In turn, these cortically derived magnitude estimates, construct context-dependent vestibulo-spatial and vestibulo-temporal, representational maps of the external world, and ensure an appropriate online scaling factor for associated action-perceptual risk. Thus, threat signals are able to exert continuous influence on planning movements, predicting outcomes of motion of self and surrounding objects, and adjusting tolerances for discrepancies between predicted and actual estimates. Such a process affects the degree of conscious attention directed to spatial and temporal aspects of motion stimuli, implying that maintaining balance may follow a Bayesian approach in which the relative weighting of vestibulo-spatial and vestibulo-temporal signals and tolerance for discrepancies are adjusted in accordance with the level of threat assessment. Here, we seek to mechanistically explain this process with our novel empirical concept of a Brainstem Cortical Scaling Metric (BCSM), which we developed from a series of neurophysiological studies illustrating the central role of interhemispheric vestibulo-cortical asymmetries for balance control. We conclude by using the BCSM to derive theoretical predictions of how a dysfunctional BCSM can mechanistically account for functional dizziness.Maintaining balance necessitates an accurate perceptual map of the external world. Neuro-physiological mechanisms of locomotor control, sensory perception, and anxiety systems have been viewed as separate entities that can on occasion affect each other . Emerging models are more integrated, that envision sensory perception and threat assessment as a fundamental component of balance. Here we present an empirically based theoretical argument that vestibular cortical areas construct magnitude estimates of our environment  Patients with psychosomatic vestibular conditions  have been extensively studied over the last four decades. Various terms have emerged to describe these patients including phobic postural vertigo , space-mClinically, patients with PPPD present with two key fluctuating or continuous symptoms; (a) a dizzy, not-truly vertiginous sensation, with patients reporting that their head is swimming and/or (b) unsteadiness, such that patients report swaying, rocking, or jelly legs. Symptoms can be exacerbated in visually complex environments, during upright posture and head movements. Typically, PPPD is triggered by an acute disruption to normal balance function; however, the development of PPPD is not attributable to the degree of otological dysfunction or failed ear recovery. Rather, psychological risk factors  and shifts in psycho-physical functioning  are strong predictive factors for determining which patients will develop PPPD following vestibular dysfunction . This isvia spatial and temporal perceptual mechanisms. Elucidating the neurobiological basis of functional dizziness is clinically pertinent, especially when considering its high prevalence , as well as the considerable functional , occupational (41% take time off work), and cognitive impairment imparted  motion stimuli , changes in conscious awareness of motion, and reduced tolerance for both perceived postural instability  and resulting adjustments to locomotor control strategies . These bottom-up and top-down alterations in functioning are affected by over-vigilant threat assessments  which in turn induce greater physiological and psychological reactivity to discrepancies between actual and perceived motion . Based ovia a process that can be viewed as an extension of “velocity storage” and “neural integration”  can be selectively biased toward smaller or larger magnitudes in a hemispheric dependent fashion, and that such biasing can disrupt the construction of representational space and time . CentralOne of the techniques we developed to disrupt interhemispheric interactions involves combining binocular rivalry (RIV)  with vestibular stimulation  or warm (44°C) water irrigations), referred to as CAL+RIV stimulation. Notably, this paradigm can selectively induce interhemispheric competition when rivalry is combined with caloric irrigations that preferentially implicate the left hemisphere  . No confThe second technique involves modulating vestibulo-cortical excitability over the posterior parietal cortex (PPC), with transcranial direct current stimulation (tDCS). Application of unipolar cathodal tDCS over the left PPC induces top-down modulation of the VOR. Right hemisphere cathodal stimulation does not modulate the VOR, despite housing the predominant vestibular representation. This lack of modulation following (right hemisphere) cathodal stimulation can be accounted for by an on-going functional interhemispheric asymmetry  between the parietal cortices enabling the right hemisphere to exert greater inhibition over the left, in right-handed individuals. Accordingly, cathodal tDCS of the left PPC not only inhibits its ability to process vestibular signals but also potentiates right hemispheric dominance .via top-down vestibulo-cortical mechanisms. Specifically, the suppression in the amplitude of elicited vestibular nystagmus reflects the degree of interhemispheric modulation using either CAL + RIV stimulation or tDCS, and thus reflects the brainstem contribution to the proposed Brainstem Cortical Scaling Metric (BCSM). Quantification of this brainstem component is made by calculating the nystagmus suppression index (NSI) which is the percentage change (before vs. after CAL + RIV or tDCS) in the peak slow phase velocity of the VOR  but can additionally bias magnitude, spatial, and temporal percepts in a proportional manner . That isRegarding temporal biasing, right hemispheric lesions bias magnitude percepts toward larger magnitude . Based oTaken together, our findings imply that disrupting interhemispheric interactions alters vestibulo-cortical functioning in turn biasing magnitude percepts that subsequently distorts the coding of representational space and time. Indeed, we have proceeded to demonstrate that such distortion of space and time impairs control of body motion as illustrated by our recent findings in healthy individuals.Our data in healthy individuals , illustrAccordingly, we postulate that patients with functional dizziness will exhibit reduced right-lateralized vestibulo-cortical dominance manifesting distorted representations of space and time attributable to biased percepts toward larger magnitudes. In turn, the BCSM’s ability to properly scale estimates of displacement and duration is altered, thereby throwing off internal predictions of space and time, which in turn impairs accurate assessment of errors between predicted and actual motion, resulting in sensations of disconnectedness from self and surroundings . These minor dissociative symptoms are consistently experienced by patients with chronic dizziness, including functional dizziness, and by normal individuals exposed to strong vestibular stimuli . Such seThe outlined conceptual principles above require a pathophysiological model of functional dizziness that can tie together threat assessment, risk tolerance, perceptual bias, and functional shifts in space-motion processing and locomotor control. Accordingly, we propose the following theoretical hypothesis and schematic model as depicted in QA conceptualized and wrote the manuscript. YS provided the technical contributions and edited the manuscript. MS edited the manuscript and drafted the figures. DK and JS conceptualized and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Persistent liver inflammation can lead to cirrhosis, which associates with significant morbidity and mortality worldwide. There are no curative treatments beyond transplantation, followed by long-term immunosuppression. The global burden of end stage liver disease has been increasing and there is a shortage of donor organs, therefore new therapies are desperately needed. Harnessing the power of the immune system has shown promise in certain autoimmunity and cancer settings. In the context of the liver, regulatory T cell (Treg) therapies are in development. The hypothesis is that these specialized lymphocytes that dampen inflammation may reduce liver injury in patients with chronic, progressive diseases, and promote transplant tolerance. Various strategies including intrinsic and extracorporeal expansion of Treg cells, aim to increase their abundance to suppress immune responses. We recently discovered that hepatocytes engulf and delete Treg cells by enclysis. Herein, we propose that inhibition of enclysis may potentiate existing regulatory T cell therapeutic approaches in patients with autoimmune liver diseases and in patients receiving a transplant. Moreover, in settings where the abundance of Treg cells could hinder beneficial immunity, such us in chronic viral infection or liver cancer, enhancement of enclysis could result in transient, localized reduction of Treg cell numbers and tip the balance towards antiviral and anti-tumor immunity. We describe enclysis as is a natural process of liver immune regulation that lends itself to therapeutic targeting, particularly in combination with current Treg cell approaches. The liver has a critical role in detoxification and hence it often becomes the site of cellular damage. Hepatocytes are liver epithelia that bear the worst of this process, and drive liver regeneration during injury. A healthy liver can cope with small amounts of tissue damage and repair itself as needed. Persistent liver injury, however, can lead to progressive liver damage, fibrosis, cirrhosis and end stage disease requiring a transplant.Mortality due to liver disease is projected to overtake coronary heart disease by 2020 in the UK , 2. GlobThe outcome of liver inflammation is determined by the balance of effector and regulatory immune cells activities: chronic hepatitis arises when effector cells persist, causing liver injury. Despite their prevalence, effector cells in chronic disease fail to control hepatocellular carcinoma, one of the two cancers with mortality projected to rise by 38% by 2035  and the remarkable ability of the liver to regenerate. We recently discovered that hepatocytes preferentially engulf live CD4+ T cells , which promote immune responses , and herein we explore how to target this process in different liver disease settings. The liver is the largest internal organ and it filters blood at a rate of ~ 1.4 L/min, enclysis could therefore have a major impact in Treg cell populations.CD4 T cells  in i) 2-esponses Figure 1esponses . We termWe demonstrated that enclysis was distinct to known cell engulfment processes , 20, incLoss of tolerance in the liver is observed in autoimmune family disorders such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), where immune-mediated injury affects hepatocytes, small and large bile ducts respectively. The trigger for these diseases is not understood. Immunosuppression in AIH and PBC can be beneficial, however this is not the case for PSC . CurrentAIH is a chronic liver disease characterized by excessive immune responses associated with effector T cells , 31. In + T cells  or rapamycin (RP) agents enhanced Treg function and decreased up-regulation of Th1/Th2/Th17 transcription factors in cells from AIH patients . FurtherEx vivo expansion of clinical grade regulatory T cells is laborious and costly, but it is certainly possible  and hepatitis C virus (HCV) are hepatotropic viruses that are the leading causes of liver transplantation worldwide. They cause progressive liver damage after decades of infection that can promote a pro-tumorigenic environment and may lead to liver failure requiring a transplant , 90. ChrSprengers et al. showed a correlation between the levels of intrahepatic CD8+ T cells and the degree of liver damage in HBV, highlighting the concept that a balance between an immune response and tolerance is essential to ensure clearance of the virus, whilst limiting any liver cell injury leading to fibrosis . AlthougThere are limited data on the immunological response to acute HBV and HCV infection in the liver because of the potential complications