Circular RNAs (circRNAs) generated by back-splicing are the vital class of non-coding RNAs (ncRNAs). Circular RNAs are highly abundant and stable in eukaryotes, and many of them are evolutionarily conserved. They are blessed with higher expression in mammalian brains and could take part in the regulation of physiological and pathophysiological processes. In addition, premature birth is important in neurodevelopmental diseases. Brain damage in preterm infants may represent the main cause of long-term neurodevelopmental disorders in surviving babies. Until recently, more and more researches have been evidenced that circRNAs are involved in the pathogenesis of encephalopathy of premature. We aim at explaining neuroinflammation promoting the brain damage. In this review, we summarize the current findings of circRNAs properties, expression, and functions, as well as their significances in the neurodevelopmental impairments, white matter damage (WMD) and hypoxic-ischemic encephalopathy (HIE). So we think that circRNAs have a direct impact on neurodevelopment and brain injury, and will be a powerful tool in the repair of the injured immature brain. Even though their exact roles and mechanisms of gene regulation remain elusive, circRNAs have potential applications as diagnostic biomarkers for brain damage and the target for neuroprotective intervention. The damage throughout perinatal period has a profound impact on brain development which is rather essential. Compared with term infants, brain damage in preterm infants, especially the very low birth weight (VLBW) infants, tends to represent the main cause of higher mortality and long-term adverse neurodevelopmental manifestations, including but not limited to motor and sensory problems, decreased cognitive development, and behavior disorders , 2. GeneAs is known to all, circular RNAs (circRNAs) have been confirmed to serve as important roles in the pathogenesis of various diseases . CurrentCircular RNAs, one class of non-coding RNAs (ncRNAs), can be mainly divided into three categories, containing intron circRNAs, exon-intron circRNAs, and exon circRNAs . The firIn spite that the production of circRNAs is not efficient in a high rate any more, they are rather resistant to degradation mediated by ribonuclease R (RNase R) for lack of free terminals. As a result, this class of RNAs owns transcript half-life exceeding 48 h longer than most of linear RNAs in cells , 16. ForA majority of circRNAs are evolutionarily conserved in mammals , 19. TheCircular RNAs are widespread found in all kingdoms of life. Their expression is validated in RNA samples from almost all of the organs and tissues, such as brain, testis, kidney, spleen, liver, heart, bone marrow, smooth, skeletal muscles, and so on –24. OwinGenerally speaking, circRNAs overall transcript levels in brain steadily grow during the developmental and aging phases, from embryonic to adulthood , 29. CirWhat's more, the expression of circRNAs is not equally distributed throughout the brain, accompanying significant differences in various brain regions . InteresAs stated above, circRNAs are dramatically enriched in CNS due to the following reasons. (A) CircRNAs are produced mainly from exons of protein-coding gene which are specific for neuronal and synaptic functions. (B) CircRNAs are unable to be identified by RNase R and get used to expressing in relatively high levels in cells. (C) On account that neurons are relatively stable cells and cell division rarely occurs, circRNAs theoretically accumulate during the process of development and aging.The superior abundance and stability in the mammalian brain prompt many researchers to explore the roles of circRNAs in the CNS. Nonetheless, the mechanisms deep into the details by which circRNAs take participated in have not been completely identified. As is well known, microRNA (miRNA), small single-stranded, and ncRNA, could downregulate post-transcriptional expression by binding 3′-untranslated region of target messenger RNA (mRNA) to adjust the progression of brain development and diseases . RNA-binCerebrovascular autoregulation is extraordinarily important to maintain the physiological function of brain. Newborns, especially those premature neonates with higher susceptibility, have imperfect cerebrovascular structures and regulation mechanisms , 49. WheDue to tissue and cellular structure specificity of circRNAs, increasing studies have been revealed that circRNAs are connected to neurological dysfunctions caused by brain damage , 51. OliThe early injury to the developing brain may cause circRNA disorder, recent, or long-term neurodevelopmental dysfunctions via diverse mechanisms. The circRNA Runx1t1, Pde5a, and Rtn4 three are differentially expressed in hippocampus and prefrontal cortex where learning and long-term memory take place, and their inhibition may perfect memory performance as well as cognitive function . Based oIntellectual deficiency seriously affects the quality of life both of children themselves and their families. Circular RNA SATB2 from corpus callosum is significantly upregulated in the late stage of pregnancy . In a caThe damage of cerebral gray and white matter has been confirmed to be closely related to cognitive abnormality in later life of preterm babies . Exon ciChildren with brain injury would exhibit abnormal behavior to some extent, such as attention deficit hyperactivity disorder . CircTLKEpilepsy with the higher risk in infants is a chronic neurological disease, of which temporal lobe epilepsy (TLE) is the most common type of epilepsy. As its name suggests, TLE seizures begin in the temporal lobe cortex and then abnormal cortical signals are exhibited, characterized by hippocampal sclerosis, neuronal death, gliosis, and so on , 67. HowP < 0.01)  .Neonatal HIE refers to hypoxic-ischemic (HI) damage in brain caused by perinatal asphyxia and hypoxia, following a series of clinical neurological manifestations. What's worse, subsequent cascading reactions after cerebral ischemia-reperfusion may cause considerably severe brain damage . In otheIt is critical to appreciate that neuroinflammation is the main driver in injury to the developing brain and greatly amplified after HI insult. That is, inflammation inhibits conveying messages between neurons but increases the sensitivity of immature brains to hypoxic so that cerebral injury will be prolonged . What's Nevertheless, apoptosis is essential for the development of immature CNS. When the energy supply is significantly reduced, apoptotic cell death will occur, and at the same time, cell neurosis would take place in rather severe cases . Lin et Blood-brain barrier selectively allows molecules to cross the barrier in order to protect the neonatal brains in physiological condition . TherefoWhite matter damage in premature infants is the predominant class of neonatal brain damage . It featTaking all the facts into consideration, there is an urgent need for early detection markers and novel therapeutic targets of WMD in preterm infants. Luckily, our team previously analyzed the whole blood samples of preterm infants who have had WMD and then identified that the expression profiles of circRNAs had greatly changed following brain injury  90). In. In90). At the same time, the white matter is featured in myelin, a critical component produced by OLs that facilitate the efficient transmission of electrical signals and then enable communication between gray matter neurons throughout various areas . MoreoveTypically, loss of glia and axons has been acknowledged for many years to be the characteristic of cystic WMD . For preCurrent researches of WMD have rarely involved the role of pro-inflammatory and anti-inflammatory in brain repair. Microglia, accounting for 10–20% of all glial cells, are the innate immune cells and the main regulator cells for the repair/regeneration of the CNS . ExcessiThe above reviewed findings emphasize the relevance of circRNAs as bioactive molecules regulating the neurodevelopmental conditions. The overall conclusions from the works presented here are: (A) Premature birth plays a major and early role in neurodevelopmental diseases; (B) Regulatory circRNAs expression and activity dynamics regulate, directly and/or indirectly, gene expression networks involved in brain damage; (C) CircRNAs have a direct impact on neurodevelopment and brain injury.The detailed biogenesis of circRNAs remains complicated. The molecular and physiological functions of most circRNAs are still unknown, but there is a tendency that the focus in this area would generate tremendous growth due to the progressed methods of overexpression, knocking out, and knocking down in specific circRNAs. At present, researches are mostly focused on cerebroma and stroke in adults. Circular RNAs wrapped by exosomes or cell vesicles could pass through the incomplete BBB resulted from brain injury, so that circRNAs are available in peripheral blood. Circular RNAs have emerged as the new type of molecules with intriguing molecular functions and potential biomarkers of related diseases. For example, due to elevated levels in plasma, circPDS5B, and circCDC14A could be potentially valuable biomarkers for acute ischemic stroke and target for therapeutics in stroke outcomes. Overexpressed circ-CDC45 has been confirmed to be active in the progression of glioma proliferation and invasion, and predict its adverse prognosis . EspeciaIn addition, the functional interaction between different classes of ncRNAs, such as circRNAs and corresponding miRNAs and RBPs, provides an