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Interleukin-6 (IL-6) trans-signalling plays a pivotal role in cancer progression and the regulation of metabolic pathways, exhibiting significant tissue specificity. IL-6, a pleiotropic cytokine, mediates cellular communication and inflammatory responses through distinct pathways with both beneficial and detrimental effects. Trans-signalling occurs when IL-6 binds to its soluble receptor (sIL-6Rɑ), forming a complex with the signal transducer gp130. This pathway is associated with a pro-inflammatory phenotype and not by chance, IL-6 trans-signalling also contributes to tumorigenesis promoting angiogenesis, resistance to apoptosis and metastasis. This review highlights the significance and tissue-specificity of IL-6 trans-signalling activation in cancer biology, metabolism, and drug resistance, underscoring its potential as a therapeutic target. Indeed, IL-6 trans-signalling influences metabolic processes by altering glucose and lipid metabolism, thereby supporting energy demands from rapidly proliferating cancer cells. Through metabolic reprogramming IL-6 trans-signalling not only fuels cancer cell growth but also contributes to development of a tumour-friendly microenvironment that is IL-6-dependent and self-sustaining. These events contribute also to development of multidrug resistance during cancer progression. In depth understanding of the molecular mechanisms underlying IL-6 trans-signalling will offer novel insights into precision medicine for cancer treatment and for the sensitisation of cancer cells to anti-tumour weapons.
Coronary artery disease (CAD) is a major global cause of morbidity and mortality, and population ageing is reshaping its clinical phenotype, disease trajectory, and therapeutic complexity. Chronological age alone cannot explain the heterogeneity of CAD outcomes in older individuals, highlighting the need to integrate biological ageing into cardiovascular disease research and management. Cellular senescence, characterised by stable cell-cycle arrest, metabolic reprogramming, and acquisition of a senescence-associated secretory phenotype (SASP), provides a mechanistic bridge between ageing and CAD. Senescent endothelial cells, vascular smooth muscle cells, immune cells, fibroblasts, and cardiomyocytes contribute to endothelial dysfunction, chronic inflammation, plaque instability, impaired myocardial stress tolerance, and adverse remodelling. Conversely, CAD-related stressors, including atherosclerotic injury, disturbed flow, myocardial ischaemia and ischaemia-reperfusion injury, can induce local senescence programmes and propagate inflammatory or extracellular-vesicle-mediated signalling beyond the initial injury site. However, whether CAD directly accelerates whole-organism biological ageing remains less established. In this review, we examine cellular senescence as a bidirectional but context-dependent interface between ageing and CAD. We summarise cell-type-specific senescence programmes in vascular and myocardial compartments, compare the strength of evidence for major molecular pathways, and discuss senescence-targeted therapies. We emphasise that senolytic and senomorphic strategies remain largely preclinical in cardiovascular disease and that their translation will require careful attention to disease stage, treatment timing, cell specificity and patient stratification. This framework may help refine ageing-informed approaches to CAD prevention, diagnosis and therapy.
The complex physiology of Parkinson's disease (PD) and its limited response to conventional therapies make it a challenging condition to manage. Evidence suggests that both environmental and genetic variables play essential roles in the progression of PD. However, the possible interplay between environment and genetics in PD etiology remains mostly unresolved. Brain-derived neurotrophic factor (BDNF) is a neurotrophin widely distributed and intensively investigated in the mammalian brain. BDNF modulates dopaminergic neurotransmission via neuronal differentiation regulation. BDNF communicates with the Tropomyosin receptor kinase B (TrkB) and activates Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) which can subsequently phosphorylate downstream CREB protein at ser133 residue. Research suggests that numerous health advantages, including significant protections for PD, have been linked to olives, a specific component of the Mediterranean diet. OLE is effective in the treatment of a variety of neurological conditions, including PD. Changes in gene expression patterns induced by aberrant histone acetylation can also aid in the causes of PD. Thus, in the context of neurological diseases, comprehending the epigenetic regulation of the neuronal survival gene is thought to be essential. OLE was first administered intraperitoneally as a pretreatment for seven days. Thereafter, OLE was administered one hour after the rotenone injection for 5 weeks. Herein, we have observed the neuroprotective role of OLE in the cellular signalling cascade associated with neuronal survival through the BDNF/ERK/CREB pathway. Subsequently, we examined the effect of OLE on the enrichment of histone acetylation AcH3K9 in the neuro-survival gene promoter region in PD cases. The data suggest that OLE regulates at both cellular and epigenomic levels by promoting the enrichment of acetylated H3K9 on the neuro-survival gene promoter region in the nigrostriatal region of PD mice.
