sensitized pain phenotypes.

C-reactive protein (CRP) has long been recognized as a biomarker of systemic inflammation and cardiovascular disease (CVD) risk. However, emerging evidence highlights the distinct and potent pro-inflammatory role of its monomeric form (mCRP), which is predominantly tissue-bound and directly implicated in vascular injury and plaque destabilization. This narrative review explores the interactions and overlapping pathways that converge within and modulate CRP, mCRP, the associated pathophysiology of diabetes mellitus, and cardiovascular disease. We examine how mCRP promotes endothelial dysfunction, leukocyte recruitment, platelet activation, and macrophage polarization, thereby contributing to the formation of unstable atherosclerotic plaques. Furthermore, we discuss the critical influence of diabetes in amplifying mCRP’s pathogenic effects through metabolic dysregulation, chronic hyperglycemia, and enhanced formation of advanced glycation end products (AGEs). The synergistic interaction of mCRP with the AGE-receptor for AGE (RAGE) axis exacerbates oxidative stress and vascular inflammation, accelerating atherosclerosis progression and increasing cardiovascular risk in diabetic patients. Understanding these mechanistic pathways implicates mCRP as both a biomarker and therapeutic target, particularly in the context of diabetes-associated CVD. This review highlights the need for further research into targeted interventions that disrupt the mCRP-[AGE-RAGE] inflammatory cycle to reduce plaque instability and improve cardiovascular outcomes in high-risk populations.

The retina consists of one of the body's most delicate organs, being sensitive to various metabolic disturbances, vascular abnormalities and inflammatory processes. Age-related macular degeneration (AMD) impacts millions of people worldwide and represents a notable cause of blindness. Chronic inflammation, implicated in several degenerative diseases including Parkinson's and Alzheimer's diseases, as well as atherosclerosis, has been linked to AMD. Both histopathological and genetic investigations have underscored the immune system's role in AMD progression. The objective of this literature review was to summarize the actual knowledge, identify research gaps and to serve as a basis for future studies regarding the correlations between inflammation and AMD. We conducted a thorough search of the primary databases (Web of Science, Cochrane Library, PubMed/MEDLINE), using keywords such as 'age-related macular degeneration', 'inflammation', 'neurodegeneration', and 'C-reactive protein'. We included systematic reviews and meta-analyses that offer the most relevant results in this research area. We also included the results from recent studies that have not yet been widely approached. Our strategy also consisted of looking for relevant articles in the reference list.

Monomeric C-reactive protein (mCRP) is a pro-inflammatory molecule generated by the dissociation of native CRP. Clinical and experimental studies suggest that mCRP deposition in the brain induces Alzheimer's disease (AD) pathology and cognitive loss. Pathological neuroinflammation is increasingly suggested as relevant in AD. Innovative therapies against neuroinflammation are desperately needed, and inhibitors of the enzyme soluble epoxide hydrolase (sEH) are a promising new generation of anti-inflammatory drugs. Mouse primary microglia and BV2 cell line cultures were exposed to mCRP to analyze its pro-inflammatory mechanisms. sEH inhibitors, both newly synthesized UB-SCG-55 and UB-SCG-65, and the reference agent TPPU, were tested for their anti-inflammatory action against mCRP. Phenotypic changes were analyzed through cell imaging techniques, as well as molecular analysis of inflammatory mediators and gene activation pathways. Results show that mCRP triggers a pro-inflammatory response through three main inflammatory pathways: iNOS, NLRP3, and COX-2, followed by increased cytokine generation. Polarization of microglia toward a M1-like phenotype was confirmed by morphological analysis. Also, mCRP can bind to and cross the cell membrane, providing further insight into its mechanisms of action. sEH inhibitors were effective against mCRP induction of a reactive microglial phenotype. The first-line compound UB-SCG-55 emerged as the most potent anti-inflammatory against mCRP injury. Therefore, the direct activation of microglia by mCRP provides evidence of its role in triggering and exacerbating neurodegenerative diseases with a neuroinflammatory component, such as AD. Furthermore, the protection given by inhibitors of sEH confirms its potential as innovative drugs against deleterious effects of neuroinflammation.