Reactive oxygen species (ROS) have physiological roles as second messengers, but can also exert detrimental modifications on DNA, proteins and lipids if resulting from enhanced generation or reduced antioxidant defense (oxidative stress). Venous thrombus (DVT) formation and resolution are influenced by ROS through modulation of the coagulation, fibrinolysis, proteolysis and the complement system, as well as the regulation of effector cells such as platelets, endothelial cells, erythrocytes, neutrophils, mast cells, monocytes and fibroblasts. Many conditions that carry an elevated risk of venous thrombosis, such as the Antiphospholipid Syndrome, have alterations in their redox homeostasis. Dietary and pharmacological antioxidants can modulate several important processes involved in DVT formation, but their overall effect is unknown and there are no recommendations regarding their use. The development of novel antioxidant treatments that aim to abrogate the formation of DVT or promote its resolution will depend on the identification of targets that enable ROS modulation confined to their site of interest in order to prevent off-target effects on physiological redox mechanisms. Subgroups of patients with increased systemic oxidative stress might benefit from unspecific antioxidant treatment, but more clinical studies are needed to bring clarity to this issue. Deep vein thrombosis (DVT) accounts for around 10 million cases of thrombosis per year and is the third most prevalent cardiovascular disease (CVD) after myocardial infarction and stroke. The incidence of DVT increases with age and its complications are ranked among the top causes of death and poor quality of life in western countries [Anticoagulation is the most common approach taken when treating DVT, but although these drugs inhibit thrombus propagation, they are associated with an increased risk of pathological bleeding such as stroke. Anticoagulants also have little effect on resolving existing thrombi, which occurs over time through a natural process of organization. Although enhanced natural thrombus resolution is associated with improved long-term outcome , interve2−) and hydrogen peroxide (H2O2), have physiological functions as second messengers in signalling pathways, while pathologic generation or decreased antioxidant scavenging of extra- and intracellular ROS (oxidative stress) lead to damage of proteins, lipids and DNA, resulting in modified functions of these molecules as well as dose-dependent programmed or unprogrammed cell death [2− into intra- or extracellular compartments [2O2. If H2O2 molecules encounter transition metals such as Fe2+ ions, they can be converted into highly reactive hydroxyl radicals . Certain intracellular ROS, such as superoxide , as welll death ), cyclooll death ), lipoxyll death ) and NADll death , Figure ll death . NOX enzartments . SuperoxReaction ), leadinReaction . SeveralReaction , catalasReaction , glutathReaction , heme oxReaction , thioredReaction ) and smaReaction , vitaminReaction ) are proReaction . These rThe development of a venous thrombus requires activation of the endothelium, platelets and sterile inflammation , stimulated by the interaction between at least two of Virchow’s triad of factors: reduced blood flow; endothelial disturbance; and the hypercoagulability of blood. This process leads to the activation of the coagulation cascade with the generation of large amounts of thrombin, converting fibrinogen to fibrin. Venous thrombi have a laminar structure consisting of layers of platelets, leukocytes and fibrin (‘lines of Zahn’) that encompass the main erythrocyte mass that is very different from the structure of arterial, platelet-rich, “white” thrombi and the amorphous clots of coagulated blood . LeukocyROS stimulates coagulation by increasing the expression of tissue factor (TF) in endothelial cells , monocyt-/-SOD mice, which is thought to be caused by reduced SOD1-mediated protein C activation and SOD1-mediated protection of TM [2O2) [ROS may favor a procoagulant state through oxidative modifications of proteins involved in coagulation. Tissue factor pathway inhibitor (TFPI), the only physiologic regulator of TF activity, can be inhibited by oxidative stress and exert a procoagulant effect . ROS canon of TM . ROS canon of TM , and redon of TM . The hepTM [2O2)  or lipidTM [2O2) . OxidizeTM [2O2) . EosinopTM [2O2) .There is increasing evidence that platelets have a role in the formation of venous thrombi , and chaROS affects the expression of P-selectin, the circulating levels of which are associated with an increased risk of venous thromboembolism (VTE) ,48, whicIntraplatelet ROS activates platelets by oxidizing arachidonic acid, thereby generating isoprostanes . PatientThe importance of ROS-mediated effects on platelet activation is evidenced by the diminished activation seen in the presence of antioxidants such as catalase , N-acetyThe essential involvement of NOX enzymes in platelet reactivity is evident from the impaired platelet activation in patients with X-linked chronic granulomatous disease (CGD), characterized by a lack of the NOX subunit gp91phox (NOX2) . SimilarThe formation of a venous thrombus is particularly dependent on sterile inflammation. One inflammatory mechanism, the release of extracellular traps (NETs), comprised of decondensed chromatin and DNA from activated neutrophils, that was originally thought to be limited to host defense in infection, is also of particular importance to DVT formation . The proMost pathways resulting in ET release involve signaling by ROS, generated by the phagocyte NADPH homologue, NOX2, which is present in both plasma and phagosome membranes . Many NO-/-PAD4 mice develop venous thrombi 48hr after IVC ligation, compared with 90% of wild-type mice [A mechanistic explanation of how ROS enables the initial steps of NETosis, involving intracellular membrane disintegration followed by enzymatic chromatin decondensation, is the ROS-dependent translocation of neutrophil elastase (NE) and myeloperoxidase (MPO) from cytoplasmic azurophilic granules to the nucleus. NE cleaves nucleosomal histones and promotes chromatin decondensation, whereas MPO aids in chromatin decondensation during later stages . Chromatype mice .Taken together, the evidence suggests that signaling involved in NETosis requires ROS as second messengers, but also that NETosis may deploy ROS to mediate its extracellular functions. For example, MPO, an ROS-generating enzyme, is among the molecules extruded with NETs. Contrary to this, however, a recent study shows that MPO inhibits phospholipid-dependent coagulation , while a2+ containing hemoglobin (Hb) to Fe3+-containing methemoglobin. The release of Fe3+ triggers a chain reaction, resulting in further erythrocyte lysis, oxidative stress and thrombus formation [Erythrocytes are the main cellular constituent of venous thrombi. Although they are not thought to be major active contributors to DVT formation, some studies suggest that they contribute in a more passive way via oxidative mechanisms. Erythrocytes are enriched in iron as they contain a high amount of the oxygen-transport protein hemoglobin. Increased oxidative stress, as encountered at the sites of venous thrombi, is able to oxidize Feormation . Hemogloormation . Endogenormation , while tormation . Extraceormation , as wellormation , both oformation .Erythrocytes therefore appear to use oxidative mechanisms to passively promote DVT formation once the process has already started and they are entrapped within the growing thrombus. The degree to which this process is relevant remains unclear, however, as studies suggesting this mechanism were based on in vitro findings , performMast cells (MCs) represent another sterile inflammation mediator that belongs to the innate immune system and has granules that contain both proinflammatory cytokines such as TNF-α and histamine, as well as antithrombotic factors, such as tissue plasminogen activator (tPA) and heparin . MCs can2O2 mediates the increased susceptibility to DVT in aged mice, whereas overexpression of glutathione peroxidase-1 is protective in mice [It is generally accepted that MCs generate ROS and can be activated by ROS ,91. The  in mice . NOX2 is in mice  and ROS  in mice .The complement system exerts its effects through an enzymatic cascade similar to the coagulation cascade, with many interactions between these two processes that confer prothrombotic capabilities to this system. High levels of the C3 fragment are associated with a high risk of DVT in man , while tCalcium is an essential component of the human diet and is required for the activity of many enzymes, including those involved in processes related to DVT. Many of these calcium-based signaling systems interact with redox signaling pathways. These interactions are bidirectional, with calcium channels on plasma and organellar membranes regulated by oxidative modifications ,99,100, Platelet activation, for instance, relies on cytoplasmic calcium surges. These calcium surges occur mainly through store-operated calcium entry (SOCE), where calcium is first released from intracellular stores, followed by entry through the plasma membrane. In SOCE, the initial calcium release from intracellular stores is mediated by the stromal interaction molecule 1 (STIM1) protein, while the following calcium influx from the extracellular space is mediated by the plasma membrane channel Orai1 . Both ofSTIM1, Orai1 and TRPC6 are also involved in angiogenesis, a process important for thrombus