associated with standard liver biopsies and the difficulty in detecting an often-asymptomatic acute phase. Therefore, most studies of intrahepatic Treg cells in HBV and HCV have focused on the chronic phases of infection. Elevated Treg levels in chronic HCV infection were associated with limited immunopathological damage, suggesting a critical role for Tregs in controlling the chronic inflammatory response to HCV thus limiting hepatic damage , 99. Howex vivo effector functions, and activation-induced death of HCV-specific memory T cells  production from hepatic stellate cells which contributes to the differentiation of conventional CD4+ T cells into induced Treg cells . In chroTo clear infection in patients with chronic hepatitis, reducing Treg cell frequencies in the liver in a specific and transient way may provide a sufficient boost to antiviral immunity. Increasing enclysis with enhancer compounds may reduce Treg cell numbers in the liver without depleting Tregs from the circulation. Indeed, depletion of Tregs has been shown to increase the immune control of acute HBV early in infection as the hepatitis B antigens HBeAg and HBsAg were cleared considerably faster in the serum of Treg-depleted mice compared to control. Further, early elimination of Tregs in acute HBV infection was shown to improve the recruitment of macrophages and DCs into HBV-infected livers, aiding viral clearance , 111. TPrimary liver cancer is the sixth most common type of cancer and is responsible for over 700,000 deaths annually, making it the fourth leading cause of cancer-related death worldwide . HepatocThe main treatments available for HCC, namely local ablation, surgical resection, or liver transplantation, are only viable if implemented at early stages of the disease. Thus, 80% of patients with HCC are not eligible for these treatments . For sucIt is well-established that chronic pathological inflammation is a key driver of HCC tumourigenesis in cirrhotic livers . RepeateThe creation of a pro-inflammatory environment also stimulates the recruitment of regulatory immune cells. In HCC, tumor-infiltrating Tregs are recruited to the neoplastic site following enhanced secretion of the chemokines CCL17 and CCL2 by tumor associated macrophages . Once acDifferent stages of HCC pathogenesis have been linked to distinct signatures of tumor-infiltrating immune cell populations . A largein vitro  and helper T cells  . UnderstAs Mujal and Krummel elegantly discussed , it is sIn viral infection, the liver needs to deal with abundant Treg populations swiftly to mount an effective immune response, thus Tregs cross the sinusoidal endothelial layers into the parenchyma. Hepatocytes engulf them by enclysis to rapidly tip the balance towards inflammation when needed. At the resolution of infection, the endothelial barriers are restored and Treg populations increase again to restore tolerance.We described how inhibition of enclysis could increase frequencies of Tregs in AIH and in transplantation, where regulatory cell-targeting approaches have started to yield promising results. Conversely, we propose use of enclysis-enhancing drugs to promote Treg deletion in a well-controlled transient and liver-specific setting, to boost antiviral and anti-tumor responses where necessary Figure 3YA, AY, JK, AB and ZS researched and composed the review. YA prepared the figures. SD provided helpful critique of the manuscript. YA and ZS finalized the review. All authors contributed to the article and approved the submitted version.This work is supported by an MIBTP studentship to YA , an NC3R trainee postdoctoral fellowship to SD (UKRI) and an MRF intermediate career fellowship to ZS  and an MRF intermediate career fellowship to ZS .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Triple-negative breast cancers  continue to present a unique treatment challenge and carry unfavorable prognoses. The elucidation of novel therapeutic targets has necessitated the re-evaluation of stratification approaches to best predict prognosis, treatment response and theranostic and prognostic markers. Androgen receptor expression and function have important implications on proliferation, tumor progression, immunity and molecular signaling in breast cancer. Accordingly, there has been increasing support for classification of androgen receptor-negative triple-negative breast cancer or quadruple-negative breast cancer (QNBC). QNBC has unique molecular, signaling and expression regulation profiles, particularly those affected by microRNA regulatory networks. microRNAs are now known to regulate AR-related targets and pathways that are dysregulated in QNBC, including immune checkpoint inhibitors (ICIs), SKP2, EN1, ACSL4 and EGFR. In this review, we explore and define the QNBC tumor subtype, its molecular and clinical distinctions from other subtypes, miRNA dysregulation and function in QNBC, and knowledge gaps in the field. Potential insights into clinical and translational implications of these dysregulated networks in QNBC are discussed. Breast cancers lacking epidermal growth factor receptor 2 (HER2), estrogen receptor and progesterone receptor, are termed triple-negative breast cancers (TNBC) and are distinguished because of a lack of response to therapies targeting these receptors. TNBC is heterogeneous at genomic, transcriptomic levels, showing varying clinical and pathological presentation genetic susceptibility factors and sensitivities for chemotherapeutics . As suchDifferential expression profiles and pathway regulation in breast cancer and TNBC in particular are integrated with the expression and regulation of transcriptional profiles by microRNAs (miRNA) . Importa. There has been increased attention given to the utility of reclassifying TNBC tumors lacking AR expression as QNBC [TNBC has classically been divided into basal-like subtypes (BL1 and BL2), mesenchymal (M) and luminal androgen receptor (LAR) subtypes, and in some systems, according to immunosuppressive versus immune active phenotypes ,11,12,13 as QNBC ,15,16. A as QNBC ,18,19,20 as QNBC . This an as QNBC . In a st as QNBC . EGFR ex as QNBC . PotentiRegardless of some controversy regarding the prognostic significance of AR expression in TNBC , the priAR is a 110 kDa protein residing in the cytoplasm with zinc finger DNA-binding, transcriptional regulation and ligand-binding capabilities . Within Proliferation of tumor cells is generally thought to be increased by AR with evidence of cell-cycle regulation downstream of various androgen-responsive transcriptional activities . AR-ligaAR expression in TNBC may also affect epithelial-to-mesenchymal transition (EMT) leading to altered invasion and metastasis. To this point, nuclear AR was found to be inversely associated with E-cadherin expression and positively associated with increased tumor grade, mesenchymal morphology, metastasis, recurrence and with poor DFS and OS in TNBC ,33. Liu While evidence for angiogenic activity of AR in breast cancer is sparse, regulation of angiogenesis by AR in prostate cancer is implicated through interactions with epigenetic and transcriptional co-activation factors to regulate VEGF, and synergy between anti-androgenic and anti-VEGF therapies .Immune killing of TNBC can also be increased through androgen deprivation therapy using enzalutamide or abiraterone, although this effect was shown to be partially independent of detection of AR expression .Androgen receptor signaling has the potential to regulate DNA repair in QNBC as anti-androgen therapy has been shown to downregulate DNA repair genes that are direct transcriptional targets of AR . In addiGiven that many of the phenotypic effects of AR are pro-tumorigenic and pro-tumor progression, much remains to be discovered regarding mechanisms by which AR negative TNBCs or QNBCs generally have poorer prognoses than AR-positive TNBCs.Subtypes of TNBC, including basal-like, mesenchymal, LAR, and immunomodulatory, are characterized by distinct molecular pathways and profiles  as outliIn addition to direct activity through androgen-response elements, non-DNA-binding mechanisms of AR function exist ,41, inclIn contrast to findings associated with increased EMT with AR expression in TNBC , expressQNBC tumors display distinct molecular profiles including that of transcriptional expression as shown by a study on African American women showing enriched classical basal-like and immune subtype signatures in QNBC . In thisBroad regulation of transcriptional, and subsequently, molecular pathways by miRNAs is known to be important to the understanding of breast cancer pathobiology and markers of the disease. As such, we continue with a detailed review of miRNA regulators of the above pathways, known miRNA dysregulation in QNBC, clinical and translational implications of miRNA regulation in QNBC and unknowns in the field.Since little is known regarding QNBC-specific miRNA regulatory networks, much of the data driving hypotheses for miRNA regulation affecting QNBC pathobiology are extrapolated from the study of TNBC, AR function in breast cancer, and from other cancers. Integration of this existing knowledge, as in this review, provides a jumping-off point for the study of miRNA dysregulation in QNBC. Among the potentially targetable molecular pathways that are known to be altered in QNBC as described above in Other miRNAs that are specifically dysregulated in QNBC have been recently discovered. QNBC was found to exhibit increased expression of miR-135b, which correlated with AR-negativity among TNBCs . DiffereRecently, Bhattari et al. identified increased copy number alterations (CNA), genomic instability and miRNA dysregulation in QNBC compared with AR+ TNBC . They idResearch into such miRNA regulatory networks may provide novel targets and allow the selection of targeted therapies based on the prediction of response of AR-positive TNBC versus QNBC to novel and existing therapeutics. Insights provided by this review and the literature cited herein may provide a foundation for the discovery of miRNA and regulated genes and pathways that may be targeted differentially in QNBC and AR+ TNBC, further justifying the stratification of TNBC according to AR expression. One example may be the tumor promoting miR-135b. Since this miRNA is associated with increased proliferation and TGF-β, Wnt and ErbB signaling in basal-like TNBC , miR-135Neoadjuvant therapy is central to therapy for TNBC given increased response rates compared with other breast cancer types . In the The field of study specific to QNBC is young, leaving much to be discovered about unique pathobiology, regulatory networks, exploitable therapeutic targets and prognostic or theranostic markers. However, there is some understanding of the unique molecular profiles in QNBC. This knowledge can be built on to extrapolate hypotheses regarding the roles of these pathways, their regulation and their targetability with therapeutic interventions. Investigation of miRNA profiles, regulatory networks and pathway analysis of these networks in QNBC compared with AR+ TNBC and other breast cancer subtypes has been sparse so far. Studies using large cohorts comparing these subtypes and additional mechanistic studies of transcript regulation by differentially expressed miRNAs and downstream phenotypic changes relevant to tumorigenesis and progression in QNBC vs AR+ TNBC are needed. Such studies will be required to appreciate the role and potential targeting of these regulators and their regulatory networks in these diseases.There is increasing evidence of unique molecular profiles and targetable pathways other than AR signaling in QNBC versus TNBC and other breast cancer subtypes. These differentiators continue to strengthen the justification for AR expression evaluation of TNBC and classification accordingly. While mutational dysregulation of targetable signaling pathways such as PI3K are more readily identified in other subtypes, these pathways may also be dysregulated in QNBC via transcript modulation by miRNAs. Recent studies have identified consistently and differentially dysregulated miRNAs targeting multiple factors that are relevant to breast cancer pathobiology, including Myc, PI3K, TP53, SOD2 and cell cycle checkpoint factors. Further research into QNBC-specific dysregulation of miRNAs, transcripts and molecular and functional networks can enable the exploitation of these unique factors for the targeted treatment in the face of an otherwise intractable therapeutic challenge.