In the adverse tumor microenvironment excessive tumor cell proliferation is accompanied by massive reactive oxygen species (ROS) production. Though tumor-derived extracellular vesicles (TEVs) have confirmed roles in cancer-associated fibroblast (CAF) interactions, the intercellular ROS transfer mechanism and its specific role in tumor-stroma communication remain unclear. Human gingival fibroblasts (HGFs), paracancerous normal fibroblasts (PNFs) and CAFs were isolated from volunteers' healthy gingival tissues and 6 OSCC patients. In vitro, autophagy and glycometabolism levels in PNFs/CAFs and HGFs/TEVs-treated HGFs were assessed via immunofluorescence and Western blot; autophagy was blocked or activated to explore its effect on glycometabolism; flow cytometry was used to detect if TEVs trigger fibroblast autophagy and glycolysis via ROS transfer. In vivo, xenograft models were established to validate TEVs' effect. CAFs had higher autophagy than PNFs. Autophagy inhibitors reduced TEVs-induced autophagy-dependent glycometabolic reprogramming, while autophagy activation enhanced CAF glycolysis. Moreover, TEV-transferred ROS drove such reprogramming via autophagy-dependent mechanisms and the HIF-1α/PFKFB3 axis. In vivo, TEVs consistently promoted autophagy and glycometabolic reprogramming. TEVs-induced intercellular ROS transmission and the regulatory role of autophagy in CAF glycometabolic reprogramming offer a novel basis for the oxidative stress transfer model in tumor-stroma crosstalk.
Inflammatory myofibroblastic tumour (IMT) is a mesenchymal tumour characterised by myofibroblastic cells and the presence of inflammatory cells, such as macrophages, neutrophils, and lymphocytes. IMT can originate from diverse anatomical locations within the body. The macrophage-rich immune microenvironment contributes to cytokine release and inflammation, but IMT is primarily driven by oncogenic alterations. Oncogenic fusions, most commonly involving anaplastic lymphoma kinase (ALK), and other genes, such as ROS1 and NTRK3, are seen in most IMTs. Upregulation of these genes activates downstream signalling pathways such as RAS/MAPK and PI3K/AKT, leading to uncontrolled cell proliferation. Constitutive tyrosine kinase activation disrupts cell-cycle control by suppressing p21/p27, inactivating Rb, and impairing p53-dependent checkpoints, thereby limiting apoptosis. Combining surgery with targeted kinase inhibitors remains the primary therapeutic approach, especially for ALK-positive IMT. On the contrary, ALK-negative IMT harbours distinct oncogenic fusions and is driven by diverse signalling pathways. Thus, it requires therapeutic methods targeting the specific molecular alterations. Resistance to ALK inhibitors can emerge during treatment. This resistance arises through bypass signalling, epigenetic changes, and secondary mutations. This review aims to analyse the interplay between inflammation and genetic fusions in the origin and progression of IMT. The review provides an overview of the therapeutic approaches currently in use, mechanisms of treatment resistance, and potential techniques to improve diagnosis and develop personalised therapeutic strategies.