resolution, as outlined later in this article . Calcium–ROS interplay is also important for processes by which leukocytes might contribute to DVT formation. In neutrophils, for instance, NOX2 is essential for neutrophils’ role in DVT formation. Activation of this enzyme in neutrophils relies on a calcium signaling pathway . In mastIt is well known that rapid natural thrombus resolution is associated with improved long-term outcome . CurrentVenous Thrombus resolution is a process of tissue organization and remodeling that resembles the processes that take place during normal wound healing. It requires the concerted action of the following processes: fibrinolysis; proteolysis; inflammation; and angiogenesis. In the early stage of resolution, a gradual process of remodeling replaces the fragile erythrocyte- and fibrin-rich matrix of the thrombus with collagen and other extracellular matrix proteins . AngiogeTissue-type and urokinase-type plasminogen activators (tPA and uPA) are found within mononuclear cells that accumulate in experimental venous thrombi ,107. It ROS are intimately involved in the regulation of the fibrinolytic system. Early in vitro studies have shown that oxidation reduces the ability of fibrinogen to activate tPA  and thatThere are, however, conflicting reports showing that ROS are capable of stimulating fibrinolysis by inactivating PAI in vitro  and may The fibrinolytic system can be modulated by ROS in a variety of ways. The conflicting observations regarding the direction of this modulation imply a complex regulation that is dependent on the cell type, stimulus and whether ROS mediate their effects as part of specific second messengers or as part of unspecific oxidative stress.Venous thrombi are quickly invaded by circulating leukocytes, and animal models have shown that thrombus resolution is impaired when the early neutrophil  or late ROS can directly act as chemoattractants for neutrophils in vitro and in vivo ,125 and 2O2 potently inhibits nuclear translocation of NF-κB, which induces the expression of proinflammatory cytokines such as IL-8, suggesting that extracellular oxidative stress reduces IL-8 production [IL-8 is a chemokine produced by endothelial cells, monocytes and neutrophils, and it recruits neutrophils and, to a lesser extent, monocytes. Increased circulating levels of IL-8 are associated with an increased risk of recurrent DVT , while ioduction . Contraroduction  and IgE-oduction  human neoduction . The conoduction , while ioduction . Besidesoduction . To whatMonocyte chemotactic protein-1 (MCP-1) is expressed by various vascular cells such as endothelial cells, VSMCs, fibroblasts, monocytes and macrophages . MCP-1 mAngiogenic stimuli drive the formation of neovascular channels within the thrombus and vessel wall during resolution. The importance of this process for resolution is evident from studies that have shown that overexpression and inhibition of the most potent angiogenic factor, VEGF, enhances and impairs thrombus resolution, respectively ,146. It 2 levels are only 10% of that in circulating venous blood. This relative hypoxia is associated with increased levels of HIF-1 and angiogenic factors within the thrombus [Within a newly formed venous thrombus, pOthrombus . Hypoxiathrombus . The maithrombus ,150. Thethrombus . Thrombithrombus . Thrombithrombus . Consistthrombus ,154,155.The purpose of thrombus resolution is to restore lumen patency and, hence, vessel function. The exacerbation or impairment of mechanisms within this ‘intravascular wound healing’ process can lead to chronic, fibrotic thrombi and vein walls, causing persistent impediment to blood flow and vessel dysfunction, respectively.During the early resolution process, the fragile erythrocyte- and fibrin-rich thrombus is replaced by collagen and, depending on the balance between profibrotic signals and degradative protease activity, the thrombus and vein wall may become fibrotic, as evidenced by the association seen between impaired thrombus resolution and elevated collagen deposition ,128. LeuTGF-β1-mediated fibroblast activation and the subsequent fibrotic response was shown to depend on NOX4-derived ROS in the lung . ConsistThese profibrotic mechanisms are counteracted by processes that drive the degradation of the ECM. Elastinolysis is believed to occur early and to be responsible for increased vein wall stiffness during the resolution process . SimilarThere is extensive evidence to suggest that ROS modulate both MMP gene expression and MMP activation . ExtraceA number of conditions increase the risk for DVT and the mechanisms regulating many of these have been identified to involve dysregulated ROS levels. An example of this is Antiphospholipid Syndrome (APS). Venous and arterial thrombi are major manifestations of this condition and endosomal redox signaling has been identified as an important pathophysiological mechanism driving thrombus formation . The forBehçet’s disease is another autoimmune disorder with an increased risk for developing venous thrombosis. A recent study of 98 Behçet’s disease patients has shown that thrombus formation was promoted by oxidatively altered fibrinogen, which was associated with neutrophil activation and enhanced NOX-dependent ROS production . Increased risk of DVT has also been reported for exposure to air pollution  and a reOxidative stress is associated with conditions that result from lifestyles common in western countries. One of these is Metabolic Syndrome, which is positively associated with the risk of venous thrombosis . The oxiChronic stress is another lifestyle factor that is positively associated with ROS levels . ChronicDVT rates increase with age and this is thought to involve oxidative stress as aging-related venous thrombosis in mice is promoted by the redox sensor, mTORC1, via the elevation of platelet reactivity, an effect that is reduced by antioxidant therapy with NAC . NAC hadAge-related prothrombotic effects also involve the down-regulation of the protective NO pathway and upregulation of the NOX- and COXs-dependent oxidative stress pathway, promoting TF expression and activity in endothelial cells . Age-depVarious nutritional factors and drugs are known to have antioxidant functions. While evidence exists that they influence various distinct processes important for DVT formation, their overall effect on DVT has yet to be established. The antioxidant effects of vitamins A, C and E for instance are well known . VitaminIn hemodialysis, the extracorporeal circuit leads to activation of the clotting cascade, which is associated with increased ROS generation and reduced antioxidant mechanisms . The useBeer contains a nutritional antioxidant, xanthohumol, for which a direct beneficial effect for the development of DVT has been shown. Xanthohumol, present in hops that are used in beer making, prevents both arterial and venous thrombosis in mice by decreasing ROS accumulation and inhibiting platelet activation without increased bleeding risk . ModeratThe beneficial effects of statins in cardiovascular disease are mainly attributed to their lipid lowering effects, but there is extensive evidence to suggest that they have pleiotropic effects in regulating disease. Statins decrease oxidative stress and platelet activation in hypercholesterolemic patients by an early and late mechanism. The early effect is dependent on the direct inhibition of platelet NOX2 and independent of any lipid lowering effect, while the late effect is associated with LDL lowering including the platelet-activating molecule, ox-LDL ,210. TheMost of these drugs have already been evaluated for their benefit in DVT patients, but there are also other antioxidant drugs that are used in other fields of medicine. Modified versions and dosages of these drugs could be repurposed for use in thrombotic diseases. Thioredoxin (TRX) inhibitors, for example, are currently under investigation in clinical trials for diseases involving an imbalance in the NADPH/thioredoxin reductase/thioredoxin system, such as cancer. TRX inhibitors also attenuate platelet function and thrombus formation, which could lead to their being repurposed as antiplatelet agents . The oraDrugs with pro-oxidant properties, such as the anticancer, estrogen-receptor-blocker tamoxifen, might negatively impact processes related to DVT. Platelet activation through tamoxifen-mediated NOX upregulation has previously been suggested to be causally involved in the increased risk of venous thrombosis in breast cancer patients treated with tamoxifen .ROS are involved in the regulation of all of the major processes that promote the formation of venous thrombi. These include coagulation; platelet reactivity; and sterile inflammation (for example NETosis) during formation. Oxidative stress also appears to favor the ‘intravascular wound healing’ processes that control the remodeling of a venous thrombus and adjacent vein wall including fibrinolysis; sterile inflammation (monocyte accumulation); extracellular matrix deposition and its remodeling; and neovascularization. Dysregulated redox control is a common feature of conditions with an elevated risk of venous thrombosis, and therefore restoring oxidative balance might represent a possible therapeutic option in some of these patients. However, the ubiquitous deployment of ROS in the regulation of both physiological and pathophysiological redox regulatory mechanisms poses challenges in determining which redox pathways can be targeted for therapeutic benefit without affecting normal hemostasis.