In recent years, many promising nanotechnological approaches to biomedical research have been developed in order to increase implementation of regenerative medicine and tissue engineering in clinical practice. In the meantime, the use of nanomaterials for the regeneration of diseased or injured tissues is considered advantageous in most areas of medicine. In particular, for the treatment of cardiovascular, osteochondral and neurological defects, but also for the recovery of functions of other organs such as kidney, liver, pancreas, bladder, urethra and for wound healing, nanomaterials are increasingly being developed that serve as scaffolds, mimic the extracellular matrix and promote adhesion or differentiation of cells. This review focuses on the latest developments in regenerative medicine, in which iron oxide nanoparticles (IONPs) play a crucial role for tissue engineering and cell therapy. IONPs are not only enabling the use of non-invasive observation methods to monitor the therapy, but can also accelerate and enhance regeneration, either thanks to their inherent magnetic properties or by functionalization with bioactive or therapeutic compounds, such as drugs, enzymes and growth factors. In addition, the presence of magnetic fields can direct IONP-labeled cells specifically to the site of action or induce cell differentiation into a specific cell type through mechanotransduction. The number of publications related to the field of regenerative medicine have increased dramatically over the last 20 years. Nanotechnology is also finding its way into biomedical research and could significantly improve and accelerate tissue regeneration due to its versatility and functionalization possibilities. The materials used are composed of a wide variety of components and exhibit a broad range of shapes, from fibrous structures or nanopatterned surfaces to particulate objects. Particulate materials, such as NPs, are specifically utilized for diagnostic purposes, as they enable multimodal and multifunctional molecular imaging ,2. MoreoOne of the most promising nanoscale materials are iron oxide nanoparticles (IONPs), which can be functionalized with other bioactive substances, embedded in composites, and bound or taken up by cells . IONPs aThe successful use of NP-based cell therapy and tissue engineering and its monitoring by MRI for regeneration or replacement of diseased or injured tissue has been demonstrated in numerous preclinical in vitro and in vivo studies. This review highlights developments in regenerative medicine and focuses on the use of iron oxide nanoparticles in cell therapy and tissue engineering. Outlined is not only the use of IONPs for cell tracking by MRI, but in particular the active use of these particles to promote cell and tissue regeneration in cardiovascular, osteochondral and neuronal diseases and defects, among others. Excluded are the broad applications of IONPs in tumor treatment or imaging, as these have been described in detail elsewhere.Over the past decades, there have been countless different IONPs developed for biomedical purposes. However, there are basically only a few synthesis methods used for the production of the raw particles, including physical, chemical or biosynthetic methods a 11,16,,18,19,20The versatility and broad applicability of IONPs is achieved by surface coating and functionalization. This provides a certain stability and biocompatibility, which are crucial for many applications, and may equip the nanoparticle surface with targeted substances to ensure specific interaction, e.g., with cells. There are many strategies to increase the stability and achieve the necessary hydrophilicity of NPs for medical research. IONPs can be stabilized as part of a composite in core-shell structures, shell-core-shell structures, matrix-dispersed structures, Janus-type structures and combinations thereof b 16]. H. H16]. H2O3 . Na. Na38]. Thrombosis is a common condition with a significant mortality rate by triggering conditions such as stroke or myocardial infarction. Thus, drugs, such as tissue plasminogen activator (tPA), which catalyzes the conversion of plasminogen to plasmin and thereby dissolves clots, are used to treat ischemic stroke . However2-IONP-tPA particles also showed increased blood and storage stability. Furthermore, magnetically targeted thrombolysis in an ex vivo model resulted in a 34% reduction in blood clot lysis time compared to the required lysis time without magnetic targeting and 40% reduction compared to free tPA. In a further study, authors from the same group evaluated the possibility of a dual targeting strategy using poly(lactic-co-glycolic acid) (PLGA) IONPs functionalized with tPA and fibrin [In a comparative study from our group, Friedrich et al. investigated different coupling methods to efficiently and functionally bind tPA to poly-coated IONPs . We found fibrin . The pard fibrin . Yang etd fibrin . The immd fibrin . In the d fibrin . The BMMd fibrin .Peptide-based targeting of tPA-functionalized IONPs was shown in other studies. In a murine model of venous and arterial thrombosis, Erdem et al. demonstrated the targeting ability of dextran-coated IONPs which were conjugated with the targeting peptide FXIIIa and functionalized with tPA . In anot2-NP-tPA-SK particles showed increased blood stability as well as increased storage stability in buffer. In addition, the thrombolysis efficiency could be significantly increased by magnetic targeting. A heparin delivery platform composed of IONPs, polyethylenimine (PEI) functionalized black phosphorus nanosheets, and heparin loading demonstrated accurate magnetic enhancement capacity and offers a promising multifunctional strategy to prevent deep vein thrombosis in patients at high risk of thrombosis [Besides tPA, there are other endogenous substances such as streptokinase (SK), heparin, urokinase (UK) and nattokinase (NK) that exhibit potent thrombolytic effects. An experimental thrombolytic therapy was developed by Tadayon et al. via co-functionalization of silica-coated NPs with tPA and SK . The SiOrombosis . Thromborombosis ,70. Afterombosis . The genrombosis . NK-conjrombosis ,74.In addition to the strategies already presented, other technologies are being developed and explored to find the most effective and rapid treatment of thrombi. Sonothrombolysis represents a technical development to increase thrombolysis efficacy. Magnetic microbubbles can be retained and set in vibration by a rotating magnetic field in the target region and then activated by ultrasound to significantly increase the lysis of blood clots ,76. In aDespite the continuous improvement in biocompatibility and performance of cardiovascular grafts made from biomaterials, their successful translation into the clinic is very slow ,81. The However, it should be noted that surgical interventions to restore blood flow, whether by percutaneous transluminal angioplasty, endarterectomy, bypass grafting or even vascular prostheses or stenting, often lead to another blockage called restenosis. For this reason, more studies have now been conducted on anti-restenosis drug delivery systems based on nanomaterials, including the utilization of IONPs .Cellular coating of tissue-engineered vascular grafts (TEVGs) with IONP-labeled cells or embedding of IONPs into the scaffold itself has been shown to be an efficient method for visualizing TEVG function and localization using MRI. One of these studies evaluated ways to reduce the production of reactive oxygen species (ROS) often induced by IONPs . For thiIn the study by Luderer et al., biodegradable scaffolds made of a polymer blend of poly(l-lactide) (PLA)/poly(4-hydroxybutyrate) in which gold, silver and magnetite nanoparticles have been embedded were investigated as a replacement for permanent metallic stents . In X-raIn another study including in vivo experiments, ultra-small IONPs were incorporated into polyvinylidene fluoride (PVDF)-based textile fibers that were knitted into vascular scaffolds. The scaffolds were then seeded with a composite of fibroblasts, smooth muscle cells (SMCs) and fibrin, and the inner lumen was seeded with ECs in a bioreactor to prevent inflammation and thrombus formation. The functionality of the grafts, as well as their suitability for MRI were successfully verified after implantation in sheep as arteriovenous shunts between the carotid artery and the jugular vein . In anotAn interesting study by Harrington et al. took the opportunity of MRI imaging to investigate the fate of cells on TEVGs . BiodegrThere are a variety of materials that can be used for TEVG production. These include hydrogels, polymers and nanomaterials, which may not only act as a support structure and provide a compatible surface for cells, but also release substances when required and promote and accelerate tissue formation.Karbastian et al. fabricated artificial blood vessels reinforced with carbon nanotubes and IONPs from biodegradable polyurethane (PU)-thermoplastic-elastin compounds that exhibited efficient tensile strength and reasonable flexibility . AnotherIn contrast to the aforementioned strategy of capturing IONPs-loaded cells by magnetizable scaffolds, the work of Perea et al. demonstrated another possibility ,96. IONPStent implantation is one of the most common invasive treatments for patients with coronary artery disease. Meanwhile, a variety of commercial stents and experimental stents made of different materials are available, based on polymer-free metal platforms, biodegradable/bioresorbable polymers, as well as stents that allow drug delivery by magnetic nanoparticles ,102. SinIn one study, a biocompatible polymer-free composite coating of magnetic mesoporous silica nanoparticles (MMSNs) and carbon nanotubes (CNTs) was prepared, which had a sufficient drug (rapamycin) release performance, and the advantage of rapid endothelialization compared with other commercial polymer-coated drug-eluting stents . Lee et Targeted cell delivery was shown by Chen et al. by using anti-CD34-conjugated IONPs with high affinity for EPCs. Magnetization of iron stents resulted in a high adsorption of IONPs and magnetically labeled EPCs, demonstrating that this method can efficiently promote EPC capture and endothelialization of iron stents .IONPs could also be used to functionalize stents with antirestenotic drugs or antiplatelet agents to prevent stenosis and thromboembolic complications until the metallic surface is covered with a neo-EC layer ,115. FurDespite immense diagnostic and therapeutic advances, atherosclerosis remains a global public health problem and will continue to require the development of new strategies. These new approaches are increasingly based on molecular understanding of the disease, allowing specific nanomedicine-based molecular imaging and therapy ,125,126.Imaging of atherosclerotic plaques is critical for diagnosis, assessment of treatment modality and monitoring of therapy progress. Numerous studies have shown that the use of IONP and its targeted delivery to atherosclerotic plaques are able to provide accurate imaging. In the following, some studies are described in which IONP were specifically applied for the detection of plaque-associated cells or cell components, such as macrophages, foam cells, monocytes, ECs, platelets, or for the detection of other potential biomarkers of atherosclerotic plaques.®) and ferumoxtran-10 (Sinerem®/Combidex®), which have an excellent safety profile and are selectively taken up by macrophages, has been widely reported [A large number of studies have reported the imaging of atherosclerotic plaques by labelling of macrophages with IONPs. In particular, the use of ultra-small IONPs or very-small IONPs particles for the detection of macrophages and pathological inflammation in atherosclerotic tissue is well established ,140,141.reported ,150,151.reported . Howeverreported  and a clreported .