additional layer of complexity, in which multiple circRNA-signaling pathways orchestrate the response to the cerebral injury. However, most of previous studies focused on a particular circRNA while ignore that various molecules are functionally altered in the CNS diseases. So, the diversity raises the challenge of aiming the regulation of circRNAs to better protect from brain damage. The cirRNA-miRNA-mRNA code is the focus of nowadays researches. Nevertheless, we can speculate that additional RNA classes present in the CNS can be affected by and associated to neurodevelopment, including highly abundant miRNAs.The increasing roles of circRNAs in neurological diseases also drew our attention. Five circRNAs were found differentially expressed through RNA high-throughput sequencing . PrelimiIn spite of numerous studies in circRNAs, there remains a few researches in diseases associated with premature infants. All these results mentioned in this article demonstrate the unique prospect of circRNAs as clinical diagnosis markers and therapeutic targets, and neuroprotective agents for brain damage of preterm infants, but still need confirming in further continuous studies by the use of large quantities of animals, clinical samples and even patients. Early neurological interventions are closely related to the patient's quality of the rest of life. So, the application of circRNAs as neuro-biomarkers can be exploited in the near future, which could unbelievably make an increase in the possibility for premature infants to live better in the world.QG was the primary author of the review. HL and JM assisted with writing and provided edits. All authors approved this version.This work was supported in part by the Postgraduate Research and Practice Innovation Program of Jiangsu Province (SJCX20_0057) and in part by the Fundamental Research Funds for the Central Universities (3224002112D).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The autonomic nervous system (ANS) confers neural control of the entire body, mainly through the sympathetic and parasympathetic nerves. Several studies have observed that the physiological functions of the eye  are precisely regulated by the ANS. Almost all parts of the eye have autonomic innervation for the regulation of local homeostasis through synergy and antagonism. With the advent of new research methods, novel anatomical characteristics and numerous physiological processes have been elucidated. Herein, we summarize the anatomical and physiological functions of the ANS in the eye within the context of its intrinsic connections. This review provides novel insights into ocular studies. The ANS plays a major role in maintaining the physiological integrity of the entire body in response to environmental alterations. Similar to the other organs in the body, the majority of intraocular muscles of the eyes are dominantly controlled by the ANS. Moreover, the pupillary light reflex (PLR) has been widely used for the detection of ANS dysfunction .Briefly, the eyes are innervated by the sympathetic, parasympathetic, and trigeminal sensory nerve fibers . The preNumerous studies have identified newer autonomic pathways and peptides secreted by these nerve fibers in various species. These studies have helped shape and enrich the knowledge about the eye under different physiological and pathological conditions. The historical and current knowledge of the anatomy and physiological processes of the ANS in the eye are summarized in this review.From around 21 weeks of gestation in humans, the Edinger-Westphal nucleus (EWn) forms a unique and complex 3D structure consisting of 2–3 parts . In primThe CG, as a transfer station for the parasympathetic nerve behind the eye, is mainly involved in ocular accommodation and pupil constriction. Around 3% of the postganglionic neurons from CG in macaques were showed heading toward the sphincter pupillae, and in cats, this portion increases to 10–15% ,13. The In avians, the CG also innervates the choroid, but there is little evidence for this connection in mammals. Some studies have reported the possibility for such connections, but without any definite evidence ,27,28,29The SSN is located approximately dorsolateral to the facial motor nucleus, while the precise location of the SSN in humans has not been identified yet. The preganglionic axons reach the geniculate ganglion as part of the intermediate nerve before separating into two branches: the greater petrosal nerve and the chorda tympani. The greater petrosal nerve contains parasympathetic nerve fibers that extend to the pterygopalatine ganglion (PPG); these fibers control the functions of the lacrimal glands, and the mucous glands of the nose, palate, and pharynx. The branch of the facial nerve, also known the chorda tympani nerve, projects to the submandibular ganglion where it mediates other functions that are not related to the eyes. The cerebral circulation is innervated by the posterior parasympathetic fibers from the PPG as well .The PPG is also known as the sphenopalatine ganglion, Meckel’s ganglion, or the nasal ganglion. Several studies have shown that the PPG is the main source of choroidal parasympathetic input in mammals ,32,33,34W.H. Gaskell, in the 1800s, identified the intermediolateral cell column (IML) as the origin of the sympathetic nerve . These sThe SCG is located at the level of the C2/C3/C4 transverse process, and it is approximately 3–5 cm long and lies proximal to the longus capitis muscle . It radiThe ophthalmic nerve, a branch of the trigeminal nerve, is mainly responsible for mediating the sensation in the ciliary body, iris, lacrimal gland, conjunctiva, and cornea of the eye. These sensations include touch, pain, and temperature. Though ophthalmic nerve does not belong to autonomic nervous system, this nerve also contains sympathetic nerve fibers that control pupil dilation . StudiesThe cornea is one of the most densely innervated parts of the human body with a rich supply of sensory and autonomic nerve fibers . SensoryThe corneal innervation was first described in detail in 1951 , but theThese sensory and autonomic nerves also play a key role in maintaining the optimal health of the ocular surface. Corneal nerves can release soluble trophic substances that promote lacrimal gland secretion, induce blinking reflexes, and maintain the integrity of the ocular surface . SubstanThe iris is a circular pigmented membrane located in front of the lens, it divides the cavity between the cornea and lens into an anterior chamber and a posterior chamber.The iris controls the amount of light entering the eye by adjusting the pupil. The preganglionic parasympathetic axons originating from the EWpg innervate the pupillary sphincter through the short ciliary nerve. These axons act on the muscarinic receptors of the pupillary sphincter, and mediate pupillary constriction. Sympathetic innervation originates from the SCG and provides a reciprocal function via the long ciliary nerves which control pupil dilation ,61. The 2+ [2+ ions for sphincter contraction was found to be altered, followed by pupillary dilation [The iris of several vertebrate species has rhodopsin, a molecule that enables photomechanical responses (PMR). Rhodopsin enables pupillary constriction in response to light without the need for a central nervous reflex. This process may involve (1) rhodopsin-activated G-protein, (2) phospholipase C, (3) inositol triphosphate, or (4) Ca2+ ,66. More2+ . After tdilation . Generaldilation .The main outflow pathway of aqueous humor (AH) comprises the trabecular meshwork (TM), the endothelial lining of Schlemm’s canal, juxtacanalicular connective tissue, collecting channels, and aqueous veins. Additionally, the outflow resistance of the TM pathway seems to be regulated by the contraction of the scleral spur (SS) cells and ciliary muscles . In almoNomura found that approximately one-third of the innervation in the TM is sympathetic in monkeys, and that two-thirds are parasympathetic . In humaThe lacrimal gland is located in the orbit of the human eye. Lacrimal secretions are vital to the health and maintenance of the cells on the ocular surface . Regulation of lacrimal gland secretion involves the following: (1) stimulation of the sensory nerve on the ocular surface and (2) parasympathetic and sympathetic activation of the lacrimal secretory cells . MechanoTear production is regulated by both the sympathetic and parasympathetic nerves. Generally, sympathetic nerves affect tear secretion via the following two methods: (1) alteration of blood flow  and (2) The neural retina is a layered structure that converts photic illumination into visual information and then transmits this signal to the brain. The retinal circulation and the choroidal circulation, both of which originate from the ophthalmic artery, are responsible for supplying oxygen and nutrition to the retina. Retinal circulation provides a low level of blood flow and a high level of oxygen extraction, contrary to that in choroidal circulation ,97. TherThe preocular CRA in humans receives adrenergic and cholinergic nerve fibers, suggesting sympathetic and parasympathetic innervation. However, SP, CGRP, and VIP were not detected in the nerve fibers, indicating a lack of peptidergic innervation . SimilarThe choroid makes up the posterior part of the uvea, located between the retina and sclera, and is mainly composed of blood vessels. Neurons in the choroid, which mainly regulate choroidal circulation, are also called choroidal ganglion cells or intrinsic choroidal neurons (ICN) ,112. TheIn mammals, the primary input of the parasympathetic nerves originates from the PPG via the facial nerve ,115. AltThe size of the pupil varies with the intensity of incident ambient light, which forms the PLR. Generally, pupil dilation and constriction depends on both autonomic innervation and local reflexes . Light iTraditionally, the PLR is divided into afferent and efferent pathways based on clinical manifestations. As shown in 2+ concentration and ryanodine receptor (RyR) channels in the iris sphincter muscle [The efferent pathway includes the projection from the PON to the EWpg and ends up at the sphincter pupillae muscle, from where the postganglionic fibers release acetylcholine (ACh), which acts on the muscarinic receptors on the sphincter muscles and leads directly to pupillary constriction . This phr muscle . Pupillar muscle .It is generally accepted that light induces pupil contraction via the activation of the parasympathetic pathway, while the sympathetic system only has a tonic role . The cenPrevious research has found the existence of neural connection from the pretectum to cervical sympathetic nerves . MeanwhiHowever, the physiological manipulations, such as the presentation of noxious or anxiety-provoking stimuli and extremes in ambient temperature, also affect the activity of LC, which lead to distinct patterns of change in arousal and autonomic function . The pupThere are no blood vessels in the normal cornea, while the limbus contains abundant blood vessels that supply nutrients and oxygen. Similar to the cornea, the scleral stromal layer has no blood vessels, except those passing through. However, the sclera surface and optic nerve lamina cribrosa are rich in blood vessels and form a vascular network. These arteries are derived from the ophthalmic artery, which is the only artery supplying the eye. This blood vessel receives autonomic innervation and mainly supplies the uvea and retina. Hence, nearly all ocular circulation is modulated by autonomic nerves, except the retinal blood vessels .The choroidal circulatory system is responsible for supplying the photoreceptors and the retinal pigment epithelium. Reduced blood flow can cause a rapid loss of photoreceptor cells . GeneralThe SSN–PPG circuit mediates choroidal parasympathetic vasodilation, which seems to contribute to ChBF pressure regulation in case of low arterial blood pressure (ABP) ,33. In mBased on immunohistochemical experiments in pigeons, the PPG seem to be composed of three to four main sub-ganglia connected to each other. Each main nerve contains 50–200 neurons, as well as several small ganglia. These neurons in birds release VIP and NO, and possibly Ach . In mammIn both mammals and birds, the sympathetic nerves innervating the choroid are derived from noradrenergic nerve fibers of the cervical ganglia . StimulaAqueous humor (AH) is a transparent fluid found in the anterior and posterior chambers. It is mainly responsible for nutrient delivery and IOP regulation. It is produced by the ciliary epithelium and exits the eye through two independent outflow pathways, which involves the trabecular meshwork (TM) and unconventional pathway . Recent evidence has suggested that another unconventional pathway (uveolymphatic route) has potential for maintaining IOP .The parasympathetic innervation of ciliary body blood flow is mediated by the postganglionic nerve fibers (VIP+) of the PPG ,181. StiNoradrenergic postganglionic neurons in the SCG provide sympathetic innervation. Unilateral sympathetic nerve stimulations (SNS) in rabbits have suggested frequency-dependent sympathetic vasoconstriction in the eyes . The micThe trigeminal sensory nerves contain SP and CGRP, which are released as vasodilators in response to pressure or temperature stimuli. An intracameral injection of CGRP produced distinct vascular effects and increases IOP .Aqueous humor production involves three mechanisms: active secretion, diffusion, and ultrafiltration. Of these, active secretion predominates and accounts for approximately 80–90%. Non-pigmented epithelial cells of the ciliary body are recognized as the sites for active AH secretion . The secNeural modulation of AH production seems to be complicated and confusing. This conclusion is based on the existence of cholinergic and adrenergic receptors and second messenger systems in the ciliary epithelium, the diurnal variation in AH generation, and the various effects of drugs  183,189,191,192.The AH is produced by the ciliary process. It enters the anterior chamber from the gap between the lens and the iris, passing through various areas of the TM and the inner wall of the Schlemm canal, before entering the superior scleral vein and returning to general venous circulation . The entBy contracting the ciliary muscles, muscarinic cholinergic agonist drugs mediate TM/SC relaxation and expansion, in which the iris does not participate . In contIn the uveoscleral pathway, the AH flows into the ciliary body from the anterior chamber, enters the ciliary body clefts, passes through the suprachoroidal space, and leaves the eye through the vortex veins or into the sclera ,201. JohThe amount of outflow via the unconventional route varies among different species, approximately ranging from 3% to 82% . Thus, tThe episcleral vasculature contains numerous arteriovenous anastomoses and a muscle-rich venous network, which provide an anatomical basis for autonomic innervation ,206. SinPrevious research on primate animals described numerous nerve endings staining for NAPDH diaphorase, TH, and relatively fewer NPY, VIP, and vesicular acetylcholine transporter-positive nerve terminals surrounded all the episcleral vessels; meanwhile, CGRP and SP-positive terminals were also observed . SimilarThe accommodation reflex, also referred as near reflex, is the response for focusing on near objects . The affRecent research on primates suggested that the premotor neurons controlling the lens of unilateral eye are distributed in the bilateral midbrain. By retrograde tracing methods, some of the premotor neurons in the supraoculomotor area and central mesencephalic formation were doubly labeled, while others were labeled from either the ipsilateral or contralateral eye, which suggest the both monocular control and binocular control of lens accommodation .Because of all the recent and past work that has been performed, lens accommodation to vergence angle and other aspects of eye movements are connected ,216,217.Because of all the characteristics of anatomy and physiological effects discussed here, more and more studies have focused on the clinical applications of ANS agents. Apart from the drugs listed in the above tables, some other progress is described below.Muscarinic receptor inhibitor (such as atropine) was proved to participate in the eye growth regulation and inhibit myopia induction in both mammalian and avian eyes ,220. AddPilocarpine, a muscarinic receptor agonist, was observed to cause axial thickening of the lens and shallowing of the anterior chamber after instillation ,227. A mAs a specific agonist of the M3 muscarinic receptor, cevimeline has beneficial effects on dry eye symptoms in patients with Sjögren’s syndrome ,231. HowThe neuroprotective effects of NPY were confirmed by attenuating retinal neural apoptosis and maintain inner retinal vascular integrity. This neuropeptide may have potential therapy values in diabetic retinopathy .This review highlights the multiple roles of the ANS in controlling the physiological processes of the eye. These roles include the adjustment of the pupils exposed to ambient light, ocular circulation in each tissue, and IOP regulation. Through these processes, the ANS contributes to regulating the accommodative status and sustaining intraocular homeostasis. Although differences exist in the precise wiring to the targets and innervation patterns among species, these autonomic nerves play an irreplaceable role in the eye.Owing to the relationship between autonomic disorders and clinical problems, several commonly used drugs, such as cholinergic and adrenergic drugs, function through these autonomic pathways to correct disordered physiological processes. However, current drugs have their limitations. Understanding the role of the ANS will enhance the understanding of disease mechanisms that may subsequently lead to new drug therapies.It has become increasingly apparent that these autonomic pathways are far more complex than that which has been explored to date. In the future, refining our understanding of the ocular ANS will provide new ideas for further investigations. Here, we list some urgent problems that need to be elucidated, as follows:(1) Central control of physiological processes in the eye was hard to detect and clarify. However, the development of new techniques makes it possible to provide new insights into the central control of the eye.(2) Detailed mechanisms of the AH outflow pathway. What we know about AH outflow pathway is pretty superficial. We still have a long way to go in understanding the normal physiology, or even the basic pathophysiology of the outflow dysfunction leading to POAG.(3) Pathways of transformation from visual information to autonomic activity. The ipRGCs are activated by ambient lighting projected widely throughout the brain, subsequently mediating visual functions and circadian rhythms. Our mood, alertness, learning, regulation of body, and even visual perception are affected as well. However, the question of how this process works remains unclear and needs further identification.