Heart failure is the terminal outcome of the majority of cardiovascular diseases, which lacks specific diagnostic biomarkers and therapeutic targets. It contributes to most of cardiovascular hospitalizations and death despite of the current therapy. Therefore, it is important to explore potential molecules improving the diagnosis and treatment of heart failure. MicroRNAs (miRNAs) are small non-coding RNAs that have been reported to be involved in regulating processes of heart failure. After the discovery of miRNAs in exosomes, the subcellular distribution analysis of miRNAs is raising researchers' attention. Growing evidence demonstrates that exosomal miRNAs may be promising diagnostic and therapeutic molecules for heart failure. This review summarizes the role of exosomal miRNAs in heart failure in the prospect of molecular and clinical researches. Heart failure is the terminal stage of various CVDs, with sustaining high morbidity and mortality contributing most to cardiac death . DespiteMicroRNAs (miRNAs) are small non-coding RNAs that have been discovered for over two decades. MiRNAs mainly function as negative regulators of post-transcription of gene expressions through hybridization of 3′ untranslated regions (3′UTRs) or open reading frames (ORFs) of the targeted mRNAs. Although they don't encode any protein, they are widely involved in the modulation of various genes at post-transcription level and thereby impacting various biological processes such as autophagy, oxidative stress and so on –5. ExosoMiRNAs distribute widely in cellular components, and recent studies revealed that miRNAs also exist in exosomes  . FurtherExosomal miRNAs are important biological products in exosomes, which are widely involved in information transmission between cells. It is worth noting that miRNAs do not enter exosomes randomly, but specific miRNAs are selectively entered into exosomes. Mature miRNA enters exosomes through four ways: (1) the miRISC related pathway; (2) sphyngomyelinase 2 dependent pathway; (3) heterogeneous nuclear ribonucleoproteins dependent pathway; (4) 3′miRNA sequence-dependent pathway. These are important ways for exosomal miRNAs to achieve directional information exchange between cells. Exosomal miRNAs participate in a variety of basic cell functions through paracrine or endocrine mechanisms, including cell proliferation, apoptosis, cytokine production, immune regulation and metastasis , 11. UndIn the cardiovascular field, exosomal miRNAs normally play the role as cardiovascular cells communicators. Almost all kinds of cardiovascular cells are proved to release and receive exosomal miRNAs, indicating their potential regulatory roles in CVDs. Cardiomyocytes and fibroblasts, the most prevalent cell types in the heart, are the main source of exosomal miRNAs. Other than that, ECs and macrophages are also proved to release exosomal miRNAs in different CVDs . DependiHeart failure is the terminal stage of almost all cardiovascular disorders mentioned above. It is characterized by a series of pathological processes including cardiomyocyte hypertrophy, cardiac fibrosis, impaired myocardial angiogenesis. Owing to the unique traits of exosomal miRNAs, investigating how they affect the pathogenesis of heart failure is meaningful.A series of miRNAs have been demonstrated to modulate the pathogenesis of cardiac hypertrophy which is the key mechanism of heart failure. MiR-199a targets the glycogen synthase kinase 3β (GSK3β)/mammalian target of rapamycin (mTOR) complex signaling pathway to impair cardiomyocyte autophagy and thereby enhancing cardiac hypertrophy (miR-199a impairs autophagy and induces cardiac hypertrophy through mTOR activation). In the model of heart failure, cardiac-specific overexpression of miR-221 significantly deteriorates cardiac function and promotes heart failure and mTOR axis-related autophagy . Howeverin vitro, suggesting that exosomal miR-217 was not only a potent marker but a promising therapeutic target for chronic heart failure  Com failure .Exosomal miRNAs are involved in the regulation of cardiac hypertrophy due to various etiology. However, based on the current evidences, the defined role of exosomal miRNAs in cardiac hypertrophy differs across disease settings and the sources, not to mention the miscellaneous mechanisms involved. We still lack further research illustrating how exosomes ensure the specificity for certain miRNAs targeting at specific cell types.Cardiac fibrosis, characterized by ECM degradation and accumulation of collagen due to proliferation of cardiac fibroblasts, is another important mechanism of heart failure. MiRNAs have been reported to regulate cardiac fibrosis. For example, miR-19a-3p and miR-19b-3p targeted TGF-β to inhibit epithelial-mesenchymal transition, ECM production and the invasion of human cardiac fibroblasts, thereby exhibiting the anti-fibroblast effect . More liMechanically, exosomal miRNAs from diverse sources participate in the regulation of different parts of cardiac fibrosis Besides of the pathologic changes in heart tissue, aberrant angiogenesis contributes to the acceleration from compensated cardiac hypertrophy to heart failure due to decreasing capillary angiogenesis and cardiomyocyte energy supply . ECs proExo-miR-21-5-p from healthy hearts inhibited PTEN and BCL2 in cardiomyocytes and ECs and activated the AKT and VEGF pathways to promote cardiomyocyte proliferation and promote angiogenesis . ExosomeThe exploration of new biomarkers of heart failure is critical for the diagnosis and treatment of heart failure. BNP and NT-proBNP are widely used in the clinical diagnosis of heart failure. Some newly found biomarkers such as ST2 and NGAL also become to be used in clinical. However, in the case of combination with some other pathological conditions, such as pulmonary embolism and renal dysfunction, the specificity of the biomarkers mentioned above could be compromised.A variety of miRNAs in circulation are involved in pathogenesis or protection of heart failure in a dynamic and stage-specific way and therefore they are potential biomarkers of heart failure. Circulating miR-23a, miR-23b, miR-24, miR-195, and miR-214 were found increased and circulating miR-423-5p, miR-320, and miR-22 were found decreased in chronic heart failure , 48. As However, none of the studies above analyzed the circulating components, especially exosome fraction and non-exosome supernatant. Wang et al. discovered that miR-425 and miR-744 expressions were altered in plasma exosome samples in heart failure patients. A further functional study proved that they negatively regulated cardiac fibrosis by suppressing TGFβ1 expression, revealing their potential role in regulating and predicting heart failure . HoweverThe stem cell-based therapies are becoming potential therapeutic strategies in many diseases and their influences radiate to heart failure, whereas the low efficiency of engraftment and potential tumorigenic risk of stem cell transplantation limits their prevalence. However, the emerging value of stem cell-derived exosomes which might improve the efficiency of stem cell transplantation motivates the further exploration of stem cell-based therapies in heart failure. Exosomes derived from different kinds of stem cells, such as ESCs, iPSCs CPCs and MSCs, have been proved to exert no less protective properties but safer in operation than stem cell transplantation . As one The types and levels of miRNAs in exosomes in the circulatory system are more closely related to heart failure compared to free miRNAs. Other than free miRNAs, their level changes may be related to the severity of heart failure. So, they can provide a more sensitive and specific diagnostic method for heart failure. However, there is evidence that no differential expression of exosomal miRNAs and free miRNAs in the circulation was detected between patients with chronic heart failure and the controls. Therefore, whether circulating exosomes miRNAs can be used as biomarkers for the diagnosis and prognosis of heart failure is still questionable. We need studies with larger number of patients and the kinds of miRNAs to determine: whether there are significant changes in the levels of circulating exosomal miRNA after heart failure, whether there is a correlation between these changes and the pathophysiological changes in heart failure, whether the sensitivity and specificity of these new diagnostic methods are better than those currently used in clinical practice.Heart failure may affect circulating exosomal miRNAs, and exosomes derived from stem cells can also play an important role in heart failure. They may serve as a new strategy for treating or preventing heart failure in the future. However, this new strategy is in its infancy. There are still several hurdles before achieving clinical application : First oRX, ZX, PH, and WT wrote the manuscript. YW drew the figure. JH, CL, and YD 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.


This study reports a case of pterygium-like proliferation containing postoperative limbal dermoid remnants and its clinicopathological features.A 79-year-old Japanese woman, with a history of congenital limbal dermoid resection at age 12, presented with a pterygium-like tissue growth in the left eye. Its temporal location and marked thickness with abundant fatty droplets were atypical of primary pterygium. We performed pterygium surgery and ocular surface reconstruction. Pathological findings included squamous metaplasia, neovessels, and elastic degeneration, as well as prominent subepithelial and stromal accumulation of collagen fibers, adipose tissue formation, and presence of a peripheral nerve corresponded with the frequent findings of limbal dermoid. Ki67, a marker for cell proliferation, was immunopositive in pterygial epithelial cells and neovascular endothelial cells, but not in dermoid components.Although the pathological finding of degenerative elastic fibers indicated the common feature of ultraviolet-induced pterygium, clinical appearances were atypical possibly due to modification with dermoid remnants. Pterygium is a triangular fibrovascular proliferation that usually extends from the nasal conjunctiva and encroaches upon the cornea. Histopathologically, primary pterygium is characterized by epithelial proliferation, epithelial-mesenchymal transition, and an activated fibroblastic stroma with inflammation, neovascularization, and matrix remodeling . We demoLimbal dermoid is a congenital benign tumor that presents in a dome shape and consists of various tissues of ectodermal and mesodermal origins . Cases oA 79-year-old Japanese woman complained of blurred vision in her left eye presumably due to a pterygium-like tissue growth. She had a medical history of limbal dermoid from birth, which was removed at 12 years of age. Her decimal best-corrected visual acuity (BCVA) was 1.2 oculus dexter and 0.5 oculus sinister (OS) with hyperopia. Slit-lamp microscopy revealed a markedly thick growth of pterygium-like triangular ocular surface tissue from the temporal conjunctiva toward the apex of the cornea. Corneal opacity was observed around the head of the tissue OS (Fig. The head of the excised tissue was histologically covered with stratified columnar epithelium mixed with goblet cells and squamous metaplasia Fig. f or the In the present case of pterygium-like proliferation, its temporal location and marked thickness with abundant adipose droplets were atypical of primary pterygium. However, the pathological findings of this case included the presence of goblet cells in the epithelial region with squamous metaplasia, subepithelial neovascularization, and elastic degeneration, all of which were typically found in primary pterygium. In contrast, the other pathological findings such as prominent subepithelial and stromal accumulation of collagen fibers, adipose tissue formation, and presence of a peripheral nerve were considered characteristic as limbal dermoid but not pterygium.Although the pathological finding of degenerative elastic fibers, typically found in primary pterygia, was theorized to reflect chronic ultraviolet exposure, the clinical findings were atypical possibly due to modification with postoperative dermoid remnants. Immunohistochemistry for Ki67 further confirmed the presence of proliferating cells in the pterygial epithelium and neovessels, but not in dermoid components. In consistence with the widely recognized non-proliferating nature of congenital limbal dermoid, the currently observed postoperative remnants showed no proliferative tendency even under the biological environment in which pterygium developed with massive cell proliferation.In conclusion, the development of the present case would thus be attributable to the etiology common to primary pterygium but modified to some extent by non-proliferative residual dermoid tissue.