Progressive neuronal loss is a hallmark of neurodegenerative diseases like Huntingtons disease (HD) and Amyotrophic lateral sclerosis (ALS) which are caused by convergent mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy and dysregulated cell death pathways. Both conditions share significant disruptions in metabolic and inflammatory signalling despite having different genetic origins and clinical manifestations; underscoring the necessity of pathway-oriented treatment approaches. In the central nervous system, peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear receptor has become an important regulator of inflammation, redox homeostasis, mitochondrial biogenesis and cellular stress responses. After giving a thorough overview of PPAR-γ structure activation and transcriptional regulation and the PGC-1α-mediated mitochondrial biogenesis axis, this chapter delves deeply into its interactions with major signalling pathways such as NF-κB, Wnt/β-catenin Nrf2/ARE and the autophagy-apoptosis networks. With a focus on experimental data showing PPAR-γ signaling's neuroprotective, anti-inflammatory, antioxidant and metabolic regulatory roles the pathophysiology of ALS and HD is critically investigated. Lastly the need for improved biomarkers, tailored multi-target strategies and selective modulators is highlighted in the discussion of current therapeutic limitations and translational difficulties.
Vaccination is the most common method used to control infection caused by Mycoplasma gallisepticum in chickens. However, concurrent immunosuppression may compromise vaccine efficacy. This study investigated the effect of immunosuppression induced by either chicken anaemia virus (CAV) or infectious bursal disease virus (IBDV), administered prior to or following vaccination with the M. gallisepticum live vaccine strain ts-304 (Vaxsafe MG304), on tracheal host responses to subsequent challenge with virulent M. gallisepticum. Tracheal responses were assessed by genome-wide transcriptional profiling in these groups and compared across unvaccinated-unchallenged, unvaccinated-challenged, vaccinated-unchallenged and vaccinated-challenged groups that had not been exposed to CAV or IBDV. Immunosuppression resulted in significant differences in tracheal transcriptional responses compared to immunocompetent groups, irrespective of the timing of infection with CAV or IBDV. Differences in transcription were more pronounced in the IBDV-infected groups than the CAV-infected groups. Functional interrogation of differentially transcribed genes revealed adverse effects of M. gallisepticum on extracellular and intracellular signalling, cell communication, cellular actin dynamics, formation of the cellular cytoskeleton, and cellular metabolic pathways in the tracheal mucosa of immunosuppressed groups. In addition, there were indications of down-regulation of both innate and adaptive immune responses, including cytokine signalling, antigen processing presentation, and immune cell receptor signalling in the immunosuppressed groups. Specifically, findings indicated that infection with CAV impaired pro-inflammatory and adaptive T-cell responses in the tracheal mucosa. The findings implied that the primary immune response induced post-vaccination and the secondary immune response induced post-challenge with virulent M. gallisepticum were both affected by infection with these two viruses. Coupled with previous observations of reduced antibody titres against M. gallisepticum, and increased rates of recovery of virulent M. gallisepticum in both CAV- and IBDV-infected groups, the significant transcriptional changes detected in the current study highlighted the roles of both cell-mediated (CMI) and humoral immunity (HI) in vaccine-induced protection, as CAV mainly affects CMI and IBDV mainly affects HI. These findings will assist in identifying the mechanisms underlying the reduced efficacy of live attenuated mycoplasma vaccines in immunosuppressed animals.
Microplastics (MPs) pollution represents a pressing global environmental challenge, with studies increasingly highlighting their associated health risks. Although MPs have been detected in human lung tissues, the majority of existing research has concentrated on their physicochemical characteristics, environmental distribution and pulmonary health risks. Consequently, our understanding of the specific biological targets and effective intervention strategies against these risks remains limited. To identify therapeutic targets, we screened for pulmonary differential metabolites between normal mice and mice exposed to airborne MPs, derived from dust fall of 10 cities in China. Proteomics results showed adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathway was one of critical targets. Through molecular docking and molecular dynamics stimulation, honokiol (HNK) was selected as therapeutic drug to regulate AMPK. In vitro results demonstrated that HNK significantly ameliorated autophagy inhibition in RAW264.7 cell, and alleviated mitochondrial dysfunction in BEAS-2B cell. Drug mechanism research revealed that HNK activated autophagy via the AMPK/mammalian target of rapamycin (AMPK/mTOR) pathway, and promoted mitophagy through the AMPK/E3 ubiquitin protein ligase parkin (AMPK/Parkin) pathway, thereby restoring mitochondrial function. Further targeted energy metabolomics analysis illustrated that HNK regulated the guanosine triphosphate to guanosine diphosphate (GTP/GDP) ratio, adenosine triphosphate ‌(ATP) production, and nucleotide metabolism. These functions accelerated the restoration of autophagic flux, mitophagy reactivation and DNA repair. In conclusion, HNK effectively alleviates airborne MPs-induced autophagy inhibition, mitochondrial dysfunction and energy metabolism disorder via AMPK signalling, providing a promising intervention strategy for pulmonary injury caused by airborne MPs.