Cell adhesion is a critical component of malignant transformation, cancer progression, and the development of chemoresistance. Adhesion molecules allow tumor cells to invade the tissues surrounding the primary tumor and to extravasate during metastasis. In addition, adhesion molecules serve as anchors that position tumor cells in close proximity to immune and stromal cells. This positioning is required to establish intercellular connections and communication, which eventually re-educates the tumor microenvironment to support the cancer.Adhesion and mechanotransduction are closely linked. Adhesion molecules enable cells to sense the physical properties of the extracellular matrix and integrate mechanical stimuli into cellular functions. This intracellular signal transduction downstream of adhesive contacts is energy-dependent. During cancer progression, malignant cells are surrounded by increasing levels of tissue pressure, density, and hypoxia, as well as altered ATP levels, reflecting the increased nutrient demand that is characteristic of malignant cells.Emerging evidence suggests that cell adhesion could be operating under the control of cell metabolism. Indeed, the second messengers and signaling pathways that control cellular respiration and nucleotide synthesis are similar to those controlling immune and cancer cell adhesion. However, we are just beginning to understand some of the common molecular links connecting metabolism and adhesion in cancer, which is underlined by the articles in this Research Topic.Urra et al. describe in their review article factors arising from the remodeling of the extracellular matrix of the tumor, which is characterized by modulations of the stiff tumor microenvironment. They describe how these modulations are linked to the malignant phenotype regarding mitochondrial oxidative phosphorylation, glutamine consumption, and increased production of mitochondrial reactive oxygen species. Among the key molecular hubs linking the migratory and metabolic transduction are focal adhesion kinase (FAK), 5′ adenosine monophosphate-activated protein kinase (AMPK), a highly conserved sensor of intracellular adenosine nucleotide levels, and its downstream target mammalian target of rapamycin (mTOR). These molecules are also central components of the bone marrow microenvironment of acute leukemias, where the interplay between cell migration, adhesion, and metabolic components is indispensable for bone marrow niche stability, as described by Ashok et al., AMPK is thereby a major link between integrins and metabolism, while serving as a stress sensor.Sharma et al.In acute lymphoblastic leukemia, central nervous system (CNS) involvement is a major clinical concern. Some of the major adhesive players of the bone marrow, e.g., the integrin very late antigen-4 and various other integrins and the downstream components described above, play relevant roles in the CNS microenvironment. However, the metabolic adaptations to create the permissive microenvironment for leukemia adhesion and thus colonization in this nutrition-poor environment are not yet understood well, as outlined by Garcia et al. focus on the brain microenvironment and its metabolic changes. The authors discuss the signaling pathways involved in glioblastoma metabolism and their contribution to tumor cell invasion. One example is the link between glutamine-related pathways and mTOR complex 1 (mTORC1) signaling. The authors illustrate the recent dynamic view of the complexity of interactions of the genotype and the microenvironment.Joechle et al. provide evidence that dual pharmacological inhibition of mTORC1 and mTORC2 has the potential to diminish oncogenic signaling in intrahepatic cholangiocarcinoma cells. Matrix metalloproteinases (MMPs) are involved in the degradation of the tumor environment to release tumor cells for migration. In this work, the authors establish a link of tumor cell motility within the extracellular matrix, modulation of MMP2 and MMP9 expression and mTORC inhibition. Dual inhibition of mTORC might offer a useful option to circumvent the compensatory upregulation of survival signaling and accompanied resistance to current therapy strategies.In their original report, Garcia-Miranda et al. dissect in their original report how the adipokine leptin influences tumor cell migration of breast cancer cell lines and suggest a role for basal autophagy or leptin-induced autophagy in leptin-induced migration and ERK phosphorylation, linking obesity and cancer cell migration.Previous data show a link between mTOR and autophagy. Upon nutrient starvation and stress condition, mTOR is itself inhibited, which results in induction of autophagy. Emerging evidence suggests an involvement of autophagy in cancer cell motility and invasiveness and in the modulation of dynamic cell adhesion, particularly in the context of epithelial-to-mesenchymal transition. Urciuoli et al. contribute to this discussion by providing evidence that modulating Lamin A/C expression impacts on osteosarcoma cell aggressiveness and adhesion properties. They suggest considering the mechano-environment of osteosarcoma as a crucial factor in the onset, development, and progression of this bone tumor.Lamins are multifunctional proteins that are often aberrantly expressed or localized in tumors and bridge mechanical forces to the cell nucleus. Misregulation or mutations in lamin, particularly lamin A can be connected to the disregulation of AMPK/TOR/autophagy signaling. The nature of lamin function in cancer is, however, very complex and its role in tumor cell migration is controversially discussed. In summary, in this research topic we have presented a collection of articles focusing on how adhesion and metabolism, two facets of the tumor microenvironment, influence each other. By describing the currently known key components of this interplay, the authors hope to contribute to a deeper understanding and better characterization of this important but not yet well understood field.


Disease ecology and disease biogeography are complementary fields for the study of infectious diseases, both fields focus on the distribution and abundance of pathogens across scales. While disease ecology focuses on the study of disease systems at the local level and during short periods, disease biogeography expands the study of disease systems over large areas and prolonged periods. What is local vs. regional extents and what is short vs. prolonged periods is debatable. We propose that the study of the ecology and biogeography of disease systems takes place along a continuum, were the limits of ecology and biogeography are blurred. To demonstrate that disease systems operate from the local to the global and can be tracked from the fine to the coarse, this Research Topic compiles study cases that highlight concepts, methods, and applications of ecology and biogeography to untangle spatial patterns of disease phenomena across scales and for diverse infectious diseases.Niehaus et al. provide a local-level characterization of the ecology of Toxoplasma gondii in wildlife across diverse landscape configurations. Toxoplasma gondii is a generalist protozoan parasite affecting hundreds of mammals and birds, and is particularly virulent in some species of Neotropical primates. In their study, Niehaus et al. employed a modified agglutination test to detect antibodies against T. gondii in serum samples from captive and free-ranging Neotropical primates from Costa Rica, a small country in Central America. The authors found widespread exposure of howler , spider (Ateles geoffroyi), capuchin (Cebus imitator), and squirrel (Saimiri oerstedii) monkeys to T. gondii. Captive primates revealed higher seroprevalence (59.6%) compared to free-ranging wild primates (11.6%). Nevertheless, among free-ranging animals seroprevalence varied among species, which could be relevant for some primates of conservation concern and for which T. gondii infections are particularly virulent. Niehaus et al. report that landscape factors such as percentage of forest cover and precipitation could explain T. gondii exposure in primates. This finding suggests that local-level microclimatic conditions could play a role in the maintenance of T. gondii in the environment, facilitating infections in wildlife.Winter et al. examined Chronic Wasting Disease in white-tailed deer (Odocoileus virginianus) in the north portion of Virginia, United States. Chronic Wasting Disease is caused by a pathogenic prion protein for which there is limited information about its ecology and biogeography. To address the question “Is the distribution of Chronic Wasting Disease predictable by landscape data?” the authors used a machine learning protocol to contrast the distribution of cases of positive deer against satellite-derived vegetation data during the 2009–2020 period. After an exhaustive evaluation of the predictive capabilities of the models, the authors concluded that Chronic Wasting Disease has a measurable and predictable ecological signal expressed as the capacities of models to predict the distribution of new cases better than by chance based solely on satellite-derived vegetation data. The mechanisms behind this phenomenon remain unknown but could be related to (i) models mirroring the ecology of deer or (ii) models reconstructing landscapes where prion transmission is more likely. The last hypothesis is supported by the fact that Chronic Wasting Disease prions remain infective during long periods (years) in the environment and that specific types of soil and vegetation have proved to augment the infectivity of prions , which is among the most relevant parasite affecting salmonid fishes. Authors explored the distributional range of sea louse along the coastal areas of southern Chile, a medium-size country in South America. In their study, Lepe-Lopez et al. linked sea louse locality reports with data of sea water temperature, salinity, and current velocity to reconstruct the suitable areas for the species to disperse and, in turn, infect salmonids. For a more comprehensive assessment of the biogeography of sea louse, Lepe-Lopez et al. projected their models to the next decades and across diverse climate change scenarios. Authors were able to reconstruct the distributional expansion, contraction, and shift of sea louse for the next 80 years across a large latitudinal gradient, which has implications to the native fishes and the intensive aquaculture industry in Chile. This contribution provides detailed recommendations to the control and management of sea louse in salmon in Chile and also brings important insights on the biogeography of parasites of marine fishes.Although fish parasites are impressively diverse and have received comprehensive attention from evolutionary and