The term “antimicrobial peptides” (AMPs) classically refers to naturally occurring molecules that are made by most living organisms as key components of innate immunity that help shape the composition of colonizing micrbiota and provide a first line of defense against invading microbial pathogens. Although AMPS have diverse primary sequences, they are typically small in size, positively-charged, amphipathic, and contain α-helix and/or β-sheet rich structures often stabilized by disulfide bonds. AMPs can be constitutively expressed or induced by infectious or inflammatory stimuli, including proinflammatory cytokines and pathogen-associated molecular patterns. Since their discovery over a half century ago, research into AMPs has primarily focused on their direct antimicrobial activity, leading to them being touted as a promising molecular resource to tackle infectious diseases and antibiotic resistance. However, the direct microbicidal function of many AMPs may be limited under physiological and pathological conditions, due to a number of issues such as low local peptide concentration, suboptimal ion concentrations, physiological polyanions  and proteolytic degradation. More recently, a growing body of evidence suggests the biology and immunology of AMPs extends beyond the classical direct antimicrobial property. To highlight the multi-functionality and complexity of AMPs, in this Research Topic, we assembled a collection of original research and review articles that encompass recent advances in AMP research, with a particular emphasis on their alternative physiological and pathological functions. In doing so, we adopted a broader and more comprehensive term, “host defense peptides” (HDPs). New strategies to leverage HDPs for therapeutic uses, through exploitations of their multifaceted activities, are also highlighted.in vivo, under conditions that are often unfavorable for their direct antimicrobial actions, suggests that their immunomodulatory activities might be attributed to other functions. Indeed, HDPs have now been shown as potent immune effectors via multifunctional and multimodal orchestration of immune responses, including leukocyte chemotaxis, cytokine induction, angiogenesis and phagocytosis, modulation of leukocyte development and survival, as well as neutralization of pathogen-associated molecular patterns (PAMPs). HDPs also provide a link between innate and adaptive immunity by mediating chemotactic recruitment of antigen presenting cells and T lymphocytes, stimulating maturation of dendritic cell (iDC) maturation, and providing adjuvant-like functions. For example, proinflammatory HDPs, including iron-sequestering lipocalin 2 (Lcn2) can amplify antimicrobial responses to enhance pathogen killing and clearance. Lcn2-deficient mice, which result in reduced neutrophil recruitment and impaired cytokine production in macrophages, are more susceptible to Escherichia coli infections . In contrast, Koeninger et al. demonstrated for the first time that systemically administered human β-defensin 2  suppresses inflammation induced by bacterial PAMPs including lipopolysaccharides (LPS), and in experimental colitis mouse models through chemokine receptor 2 (CCR2) targeting. The anti-inflammatory functions of HBD-2, and likely other HDPs, are required for controlling bacteria killing-associated inflammation and maintaining immune homeostasis, thus limiting unwanted inflammation-induced tissue damage. Similarly, cathelicidins attenuate LPS-induced Toll-like receptor-dependent inflammation through direct LPS-cathelicidin interaction. However, they can also bind to and stabilize bacterial DNAs and RNAs, promoting nucleic acid-sensing TLR activation. In their review, Scheenstra et al. provided a comprehensive discussion of these contrasting cathelicidin-mediated TLR modulations in reducing pathogen burdens during infection and resolving excessive inflammatory responses. From these articles, we can appreciate that it is not always straightforward to classify HDPs as either pro-inflammatory or anti-inflammatory. Instead, it may be appropriate to define them as inflammation regulatory molecules that balance host inflammatory responses and sustain immune homeostasis.The ability of HDPs to mediate protection against microbial infection Coates et al.). To this end, colonic HDPs  form an interactive network, as proposed by Blyth et al. and function synergistically and multimodally to prevent enteropathogenic colonization. Puértolas-Balint and Schroeder reviewed the complex interactions between diet, commensal microbiota and HDPs in gut homeostasis and diet-associated inflammatory diseases. They document that nutrient-sensing signaling mediators are involved in diet-associated modulation of HDPs, while immune mediators and effectors shape microbe-dependent HDP regulation. Furthermore, intestinal HDPs display unique mechanisms of action and spectrum of activity to regulate microbiota composition, evidently beyond direct antimicrobial activity. Of note, HDP-mediated control of gut microbiota is dependent on localization and the specific regulatory mechanisms of expression and activation. In support of this, in their original study, Nakamura et al. showed that Paneth cell-secreted α-defensins are topographically regulated from duodenum to ileum. Their findings of ex-germ free-dependent regulation of α defensins also suggest that the intestinal microbiota may partially affect HDP activity. Nevertheless, it remains to be determined precisely how microbes and certain dietary components can signal to the epithelium and mediate HDP function, as well as how HDPs mechanistically modulate gut microbiota through immunomodulation. Beyond human epithelial barrier, Le Bloa et al. discovered type IIa crustin, as a novel HDP in the deep-sea shrimp Rimicaris exoculate. This investigation uncovered an expression pattern of type IIa crustin that is spatio-temporally correlated with ectosymbiotic colonization through different life stages. These findings further signify the importance of HDPs in the establishment of vital and heathy host-symbiotic microbiota through their multifaceted functions.Beyond their involvement in innate defense against pathogens, recent studies have uncovered the importance of HDPs in tissue homeostasis, dictated not only by their canonical antimicrobial function but also by their immunomodulatory properties. Notably, within protective epithelial barriers, it is clear that HDPs are critical, not only in defending against pathogenic pathogens, but also in regulating commensal microbiota as well. This microbiota balance within epithelial tissues is key for heathy epithelial homeostasis and immunity . These review articles collectively provide a thorough overview of HDPs' functions in pathology and converge to highlight the “double-edge sword” nature of HDP-mediated immunomodulatory responses. Of note, Lee et al. highlighted the unexpected similarities between Aβ amyloid aggregates and HDP protofibrils, hence posing new perspectives for HDP-associated pathogenesis. Intriguingly, by using ecogenetic analyses, Hanson et al. described an independent loss of immunologically costly and deleterious HDPs, such as diptericin, in true fly lineages in the absence of microbial challenges. The complexity of HDP-associated pathogenesis is further complicated by the heterogeneity of HDP (dys)regulation. In an original research contribution, Hemshekhar et al. showed that murine cathelicidin (CRAMP) and calprotectin (S100A8 and S100A9) are differentially regulated in the local tissues  in two immunopathologically-related mouse models of inflammatory arthritis and airway inflammation. Together, these reviews and research studies highlight that host immunity needs to strike a delicate balance in HDP regulation, to mediate an antimicrobial defense response on the one hand, whilst avoiding HDP-induced pathological perturbance on the other.As our understanding of molecular and cellular mechanisms underpinning HDP immunomodulation improves, the roles of HDPs in various diseases and chronic inflammatory conditions are drawing an important focus. This Research Topic features several reviews on the multitude of pathological outcomes associated with dysregulation of cathelicidins and defensins, including skin disorders , inflammatory bowel diseases , autoimmune diseases, lung disorders , and tumorigenesis , fungal infection (Mercer and O'Neil), and cancer (Xu and Lu) to autoimmune disorders (Liang and Diana) and chronic inflammatory diseases . The broad-spectrum antimicrobial effects of HDPs have long-inspired the development of these peptides for treatment of infectious diseases. In addition, their actions on bacterial biofilms may benefit rational engineering and designs to tackle the biofilm-associated resistance against host immunity and antibiotics. For instance, Parducho et al. reported the antibiofilm activity of HBD-2 against Pseudomonas aeruginosa and Acinetobacter baumannii, is independent of biofilm regulatory pathways and instead mediated via induced alteration of biofilm integrity. It should also be noted that in the non-infection settings, the immunomodulatory functions of HDPs can also potentially be exploited to restore the balance to dysregulated immune responses that contribute to disease pathologies.Insights into HDP mechanisms and functions have opened new and exciting therapeutic avenues, and have provided novel platforms for therapeutic design. In this Research Topic, potential clinical uses for HDPs are extensively discussed in various disease conditions, ranging from multidrug-resistant bacterial infection , but also expand the HDP arsenal for therapeutic exploitation.However, there are several challenging obstacles for HDP applications, notably their potential toxicity, proteolytic instability, salt intolerance and low Together, the papers in this collection highlight and add new knowledge on the multifaceted function and importance of HDPs in contributing to the shape and complex nature of host immunity, as well as in regulating health and mediating disease progression. As our knowledge of HDP biology expands, the repertoire of HDP functions, particularly direct antimicrobial activity and immunomodulation, demonstratively opens the door for novel therapeutic development for treating infectious diseases, as well as inflammatory conditions. Nevertheless, while the classical microbicidal property of HDPs has been extensively studied, the research journey has only just begun for their non-antimicrobial properties. Forsaking the classical term “antimicrobial peptides” and embracing “host defense peptides” can not only properly acknowledge the multi-functionality and complexity of HDPs, but may also imprint the currently underexplored activity landscapes and enshrouded therapeutic potential of HDPs. We would like to take this opportunity to thank the authors for their invaluable contributions to this Research Topics, as well as all the reviewers for their time and constructive inputs.TKP wrote the manuscript. CB and MH critically revised and approved the final version of the manuscript. All authors conceived the outline of the manuscript.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.