Gastrulation is the morphogenetic process by which the single-layered pluripotent epiblast is reorganised into the three germ layers and the basic body plan is established. While the metabolic state of pluripotent stem cells is well characterised, the metabolic remodelling that coincides with germ layer specification is less well understood. Emerging evidence suggests that metabolism functions as more than a passive housekeeping process and instead acts as a dynamic regulator of cell state during these developmental transitions. Here, we review recent work that implicates a role for metabolic pathways in regulating cell fate and morphogenesis during gastrulation. In particular, glucose metabolism appears to serve as a critical regulatory layer, modulating morphogen signalling to promote the emergence and function of mesodermal and endodermal populations. We also discuss the role of the tricarboxylic acid cycle and one-carbon metabolism in epigenetic remodelling and highlight the role of lipid metabolism in coupling the biophysical properties of membranes to cellular identity and morphogenetic movements. A current challenge is to distinguish in which situations metabolic shifts act as instructive drivers or permissive gatekeepers of development. Technological advances in spatial metabolomics, biosensors, and optogenetics are now facilitating the visualisation and manipulation of metabolic activity, paving the way for a mechanistic understanding of how metabolism shapes cell fate and behaviour during gastrulation.
Lead is a persistent environmental heavy metal and a potent neurotoxin that continues to threaten global public health despite regulatory restrictions. Chronic and developmental exposure, particularly during early life, leads to persistent structural and functional disturbances in the central nervous system. This review provides a comprehensive analysis of the mechanisms underlying lead-induced neurotoxicity, integrating molecular, cellular, histopathological, and behavioral evidence from both rodent and zebrafish models. The review further summarizes blood-brain barrier disruption, oxidative stress, mitochondrial dysfunction, synaptic impairment, neuroinflammation, apoptosis, neurotransmitter dysregulation, and neurodevelopmental alterations associated with lead exposure in experimental animal models. Lead crosses the blood-brain barrier by mimicking essential divalent cations such as Ca2⁺, Zn2⁺, and Fe2⁺, thereby disrupting calcium signalling and impairing neuronal communication. Once in the brain, lead induces oxidative stress through excessive reactive oxygen species generation, mitochondrial dysfunction, lipid peroxidation, DNA damage, and depletion of antioxidant defenses. Lead also impairs synaptic plasticity by altering NMDA receptor subunit composition, reducing synaptic protein expression, and dysregulating genes involved in neurodevelopment. In parallel, it activates both intrinsic and extrinsic apoptotic pathways and enhances neuroinflammatory signaling through microglial and astrocytic activation, further contributing to neuronal injury. Experimental studies demonstrate hippocampal degeneration, Purkinje cell loss, synaptic ultrastructural alterations, impaired long-term potentiation, and cognitive dysfunction in rodents. Zebrafish models reveal disrupted neurodevelopment, altered expression of gfap, huC, neurexin, and antioxidant-related genes, behavioral abnormalities, and circadian rhythm disturbances. Overall, the study indicates that lead neurotoxicity arises from interconnected mechanisms involving oxidative stress, synaptic dysfunction, apoptosis, mitochondrial impairment, and neuroinflammation. A comprehensive understanding of these pathways is essential for early risk assessment, therapeutic target identification, and the development of effective neuroprotective interventions against lead-induced brain injury.