ecological approaches , the litGettings et al. assessed the spatial and temporal trends of Anaplasma spp. and Borrelia burgdorferi, two widespread zoonotic pathogens, across the continental United States. The study included over 30 million serological test results for Anaplasma spp. and B. burgdorferi in dogs during the 2013 and 2019 period. Using a Bayesian spatio-temporal binomial regression model, the authors found spatial correlation on the distribution of cases: higher prevalences clustered in neighbor counties, and prevalence decreased when geographic distance increased. Gettings et al. studies show that Anaplasma spp. and B. burgdorferi occur in tractable and predictable “hotspots” where transmission is more likely, especially along the Northeast region of the United States. The authors note a plausible relationship between the rise of Anaplasma spp. seroprevalence and cases of human anaplasmosis. This study exemplifies the role of dogs as sentinels of zoonotic pathogens transmitted by ticks at the continental scale. Similarly, detection of patterns of decrease in prevalence of these pathogens in dogs in some endemic areas could represent encouraging effects of public education and use of preventative practices. Overall, the study concludes in that the data suggests an increase in seroprevalence of Anaplasma spp. and B. burgdorferi in areas known to already have high prevalence.At a larger geographic extent, Robles-Fernández et al. explored aspects of the biogeography of dengue spillover using a macroecological approach. The authors measured the linkages between species known to be susceptible to dengue virus infection and those unknown to be susceptible. Linkages were measured based on geographic, climatic, and phylogenetic similarities between a set of 10 wildlife species broadly reported susceptible to dengue and a set of 1,778 species of mammals across the America. The authors measured the geographic, climatic, and phylogenetic distances between known and unknown dengue hosts to determine the likely host breath of dengue virus across the continent. Their analytical approach combines datasets from diverse sources, at different scales, and from hundreds of taxa, integrated using correlative machine learning classification tools. Their multiscale analytical framework was guided using biogeographic theory that overcomes previous methods to predict suitable hosts for pathogens based solely on phylogenetic distances and traits of candidate hosts. From this disease biogeography approach, we learned that dengue transmission can occur in specific areas, across narrow landscape characteristics, and in predictable wildlife species. More specifically, Robles-Fernández et al. found that wildlife susceptibility to dengue infection was more likely among species phylogenetically close to known hosts, occurring in warm and arid landscapes, and distributed in the tropics. Among the potential new hosts of dengue, the common vampire bat (Desmodus rotundus) was predicted with the highest probability.Morand and Lajaunie assessed the potential relationships between human infectious diseases and deforestation and expansion of monoculture crops. In their study, the authors measured data on forest cover, oil-palm monoculture harvested area, and human demography during the period 1990 and 2016, combined with outbreak data from 116 zoonotic and 69 vector-borne diseases for the same period. The study revealed an alarming rate of increase in the number of zoonotic and vector-borne diseases outbreak in the last three decades. Morand and Lajaunie also found that, during this period, the area of oil palm monoculture has dramatically increased at the same rate of disease outbreaks. Indeed, the study reports significant association between the increase of oil palm and vector-borne diseases, especially in tropical countries. Nevertheless, relationships between landscape change and disease were asynchronous among global regions. For instance, tropical regions showed high forest loss in association with increasing outbreaks of vector-borne diseases, while temperate regions showed forest gain associated with increasing outbreaks. Together, Morand and Lajaunie studies add to the limited available quantitative evidence linking deforestation with human infectious diseases.Toxoplasma gondii antibodies in primates, prion-derived Chronic Wasting Disease in deer, and sea louse in salmonids were conducted at spatial resolutions going from hundreds of meters to a few kilometers. Thus, these investigations elucidate elements acting locally on the ecology of the disease systems studied. The regional-level study of zoonotic vector-borne pathogens in dogs used counties as the finest geographic unit and moths as the finest temporal unit to cover a comprehensive portion of the North America region. The study of likely wildlife hosts of dengue virus in the Americas used data form the molecular level, to the climatic level at ~20 km, to the geographic contexts covering entire species ranges that included multiple Latin American countries. A global-level study explored the effects of global landscape change on the risk of zoonotic diseases and revealed that patterns found in tropical regions are not necessarily consistent with patterns in many temperate countries. This overview of disease ecology and biogeography exemplifies the need for multiscalar assessments of infectious diseases, going from ecology to assess local processes, to biogeography to assess continental and global patterns.The local-level studies of Local-level disease investigations were the most frequent study cases presented in this Research Topic. Local-level disease ecology research has advanced our understanding of the spread of infectious diseases. Abundant local-level studies and limited availability of regional- and global-level studies seem to be the dominant pattern in disease ecology research . Thus, mper se is needed. Third, due in large part to data limitations, models are simplified views of complex host-pathogen dynamics. That is, most disease modeling experiments assume species to be susceptible or resistant to infection (a binary representation of infection), instead of considering susceptibility as a continuous dimension where different levels of susceptibility are considered across individuals, populations, and species. Fourth, empirical evidence suggests that the capacities of a pathogen to cause disease, as a decrease in the fitness of the host, also known as virulence, is also a property of the host, not only of the pathogen , data of the presence of the source of transmission , or data of the source of the pathogen ; thus, ecology and biogeography research accounting for the pathogen pathogen . In otheLEE and SM were involved in writing the article and agreed to the final version of this editorial. All authors contributed to the article and approved the submitted version.LEE was supported by the Center for Emerging, Zoonotic, and Arthropod-borne Pathogens (CeZAP) Interdisciplinary Team-building Pilot Grant, the Virginia Department of Wildlife Resources, and the National Science Foundation Human-Environment and Geographical Sciences Program, grant 2116748. SM is supported by French ANR project FutureHealthSEA (ANR-17-CE35-0003-01).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cardiovascular diseases such as ischemic heart diseases or stroke are among the leading cause of deaths globally, and evidence suggests that these diseases are modulated by a multifactorial and complex interplay of genetic, environmental, and lifestyle factors. Genetic predisposition and chronic exposure to modifiable risk factors have been explored to be involved in the pathophysiology of CVD. Environmental factors contribute to an individual’s propensity to develop major cardiovascular risk factors through epigenetic modifications of DNA and histones via miRNA regulation of protein translation that are types of epigenetic mechanisms and participate in disease development. Periodontal disease (PD) is one of the most common oral diseases in humans that is characterized by low-grade inflammation and has been shown to increase the risk of CVDs. Risk factors involved in PD and CVD are determined both genetically and behaviorally. Periodontal diseases such as chronic inflammation promote DNA methylation. Epigenetic modifications involved in the initiation and progression of atherosclerosis play an essential role in plaque development and vulnerability. Epigenetics has opened a new world to understand and manage human diseases, including CVDs and periodontal diseases. Genetic medicine has started a new era of epigenetics to overcome human diseases with various new methodology. Epigenetic profiling may aid in better diagnosis and stratification of patients showing potential predisposed states for disease. A better understanding of the exact regulatory mechanisms of epigenetic pathways driving inflammation is slowly emerging and will aid in developing novel tools for the treatment of disease.  Cardiovascular diseases (CVD) are considered among the leading causes of deaths worldwide . GeneticPeriodontal disease (PD) among the most common oral diseases is well known to affect the world population  and is cOral and systemic disease connections have been a constant issue of discussion in scientific literature as “infections in the mouth can cause damage elsewhere in the body”, and two hundred possible associations between oral and systemic conditions are reported . The relAdditional research is warranted to better understand the relationship of PD and CVD to find out whether oral health assessment and management of PD could improve oral and general health and quality of life and be of relevance in the management of patients with CVD. This review aims to explore the current research to appreciate the plausible biological mechanism that links periodontitis with CVD, especially focusing on the emerging field of epigenetics. In this review, we have explored different frontiers in epigenetics and observe its implications in PD and CVD associations.Epigenetics is the study of mitotically and meiotically heritable changes in gene expression that are not dependent on DNA sequence, and the epigenome is the overall epigenetic state of an organism ,29. EpigHelicobacter pylori [The environmental determinants, known and theorized, responsible for driving the epigenetic mechanisms forward include but are not limited to external factors such as life style, exposure to heavy metals such as mercury, radiations such as ultraviolet (UV), smoking, and infectious agents such as r pylori ,34,35. Tr pylori .A number of epigenetic processes have been identified in the literature and discussed in the below headings specifically periodontal diseases and