The epithelial to mesenchymal transition (EMT) is an evolutionarily conserved process. In cancer, EMT can activate biochemical changes in tumor cells that enable the destruction of the cellular polarity, leading to the acquisition of invasive capabilities. EMT regulation can be triggered by intrinsic and extrinsic signaling, allowing the tumor to adapt to the microenvironment demand in the different stages of tumor progression. In concomitance, tumor cells undergoing EMT actively interact with the surrounding tumor microenvironment (TME) constituted by cell components and extracellular matrix as well as cell secretome elements. As a result, the TME is in turn modulated by the EMT process toward an aggressive behavior. The current review presents the intrinsic and extrinsic modulators of EMT and their relationship with the TME, focusing on the non-cell-derived components, such as secreted metabolites, extracellular matrix, as well as extracellular vesicles. Moreover, we explore how these modulators can be suitable targets for anticancer therapy and personalized medicine. Epithelial to mesenchymal transition (EMT) has been described as an evolutionarily conserved process, where polarized epithelial cells undergo phenotypical changes and assume a motile migrating mesenchymal cell phenotype . Such prin vitro and to be tumorigenic in vivo  to acquire a more mesenchymal phenotype, presenting increased migratory and invasiveness capacity, apoptosis resistance, and enhanced extracellular matrix (ECM) secretion , 8. More in vivo .The regulation of EMT is a complex process and can be triggered by different components present in the tumor microenvironment (TME) like inflammation, hypoxia, and secreted bioactive molecules . In partIn this review, we summarize the more relevant intrinsic and extrinsic signals affecting metabolic reprogramming and EMT process in cancer cells. Moreover, we dissect the complex interaction between tumor cells and the surrounding TME components and how they can be modulated by the EMT process toward tumor progression and metastasis.During primary and then metastatic neoplastic transformation, tumor cells have to adapt their metabolism according to environmental changes . Recentlin vitro and in vivo, which is essential for EMT  and stearoyl-CoA desaturase (SCD) activates EMT, increasing migration, invasion, and colony formation . From thin vivo breast cancer model induces the alteration of Twist Family BHLH Transcription Factor 1 (Twist1) and E-cadherin expression only at the metastasis site, which indicates an impaired EMT behavior , and its partner, the transcriptional coactivator with PDZ-binding motif (TAZ) , 60. WanDownregulation of Hippo pathway components has been observed in various human cancers and strongly correlated with EMT and aggressiveness . MorvariToday, it is well-known that TME consists of different stromal players, which coevolve with cancer cells and contribute to cancer progression and metastasis: fibroblast , immune in vivo . TAMs are macrophages that are recruited at the tumor site by tumor-derived chemokines and acquired a tumor-promoting effect . In thisd Segall  demonstrd Segall .via monocarboxylate transporter 4 (MCT4) that is upregulated under hypoxia  activates Wnt and TGFβ signaling pathways and intensifies HCC progression , as well as the acquisition of a cell migratory behavior  and non-structural secreted enzymes . Initially considered as an amorphous scaffold upon which cells are organized, in the past years, ECM has been proposed as a crucial player in tumor progression and diffusion. The involvement of ECM in EMT was anticipated by the seminal paper of Greenburg and Hay . They suin vivo . From thin vivo . In addig et al.  demonstrcadherin . Park etcadherin  highlighbehavior . Also, ibehavior .de novo production of LOX by mesenchymal stromal cells (MSCs) associated to tumor is able to transduce the same signal along the CD44–LOX–Twist axis  is another component of the ECM that in the TME provides a cancer cell–ECM anchoring site and is associated with a poor prognosis in advanced cancer patients . HA exerist axis .high-tumor cells exhibiting stem cell-like properties and mesenchymal phenotype able to bind HA through their receptor CD44. This interaction was instrumental in promoting a spheroid formation, as well as cell growth/self-renewal properties in CD44+ tumor cells. These findings strongly indicated that HA–CD44 interaction in the ECM of highly metastatic cancer cells is correlated with the transcription of stem cell markers which are important contributors to the head and neck squamous cell carcinoma progression  signaling transduction on organ-specific locations or recipient cells. A body of evidence suggests that tumor-derived EVs or EVs secreted by CAFs in the TME play a fundament role in triggering EMT, tumor invasion, and metastasis , a particular subclass of EVs is largely involved in EMT plasticity . ExosomeInterestingly, some work highlighted that also stromal cells secrete exosomes that could promote EMT in cancer cells. Luga et al. . reporteDuring the EMT, tumor cells contribute to several interactions with the surrounding TME, composed of cell components and ECM as well as cell secretome elements . As a reIn cancer, as described above, ECM remodeling plays an important role by affecting different processes such as tumor growth  and metaADAM19 and its epigenetic regulation as a robust new biomarker of EMT in vitro and in vivo  stress signaling has been strongly connected to cancer cell migration and invasion through adaptive stress responses that include the unfolded protein response (UPR) . UPR acthigh/CD24low tumor cells (via mitogen-activated protein kinase (MAPK)/ ERK signaling pathway, highly metastatic hepatocarcinoma cells (MHCC97H) are able to similarly stimulate the migration and invasiveness ability of low metastatic hepatocarcinoma cell line.EMT process is strongly associated with the change in the cellular secretome including EVs. EVs as carriers of molecular information have been demonstrated to influence the EMT process. In a complementary way, tumor cells undergoing EMT can generate EVs able to modify the surrounding TME . In partor cells . This moor cells . Furtheror cells  demonstror cells . Additioor cells . In anotor cells . These mor cells . Moreoveor cells . In anotor cells  demonstr+ CSCs can release EVs able to activate angiogenesis and enhance lung metastasis, accounting for the preparation of a pre-metastatic niche in the lung. The same EVs were able to educate MSCs to a pro-tumorigenic phenotype by stimulated pro-angiogenetic and pro-invasive actions  through cancer and non-cancer EVs is a potential mechanism of intercellular communication in TME. Therefore, modulating or changing the genetic content of EVs might be a strategy to prevent cancer propagation. In this direction, EVs have also been proposed as a delivery carrier for antitumor molecules. This is in line with previous reports that demonstrated that naive EVs from different sources of MSCs were able to exert an antitumor activity in different cancer cell models –171. By of COX-2 .Recent studies have proposed the use of tumor-derived EVs as tools for cancer detection and monitoring . EVs arein vitro invasive properties in UBC cell lines, suggesting a cardinal role for exosome-derived HOTAIR in tumor initiation and progression  a sensitive detection method that considers the small proportion of tumor-derived EVs in respect to the total non-tumor secretome in the body fluids; (ii) the selectivity in the chosen molecules that can separate tumor from non-tumor EV background; and (iii) the representativity in the tumor metabolic state that can discriminate stages and progression/relapse during the clinical treatment.In cancer, EMT appears as a key pathological process characterized by abnormal metabolic reprogramming of cancer cells toward an invasive and pro-metastatic phenotype. The signals responsible for the activation of the EMT can derive directly from an alteration of cancer cell metabolism. However, extrinsic inductors, coming from the cellular and non-cellular TME components, can directly participate in the EMT process modulating cancer cells toward a pro-tumorigenic and pro-invasive phenotype. In turn, tumor cells undergoing EMT modify the surrounding environment that actively helps the tumor to invade and metastasize. The non-cell TME-derived components, participating actively in the tumor spread, have been proposed as possible tools for cancer monitoring and treatment, being on one side biomarkers of disease regression/relapse  and on the other side possible direct targets for new-combination anticancer personalized medicine.FC and MA planned the manuscript. ED'A, RL, FS, and FC contributed in writing the manuscript and screened international scientific literature. BB and SP helped in revising the manuscript. FC designed the figure. All authors 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.


Senescence is a cellular stress response triggered by diverse stressors, including oncogene activation, where it serves as a bona-fide tumour suppressor mechanism. Senescence can be transmitted to neighbouring cells, known as paracrine secondary senescence. Secondary senescence was initially described as a paracrine mechanism, but recent evidence suggests a more complex scenario involving juxtacrine communication between cells. In addition, single-cell studies described differences between primary and secondary senescent end-points, which have thus far not been considered functionally distinct. Here we discuss emerging concepts in senescence transmission and heterogeneity in primary and secondary senescence on a cellular and organ level. Cellular senescence is a stress response programme that irreversibly and stably arrests the cell cycle following a variety of intrinsic and extrinsic stressors such as shortening of the chromosomal termini, DNA damage, oxidative stress, oncogenic and mitogenic stimuli –3. Cellu) locus encodes p16 and ARF, with the former repressing CDK4/6 while the latter cross-talking with the TP53/CDKN1A network.In the replicative senescence model of proliferating human cells, successive telomere erosion in each cell division ultimately uncaps the free double-stranded chromosome ends, causing them to be recognised as DNA double-strand breaks (DSBs) and activating the DNA damage response (DDR) pathway , 8. The Unlike quiescent or terminally differentiated cells, senescent cells do not respond to mitogenic cues and are not specialised cells resulting from a developmentally differentiated program. Senescent cells display distinguishing characteristics morphologically and biochemically. They are generally characterised by an enlarged and flattened shape and robustly express the lysosomal enzyme β-galactosidase, detectable by senescence-associated b-galactosidase  staining at sub-optimal pH . IncreasRas, HrasV12, was ectopically expressed in primary cell culture of human lung fibroblasts IMR90. Senescent growth arrest is also stably established in vivo with a notable example being the ectopic expression of Ras in mammary epithelial cells 2]. SinglAs research on secondary senescence is still in the nascent stage, the exact role and biological significance of NOTCH-mediated juxtacrine senescence and secondary senescence, in general, remain elusive. At least, it has become increasingly apparent that throughout the course of OIS, cells mature from pre-senescence to complete senescence, undergoing different stages where secondary senescence signals are dynamically transmitted to adjacent cells. Principally, secondary senescence encompasses both paracrine and juxtacrine modalities, but exact nature and timing of their operation and regulation is just beginning to emerge. In combination with the proposed model of the transient NOTCH/TGF-β-dominant secretome in the early phase of OIS and pro-inflammatory C/EBPβ-rich SASP in the late phase, the results from the single cell RNA-sequencing experiment of OIS cells suggest that juxtacrine senescence is predominantly achieved in the early NOTCH phase, while paracrine senescence takes on a more influential role when OIS is fully established , 27, 54.From a biological point of view, a conjectural interpretation of the composite transcriptional NOTCH and SASP signature in secondary senescence represents a fine control of cell proliferation activity and immune surveillance in the senescent milieu. Dysregulation of the initial stage of NOTCH-mediated senescence might promote tissue fibrosis through overexpression of collagen. Likewise, long-term persistence of inflammation or downregulation of NOTCH signalling in the late SASP-rich phase would in turn result in immunosuppression in the cellular neighbourhood and decrease the efficiency of immune-clearance of tumour-prone senescent cells, thereby favouring pre-neoplastic transformation in normal bystander cells . In thisSenescent cell accumulation takes place in many tissues and organs, including the liver and the kidney, often in association with a functional decline and homeostatic capacity of those organs . In hepafl/fl model can spread the senescence phenotype to nearby normal hepatocytes via SASP and the reliance on TGFβ signalling [Compelling evidence suggests that hepatocytes undergoing primary senescence upon acute liver injury in the AhCre-Mdm2gnalling . The TGFgnalling . Combinegnalling , it is pThe kidney is also known to be affected by constituents of SASP –62. A vaOncogene-induced senescence unmistakably represents a tumour suppressor mechanism, but our understanding of its induction and establishment is not yet complete. The heterogeneity of the OIS programme is only beginning to be elucidated through the use of single-cell technologies. Among the key questions that need to be addressed are whether all cells respond similarly to the same oncogenic activation and whether the same oncogenic insult always results in a heterogenous OIS population. We have summarised current evidence for a functional heterogeneity in the senescence response in a recent review . StudiesOIS, primary or secondary, is traditionally believed to have only one functional endpoint, but recent research has favoured the notion that primary and secondary senescent cells are in fact functionally distinct stages of OIS. Furthermore, transcriptomic analyses have challenged the prevailing view that paracrine induction of senescence is the only main mediator of secondary senescence in OIS, with juxtacrine NOTCH signalling emerging as a synergistic driver of secondary senescence. This means that OIS is a far more complex state than previously anticipated, with autocrine, paracrine and juxtacrine signalling pathways being at play. The precise mechanisms that govern the induction of senescence through paracrine or juxtacrine signalling, however, remain elusive. It is highly possible that the secondary induction of OIS is dictated by the dynamically spatiotemporal patterns of the senescence-associated secretomes as well as cell-to-cell interactions, which in turn shape the varied quality, quantity, output and changes of OIS functionality. To obtain a better insight into the molecular basis for the regulation of secondary senescence, novel technologies such as single-cell transcriptomics and genomics will prove valuable in identifying and characterising more subtle events taking place over the course of OIS, primary or secondary. Accordingly, investigating the heterogeneity of a senescent cell population is one approach to uncovering the actual contribution of each mode of senescence transmission, and will significantly highlight directions for the strategic development of new and specific drugs that target deleterious senescent cells.