Pain is a common neurological manifestation of COVID-19, yet the mechanisms by which SARS-CoV-2 spike protein fragments contribute to nociceptive processing remain poorly understood. We investigated whether spike-derived peptides directly activate spinal neuroimmune pathways involved in pain signalling. Male C57BL/6 mice received intrathecal administration of three synthetic SARS-CoV-2 spike-derived peptides (PSPD2001, PSPD2002 or PSPD2003) or saline. Mechanical nociception was assessed using the von Frey test. The involvement of spinal Toll-like receptor 4 (TLR4), microglia and p38 MAPK/NF-κB signalling was investigated using pharmacological antagonists, TLR4 knockout mice, RT-qPCR, ELISA, immunofluorescence, CX3CR1GFP/+ mice, human C20 microglial cells and molecular dynamics simulations. All spike-derived peptides induced mechanical nociception, with PSPD2003 producing the most pronounced response. PSPD2003 increased spinal TLR4 expression, elevated TNF-α and IL-6 levels and promoted activation of dorsal horn microglia, demonstrated by increased TMEM119- and CX3CR1-positive cells. These nociceptive and neuroinflammatory effects were abolished by pharmacological inhibition of TLR4, microglia, p38 MAPK and NF-κB signalling, as well as in TLR4-/- mice, demonstrating that TLR4 signalling is essential for PSPD2003-induced pain. PSPD2003 also induced a hypertrophic phenotype in human microglial cells, while molecular dynamics simulations supported a stable interaction with the TLR4/MD-2 complex. These findings identify a previously unrecognized neuroimmune mechanism whereby a SARS-CoV-2 spike-derived peptide triggers spinal nociception through TLR4-dependent microglial activation and downstream p38 MAPK/NF-κB signalling, highlighting the spinal TLR4-microglia axis as a potential therapeutic target for COVID-19-associated and post-viral pain. This study provides the first evidence that SARS-CoV-2 spike-derived peptides directly activate a spinal TLR4-dependent neuroimmune pathway to induce nociception. By integrating behavioural, pharmacological, genetic, cellular and computational approaches, it identifies microglial activation and p38 MAPK/NF-κB signalling as key mechanisms linking viral peptides to pain, providing a mechanistic framework for COVID-19- and post-viral pain and supporting TLR4 as a potential therapeutic target.
Intervertebral disc degeneration (IVDD) is characterized by excessive inflammation and extracellular matrix (ECM) degradation in the nucleus pulposus (NP), with limited current therapeutic options. Specialized pro-resolving mediators (SPMs) such as Maresin 1 (MaR1) have emerged as key regulators of inflammation resolution and tissue repair. Here, we report that MaR1 and its receptor LGR6 are significantly downregulated in degenerated human NP tissues, suggesting a loss of endogenous resolution capacity. Exogenous MaR1 administration effectively attenuated IL-1β-induced inflammation and ECM degradation in human NP cells and alleviated IVDD progression in rat models. Mechanistically, MaR1 simultaneously suppressed the catabolic AP-1/MMP pathway and activated the pro-anabolic OSR1/GDF7 axis, rebalancing ECM homeostasis. Notably, the therapeutic efficacy of MaR1 was completely abrogated in Lgr6-knockout mice, demonstrating that LGR6 is the indispensable mediator of MaR1's protective effects in vivo. Our findings identify the MaR1-LGR6 axis as a critical regulator of disc homeostasis and highlight MaR1 supplementation as a novel and promising strategy for IVDD treatment.
Inflammatory diseases of connective tissues such as periodontitis and rheumatoid arthritis exhibit localized destruction of matrix collagen and loss of tissue function. These diseases are driven by interconnected signaling pathways that determine disease progression and severity. Both periodontitis and rheumatoid arthritis involve the release of extracellular Vimentin (ECV) from stromal and immune cells at diseased sites, but the processes by which ECV binds to cells and promotes inflammatory signaling are not well defined. Recent data point to several putative ECV receptor proteins, one of which is Leucine-Rich Repeat Containing 15, an orphan receptor and cancer-associated fibroblast marker that contributes to inflammation and matrix destruction. Here, we consider the roles of ECV and LRRC15 in connective tissue diseases and discuss how their interactions may promote matrix destruction. We propose that ECV and LRRC15 signal through β1-integrin/FAK, Wnt/β-catenin, and NF-κB to promote cell adhesion, migration and matrix degradation by local fibroblast and immune cell populations. To obtain further insights into ECV-LRRC15 engagement, we used in silico modelling to predict the most likely binding conformation of the ECV-LRRC15 interaction with MEGADOCK. The most probable model suggests that the convex face of the LRRC15 leucine-rich repeat loop binds to two sites on the α-helices of Vimentin rod domains and to one site on Vimentin's N-terminal head domain, potentially signaling through this interface. In this review, we provide an in-depth overview of the functional links between ECV and LRRC15 and discuss their potential roles as drivers of matrix destruction in periodontitis and rheumatoid arthritis.