cardiovascular diseases. Some of the essential mechanisms include DNA methylation, post-transcriptional histone modifications, including methylation, acetylation, ubiquitylation, sumoylation, and phosphorylation, which also affect the structure of chromatin and RNA-associated gene silencing  ,36. Rega3) at the cytosine residues present within the cytosine–phosphate–guanine (CpG) dinucleotides found at the promoter region of the specific gene [The process of DNA methylation and histone modification has been deemed the most common of the epigenetic processes in the medical literature taking place in human cells ,37. DNA fic gene ,38. It ific gene . As a reHistone modifications include the process of acetylation or deacetylation through enzymatic action, which results in chromatin remodeling that then influences gene expression ,39. The Epigenetics has, as a matter of fact, been used to explain the inexplainable genetic conundrums occurring in the fields of medicine and, more recently, dentistry as well. For example, some diseases to have suspected potential epigenetic mechanisms in their pathogenesis include cancer, depression, asthma, chronic obstructive pulmonary disease (COPD), and major psychosis, among others . Even inPeriodontal disease entails a pathological process that involves the whole of the tooth-supporting structures of the tooth, known as the periodontium; the gingiva, alveolar bone, cementum, and periodontal ligament (PDL) . PeriodoAs is apparent in the literature, the effect of genetics and its impact of periodontitis pathogenesis has been a source of concern and research . DNA metPeriodontitis and periodontal disease construe significant destruction of the tooth-supporting structures and loss of bone with eventual loss of teeth themselves. Epigenetic mechanisms in turn regulate the effect of cytokines, such as interleukin-1 (IL-1) and IL-6, which are responsible for the progression of periodontitis . In theiPorphyromonas gingivalis into their oral cavities. A novel histone deacetylase inhibitor (HDACi), 1179.4b, was then administered to the one of the experimental groups of mice, which showed a significant reduction in bone loss indicating that suppressing the associated epigenetic mechanism is responsible for osteoclast-mediated bone loss. Similarly, Treponema denticola also acts through various epigenetic mechanisms leading to a consequent loss of tooth-supporting alveolar bone frequently seen in periodontal disease [Of the many signs and symptoms related to periodontal disease, one of extreme significance includes alveolar bone loss leading to the subsequent loss of teeth. Cantley et al.  in their disease ,48.As the first line of defense in the oral cavity is the oral epithelial cells against foreign bodies including bacterial/viral pathogens, specific epigenetic changes can be induced by the pathogens resulting in histone acetylation and demethylation. Furthermore, the activation of toll-like receptors (TLRs) and pathogen-recognition receptors (PRRs) can substantially stimulate modifications of histones in the epithelial cells of the oral cavity . Loss ofEpigenetics have opened a new world to understand and manage human diseases, including CVDs . GeneticEpigenetic modifications involved in the initiation and progression of atherosclerosis play an essential role in plaque development and vulnerability . AccumulMethylation is also suggested as an indicator of MI . AbundanOral inflammatory diseases have been shown to contribute to disease states and inflammatory pathology at sites distant from the oral cavity. Studies highlight how the inflammatory status of the oral cavity can have a profound impact on systemic health. Periodontitis, an inflammatory disease of the oral mucosa, is epidemiologically associated with other chronic inflammation-driven disorders, including cardio-metabolic, neurodegenerative, and autoimmune diseases and cancer.The potential causal link between periodontitis and its comorbidities is further strengthened by recent experimental animal studies establishing biologically plausible and clinically consistent mechanisms whereby periodontitis could initiate or aggravate a comorbid condition. This multi-faceted “mechanistic causality” aspect of the link between periodontitis and comorbidities is the focus of this review. The understanding how certain extra-oral pathologies are affected by disseminated periodontal pathogens and periodontitis-associated systemic inflammation, including adaptation of bone marrow hematopoietic progenitors, may provide new therapeutic options to reduce the risk of periodontitis-associated comorbidities. Emerging evidence from interventional studies indicates that local treatment of periodontitis ameliorates surrogate markers of comorbid conditions. In recent years, genetic medicine has started a new era of epigenetics to overcome human diseases with various new methodology . The curA most recent prospective study conducted over 13 years has demonstrated that severe periodontitis is associated with an increased incidence of CHD independent of established risk factors . Risk fa


Recent evidence that microbes influence mood and behavior via the gut-brain axis has opened up new avenues for research into neurological disorders. Hence, many studies now employ multidisciplinary approaches assessing for changes in microbial diversity, neuroinflammation as well as alterations in neuronal circuitry that impact brain function in health and disease. Such collaborative research was virtually unheard of in previous decades but holds remarkable promise for identifying novel pathways and therapeutic targets within the gastrointestinal tract to treat brain disorders. This editorial highlights these exciting developments in neuroscience, microbiology, and immunological research by examining 13 articles focused on how the nervous system interacts with bacteria in preclinical and clinical settings. A common theme is the dissection of complex interactions between the nervous system and bacteria as well as the resulting influences on inflammatory pathways, symptoms, or behavior in patient studies and mouse models. Specifically, neuronal-microbial interactions in the context of nervous system disorders ranging from autism, Attention Deficit Hyperactivity Disorder, Alzheimer's Disease and Major Depressive Disorder to migraine and epilepsy are investigated. Overall, we propose that via leveraging our understanding of the gut-brain axis, the modulation of gut microbes leading to significant benefits for brain health can become a reality.The recent years have seen substantial progress in the understanding of gut-brain interactions. Today, evidence is mounting that the microbiota-gut-brain axis is a key contributor to healthy brain development and function. Accordingly, gastrointestinal (GI) problems and microbial dysbiosis have been linked to several neurological and neuroinflammatory disorders. Consequently, targeting gut microbiota composition to regulate peripheral and central inflammation could serve as means of developing novel treatments or disease modifying strategies for several key neuroinflammatory conditions. This is a rapidly emerging field of neuroscience research and is highlighted in the current issue.Zhao et al. showed that emotional behavior is among those behaviors affected. Antibiotic-treated mice with a lower richness and diversity of microbiota display increased anxiety-like, depression-like, and aggressive behaviors . These effects on behavior may be caused by a dysregulation of the immune and endocrine system. In line with this, a link between altered microbiota composition and immune system abnormalities was also reported by Sauer and Grabrucker. In their study, a deficiency in the essential trace metal, zinc, changed the composition of the microbiota. Of interest, zinc deficiency has been linked to depression-like behavior in rodents. In this study, the microbial changes were accompanied by increased inflammatory cytokine levels. Furthermore, this study reported abnormal GI morphology and increased GI permeability in these mice, hinting that an increase in intestinal barrier permeability may mediate pro-inflammatory processes (Sauer and Grabrucker).This Research Topic is dedicated to understanding the influence of microbes on brain health. Alterations in the gut microbiota may affect gut-brain signaling via neuronal, endocrine and immunological mechanisms, thereby influencing a range of neuronal network activities and ultimately host behaviors. Sauer and Grabrucker, the role of microbes in modifying the permeability of the mucosal epithelium lining the GI tract was discussed in a review of microbiome-derived neurotoxins by Lukiw. How microbiota might impact the properties of the mucus membrane in the GI tract could also be important in brain disorders. Lukiw discussed the role of the zinc metalloproteinase , which is released by Bacteroides fragilis microbes. Fragilysin cleaves tight junction components such as cadherins which can alter the permeability of mucosal and blood-brain barriers. This action would also alter neuro-immune interactions and is age-related and progressive. An important part of the epithelial barrier of the GI tract is the mucus biofilm, which provides a supportive environment for specific microbial populations. Because patients with many neurological diseases have GI issues and microbial dysbiosis, Herath et al., reviewed the evidence for mucus as a potential treatment target in the context of neurological disease . This review outlined a range of pathways by which gene mutations associated with brain disorders could influence the GI tract's mucus and its microbial populations.Relevant to the findings of Sharna et al.). Surprisingly, the weight of the caecum  was reduced in these mice. When analyzing the enteric nervous system in the caecum, mutant mice had more neurons overall and a higher proportion of neurons synthesizing the major inhibitory neurotransmitter (nitric oxide) of the gut. In the same study, Sharna and coauthors found changes in the gut immune system. In these mice, macrophages were labeled with Iba-1 (a marker of microglia in the brain) in the gut-associated lymphoid tissue of the caecal patch. Mutant mice had more Iba-1 labeled macrophages, and these macrophages were smaller and rounder in shape. Interestingly, this could indicate increased immune activity in the autism model. More broadly, these findings suggest that communication between the nervous system and immune cells could be altered in neurological disorders such as autism, and that the gut microbiota plays a key role in regulating such interactions.Sharna and colleagues investigated neuro-immune interactions in a mouse model of autism expressing a gene mutation in the nervous system  and