Vestibular disorders pose a substantial burden on the healthcare system due to a high prevalence and the severity of symptoms. Currently, a large portion of patients experiencing vestibular symptoms receive an ambiguous diagnosis or one that is based solely on history, unconfirmed by any objective measures. As patients primarily experience perceptual symptoms , recent studies have investigated the use of vestibular perceptual thresholds, a quantitative measure of vestibular perception, in clinical populations. This review provides an overview of vestibular perceptual thresholds and the current literature assessing use in clinical populations as a potential diagnostic tool. Patients with peripheral and central vestibular pathologies, including bilateral vestibulopathy and vestibular migraine, show characteristic changes in vestibular thresholds. Vestibular perceptual thresholds have also been found to detect subtle, sub-clinical declines in vestibular function in asymptomatic older adults, suggesting a potential use of vestibular thresholds to augment or complement existing diagnostic methods in multiple populations. Vestibular thresholds are a reliable, sensitive, and specific assay of vestibular precision, however, continued research is needed to better understand the possible applications and limitations, especially with regard to the diagnosis of vestibular disorders. The vestibular system senses head motion, including rotation, translation and orientation relative to gravity, via input from the semicircular canals (SCC), otolith organs, and their subsequent central integration. Signals from the vestibular periphery have a wide range of reflexive functions, including gaze stabilization via the vestibulo-ocular reflex (VOR), postural control, and autonomic regulation. The vestibular system also contributes to percepts of head motion and spatial orientation, along with contributions from vision, somatosensation, and proprioception. When an injury occurs to the peripheral end organs or central vestibular structures, patients may report abnormal perception of self-motion, imbalance, blurring of vision, and oscillopsia.Diagnosis and management of patients with vestibular disorders can be challenging due to poor understanding of the underlying pathology, and the lack of reliable objective tests capable of fully evaluating peripheral and/or central vestibular function. Standard physiological assessment of the vestibular system focuses on reflexes including the VOR  as an assay of SCC function and vestibulospinal reflexes (VSR)  as an assay of otolith function. In general, these measures can be effective at localizing lesions or supporting/refuting certain pathologies; however, the results of such tests are often nonspecific to common vestibular pathologies  , have poThere is evidence that vestibular perception has qualitatively different underlying mechanisms than vestibular reflexes –10, thusVestibular thresholds can also describe each of the peripheral vestibular organs using a single methodology, both independently – yaw rotation for the horizontal SCC, roll or pitch rotations about an earth vertical axis for the vertical canals , z-axis While the theoretical benefits of studying vestibular perceptual thresholds is clear, their specific utility with respect to clinical medicine has only recently been examined. Thus, our goal with this review article is to highlight the methodology and clinical contributions that have been published and discuss how these findings may be useful to clinicians in the future, particularly as it pertains to the diagnosis of vestibular disorders.Vestibular perceptual thresholds refer to the smallest appreciable stimulus, or in this case motion, detected by the participant in some proportion of trials set by the investigator , 21. SimAn important aspect to consider is that motion detection is inherently dependent upon multisensory cues, with many extra-vestibular senses contributing to self-motion perception, including vision, somatosensation, proprioception, and audition , 30, 31.The units of measure used to report vestibular perceptual thresholds has varied between studies; this choice is largely dependent on the test stimuli employed and the targeted end-organ. Many studies report vestibular perceptual thresholds in terms of peak velocity of the motion stimulus e.g., , 34, 35], 3534, 3Yaw rotation about an earth-vertical axis has been the most widely studied motion trajectory and primarily reflects horizontal SCC function . Yaw perYaw rotation velocity thresholds have been found to display high-pass characters with a characteristic increase below 0.2 Hz and a plateau between 0.5 and 5.0 Hz , 27, 40.The otoliths (saccule and utricle) encode the net gravitoinertial force, the sum of linear acceleration and gravity. Vestibular perceptual thresholds assess otolith function using translations in the naso-occipital or x-axis (predominantly utricle), inter-aural or y-axis (utricle), and superior-inferior or z-axis (saccule) planes see . AdditioVestibular pathology has been shown to exert a greater impact on earth-vertical translations  compared to earth-horizontal translations  , 35; in One unique aspect of vestibular perceptual testing is the capability to assess the central integration of SCC and otoliths cues. Internal models parse the net gravitoinertial force, encoded by the otoliths, into separate estimates of tilt and translation, using the SCC inputs to estimate head orientation relative to gravity during tilt , 50–52. Vestibular hypofunction can result from a broad array of pathologies. Etiologies include medication side effects, post-surgical, neoplastic, autoimmune, Meniere's disease and idiopathic hypofunction. Bilateral vestibular hypofunction (BVH) causes progressive symptoms of imbalance, and in severe cases, oscillopsia; BVH is of particular interest in clinical medicine as it remains a poorly defined chronic disorder, with an unknown etiology . The curWhile this is the only study to date to include patients with complete vestibular loss, several studies have assessed vestibular perceptual thresholds in patients with incomplete bilateral vestibulopathy and have identified deficits in perception consistent with varying degrees of end organ dysfunction , 20, 40.Translation thresholds were also assessed by Agrawal et al. in a group of patients with bilateral horizontal SCC weakness identified via calorics and/or head impulse testing . ThreshoNotably, determining laterality of vestibular responses in those with a vestibular injury is obscured by the fact that motion stimuli stimulate both labyrinths simultaneously, thus limiting application of published methodologies when lateralization of pathology is needed. Vestibular detection thresholds using yaw acceleration steps revealed asymmetrically elevated thresholds for ipsi-lesionally directed stimuli when testing in the acute stage (1–5 days post onset of vestibular neuritis); however, these thresholds become symmetric within weeks of onset, despite lack of recovery of calorics, revealing a persistent asymmetry in peripheral function . As wellSeveral studies have investigated changes in vestibular thresholds seen in episodic vestibular disorders, namely vestibular migraine (VM) and Meniere's Disease (MD) see . VestibuTranslation thresholds for naso-occipital (x-axis), inter-aural (y-axis) and superior-inferior (z-axis) motions were not significantly different between patients with VM and healthy controls . ConsistIn an apparently contradictory finding, a significant decrease in roll tilt thresholds has been demonstrated for VM patients in comparison to both healthy and non-vertiginous migraine controls , 54, 63.Vestibular thresholds have also been assessed in Meniere's disease (MD), another frequently encountered episodic vestibular disorder. MD is characterized by episodic vertigo and auditory symptoms, which include fluctuating hearing loss, aural fullness, and tinnitus . HistopaDegradation of vestibular function with age has been well documented in the literature –78; suchSimilarly, several other studies have failed to detect a significant increase in yaw rotation thresholds with age. Seemungal et al. found similar yaw acceleration thresholds between healthy young adults aged 19–37) and older adults (aged 56–75) using a triangular velocity trajectory . Likewis–37 and on = 3), as another study of 34 healthy subjects saw a significant positive correlation with age for 1 Hz naso-occipital, inter-aural, and head vertical translation thresholds , a substantial improvement upon current vestibular assessments. As an example of possible clinical utility, Priesol et al. was able to show a specific pattern of end-organ damage in individuals with idiopathic bilateral vestibular hypofunction, which included elevated thresholds during yaw rotation and low frequency interaural translation . RoutineVestibular thresholds may also be useful to assess treatment response or disease progression for those with unilateral or bilateral vestibular hypofunction , 58. StaDifferentiation between other, more ambiguous vestibular disorders  appears particularly promising. Many patients with vestibular disorders present with symptoms that result from an unknown etiology, without clear indication of a specific disease process or of an individually culpable vestibular organ. Traditional diagnostic methods are typically exclusionary, excluding the more obvious etiologies prior to confirming a diagnosis based upon patient symptoms , 71. Howasymptomatic adults without complaints of vestibular impairment, suggesting that roll tilt thresholds may prove to be a sensitive screening tool to detect sub-clinical vestibular impairment and fall risk in asymptomatic adults over age 40.The comprehensive nature of vestibular thresholds also allows for potential improvements in our understanding of how age influences vestibular function. This point is not trivial, given the well-documented association between aging, vestibular decline, and fall risk –78. RollFrom a logistical standpoint, an advantage of vestibular perceptual testing is the relative ease of testing, the task is simple and intuitive and can be readily learned by most, if not all, patients. This testing is similar to a standard hearing test, which may be the most commonly performed threshold procedure. Furthermore, algorithms that yield efficient data collection and precise data analysis have already been automated, making it possible for non-specialists to perform testing with minimal training. Unlike the heterogeneity in some other vestibular tests, this automation may serve to help standardize procedures across laboratories.Several methodological limitations do however influence the potential clinical use of vestibular thresholds. The principal limitation with vestibular perceptual threshold testing is the time and equipment required to perform an accurate