A high-affinity antibody response to both infection and vaccination critically relies on the ability of B cells to capture and process antigen for presentation to CD4+ T cells. The cellular processes from antigen recognition to full B cell activation require a finely orchestrated series of events, involving signalling and intracellular trafficking mechanisms. Here, we describe a novel regulator of B cell receptor (BCR) endocytosis and intracellular trafficking. Multidomain trafficking protein sorting-related receptor with A-type repeats (SorLA) associates with the BCR and regulates uptake of both soluble and substrate-bound antigens. SorLA deletion results in altered BCR-antigen intracellular trafficking to degradative compartments, modulating eventual antigen presentation. Crucially, this change in antigen trafficking results in a significant reduction in plasma cells and humoral responses in vivo. Given the critical importance of antigen presentation in immunity, as well as autoimmune disease and malignancy, these results identify a new cellular pathway in B cell biology with potential implications for immune regulation.
Atherosclerosis (AS), which causes chronic inflammation, aberrant lipid metabolism and vascular endothelial damage, is the main cause of cardiovascular disease. The Ce-Bai-Si-Wei decoction (CSD) may reduce AS, although its molecular mechanisms are unknown. This study investigates core molecular pathways using multi-omics integration and experimental validation. Network pharmacology prediction: Construct a 'drug-component-target-disease' interaction network using databases like TCMSP, HIT and ETCM to identify active components and targets of CSD. AS regulatory targets and signalling pathways can be identified by integrating microarray data and single-cell transcriptomics data. In vitro validation: Utilise the OX-LDL-induced model of macrophage foam cells to test CSD's effects on lipid accumulation utilising CCK-8, Oil Red O and TC/TG quantification. Validate CSD's regulatory effects on core targets using molecular docking, molecular dynamics simulation, RT-qPCR and Western blot. Four core genes, HMOX1, SELE, CD4 and FLT1, were identified as key regulators of inflammation and oxidative stress in AS, and they bind stably to the active components of CSD. Single-cell data analysis suggested that CSD may improve AS by targeting macrophages and endothelial cells. In vitro, CSD reduced ox-LDL-induced lipid accumulation in macrophages and downregulated TNF-α and IL-1β. Mechanistically, the anti-AS effect of CSD depends on the NRF2/HMOX1 pathway. CSD also downregulated FLT1 and SELE in damaged endothelial cells. This study investigated the mechanism of CSD in treating AS. CSD acts on the core targets HMOX1, SELE, FLT1 and CD4, with macrophages and endothelial cells as key effector cells. It exerts anti-AS effects by inhibiting inflammation, reducing lipid accumulation and protecting endothelial function.
COVID-19 continues to present ongoing global health challenges driven by diverse immune responses and heterogeneous clinical outcomes. The ACCORD trial evaluated 3 investigational treatments-bemcentinib, tozorakimab, and zilucoplan-in patients hospitalized with COVID-19, each of which has demonstrated clinical efficacy. To better understand their molecular mechanisms, we conducted a mechanistic follow-up study, integrating transcriptomic and clinical data from 65 patients and applying cellular deconvolution, differential expression, coexpression, and pathway enrichment analyses to uncover treatment-specific immune responses. Each therapy induced transcriptional shifts and modulated distinct immune pathways implicated in severe disease. Bemcentinib primarily modulated myeloid cell populations and inflammatory signalling; zilucoplan enhanced B-cell signalling and lymphocyte-associated pathways; and tozorakimab exerted broad immune and cellular responses across immune cell types. Co-expression analysis revealed gene networks associated with clinical improvement, each driven by distinct treatment-specific hub genes, indicating diverse regulatory mechanisms across treatments. Improved outcomes correlated with gene expression shifts in 4 key immunological pathways: B-cell signalling, antiviral defense, innate inflammation, and platelet/coagulation activity. In contrast, nonresponders had persistent dysregulation of 1 or more of these gene signatures. Our findings define molecular signatures of treatment response and failure in COVID-19, providing mechanistic insight into how distinct therapies modulate the immune system. These insights support the need for adaptive precision medicine approaches tailored to individual, evolving immune trajectories. Moreover, the immunological mechanisms targeted by these repurposed immunomodulatory therapies may inform treatment strategies across a broader spectrum of immune-mediated diseases beyond COVID-19.