®) and showed higher delivery of iron oxide in form of composite nanoparticles to macrophage-rich carotid artery lesions in mice compared to free ferucarbotran [−/−) mouse model, DNA-IONPs were shown to accumulate effectively in macrophages of atherosclerotic plaques, most likely by binding to SR-A and lipid rafts, thus providing an effective strategy to enhance systemic delivery of NP to atherosclerotic plaques [−/− mice [−/− mice [To improve the labeling efficiency of macrophage-rich plaques, IONPs can be functionalized with substances for increasing the IONP accumulation or targeting efficiency. Nakamura used heparin-modified calcium phosphate nanoparticles loaded with ferucarbotran  peptide motif accumulated in the aorta of atherosclerosis model mice that exhibited monocyte accumulation, and thus could serve as a diagnostic tool for atherosclerosis .−/− mice. In similar studies, magnetic NPs modified with VHPKQHR peptides were used for targeting VCAM-1-expressing cells [−/− mice [While the healthy endothelium has a protective function, activation and dysfunction of endothelial cells affects, among other things, leukocyte adhesion and recruitment, platelet activation and thrombus formation, ultimately promoting the formation of atherosclerotic plaques . Endotheng cells , which cng cells . In the −/− mice . HistoloFor early detection of atherosclerotic plaques and activated platelets, which play a central role in thrombosis, atherosclerosis and inflammation, Prévot et al. coupled the platelet-specific scFv-Fc TEG4-2C antibody with a IONP-containing magnetic oil-in-water nano-emulsion and achieved significant labeling of atheroma plaques both in vitro and ex vivo in animal models using magnetic particle imaging (MPI) and MRI . Specifi−/− plaque model using poly (PMAO)-coated IONPs showed that the IONPs accumulated in similar vascular regions as an elastin-targeting gadolinium-based contrast agent which accumulated in plaques [−/− mice was similarly enabled by profilin-1-targeting IONPs, through conjugation of a polyclonal profilin-1 antibody and an NHS-Cy5.5 fluorescent dye [−/− mice [There are abundant biomarkers suitable for NP-based homing to atherosclerotic plaques. One study used hybrid metal oxide-peptide amphiphile micelles (HMO-Ms), which are designed to enable MRI imaging of thrombosis at atherosclerotic plaques through the fibrin-targeting sequence CREKA . In vivo plaques . Kim et  plaques . Of the  plaques . Histolocent dye . Wie et −/− mice .−/− mice, the iron oxide nuclei were found in large amounts within the atherosclerotic plaques of the aorta and thus penetrate into the plaques, similar to native HDL. In a similar study, multimodality imaging confirmed that HDL-labeled IONPs and quantum dots accumulated in atherosclerotic lesions in mice after intravenous and especially after intraperitoneal injection [−/− mice [Another approach to detect atherosclerotic plaques is the use of IONPs with high-density lipoproteins (HDL) . After injection . Another−/− mice . Li et a−/− mice .−/− mouse model [−/− mouse model confirmed high specificity and sensitivity of the particles and allowed quantitative assessment of the degree of inflammation. Finally, to identify vulnerable plaques and rupture plaques, dimercaptosuccinic acid (DMSA) was bound to ultra-small IONPs and showed high specificity and sensitivity for early detection of vulnerable plaques and ruptured plaques after injection into an atherosclerotic rabbit model [A further study demonstrated that tenascin-C, a multifunctional extracellular glycoprotein that is highly expressed in advanced atherosclerotic plaques and is associated with inflammatory changes and plaque rupture, can serve as a marker for atherosclerotic plaques . After ise model . GEBP11-se model . In the se model . MPI, flit model .−/− mice [IONP not only enable the imaging of artherosclerotic plaques, but can also serve as vehicles for therapeutic agents. The efficacy of drug delivery is mostly achieved by passive aggregation provided by the enhanced permeability and retention effect. Active drug delivery can also be achieved using targeting molecules, or specific stimuli such as magnetic fields or ultrasound, to effectively target atherosclerosis at the molecular level . The stu−/− mice . Another−/− mice . Adminis3O4/CeO2 core-shell nanoparticles, it was shown that they can effectively capture ROS and are well detectable by MRI, making them potentially suitable for the treatment and diagnosis of ROS-related inflammatory diseases [Reactive oxygen species (ROS) play an important role in inflammatory reactions such as those associated with atherosclerosis. In an in vitro study with theranostic Fediseases .Another theranostic strategy for vulnerable plaques using an adaptable nanoparticle platform was demonstrated in the work of Bonnet . They de−/− mice [The combination of IONPs with the phase transition material perfluorohexane and with dextran sulfate (DS) targeting SR-A enabled specific targeting of activated macrophages in an atherosclerotic plaque model of ApoE−/− mice . Low int−/− mice . Finally−/− mice . PLGA-NPTargeted enhancement of IONPs can be achieved by the presence of local magnetic fields, promising enhanced and improved diagnosis of inflammatory plaques by MRI. By applying an external magnetic field, Shi et al. achieved a slowdown of IONPs in blood flow, alteration of their trajectory, and ultimately efficient uptake into inflammatory cells, resulting in a clear visualization of plaques via MRI . SimilarApart from pure IONP-based treatment of atherosclerotic plaques, cells, especially EPCs, may also be used for therapeutic angiogenesis and vascular repair and, after loading with IONPs, to monitor the cell migration into vessels. For instance, after transplantation of ultra-small IONP-poly-l-lysine-labeled EPCs into an atherosclerotic rabbit model, results suggest that ultra-small IONP-labeled EPCs may play a role in repairing endothelial damage and preventing atherosclerosis .Currently, there are a variety of pharmaceutical drugs for the treatment of cardiovascular diseases, including calcium channel blockers, antioxidants, oxygen free radical scavengers and anti-apoptotic agents, but they are often associated with side effects. The use of IONPs as vehicles for targeted drug delivery could significantly reduce systemic effects. Moreover, NPs can either be coupled with drugs or other active substances or enable gene transfer for overexpression or silencing of relevant genes by binding DNA or RNA. Xiong et al. have demonstrated cardio protective activity of DMSA-IONPs after intravenous injection . The IONFunctionalized IONPs can also be used to reduce leukocyte migration and thereby attenuate inflammatory responses. In one study, siRNA against chemokine (C–C motif) receptor 2 (CCR2), a chemokine receptor critical for leukocyte migration, was encapsulated in nanoparticles to treat inflammatory cell infiltration of the heart and subsequent deterioration of cardiac function in myocarditis . CCR2 siAlternative approaches for magnetically-based targeted drug delivery are currently under intense investigation, as this technique is expected to enable the local enrichment of IONPs and improve the therapeutic outcome by specifically enhancing tissue production. IONPs externally navigated by applied magnetic fields could help to regain tissue function, e.g., in the treatment of cardiac arrhythmias . Improve2-coated and PEG-decorated IONPs functionalized with two antibodies, one against CD63 antigens on the surface of extracellular vesicles and one against myosin light chain surface markers on injured cardiomyocytes, and performed magnetically directed accumulation of exosomes on injured cardiac tissue in rabbit and rat models of myocardial infarction [As an alternative cell-free therapy, angiogenesis and cardiac function in infarcted heart tissue could be enhanced by the accumulation of extracellular vesicles, which are necessary to maintain tissue homeostasis. To this end, Liu et al. used SiOfarction . Anotherfarction . After ifarction .Stem cell therapy has been considered the greatest hope for the treatment of cardiovascular diseases. In principle, their use could promote regeneration of all injured and diseased tissues. In the treatment of cardiovascular and cerebrovascular diseases, the promotion of angiogenesis in ischemic tissues and organs represents a particular challenge . FunctioConcomitant noninvasive in vivo MRI monitoring of therapy and visual differentiation of any implanted cells or grafts from a host tissue can be achieved by labeling with paramagnetic agents, such as IONPs due to their inherent imaging properties ,224. HowDespite the previous reports, the study by Chung et al. demonstrated a strategy in which long-term in vivo assessment of transplanted cells by MRI is possible . For thi®/Endorem®) and injected into explanted mouse hearts as well as in vivo into the anterior left ventricular wall of rats [Up to date several stem cells of different origins has been utilized for cardiovascular tissue regeneration. A relatively new therapeutic approach for the treatment of cardiac and other diseases is the usage of human ESCs (hESCs). For in vivo visualization of transplanted hESCs, the cells can be labeled with IONPs and tracked with MRI. In an early study, hESCs cells were loaded with dextran-coated ferumoxides  could be used to regenerate the injured endothelium by differentiating into mature ECs while monitoring the regeneration process. In a rat embolization model of abdominal aortic aneurysm, IONP-labeled BM-EPCs were shown to settle mainly in the aneurysm neck and accelerate the formation of fibrous tissue, indicating that BM-EPCs can play a crucial role in the repair and remodeling of the aneurysm neck orifice .−/− mouse model with hind limb ischemia [The success of vascular regeneration was demonstrated by IONP-labelled adipose-derived stem cells (ASCs) after intravenous injection into the tail vein of a mouse carotid artery injury model . MRI conischemia . Implantischemia . After i2O3 NPs improved cell migration and angiogenic potential and provided them with higher resistance against apoptosis. Hill et al. demonstrated that labeling of MSCs did not affect proliferation or differentiation ability and also provided long-term detection after injection into normal and freshly infarcted myocardium in pigs. The IONP-loaded cells even provided sufficient MRI contrast for in vivo detection in a beating heart [Hence, several studies have demonstrated the feasibility of tracking stem cells with incorporated IONPs. However, biological safety must also be ensured when using NPs. In this context, the work of Elkhenany et al. showed large differences in the effects of different IONPs, either uncoated or coated with starch, after labeling ASCs . In partng heart .In addition to the numerous and promising research results on monitoring stem cell-based treatment of cardiovascular diseases using IONP-loaded cells, first clinical studies have now been launched. In one trial, administration of ultra-small IONP-labeled autologous BM-MSCs after intramyocardial injection in patients with chronic ischemic heart disease was shown to be safe and the cells were detectable at the injection sites by MRI for up to two weeks after transplantation .The use of nanoparticles in stem cell therapy is not limited to monitoring transplanted cells, but can also be used to target cells to specific sites by specific functionalization or/and magnetic forces . In thisIn particular, magnetic targeting has been shown to significantly increase cell homing. In a heart failure rat model, IONP-loaded MSCs could significantly improve cardiac function and myocardial hypertrophy and reduce fibrosis in the presence of a magnetic field . MagnetiCheng et al. enabled targeted accumulation of cells to injured tissue using antibodies and magnetic fields . IONPs wDangerous vessel occlusions can be restored in the clinic with