assessment. This is particularly an issue with lower frequency testing where each individual motion can require a significant amount of time . Automatic computer-based threshold environments and adaptive methodological approaches  have reduced test durations, yet the average assessment still requires between 10 and 20 min  per test motion. We cannot directly observe one's internal perception of a sensory stimulus, and instead we are forced to rely upon a subjective report of their perceived world state . Thus, aside from logistical concerns, the increased time for threshold testing introduces potential errors related to subject inattention and fatigue. This problem can be mitigated by ensuring the subject receives adequate rest, that testing occurs at a time of day where the subject is more alert, and by using statistical techniques that exclude attentional lapses from the threshold analysis , 94.In addition, particular care must be taken to avoid the introduction of potentially confounding extra-vestibular cues . Veridical visual cues  and eartFrom an equipment standpoint, vestibular perceptual threshold measurements require only a few simple components . Yaw perceptual thresholds could be performed using a rotary chair, which is found in most tertiary care vestibular referral centers and audiology clinics. However, immediate implementation is not feasible with most commercially available systems and will be dependent upon thedevelopment of appropriate software and hardware by the device manufacturers. The primary limitation of the rotary chair in comparison to a 6DOF motion platform is the limitation in test conditions, as the rotary chair can only be used to assess yaw thresholds within a limited frequency range. Therefore, a motion platform with multiple degrees of freedom is likely necessary for a comprehensive assessment of vestibular thresholds. While currently 6DOF motion platforms  are not commonly available, we feel that their implementation would be very straightforward. This equipment could fit in a small room and the total cost is estimated to be < $200 K, an estimate that is based upon our own lab set-up. We emphasize that all aspects of both central and peripheral vestibular function would be tested using the single motion device, and as a result this equipment would almost certainly cost less than the total cost of the devices currently used today .Vestibular thresholds are arguably the most direct, sensitive, and specific assay of vestibular noise currently available , 63, 95.MK, AW, DM, and JM wrote the manuscript and approved the final version prior to publication. MK created all tables and figures presented herein. 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.


The success of free vascularized fibular bone graft (FVFBG) has accelerated the osteo reconstruction which results from trauma, resection of a tumor or an infectious bone segment, or correction of congenital deformity. But the complication behind should not be overlooked. The failure could necessitate a second surgery, which prolong the rehabilitation period and produce further health cost. Worst, the patients may suffer a permanent impaired ankle function, or a sustained morpho-functional loss on reconstructive area which are hard to save. To provide an overview of the complication related to reconstruction by FVFBG, a narrative review is conducted to identify the complications including their types and rates, the contributing factors, the approaches to measure and the techniques to avoid. Methodologically, by quick research on Pubmed and abstract reading of reviews, we characterize five reconstructive areas where FVFBG were most frequently applied: extremities, mandible, spine, osteonecrosis of femoral head, and penile. Following, the complications on different reconstructive areas are retrieved, studied and presented in five  separate sections. By the way, meaningful difference between FVFBG and other bone flap was presented in a few words if necessary. Donor-site morbidities were studied and summarized as a whole. In these literatures, the evidences documented on limb and mandibular reconstruction have the fullest detail, followed by the spine and lastly the penile. In conclusion, FVFBG, though a mature technique, needs further deep and comprehensive study and maybe device-based assistance to achieve better reconstructive effect and minimize donor-site damage. Since 1986, the free vascularized fibular bone graft (FVFBG) has been increasingly applied in restoration of bone defect because of trauma, tumors, infection or congenital anomalies. Due to its integration potential and abundant blood supply, it also has a varied utilization in spinal fusion and osteonecrosis of femoral head. What is more, its advantages in rigidity extend its application in phalloplasty. Owing to the advancements in microsurgery, vascular compromise and flap failure have largely been avoided and many researches declare a low incidence rate of complication both on recipient site and donor site. However, complication like stress fracture and non-union could fail the rebuilding process, and donor-site morbidities like valgus ankle deformity or great-toe flexing contracture could lead to impaired walking ability and low-quality life. This review is aimed to summarize complication in types, incidence rates, and contributing factors of complication on donor and recipient site, and meanwhile update the measurement to quantize complication, technical refinement to avoid the complication. To the best of our knowledge, this is the first review focusing on complication both of donor and recipient area, covering all kinds of osteo reconstruction  by free vascularized fibular bone graft.Initially, a quick search was conducted by using term “(fibula [Title/Abstract]) AND (((flap [Title/Abstract]) OR (transfer [Title/Abstract])) OR (graft [Title/Abstract])) AND (review [Filter] OR systematic review [Filter])” on Pubmed to identify the complication types relevant to free vascularized fibular bone flap or fibular chimeric flap which has a bone component. In a generalized sense, the applied range of fibula bone flap may be roughly divided into four categories: extremities, spine, mandible and penis. However, according to the retrieved result-180 search results on fibular flap transfer, we found that the femoral head and the special condition of extremity reconstruction which necessitates a proximal fibular epiphyseal transfer are usually studied as isolated unit in published literatures. In fact, the purpose of hip-preserving treatment for femoral head necrosis is to introduce a new and stable blood supply, which is slightly different from that of repairing a segmental bone defect on extremities. In addition, the objective of proximal fibular epiphyseal transfer is to rebuild a near-nature growth potentiality for immature bone, or to reconstruct the spherical joint head (hip or shoulder joint) with the spherical fibular head. Both the reconstructive goal and the flap design have particularity. Therefore, we classified the applied ranges of FVFBG more detailedly into six categories: extremities, proximal fibular epiphyseal transfer, mandible, spine, osteonecrosis of femoral head, and penile. Accordingly, the complications on different reconstructive area were searched once again on Pubmed and studied in different separated section, such as “(extremit [Title/Abstract]) AND ((fibula [Title/Abstract]) AND (((flap [Title/Abstract]) OR (transfer [Title/Abstract])) OR (graft [Title/Abstract])))”. For the retrieval of donor site complications, we performed a separate search and excluded the fibular flap without bone component. Generally speaking, this is a Pubmed-based narrative review aimed to summarize all the potential risk involved in reconstruction by free vascularized fibular bone transfer. Evidences from systemic review, meta-analysis, and large-scale studies have been meticulously studied and updated if necessary. Certain emphasis is put on the highly-cited literatures. Sporadic cases are only adopted when uncommon complication is discussed, and would be presented as a whole after generalized search.FVFBG has been reported with higher success rate , superioWound healing problems in fibular flap donor areas, such as infection, bleeding, and delayed healing, are common early complications. But usually these do not affect the functional outcome, and will not cause long-term problems . As longSurgical detail is significantly related to the donor-site function. Approach to harvest is the first consideration: Medial approach refers to a surgical alternative by which the fibular graft was elevated from the medial side. Technically speaking, lateral approach is more convenient in clinical practice because the fibular bone lies on lateral side just beneath the skin. But a comparative study by Philip  showed tPreoperative angiography of both legs should be carried out routinely to specify the distribution of blood vessels in the donor area. Anatomic variations where peroneal artery is absent or is the dominant artery supplying the leg and foot  should be detected in advance, otherwise harvest failure or ischemia of the distal limb would happen . PreoperValgus ankle deformity happens particularly where there has been no fibular transfixion or where too little residual fibular bone has been left. In skeletally immature patients, the remaining distal fibula should be at least 6 cm or 10 cm  long andFlexion contracture of the great toe is caused by the contracture and a tenodesis effect of the long-toe flexor tendons due to loss of muscle origins after fibular graft removal. Biomechanical model  showed tp = 0.05) which are an important phase in a gait cycle [p < 0.05) decrease in the time-distance parameter and the peak plantarflexion, and dynamic range was seen. But at 3 months postoperatively only peak plantarflexion in swing was significantly (p < 0.05) decreased [Since 1988 , measureit cycle . It has it cycle  found thecreased . Completecreased . General. Ling [Incidence rate of function loss is confusing. In spite of these small-sized study in which evidence is not so convincing, and whether they are the different or the same reconstruction sites , the donor-site complication has widely-ranged incidence rates. In a prospective study with 157 Consecutive Patients, Adeyiza  found a . Ling  reported. Ling .Complication on reconstructed area can be classified into three types: one is about graft survival and usually happened at early stage. Another type is about incomplete reconstruction objective, for example, persistent malformation, repressed bone growth, delayed or unachieved bone union, stress fracture. The third type is recurrence of infection, tumor and radioactive ulcer which completely comes from problematic reconstructive area itself and is absent in reconstruction of congenital deformity. Vascular compromise is first noteworthy