discuss the associated pathogenic role of LPS in neurons of Alzheimer's disease brains . The encapsulation of neurons by LPS reduces the release of mRNA from the neuronal nuclei, likely via the interaction of Aβ42 with nuclear pore complexes. Therefore, manipulating the gut microbiome by diet and pre/probiotics to reduce neurotoxic effects within the CNS is an exciting avenue for future research. In line with these findings, Askarova and colleagues brought together a wide range of research to link the brain-gut-microbiota axis and Alzheimer's Disease . These authors noted that several lifestyle factors linked to Alzheimer's disease also drive microbiome changes, such as dietary habits, sedentary behavior, and disturbances in circadian rhythms. Changes in the oral microbiome in addition to chronic periodontitis have also been associated with Alzheimer's Disease , lifestyle factors, and both the oral and GI microbiome in Alzheimer's Disease. The accumulation of gut bacteria-derived LPS in neurons is associated with Alzheimer's disease. Wan et al. investigated the gut microbiota in children with ADHD. Their results of a case-control study reveal that specific bacteria are significantly increased or decreased in children with ADHD and align with alterations in neurotransmitter metabolic pathways . However, as Isaiah et al. point out, in addition to the gut signaling to the brain, the reverse  may occur as well , a phenomenon that is currently understudied in the context of ADHD. Yong et al. discussed the role of the microbiota-gut-brain axis, stress, and lifestyle factors for major depressive disorder (MDD) . The antidepressive effects of probiotics and potential biological mechanisms (including the production of metabolites) to benefit gut health were compared in clinical and animal studies. In addition, Westfall and Pasinetti discussed the role of dietary polyphenols as a possible diseases-modifying treatment for depression . Their review highlighted that synbiotics that combine probiotics with dietary polyphenols such as those found in fruits, tea, herbs, cereal, or wine might be a novel therapy for MDD. This may occur via modulation of multiple metabolic pathways, including the breakdown of kynurenic acid and tryptophan , serotonergic mechanisms, and immune pathways, including via interferon-gamma and inflammasome activation. Importantly, these authors highlight that the heterogeneity of MDD must be taken into consideration when evaluating the potential therapeutic effects of probiotics.Gut microbiota profiles may contribute to behavioral symptoms associated with a range of neurological disorders, including attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD). Chen et al.). Future randomized control trials that assess the efficacy of controlled delivery of “safer” and “less inflammatory” microbiota as a means of controlling migraine frequency are warranted.Migraine is a common, recurrent, and disabling neurological disorder that is associated with alterations in the neurovascular and immunological system. The changes in the nervous system activity that occur in the setting of migraine are commonly associated with gut disorders such as irritable bowel syndrome and inflammatory bowel disease. Chen and others examined the potential for interactions between the nervous system and bacteria in their study of fecal samples from 108 elderly women with and without migraine, which revealed a significant decrease in species diversity and metabolic functions in the gut microbiota of migraine sufferers. These findings suggest that monitoring harmful bacteria such as Clostridium could help with alteration of migraine frequency and potentially even prevention of disease  in epilepsy (Rubin and Glazer). This work highlighted that cases of subclinical infection are vastly more prevalent than reported pertussis cases and describe incidences of epilepsy occurring after BP infection. Further research into the relationship between epilepsy and BP infection, including BP screening, medical history, and pertussis vaccination is required to assess for an association between BP and seizures.Epilepsy is another neurological disorder for which a role for the microbiome is understudied. The ketogenic diet is commonly used to treat medically refractive seizures and epilepsy. Importantly the anti-seizure effects of the ketogenic diet are thought to be mediated by the gut microbiome (Olson et al., In summary, this Research Topic brings together evidence for microbial influences in a range of neurological, neuropsychiatric and neurodegenerative disorders including autism, Alzheimer's Disease, Major Depressive Disorder, migraine, and epilepsy. Gut microbiota are thought to influence not only local immunological processes, but also exert effects on the CNS through the disruption of the gastrointestinal mucosal barrier and BBB. The future of gut-brain research holds promise for identifying novel therapeutic approaches to treat many disabling CNS conditions traditionally considered to be associated with dysfunction of the CNS itself. Further research into how modifying gut microbes influence processes in the brain has enormous potential.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.MM has served on an advisory board for Merck and received speaker honoraria from Merck and Biogen. Her institution receives funding from Merck, Australian National Health Medical Research Council, Brain Foundation, Charles and Sylvia Viertel Foundation, and MS Research Australia. The remaining 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.


Metastasis is the leading cause of cancer death and can be realized through the phenomenon of tumor cell fusion. The fusion of tumor cells with other tumor or normal cells leads to the appearance of tumor hybrid cells (THCs) exhibiting novel properties such as increased proliferation and migration, drug resistance, decreased apoptosis rate, and avoiding immune surveillance. Experimental studies showed the association of THCs with a high frequency of cancer metastasis; however, the underlying mechanisms remain unclear. Many other questions also remain to be answered: the role of genetic alterations in tumor cell fusion, the molecular landscape of cells after fusion, the lifetime and fate of different THCs, and the specific markers of THCs, and their correlation with various cancers and clinicopathological parameters. In this review, we discuss the factors and potential mechanisms involved in the occurrence of THCs, the types of THCs, and their role in cancer drug resistance and metastasis, as well as potential therapeutic approaches for the prevention, and targeting of tumor cell fusion. In conclusion, we emphasize the current knowledge gaps in the biology of THCs that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression. Metastasis accounts for most cancer fatalities and is the least understood stage of tumor progression. The process of metastasis consists of a series of linked and sequential steps: invasion, intravasation, survival during circulation, extravasation, the establishment of micrometastases, and the growth of macrometastases . The undAccording to the “seed and soil” hypothesis, metastasis is governed by interaction and cooperation between the cancer cells (seeds) and the host organ (soil) . HoweverCell fusion is a process in which two or more cells fuse and become one due to a common membrane. Cell fusion leads to tumor hybrid cells (THCs) with a common genotype of parental cells  but withIn this review, we discuss the factors and mechanisms involved in the occurrence of THCs, their types and role in cancer drug resistance and metastasis, and potential therapeutic approaches for the prevention and targeting of tumor cell fusion. In conclusion, we emphasize the current knowledge gaps in the biology of THCs that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression.The mechanisms governing tumor cell fusion are poorly understood. Under normal conditions, fusion events are rare but increase dramatically in pathological conditions such as tissue injury and inflammation . The proCell fusion is promoted by fusogenic proteins. These proteins assemble into unilateral or bilateral complexes, which determine the site of cytoplasmic membrane fusion and overcome the energy barriers. The main fusogens are syncytins, which play a key role in developing human placental syncytiotrophoblasts . SyncytiViruses are another trigger for cell fusion , facilitWhen fusogens are not activated, or the fusion mechanism remains unknown, and the actin skeleton can serve as another driver of the occurrence of THCs. Examples include the formation of actin protrusions that promote the fusion of macrophages and myoblasts . For insThe phosphatidylserine (PS), a membrane phospholipid, is also involved in cell fusion . A link Cell fusion depends on the type of cancer and normal cells, as observed in the co-culture of human glioblastoma U87 and U373 cells with MSCs. In particular, more hybrids were formed from U87 cells than from U373 cells. The underlying mechanisms are not yet clear and most likely related to specific gene expression features of these types of glioblastoma cells . FurtherThus, tumor cell fusion is a complex regulated process initiated by different external and internal factors . HoweverHowever, what changes occur in the cells before fusion, what signaling pathways are induced by cell fusion drivers, and what processes are activated and suppressed in THCs are currently unknown. These and other questions need to be answered, and a lot of work remains to be done in the future to understand more deeply the mechanisms of THC formation.Cancer cells may fuse with other cancer cells and different normal cells such as immune cells, MSCs, and fibroblasts . All theCancer cells tend to fuse with other cancer cells regardless of the type of cancer. Such fusion can afford cancer cells to change genomic material faster and much larger scale than genetic mutations. The resulting hybrid cells acquire new properties such as drug resistance and increased metastatic potential .The fusion of leukocytes and cancer cells can initiate metastasis. This theory was proposed more than a century ago by Prof. Otto Aichel . Recentl+ CD24-/low phenotype and features of the epithelial-mesenchymal transition. These THCs are characterized by aggressive demeanor, including increased migration, invasion, and tumorigenicity, but have reduced proliferation compared to parental cells (Macrophages are divided into two main types: M1 and M2. M1 macrophages are pro-inflammatory and characterized by the release of inflammatory cytokines. M2-macrophages are considered anti-inflammatory and associated with releasing interleukins (IL)-4, IL-13, and IL-10, and promote tumor growth and