interventional balloon angioplasty. However, the injury to the vessel walls that occurs during this procedure carries the risk of restenosis and neointimal hyperplasia. In one study, magnetic cell targeting of IONP-loaded MSCs in a rabbit model was shown to result in a six-fold increase in cell retention and ultimately a reduction in restenosis . The stuThe modulating capacity of IONPs towards cells was investigated by Han et al. . The theAnother approach to restore functional cardiac tissue is the use of biomaterials, which can be manufactured from a broad variety of components and exhibit a wide diversity of structures. To achieve long-term cell retention and thus enhance the efficacy of cell-based therapies, Blocki et al. developed injectable microcapsules of agarose, supplemented with the ECM proteins collagen and fibrin and the glycosaminoglycan-like dextran sulfate, with embedded IONP-labeled MSCs, and administered them into the infarcted heart wall . In contOne promising manufacturing method is electrospinning. In one study, to improve mechanical properties and surface area, casein-coated IONPs were incorporated into electrospun silk fibroin nanofibers . After sThe generation of heart-mimicking tissues can also be achieved based on hydrogels. Zwi-Dantis et al. produced MRI-detecTable 3D collagen hydrogels with aligned human cardiomyocytes from collagen by embedding IONP-loaded cells and transient application of a magnetic field, which resulted in no alteration of normal cardiac function after transplantation onto rat hearts . AnotherAllginate scaffolds are among hydrogels most commonly tested in tissue engineering of cardiac patches. It has been shown that prevascularization, by the addition of a mixture of prosurvival and angiogenic factors, significantly increases the repair capacity of such transplanted patches . The samIn a rat model of chronic myocardial infarction, Blondiaux et al. showed that fibrin patches containing IONPs-loaded human BM-MSCs enhanced myocardial regeneration, and presumably serve as paracrine reservoirs that allow increased release of soluble mediators . In a siA potential treatment of myocardial infarction or severe ischemic diseases by magnetic tissue engineering of multilayered cell sheets was proposed by Ishii et al. ,280. In Scaffoldless multilayered cell sheets of cardiomyocytes (CMs) were prepared by Shimizu et al. using cationic magnetite liposomes-loaded rat CMs by magnetic tissue engineering . ImmunofKito et al. generated induced pluripotent stem (iPS) cell layers for therapeutic angiogenesis . For thiMechanical stimulation and physical forces can lead to cell differentiation or conditioning. Chouhan et al. developed a silk fibroin-based and magnetically responsive matrix by incorporating IONPs and seeded it with neonatal rat cardiomyocytes and H9c2 cells . The infFunctional tissue engineering of heart valves is a major challenge. To observe cell migration into the developing tissue structure under dynamic conditions, human vascular SMCs, ECs and BM-MSCs were labeled with IONPs and then seeded onto a nonwoven scaffold of a mixture of polyglycolic acid (PGA) and PLA in a hybridization tube . MechaniIn the following chapter, relevant work in the field of stem cell therapy and tissue engineering for cartilage and bone defects in which IONPs were utilized are described . ConsideIONPs represent a commonly used labeling agent that can effectively and rapidly label most cells in vitro without exerting excessive negative interference on cellular functions, such as proliferation or differentiation. This labeling allows the non-invasive in vivo control and monitoring of cells applied for cartilage regeneration or cartilage tissue engineering ,287. In In addition to the possibility of enhancing proliferation, differentiation, and migration of stem cells by mechanical stimulation of an applied external magnetic field, magnetically based enrichment of IONPs or IONP-loaded cells at diseased or defective sites is another promising approach in the field of tissue regeneration . Chiang 3O4, polyvinyl alcohol (PVA) and type II collagen, which exhibited good physical properties as well as good swelling behavior and cell compatibility [One of the most widely used scaffold materials, especially for tissue engineering of bone and cartilage, is collagen. Mertens et al. incorporated ultra-small IONPs passively or actively by chemical conjugation during crosslinking into collagen-based scaffolds. The study showed not only a high biocompatibility of the structures towards different cell types, but also that they can be easily, efficiently and stably labeled with ultra-small IONPs. The collagen patches could be precisely monitored by MRI for up to 22 days after subcutaneous implantation into the hind limb of mice . In the tibility . In anottibility . The resChen et al. demonstrated the noninvasive monitoring of hydrogel degradation by multiparametric MRI during cartilage regeneration using a hydrogel system composed of ultra-small IONPs, cellulose nanocrystal and silk fibroin and confirmed it by histological analysis in a rabbit cartilage defect model . FurtherNedopil et al. developed a protocol for the preparation of matrix-associated stem cell implants from agarose and ferumoxides-loaded adult MSCs for articular cartilage repair and noninvasive in vivo tracking of the therapeutic progress . AnotherMagnetic stimulation can be used to release growth factors and drugs from stimuli-responsive polymeric systems in a controlled manner to influence the differentiation of cells in a required direction . Fan et In addition to fabricating composites based on cells and biomaterials, there are approaches to generate tissues using only cells without supporting materials. Son et al. loaded human BM-MSCs with IONP from Magnetospirillum sp. AMB-1 and exposed them to a static magnetic field after pelleting . MagnetiReconstruction of bone tissue is an important goal in regenerative medicine. Promising approaches include the controlled differentiation of stem cells and the use of different materials to generate bone scaffolds . The useAs in other cell-based therapies, stem cell therapies for bone regeneration can be non-invasively monitored and tracked after pre-loading of the administered cells with IONPs. For example, Kérourédan et al. used a laser-assisted in situ bioprinting method to print viable human stem cells from apical papilla onto a mouse calvarial defect. Printed patterns of cells with superparamagnetic microspheres demonstrated the feasibility of noninvasive cell tracking by MRI .Apart from the suitability for imaging, the tissue repair-stimulating effect of IONPs has been known for a while, but the exact underlying mechanisms are still unclear. Using gene microarray assays and bioinformatics analyses, Wang et al. have shown that gene expression of human BM-MSCs is strongly regulated after treatment with IONPs and that the classical mitogen-activated protein kinase (MAPK) signaling pathway is activated, thereby regulating downstream genes and promoting osteogenic differentiation . SchulzeAnother possibility to positively influence cell differentiation is mechanotransduction. The application leads to a conversion of an external force acting on a cell into internal biochemical signaling pathways and affects cell differentiation, proliferation and ECM composition, among others, and can be used in regenerative medicine for tissue-forming approaches ,320,321.The addition of IONPs to scaffolds can promote protein adsorption and the formation of a protein corona, which exerts a positive influence on tissue regeneration. Zhu et al. have provided insight into the underlying molecular mechanisms of the osteoinductive effect of IONPs in magnetic hydroxyapatite (HA) scaffolds and demonstrated that functional proteins enriched in the corona efficiently activate the MAPK/ERK signaling pathway, ultimately leading to the promotion of cell proliferation ,325. In HA is one of the most frequently used substances for bone tissue engineering, mostly as part of biocomposites. Heidari et al. examined the properties of pure chitosan, chitosan /HA, chitosan /HA/magnetite and chitosan/magnetite, materials used for bone tissue engineering, and showed that all composites are cytocompatible and that the addition of HA and magnetite to the chitosan matrix can significantly improve the mechanical properties of pure chitosan . In a stIn addition to the widespread use of HA-containing biocomposites in bone tissue engineering, several other studies have demonstrated the functionality of biocomposites without the involvement of HA. Cojocaru et al. developed biodegradable composites with a macroporous structure containing chitosan, calcium phosphates, hyaluronic acid, and bovine serum albumin and IONPs that showed good biocompatibility toward osteoblast cells . To enhaDue to their biocompatibility, gelatin-containing scaffolds were also utilized for tissue engineering. In a study by Wang et al. biodegradable bone scaffolds were fabricated from shape memory PU, IONPs and polyethylene oxide (PEO) or gelatin by 3D printing . After cApart from the above-mentioned possibilities for tissue engineering, there are also other innovative methods including electrospinning. Wei et al. developed a biodegradable magnetic nanofiber material of IONPs/chitosan/PVA, which exhibited improved cell adhesion and proliferation over MG63 human osteoblast-like cells compared to cell culture plates . The bioZhuang et al. presented a magnetically assisted electrochemical technique to deposit type I collagen nanofibers onto a substrate. The embedded IONPs and an external magnetic field resulted in aligned collagen coatings that promoted the growth of BM-MSCs in the form of elongated morphology, which strongly promoted cellular osteogenesis .In contrast to the aforementioned biocomposites, cell sheet techniques offer the possibility of producing a tissue without the use of supporting structures. Silva et al. produced hierarchical vascularized heterotypic 3D cell constructs from IONPs-loaded human umbilical vein ECs (HUVECs) and ASCs by magnetic force-based cell sheet engineering . The hetMagnetic scaffolds have the potential to enhance bone tissue formation by plain magnetic stimulation. Russo et al. addressed the preparation of PCL matrix and IONPs and the effect of time-dependent magnetic field on adhesion, differentiation and proliferation of human MSCs . The resMany studies on bone tissue engineering are based on the preparation of hydrogels with embedded IONPs. These biocomposites have demonstrated a strong impact on cell differentiation under magnetic fields. Filippi et al. prepared magnetizable nanocomposite hydrogels by incorporating IONPs into PEG-based hydrogels containing cells derived from human adipose tissue . Under aIn addition to the usual techniques for producing scaffolds, such as blending for hydrogel formation, some other techniques are used as well. By electrospinning IONPs, HA-NPs, and PLA, Meng et al. fabricated magnetically responsive nanofibrous scaffolds that accelerated the formation of new bone tissue under an external static magnetic field after transplantation into a rabbit model of lumbar transverse defects by stimulating osteoblast cells proliferation and secretion of new ECM . Using a2O4 NPs, which stimulated the proliferation of preosteoblasts by applied magnetic fields [By a solvent-casting method, Fernandes et al. fabricated a magnetoactive scaffold of three different fiber diameters with different pore sizes using a piezoelectric polymer, poly(vinylidene fluoride) (PVDF) and CoFec fields . Marycz c fields . In a stc fields . Finallyc fields .Magnetic scaffolds are suitable for transporting magnetically labelled soluble factors such as growth factors, hormones and polypeptides or cells directly to the site of implantation. A method for in vivo loading of scaffolds with bio-agents was demonstrated by Bock et al. . By immeIn the meantime, techniques have been invented that allow a differentiated development of tissues, e.g., the simultaneous locally separated formation of bone and cartilage