Haemoglobin is a ferrous iron (Fe2+)-containing intracellular protein that is crucial for multiple homeostatic functions, including transport of oxygen and carbon dioxide, acid-base buffering and cellular signalling through nitric oxide oxidation and nitrite reduction. When erythrocyte membranes are disrupted, a process known as haemolysis that is caused by either disease or an exogenous stressor, haemoglobin is liberated into the plasma. This plasma free haemoglobin is highly pathogenic, disrupting a range of physiological processes and causing downstream organ damage through multiple mechanisms, including nitric oxide scavenging, vasoconstriction, generation of reactive oxygen species, activation of innate immune inflammation, disruption of cellular signalling, activation of the coagulation cascade and direct end-organ injury. Haemolysis and an elevated level of plasma free haemoglobin are associated with increased cardiovascular mortality, haemodynamic derangements, renal dysfunction and immune system dysregulation. These injurious pathways are exacerbated as the plasma free haemoglobin concentration and duration of exposure increase and are mitigated by endogenous scavenging pathways. In cardiovascular disease, proliferation of the use of mechanical circulatory support technologies, as well as an ageing population with chronic low levels of haemolysis, has increased exposure to plasma free haemoglobin and its detrimental effects. In this Review, we summarize the relationship between chronic haemolysis and cardiovascular disease and discuss current and future approaches towards the prevention and treatment of haemolytic injury.
Functional sensory innervation remains one of the most unresolved challenges in skin tissue engineering and biofabrication. Progress has been achieved in recreating epidermal and dermal architecture, but most engineered skin substitutes fail to reproduce the complex neurocutaneous interactions required for sensation, neuroimmune communication, and tissue homeostasis. This review provides a comprehensive analysis of current strategies for engineering innervated skin constructs, with an emphasis on the convergent integration of biomaterials, sensory neurobiology, biofabrication technologies, multicellular co-culture systems, and functional validation methodologies. Additional focus is placed on the biological determinants governing sensory integration, including neuronal subtype specification, Schwann cell-mediated regulation, endogenous neurotrophic signalling, neurovascular coordination, and neuroimmune crosstalk. Emerging humanized platforms, including induced pluripotent stem cell-derived sensory neurons, organ-on-chip systems, and bioelectronic interfaces, are discussed in the context of translational relevance and disease modelling. Beyond conventional electrophysiological assessment, the review also examines neurochemical and modality-specific functional validation approaches, including neuropeptide release assays and receptor-targeted stimulation paradigms. A Minimum Functional Validation Framework is proposed to classify structural, functional, and translational benchmarks for engineered sensory skin systems. This review highlights the need to move from simple neurite incorporation toward the development of integrated neurocutaneous platforms that can reproduce higher-order sensory physiology for applications in regenerative medicine, drug screening, disease modelling, and neuroprosthetic engineering. STATEMENT OF SIGNIFICANCE: Restoration of sensory function remains a challenge in engineered and bioprinted skin with advances in tissue architecture and vascularization. This review evaluates current strategies for neural integration and highlights the persistent gap between structural innervation and functional sensory performance. We introduce a determinant-based framework encompassing cellular viability, spatial organization, molecular signalling, and functional activation, together with a Minimum Functional Validation Framework (MFVF) that differentiates structural neural presence from true sensory competence. By integrating biological, biomaterial, architectural, biochemical, and electroactive design strategies with standardized validation criteria, this review provides a roadmap for developing sensory-capable skin constructs. The framework supports improved experimental design, functional assessment, and translational advancement towards clinically meaningful sensory restoration.