complication which could completely leads to transplantation failure. However, the common flap-monitoring methods like SPECT/CT , scintigThe vascularity of the graft, which depends directly on the vascular anastomosis, has been described as a major factor influencing the outcome after FVFBG . HoweverUnlike the common vascularized fibular graft, the blood supply of vascularized fibular epiphyseal (VFG) transfer does not always come from fibular artery. Actually, the pedicle harvest has been provided with five different choice in chronological order: peroneal vessel , bi-pediVFG has been used to reconstruct a lost growth plate in the skeletally immature subject and articular surfaces. David  reviewedThe common complications in the radius reconstruction are radial deviation and wrist subluxation, which often necessitate second surgery to correct or stabilize. Salah  reviewedThe cases of using vascularized fibular epiphysis to reconstruct the lower extremity is small and the effectiveness is dissatisfactory. There were overall only 4 cases about hip , 52, 3 aOverall speaking, this technique still leaves much to be desired for its high complication rate. However, the fibular head provides a good growth potential and its sphericityis close to the shape of humeral head and femoral head. At present, it is the most suitable choice for the repairing bone defects on immature skeleton, and the only autograft which could reshape into an articular head.Fibular graft is the workhorse in mandibular reconstruction , for itsRadiological change of non-union and bone absorption of fibular graft has been well documented and compared with those of other flap types . TransfeJust like the limbs, to assure a stable mechanical support to large defect, two-section or bilateral fibular grafts should be administrated in mandible reconstruction when necessary. In pediatric patients, impaired mandible growth after the reconstruction with fibular growth possible leads to malocclusion and facial asymmetry . LuckilyOld age does not increase the risk of donor site complication or flap failure , but it Complication relevant to plate system, which are used to stabilize the fibular graft, has also been debated. The evolution in type of metal, the size and malleability of the plates, and the locking mechanism has lower down the risk of complication like plate exposure, plate fracture, infection, screw loosening and worst surgical removal. Mandible plate, locking plate and reconstruction plate have been applied in mandibular reconstruction to fix the fibular graft, and mini-plate has gained an increasing use and currently become the dominant one, for its lower profiles and smaller screw diameters, which minimizing the risk of plate exposure , 71. HowVascular pedicle ossification refers to graft pedicle experiencing calcification which could be identified both on CT scanning and with naked eyes under operation. Though it has a low incidence (4.4%)  and onlyComputer-aided design and manufacturing (CAD/CAM) technology  in mandiFibular graft is indicated when there are complex primary or secondary defects and/or loss of structural integrity of one or more spinal segments that require adequate, long-term, mechanical stability. The application of fibular flap in spine reconstruction is based on the success of limb reconstruction. As a result, the developmental history is short and only sporadic cases are available, the documented complications of spine reconstruction are not as complete as the that in extremities.Non-union is the most-common complication and has been reported with a incidence rate of 4% , 6.3% 9 and 14% To ensure an adequate mechanical support to avoid fracture and collapse, the fibular should be double-, triple- or quadruple-barrel construct if necessary. But when multi-barrel fibular grafts are applied, it should be realized that there is a risk of pushing the most posterior fibular strut into the direction of the spinal cord . AnotherVascularized grafts can be used in the treatment of osteonecrosis at a variety of anatomical sites, but most commonly used in young patients with ONFH. In a systemic review of 1270 procedure at an average of 8.3 years  (32%) arThe incidence of conversion to total hip arthroplasty and radiographic necrosis progress are major parameter studied in literatures. Not included as complications though, they are definitely surgical failure to arrest necrosis progression. Risk factors for reconstructive failure or graft absorption has been routinely studied, like age, sex, different predisposition  and different disease stage. However, as the bone flap survivorship is monitored indirectly by radiography  and based on bone viability, there is an absence of key evidence for the vascular-anastomosis quality. Once this confounding viable-the quality of vascular anastomosis is not controlled. The true relationship between the risk factors and reconstructive failure will be deviated. Histopathological analysis should be the most convincing examination but is limited by small size , 102 . HCompared with non-vascularized fibular graft and core compression, the vascularized fibular graft is a superior choice for lower rate of conversion to THA or radiographic necrosis progress . But no Recipient vessel and surgical approach have also been studied. Different recipient vessels  (three kIn previous-published literature of 1196 patients under phalloplasty, only 141 patients were operated with fibula osteo-cutaneous flap including 5 without osteo component, which is secondary to the workhorse-the radial forearm flap . AdvantaIn summary, the complication of osteo reconstruction by vascularized fibular is acceptable and need further improvement. Technical tips on flap harvest and transplantation have been provided to lower down the risk of vascular compromise and other complications. Computer assistance is still under exploration and might be good option to avoid mismatch of graft, implant, and mandibular residual. Proximal fibular epiphyseal transfer is more challengeable than a diaphyseal transfer and further basic research is needed to ensure the growth of transplanted fibular proximal adjustable to the recipient site. Current monitoring devices on fibular flap survivorship is mainly rely on indirect approaches like SPECT/CT, scintigraphy, intraosseous microdialysis and so on. We are looking forward to more direct and real-time monitoring device on fibular flap perfusion. Dynamic measurement of functional loss on donor-site needs the large-scale research to quantize the complication and guide gradual weight-bearing.


Cc) for 5 weeks, to determine if the prevention of synaptic mitochondrial dysfunction could attenuate memory loss. Our results indicate that reducing synaptic mitochondrial dysfunction is sufficient to decrease age-associated cognitive impairment. In conclusion, our results indicate that age-related alterations in ATP produced by synaptic mitochondria are correlated with decreases in spatial and object recognition memory and propose that the maintenance of functional synaptic mitochondria is critical to prevent memory loss during aging.Aging is a process characterized by cognitive impairment and mitochondrial dysfunction. In neurons, these organelles are classified as synaptic and non-synaptic mitochondria depending on their localization. Interestingly, synaptic mitochondria from the cerebral cortex accumulate more damage and are more sensitive to swelling than non-synaptic mitochondria. The hippocampus is fundamental for learning and memory, synaptic processes with high energy demand. However, it is unknown if functional differences are found in synaptic and non-synaptic hippocampal mitochondria; and whether this could contribute to memory loss during aging. In this study, we used 3, 6, 12 and 18 month-old (mo) mice to evaluate hippocampal memory and the function of both synaptic and non-synaptic mitochondria. Our results indicate that recognition memory is impaired from 12mo, whereas spatial memory is impaired at 18mo. This was accompanied by a differential function of synaptic and non-synaptic mitochondria. Interestingly, we observed premature dysfunction of synaptic mitochondria at 12mo, indicated by increased ROS generation, reduced ATP production and higher sensitivity to calcium overload, an effect that is not observed in non-synaptic mitochondria. In addition, at 18mo both mitochondrial populations showed bioenergetic defects, but synaptic mitochondria were prone to swelling than non-synaptic mitochondria. Finally, we treated 2, 11, and 17mo mice with MitoQ or Curcumin (  •Hippocampus-dependent learning and memory are impaired with age, which correlated with synaptic mitochondrial dysfunction.•Synaptic mitochondria fail before non-synaptic mitochondria, indicating premature synaptic mitochondrial damage in aging.•Reducing synaptic mitochondrial dysfunction, with MitoQ or Curcumin, decrease age-associated hippocampal memory impairment.•Age-related changes in ATP production of synaptic mitochondria correlated with decreased hippocampal memory.•Maintenance of functional synaptic mitochondria is critical to prevent memory loss during aging. MitochoIn the brain, mitochondria have been classified into non-synaptic and synaptic mitochondria . Non-synCc) for 5 weeks. MitoQ consists of a ubiquinone moiety linked to a triphenyl-phosphonium moiety by a 10-carbon alkyl chain  in old age [Another important function of the mitochondria is to regulate calcium concentrations . The mPT old age ,90. Anot old age . In fact old age . AdditioAdequate function of synaptic mitochondria is fundamental to synapses and therefore to the processes of synaptic plasticity that promotes memory formation, such as exocytosis of vesicles containing neurotransmitters ; spinogeOur work corroborates these earlier findings by showing that the dysfunction of synaptic mitochondria of the hippocampus contributes to the memory loss observed in aging. This last is showed by Pearson's correlation analysis, which demonstrates a positive correlation between the ATP concentration produced by synaptic mitochondria and the hippocampus-dependent cognitive capacities. For this, we exposed mice to treatment with MitoQ or Curcumin. Studies have been conducted in which MitoQ offers protective and favorable effects against neurodegenerative diseases ; proposiIn conclusion, we demonstrated for the first time that synaptic mitochondria of the hippocampus fail before non-synaptic mitochondria, which results in impairments in recognition and spatial memory. This proposes that the age-related cognitive impairment could be a consequence, almost in part, of the premature dysfunction of mitochondria at the hippocampal synapses. Also, we reported that preventing the dysfunction of synaptic mitochondria could be a new target for treating or impeding age-associated cognitive damage.The authors declare no conflict of interest.