tissue. Su et al. produced biphasic type II collagen-chitosan/PLGA scaffolds with IONP-labeled rabbit chondrocytes, whose cellular distribution and proliferation within the scaffold could be magnetically controlled and also exhibited increased gene expression of type II collagen and aggrecan . In anotSaldanha et al. demonstrated that ferumoxides-labeled MSCs can be detected in vitro in natural and synthetic polymers as well as distinguished in vivo from the native tissue environment in rat intervertebral disc degeneration by MRI, thus appearing potentially suitable for longitudinal in vivo tracking of stem cell-based disc regeneration . MultipoMusculoskeletal tissue injuries such as tendon and ligament pathologies are common in the elderly and especially in athletes, with traumatic rupture of the anterior cruciate ligament and Achilles tendinopathy being the most common . Scharf The feasibility of IONP-based cell tracking was also demonstrated by Kremen et al. . They usThe use of decellularized tendon tissue as a basis for tendon tissue engineering represents a very promising therapeutic approach. Ideally, in addition to the required biocompatibility, scaffolds should approximate natural biomechanical properties as closely as possible. Therefore, decellularization of donor tissue offers the possibility to obtain hypoimmunogenic scaffolds with a natural ECM structure that supports subsequent repopulation with cells. Burk et al. has shown that decellularization of horse tendons by repeated freeze-thaw cycles, especially in combination with Triton X-100, was cytocompatible with IONP-loaded MSCs and showed no morphological changes of the ECM .Another study follows the approach of generating magnetic polymer scaffolds . AlignedInterest in regenerative methods in dentistry is growing steadily. There are now a variety of approaches in tissue engineering for almost all anatomical areas of the tooth, in particular the enamel, dentin and pulp . AnastasLi et al. developed a magnetic adhesive composed of dimethylaminohexadecyl methacrylate, amorphous calcium phosphate NPs and magnetic NPs that exhibited significantly higher dentin adhesion than the commercial control and reduced S. mutans biofilm colony-forming units by 4 logs . Thus, tIn a recent paper, a multifunctional periodontal hybrid scaffold was developed that mimics the various compositional and microstructural features of alveolar bone, periodontal ligament and cementum . The scaStem cells and progenitor cells, as well as differentiated cells such as adult neurons, Schwann cells and astrocytes, have been used to treat many different pathologies of the central and peripheral nervous system, including various neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), ischemic stroke, amyotrophic lateral sclerosis (ALS), spinal cord injury and multiple sclerosis (MS) ,384,385.The use of nanotechnology in diagnostics but also in drug delivery and tissue engineering could significantly improve the treatment of patients with injured neuronal tissue ,389,390.In the following, we highlight other interesting approaches in the treatment of specific PNS and CNS injuries by stem cell therapy or by the use of nanomaterials as tissue engineering scaffolds. Possible targets for IONP-assisted tissue engineering and regeneration of tissues within PNS and CNS are depicted in Sensory neurons of the dorsal root ganglia (DRG) transmit information from stimuli that trigger feelings of touch, pain, muscle tension and temperature, among others, from the body to the CNS. There a variety of diseases and disorders that directly and indirectly lead to degeneration or dysfunctionality of sensory neurons. In addition to hereditary diseases such as Charcot Marie Tooth Disease and Friedreich’s Ataxia, as well as autoimmune diseases and toxic substances such as alcohol, DRG neurons can be severely damaged by physical trauma . MeanwhiFor example, in one study, the neurotrophic factors including nerve growth factor (βNGF), bFGF-2, and glial cell-derived neurotrophic factor (GDNF) were coupled to IONP to increase the very short half-life of these compounds. Liu et al. showed that nano-hydroxyapatite (n-HA)-coated IONPs could potentially be used for nerve regeneration by effectively increasing the viability of primary cultured DRG neurons and promoting axonal elongation through activation of the Netrin-1 signaling pathway .The combination of IONPs with hydrogels are another promising approach for the regeneration of DRGs. In NVR-Gel, which is mainly composed of hyaluronic acid and laminin, the functionalized NPs were able to enhance early nerve fiber sprouting compared to free factors in organotypic DRG cultures and significantly accelerate the progression of myelin formation . The stuOther studies were based on the use of electrospun fibers. Zuidema et al. controlled the preferential DRG neurite outgrowth along aligned electrospun PLA microfibers in the presence of nerve growth factor (NGF)-releasing IONPs . SimilarAutologous nerve transplantation is an accepted therapy for peripheral nerve repair. Since, among other things, available donor nerves are scarce, there are promising approaches for replacement with biomaterials or biomaterials in combination with cells.Lacko et al. presented the preparation of aligned tubular hydrogel scaffolds of glycidyl methacrylate hyaluronic acid and collagen I by magnetic templating of dissolvable magnetic alginate microparticles and their subsequent dissolution . The tubLiu et al. developed a Schwann cell-loaded magnetic nanocomposite scaffold composed of a biodegradable chitosan-glycerophosphate polymer and IONPs . When inTseng and Hsu investigated the effect of MSC-derived spheroids compared with single cells on the regeneration of transected rat sciatic nerves . They deNanotechnology, in combination with stem cells, offers great potential in the treatment of brain and spinal cord injuries ,431. To Optic nerve diseases, such as diabetic retinopathy and glaucoma, are the most common causes of blindness . Vision In one study, rat whole-animal MRI and fluorescence analyses demonstrated that IONP-labeled polymeric nanospheres remain at the injury site after injection and also partially penetrate injured axons and are transported to the parent somata, thus offering the possibility of delivering therapeutic agents to the injury site and somata of injured CNS neurons . The worSpinal cord injuries often lead to pain and permanent loss of sensory and motor functions. Currently, there is still no established therapy to restore the lost functions in patients, although research into possible solutions has been ongoing for a long time. Despite reports that transplantation of IONP-labeled BM-MSCs did not result in clinical improvement in neurologic function , there aBesides the very advantageous possibility to observe IONP-loaded cells during therapy by imaging methods, cells and their regenerative capacity can also be positively affected by uptake of IONPs—either by magnetically controlled targeting or/and by specific functionalization.In a study by Cho et al., a pulsed electromagnetic field (PEMF) directed IONP-loaded human BM-MSCs to the vicinity of the spinal cord-injured site in rats, resulting in improved behavioral tests . Other sSeveral other studies demonstrated positive effects of cell therapy with incorporated functionalized IONPs. Choi et al. demonstrated that human ASCs loaded with core-shell particles made of IONPs with a ZnO envelope enhanced the regenerative activity and effectively alleviated neuropathic pain in induced traumatic spinal cord injury mouse models . HoweverThe transplantation of olfactory ensheathing cells (OEC), a type of glia which ensheat axons of the olfactory receptor neurons, have shown promising results in promoting the regeneration of CNS axons after transplantation into the injured CNS . IONP-laEven without cells, IONP can be applied to regenerate spinal cord injuries, particularly when combined with directed magnetic fields or/and used as vehicles to deliver therapeutic agents across the blood-brain-barrier (BBB) to the site of injury . HoweverOther studies exploited the magnetic properties of the particles. For instance, Kim et al. investigated the therapeutic efficacy of exosome-mimetic and IONP-containing nanovesicles from IONP-treated human MSCs in a mouse model of spinal cord injury . The exoDue to the influence of external magnetic fields and transactivation transduction protein (TAT), which has a remarkable membrane translocation ability, TAT-conjugated PEGlated magnetic polymeric liposomes accumulated significantly around the site of SCI and even within neurons .In another study, Song et al. showed that the combination of magnetic field-mediated gene transfer and TAT-assisted intracellular delivery provides an improvement in transfection efficiency in rat spinal cord after lumbar intrathecal injection and that transgene expression can even be mediated by a magnetic field in a remote region . In contOther tissue regeneration strategies include biocomposites consisting of IONP and other biocompatible materials such as hydrogels. For instance, Bhattacharyya et al. prepared a gelatin–genipin hydrogel system impregnated with IONPs that was injected into rats in a spinal cord injury model . After rSome strategies also rely on biocomposites that have been pre-loaded with cells. In an in vitro work, a structured neuronal microphysiological system was fabricated by bio-printing IONP-loaded spheroids and PEG-based hydrogels to mimic the hierarchical structure of the nervous system . The stuStem cells are promising candidates for the treatment of stroke, multiple sclerosis, Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and epilepsy, among others ,504,505.IONP-labelled cells have been shown to crucially enhance the regeneration of brain tissue. Jenkins et al. showed clear differences in magnetic particle uptake and intracellular processing between neuronal subtypes . They alThe intrinsic capability of IONPs enable magnetic guided cell targeting and manipulation. Schöneborn et al. and Raudzus et al. functionalized IONPs with RAS or SOS proteins, which are involved in the regulation of axonal growth as a strategy for the treatment of Parkinson’s disease (PD) that is accompanied by loss or dysfunction of dopaminergic neurons in the substantia nigra (SN). The magnetic translocation of the functionalized IONPs into the cytoplasm and from the cytoplasm to the neurite tip of human dopaminergic neurons led to the accumulation of endogenous RAS protein and the elongation of the growth cone elongated in the desired direction ,527. A pTo treat and alleviate intracerebral hemorrhage, a rat model underwent intravenous injection of human ESC-derived spherical neural masses loaded with magnetosome-like ferrimagnetic iron oxide nanocubes. In the group with an external magnet attached to the helmet, there was significant downregulation of proinflammatory cytokines, decreased recruitment of macrophages and neutrophils, and improved neurological function .IONPs are frequently used as theranostic drug carriers. However, their potential neurotoxicity to the brain has not been well studied and reports show that IONPs may well have negative effects on neuronal viability. For example, Liu et al. showed dose-dependent cytotoxicity on neuronal cells and reduction in motor coordination and spatial memory in mice . DespiteTreatment of aneurysms often leads to thrombus formation and rupture near the arterial walls. In one work, revascularization of a stent was improved by coating with an elastic, magnetic and biocompatible biopolymer hydrogel based on bacterial nanocellulose (BNC) and IONPs . A similThe use of IONPs is considered a promising strategy tor functional restoration of different soft tissues and organs, beyond the heart and the brain. The possible targets of IONP-assisted tissue engineering and regeneration approaches reported in literature are shown in Stem cell transplantation is considered to be a promising strategy tor functional restoration of inner ear damage, such as sensorineural hearing loss. Thereby, it would be of greatest advantage if the course of therapy can be reliably tracked and monitored. Watada et al. showed that MSCs labeled with IONPs could be reliable monitored by MRI after transplantation into the cochleae of living animals . AnotherStem cell therapies are since long being explored for treatment of degenerative eye diseases ,543. MeaIntranasal delivery and magnetically controlled enrichment of IONP-loaded MSCs could also be used to treat olfactory damage. In an olfactory damaged mouse model, enhanced migration of magnetized MSCs could be achieved using external magnets. .The treatment of voice defects, e.g., vocal fold damage, is a strong challenge in regenerative medicine. So far, there are only a few surgical or tissue engineered approaches for the restoration of such defects ,549,550.The loss or hypofunction of salivary secretory epithelial cells, e.g., due to autoimmune diseases or radiation therapy for the treatment of cancer, could be compensated by stem cell or tissue engineering techniques. In a mouse model, the function of damaged salivary glands could be restored by cell therapy with ultra-small IONP-labeled BM-MSCs and acinar-like cells, however, the acinar-like cells showed better therapeutic potential than the BM-MSCs . In anotChronic kidney disease and acute kidney injury leads to high mortality rate. Current treatment options are limited to dialysis and kidney transplantation. However, tissue engineering and regenerative medicine could help reduce the problems encountered during treatment, such as graft failure, shortage of donor organs, and numerous other complications . In addiThe use of nanomaterials in nephrology has not yet been widely explored, but may be beneficial for diagnosing renal function, monitoring the course of chronic kidney disease, and producing renal drugs nanotherapies ,561. In In the past, the overall mortality of chronic liver disease has steadily increased, causing a significant health and economic burden . The mosAlthough there is evidence that long-term observation of IONP-loaded cells is not reliable, several studies have shown that IONP-labeled cells allows safe monitoring during liver therapy . For insFunctionalized IONPs have also been shown to be advantageous for liver regeneration. Fibroblast growth factor 2 (FGF2) is known to possess antifibrotic effects and promote tissue regeneration in fibrotic diseases. Eftekhari et al. found that FGF2-IONPs improved early liver fibrogenesis in vivo in the acute carbon tetrachloride-induced liver injury mouse model in contrast to free FGF2 .One of the first approaches to generate in vivo-like 3D liver tissue using IONPs was in 2004 when Ito et al. used human aortic ECs loaded with cationic magnetite liposomes to form a magnetic-based accumulation of ECs on hepatocyte monolayers and thus a heterotypic, layered construct . This “mRepair and replacement of diseased bile ducts is another area of regenerative medicine. Li et al. described a method to create biocompatible artificial bile ducts by tissue engineering . A tubulDiabetes mellitus is a serious disease, characterized by abnormally elevated blood glucose levels due to a defect in insulin production or a reduction in insulin sensitivity and function . A promiLi et al. demonstrated the therapeutic efficacy of magnetically enhanced targeting of umbilical cord–Wharton’s jelly-derived MSCs loaded with polydopamine-coated IONPs in a clinically relevant rat model of streptozotocin-induced diabetes . MagnetiEspona-Noguera et al. followed a different approach in which IONP-loaded INS1E pseudoislets were encapsulated in alginate and alginate-poly-L-lysine-alginate (APA) microcapsules . Prior tOther studies investigated ways to reduce the loss of transplanted cells. Loading islet cells with IONPs functionalized with siRNA against caspase-3 decreased caspase-3 expression and cell apoptosis in pancreatic islets which were transplanted into the left kidney capsule of NOD-SCID mice or infused into diabetic baboons, thereby increasing the survival of the transplanted cells ,585.Due to the instant blood-mediated inflammatory responses (IBMIR), engraftment of a majority of the transplanted cells fails. By using anticoagulant heparin-conjugated IONPs, IBMIR could be attenuated and stable visualization of implanted islet cells could be obtained for more than 150 days without reduction of the MRI signal . PancreaCell therapy is also a promising method for the treatment of diseased or injured bladder or ureter, which can be monitored noninvasively by using IONPs. Lee et al. demonstrated that transplantation of magnetic NP-labeled B10 human MSCs into the bladder wall of rats with spinal cord injury inhibits bladder fibrosis and ameliorates bladder dysfunction  and Kim The use of external magnetic fields can significantly enhance the regenerative effect of IONP-loaded cells. A study by Sadahide et al. demonstrated improved repair of resected bladder tissue in rabbit models with damaged bladder by injection of IONPs-loaded MSCs and the presence of a directed external magnetic force than without a magnetic field or when using unlabeled MSCs . A potenBiocomposites may also be utilized for tissue engineering of bladder and urethral tissues. In one study, a minimally invasive approach was developed to treat SUI using an injectable bulking agent composed of ECM fragments of ASC sheets . The fraThe main causes of the penetration of dangerous pathogens, bleeding or postoperative wound complications are injuries or insufficient wound healing of the barrier function of affected surfaces, tissues or organs.Tissue adhesives represent one possibility for non-invasive wound closure . In the P. aeruginosa and S. aureus.Grumezescu et al. demonstrated the development, characterization and evaluation of an absorbable and antimicrobial wound dressing based on anionic polymers  and Fe₃O₄ nanoparticles loaded with usnic acid . The resThe magnetic properties of IONPs can also be exploited to achieve accelerated wound healing. Accelerated wound repair using IONPs functionalized with fibroblast growth factor bFGF and an external magnetic field (eMF) was shown by Wu et al.  The partIn addition to a wide variety of approaches to skin regeneration, there are also efforts toward skin tissue engineering . Zhang eSkeletal muscle repair requires tissue engineering strategies that incorporate scaffolds of biomaterials and cells capable of successfully restoring physiologically relevant functions . In addiThe in vivo distribution and migration of MSCs containing very small IONPs could be reliably observed by MRI after transplantation into the soleus muscle of rat model of open crush injury . In anotFabrication of well-organized structures remains a challenge in tissue engineering. In the study by Lee et al., a three-dimensional (3D) cell-dense tissue was fabricated from fiber bundles consisting of composite fibers of PLGA/IONPs using an electrospinning technique and then seeded with C2C12 myoblasts that differentiated into multinucleated myotubes . An applIn regenerative medicine, there are efforts to restore defective adipose tissue. In one work, hyaluronic-based magnetic nanospheres were prepared with covalently immobilized dexamethasone (Dex) as an adipogenic factor to induce adipogenesis for adipose regeneration . The delOne of the most common complications in spine surgery is epidural fibrosis, which results from destruction of epidural adipose tissue after laminectomy. ASC isolated from subcutaneous fat and a porous PLGA scaffold were used to form an engineered adipose tissue, which successfully led to the regeneration of epidural fat and prevented the formation of an epidural scar in a rabbit model of dorsal laminectomy . In addiWhite adipose tissue (WAT) is of great interest for tissue engineering and cell-based therapies because it is a rich source of differentiated adipocytes, stromal mesenchymal progenitors/ASCs, and ECs and infiltrating leukocytes. Tseng et al. and Daquinag et al. developed and used a three-dimensional (3D) levitation tissue culture system based on magnetic nanoparticles ,633. TheStem cells have been extensively studied in the field of regenerative medicine and can be effectively delivered to the target site by magnetic targeting to increase the number of cells and their retention and improve the effect of the delivered cells . Silva eOther pulmonary diseases, such as cystic fibrosis (CF) and tuberculosis (TB), can also benefit from NP-based diagnostic and treatments ,637,638.There are only limited reports about lung tissue engineering. In the study by Dzamukova et al., adenocarcinomic human alveolar epithelial cells (A549) and human skin fibroblasts were labeled with (poly)allyl amine-coated IONPs . A magneIn recent years, many advances in the development and use of nanomaterials for medical applications have been reported. The use of NPs is favored by their high modifiability, where the properties of the particles can be tailored exactly to the specific application by the selected manufacturing method, coating or/and functionalization. Besides the possibility of IONP-based visualization of scaffolds in the field of tissue engineering, IONPs can be adapted to any specific application where cellular effects are controlled by loading and delivery of bioactive agents. Especially in the field of cell therapy, there are countless possibilities to beneficially influence the therapeutic outcome, be it through non-invasive monitoring of IONP-labeled cells or through a positive effect of NPs on the differentiation and regeneration capacity of the administered cells. Thus, IONPs offer a wide range of potential applications.However, there are many challenges for successful translation to the clinic . FirstlyThus, to achieve translation to the clinic, the complete workflow from nanoparticle synthesis according to the current good manufacturing practice standards with accurate physicochemical characterization, to comprehensive in vitro and in vivo toxicological studies including biodistribution and efficacy studies must be performed . Hence,


Oxidative stress is likely to play a major contributing role, or at least a causal role, in the etiology and pathogenesis of neurological disorders. So far, limited therapeutic options are available for people with these debilitating disorders. Oxidative stress is caused by multiple factors, including aging, greater vulnerability of easily oxidizable unsaturated fatty acids in the brain, higher metabolic activity by the brain, increased production of mitochondrial-derived free radicals, calcium dyshomeostasis, and glutamate-induced excitotoxicity. Moreover, environmental chemicals/toxins, heavy metals, and an imbalanced diet can contribute significantly to the accumulation of oxidative stress, potentially leading to reduced cellular viability, cognitive decline, and eventually death. In this special topic, a series of articles review recent trends in the molecular mechanisms of oxidative stress in the development and progression of neurodegenerative disorders, and highlight previously undescribed potential therapeutic options.Arslan et al. systematically reviewed studies conducted on humans where several oxidative stress markers have been used as biomarkers in Alzheimer's disease (AD) at an early stage. The study found that non-invasive oxidative stress markers may be useful for the detection of MCI and AD, but are limited due to poor specificity and sensitivity. However, many of these markers may be used in combination with family history and other biochemical tests to detect the disease at an early stage. The study further showed that long-term use of selected vitamins and polyphenol-rich foods may be useful for managing AD pathology, although further work is needed to justify the use of natural antioxidants in clinic. Kandlur et al. reviewed the implications of age-associated oxidative damage on learning and memory and the molecular events, with special emphasis on associated epigenetic machinery. Increased understanding of these mechanisms may provide renewed insight in to the development of potential therapeutic targets within the oxidative system.Oxidative stress represents a major factor which promotes neuronal degeneration, resulting in a wide variety of disorders, including mild cognitive impairment (MCI), which usually progresses to dementia. Iqbal et al. further showed that, with increasing age, accumulation of metals was significantly associated with the tau and amyloid pathology. In addition, serum levels of various lipoproteins were associated with severity of MCI in a well-sized Pakistani population. Findings from this study can help in the translation of some commonly measured substances in serum levels to help in predicting the MCI. Hongo et al. explored carotenoid astaxanthin, mitigated memory deficits, and significantly reversed pathological hallmarks of AD, including Aβ42 deposition, pTau formation, GSH decline, and PV-positive neuronal deficits. In line with the clinical findings by Iqbal et al. elevated GSH levels may ameliorate pathological processes in the AD.The cross-sectional study by Kowalczyk et al., showed that Bergapten (furanocoumarin), a naturally occurring compound found in the Apiaceae family, could enhance memory performance against scopolamine-induced memory impairment. More specifically, the study demonstrated that Bergapten (both the single and repeated doses) increased memory acquisition and consolidation, suggesting its beneficial effects on multiple cognitive domains. Clinical translation of Bergapten is a promising approach to attenuate oxidative damage due to aging and age-related disorders.AD is characterized by progressive loss of basal forebrain cholinergic neurons and reduced cortical choline acetyltransferase activity is associated with cognitive decline. Most of the drugs available for the management of symptoms for AD are cholinergic modulators, and targeting the cholinergic system may be beneficial in neurocognitive disorders. The original research article by Ali et al. explored the neuroprotective effects of atorvastatin, cephalexin, and mycophenolate against NF-κB in ischemic stroke, as compared to the standard NF-κB inhibitor caffeic acid phenethyl ester (CAPE). The study demonstrated that these novels NF-κB inhibitors could attenuate ischemic stroke-induced neuronal toxicity by targeting NF-κB, a potential therapeutic approach in ischemic stroke, suggesting a frontier for emerging research. Furthermore, Ling et al. used a mouse model of middle cerebral artery occlusion to show that treatment with melatonin prior to ischemic injury could protect against neuroinflammation and oxidative stress and modulate the endogenously produced antioxidant enzyme, thioredoxin (Trx) pathway. These findings suggest that melatonin can represent a pharmacophore for the development of therapeutic strategies for enhancing recovery, prevention, and progression of ischemic injury.Stroke is the leading cause of morbidity and mortality worldwide and represents a major risk factor for dementia. More than 85% of the stroke cases are ischemic, which result in major loss in physiological activity of the brain, leading to complex pathophysiological events culminating in cognitive decline and death. Zhuang et al. demonstrated that hydrogen inhalation could protect against SAH-induced endothelial cell injury, BBB disruption, microthrombosis, and vasospasm in rats, and neurobehavioral effects at least in part by inhibition of activation of the ROS/NLRP3 axis. Liu H. et al. demonstrated that Bakuchiol, an analog of resveratrol, could protect against early brain injury following SAH by ameliorating BBB disruption, oxidative stress, and apoptosis via modulation of Trx1/TXNIP expression and the phosphorylation of AMPK. Taken together, hydrogen inhalation and naturally occurring compounds such as Bakuchiol represent promising therapeutic strategies for protection against brain injury after SAH.Subarachnoid hemorrhage (SAH) represents another cerebrovascular disease with significant detrimental effects on the brain and cognitive performance. SAH can lead to endothelial cell injury and blood-brain barrier (BBB) disruption. The original research article by Abdul Hannan et al. reviewed recent literature on the neuroprotective effects of phytochemicals that can co-activate cellular antioxidant defense and TrkB signaling-mediated cell survival systems. Yang et al. demonstrated that Catalpol (CAT), an iridoid glycoside compound, showed neuroprotective effects by attenuating microglial-mediated neuroinflammatory response through the inhibition of the p53-mediated Bcl-2/Bax/caspase-3 apoptosis pathway and regulating Keap1/Nrf2 pathway. These results collectively indicate the potential of CAT as a highly effective therapeutic agent for neuroinflammatory and neuro-oxidative disorders. In the original research article by Zhang et al., the authors used a cell culture system to demonstrate that the polyphenol Fisetin can protect against hyperglycemia-induced neurotoxicity through the PI3K/Akt/CREB pathway. Fisetin, which is abundant in fruits such as strawberries, grape seed, apple, and onion, can cross the BBB and demonstrated limited adverse effects. Liu P. et al. demonstrated that harmine, an analogous β-carboline alkaloid compound, ameliorated cognitive impairment by inhibiting NLRP3 inflammasome activation and enhancing the BDNF/TrkB signaling pathway in diabetic rats, and represents a potential therapeutic drug for diabetes-induced cognitive dysfunction. Dong et al. demonstrated that nicotine could protect against exposure hydrogen peroxide toxicity in vitro through the activation of the α7-nAChR/Erk1/2 signaling pathway, which suggests that nicotine usage may be a novel strategy for the treatment of neurodegenerative disorders associated with increased oxidative stress.In recent years, there has been a concerted effort to identify and develop potential drugs with multi-target and multi-pathway neuroprotective effects in the treatment of neurocognitive disorders. Dare et al. used a neurotoxicity model induced by Aβ in rats to demonstrate that physical and cognitive exercise could reverse recognition memory deficits, lower hippocampal lipid peroxidation, and maintain optimal acetylcholinesterase activity following exposure to pathophysiological concentrations of Aβ. This suggests that physical and cognitive exercises may partially reverse hippocampal tissue disorganization.Apart from pharmacological therapeutic strategies for the treatment of neurocognitive disorders, non-pharmacological strategies have been developed to improve brain plasticity and minimize the neurotoxicity effects of amyloid-beta (Aβ) peptide. The original research article by Taken together, the articles add to our recent work in the area of oxidative stress and neurodegenerative diseases. Collectively, they demonstrate that oxidative stress plays a central role in the pathobiology of neurodegenerative diseases and AD in particular. The articles are suggestive of the potential beneficial effects of antioxidant therapy for the prevention and treatment of neurodegenerative diseases. These findings are mostly from preclinical studies; further support from clinical data can authenticate the use of these agents.TA and NB wrote the manuscript and approved it. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Frontiers in Oral Health sheds light on recent research regarding the tumor-related angiogenesis in oral cancer, including the present challenges of anticancer therapy targeting angiogenesis. Indeed, angiogenesis is a hallmark of solid tumors and it has important prognostic and therapeutic implications in cancer patients. This issue covers different relevant topics ranging from characterizing angiogenic signaling pathways to newly suggested paradigms of tumor neoangiogenesis revealing new putative therapeutic targets.This special issue of Oral squamous cell carcinoma (OSCC) is a common cancer worldwide, and the incidence has been rising steadily. Of great concern is the growing proportion of younger patients without a history of smoking or alcohol abuse among OSCC patients. Currently, the primary treatment of OSCC patients comprises surgery and (chemo) radiotherapy, either alone or in combination. Other clinically approved approaches, such as targeted- and immuno-therapies, remain inconsistently applied as a first-line treatment for OSCC patients. Unfortunately, despite the advancement in cancer management, these treatments offer limited efficacy and the 5-year survival rate among OSCC patients is around 50–60% , 2.Angiogenesis is a key process in the tumorigenesis of solid cancers, promoting tumor growth, recurrence and metastasis. A large body of evidence suggested that targeting angiogenesis could provide a clinical benefit in the treatment of solid tumors . Thus, tSalem and Salo reviewed the vasculogenic (or vascular) mimicry (VM), a new paradigm of tumor cell-associated neovascularization that was introduced at the end of the previous millennium. VM describes the ability of certain aggressive tumors to initiate perfusable, matrix-rich, vessel-like networks in collagen-rich matrices in vitro and in vivo. This phenomenon has ignited a vibrant research interest and revealed promising prognostic and therapeutic implications. Further, it provides a possible explanation of the modest anti-angiogenic drug response in cancer patients. This review summarized the available knowledge regarding VM formation in HNSCC ranging from the characterization protocols to the prognostic value and limitations. Finally, the authors presented a potential novel mechanism of lymphatic metastasis in HNSCC—lymphatic mimicry (LM). Mirroring VM, this concept describes a process whereby tumor cells form mosaic vessel-like structures expressing tumor and lymphatic cell markers in OSCC tissues and in vitro. These LM structures influenced tumor cell invasion and metastasis and could provide avenues for developing anti-lymphangiogenic drugs in HNSCC [In spite of the promising results from some preclinical models, anti-angiogenic agents have revealed a considerable toxicity and limited clinical success in HNSCC patients . This coin HNSCC .Pang et al. showed that GT198, a protein inducing angiogenesis in OSCC, can be targeted by anticancer agents and herbs. Of interest, several clinically valid drugs inhibited the activity of GT198, including but not limited to mitoxantrone, doxorubicin and imatinib. A strong inhibition was further seen when applying certain anticancer herbs such as allspice, Gleditsia sinensis or honey locust. These findings could open an opportunity to identify potential antiangiogenic natural drugs with high efficacy and low toxicity for treating patients with oral cancer.In their research on medicinal natural compounds, Suzuki et al. studied an angiogenesis-associated pathway in salivary duct carcinoma (SDC), a cancer that can arise as a primary tumor (de novo) or from recurrent carcinoma ex-pleomorphic adenoma (Ca-ex-PA). Similar to the ductal breast carcinoma, SDC is characterized by an induced human epidermal growth factor receptor 2 (HER2) status. In the study included in this Research Topic, authors conducted immunostaining and dual color in situ hybridization of HER2  for patients with SDC, and analyzed the expression levels of 84 functional genes using PCR. Of note, significant differences in gene expression were found between Ca-ex-PA and de novo tumors. VEGF-A was significantly induced in the Ca-ex-PA, which can be a crucial factor in the malignant conversion to SDC through angiogenesis and the AKT/PI3K signaling pathway. Multiple machine learning methods confirmed that the prominent proangiogenic factor VEGF-A can be a candidate for differentiating Ca-ex-PA from de novo lesions.Although OSCC is the most common tumor type in the head and neck region, other less frequent, yet highly aggressive, tumors can also be encountered in the oral cavity. In this regard, Since oral cancer continues to constitute a substantial health and economic burden worldwide, we hope that this Research Topic will be informative to clinicians, researchers, and health care providers.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.