progression . Some stal cells . The appHowever, the place of fusion of cancer cells and macrophages remains an open question. Does it occur in the blood, the tumor, or the lymphatic system? The impact of cancer-macrophage fusion cells on the immune system is also unclear and is of great interest for future research.in vitro and in vivo showed that MSCs fuse with breast cancer cells and novel hybrids possess more aggressive properties than parental cells  when compared to the primary breast tumor, suggesting that hybrid cells can be formed in the primary tumor, metastasize, and then proliferate at the metastatic site  and B16F10 (melanoma) possessed fused nuclei exhibiting neoplastic transcriptional identity, while notably, retained macrophage gene expression signatures. They also exhibited contact inhibition and mesenchymal histologic sheet-like features. In vivo, hybrid cells are a rare subpopulation (0.03–0.69%), but have a shorter doubling time and enhanced metastatic ability. In patients, circulating hybrid cells (CHCs) were identified based on co-expression of CD45 (leukocyte marker) with CK . The frequency of CHCs, but not that of CTCs , was observed to be a prognostic marker for patient survival, regardless of disease stage. Intriguingly, fused cells demonstrated a combination of adhesion biases, as identified by a microenvironment microarray (MEMA) platform . Similar observations are reported in the fusion of lung cancer cells  and functional (mammosphere) assays  assays . Similar) assays . Hybrid ) assays , but ove) assays . Cell-to) assays , but whein vivo spontaneous fusion of MSCs with MDA-MB-231 cells had reduced tumor-forming and metastatic ability compared to MDA-MB-231 cells, despite having enhanced proliferation  and triple-negative breast tumor cells (MDA-MB-435) . The supToll-like receptors (TLRs) belong to the pathogen recognition receptors that play a crucial role in the innate immune system. TLR4-mediated signaling is implicated in tumor cell invasion, survival, and metastasis in various cancers . TLR4 anThe activation of the Wnt/β-catenin signaling pathway is crucial for the artificial fusion between breast tumor cells (N2O2) and macrophages using polyethylene glycol hydrogels and the promotion of proliferation, migration, invasion, and colony formation of THCs . In turnCell fusion modifies epigenetic landscape unlocking the expression of transcription factors, for example, Nanog, which is directly involved in cell reprogramming. It was shown that Nanog is strongly expressed by spontaneous mesenchymal hybrid cells generated from sarcoma cells  and fibroblasts (IMR90) . InhibitTumor cell-macrophage hybrids express both macrophage  and tumor-specific markers  . These fin vitro (+ and CD8+ T cells, activating the antitumor immunity (in vivo models.THCs themselves can act as antitumor therapeutic options. Purified dendritic cell-tumor fusion hybrids supplemented with the non-adherent dendritic cell population elicit the robust antitumor immune response in breast cancer model in vitro . Similarimmunity . These rin vitro, and further studies on in vivo and clinical models are required, especially in terms of understanding the mechanisms of THC formation in the multilevel organism systems and the development of instruments for their control.Thus, different therapeutic options can be addressed to prevent tumor cell fusion and destroy THCs. However, the efficiency of all of them was demonstrated Cell fusion promotes tumor growth and progression by formating new cells with increased drug resistance, immunotolerance, and metastatic properties. Therefore, the identification of THCs and revealing their molecular features may be effective in developing therapeutic approaches against cancer metastasis. Despite the abundance of studies devoted to THCs, several critical points are unclear.The problem of identifying THCs remains unresolved. At present, THCs are identified focusing on the specific markers of parental cells. However, fusion cells that lack those markers cannot be categorized as THCs. Therefore, there is an urgent need to identify surface molecules and/or genetic alterations that can act as THC markers, regardless of the parental cells. This challenge is difficult because of the same or largely overlapping genetic content of parental cells and THCs and can be overcome through a deep understanding of the molecular landscape of different types of THCs. For example, comparative analysis of THCs and parental cells using single-cell DNA sequencing combined with oligo-conjugated antibodies or cell sorting followed by DNA sequencing may identify genetic mutations associated with cancer cell fusion. Single-cell RNA sequencing of different tumors followed by bioinformatic analysis of differentially-expressed genes, DNA ploidy, and genetic alterations may identify new types of THCs and their unique features not present in parental cells.Another unresolved problem is related to the absence of information on the specificity of THCs to various cancers. Due to specific etiology and pathogenesis, different cancers may harbor individual repertoire of THCs. It is also unknown whether the occurrence of THCs depends on the stage and histological and molecular properties of cancers. These questions can be addressed by a comparative analysis of the proportion and composition of THCs between different cancers and their association with histological/molecular type and clinicopathological parameters of a particular type of cancer.The current data indicate the strong heterogeneity of THCs, which results in cell populations with varying degrees of drug resistance, immune tolerance, and invasive, and metastatic potentials. Together with a diversity of tumor cells, this evidence significantly increases the level of intra- and inter-tumor heterogeneity and thus the chances of treatment failure and poor outcome. Therefore, deciphering cell heterogeneity and identifying the most aggressive cell populations are one of the key aims to uncover the nature of THCs. The questions about genetic alterations that can trigger tumor cell fusion, the molecular landscape of cells after fusion, and the lifetime and fate of different THCs also remain unanswered. In this case, the potential instrument can be the use of single-cell omics and fluorescent protein-based cell tracking technologies, as already mentioned above.Thus, further research should focus on a comprehensive and multi-omic analysis of THCs to reveal genetic alterations leading to tumor cell fusion and specific markers of THCs, to investigate how strong the molecular landscape of hybrid cells changes compared to parental cells, and to understand the specificity of THCs to various cancers, and their correlation with clinical and pathological parameters.


This review describes the heterogeneity of peripheral glial cell populations, from the emergence of Schwann cells (SCs) in early development, to their involvement, and that of their derivatives in adult glial populations. We focus on the origin of the first glial precursors from neural crest cells (NCCs), and their ability to differentiate into several cell types during development. We also discuss the heterogeneity of embryonic glia in light of the latest data from genetic tracing and transcriptome analysis. Special attention has been paid to the biology of glial populations in adult animals, by highlighting common features of different glial cell types and molecular differences that modulate their functions. Finally, we consider the communication of glial cells with axons of neurons in normal and pathological conditions. In conclusion, the present review details how information available on glial cell types and their functions in normal and pathological conditions may be utilized in the development of novel therapeutic strategies for the treatment of patients with neurodiseases. Schwann cells (SCs), or neurolemmocytes, are a type of glial cells that originate from neural crest cells (NCCs). Post delamination from the dorsal neural tube, these cells migrate to the embryo’s body and give rise to multiple cell lineages during early vertebrate development . NCCs giSox9/10, FoxD3, and Tfap2a/b, as well as membrane molecules such as Plp1 and Erbb2/3 in both SCPs and NCCs  including and NCCs . Despiteand NCCs .Several tumors originate from SC lines, which include schwannomas, neurofibromas and malignant tumors of the peripheral nerve membranes (MPNST) . Given tThe mechanisms of attachment NCCs to axons, and their subsequent transformation into SCPs, that either remain attached or detach from nerves to undergo further differentiation into diverse cell types is not fully understood. However, multiple studies on the specialization of glia into different cell types, report a downregulation of the glial program, concomitant with an upregulation of the said cell type program  . The NRGThe decision of iSCs to differentiate into either myelinating or non-myelinating SCs is dictated by the expression levels of neuregulin 1 (NRG1). While lower levels of NRG1, released by a comparatively smaller axon leads to the maturation of iSCs into non-myelinating SCs, higher levels, result in the development of myelinating SCs . NotablyDespite the discovery of the ability of SCPs to transform into various cell types, the underlying molecular mechanisms responsible for these transitions remain unelucidated. While the overall pattern of molecular changes evidently involves the downregulation of glial genes and upregulation of cell-specific genes during early development, detailed information on the accompanying changes in gene cascades are not well understood. However, single cell trancriptomic analysis, has led to the revelation of changes in expression patterns of TFs and other molecules, that occur during the transition of NCCS and/or SCPs to specialized cells of the autonomic nervous system, sensory neurons, mesenchymal cells, and chromaffin cells . This daFOXD3 and SOX10), along with BCCs -specific TFs   is a subpopulation of multipotent cells that originate from NCCs, and give rise to cells of different lineages . BCCs cond HEY2) . Supportnd HEY2) .Neural crest cells generate a diverse set of specialized non-myelinating cells during prenatal development. These include satellite glial cells of sensory and autonomic ganglia , olfactoPerisynaptic Schwann cells (PSCs) are localized at neuromuscular junctions and play a key role in synapse formation during development . AlthougThe function of the PSC is not limited only to clearing neuronal debris during early development. PSCs have been demonstrated to function as major phagocytic cells such disease as Guillain-Barre syndrome . After dIn the early stages of synaptogenesis, PSCs connect with pre-patterned acetylcholine receptor clusters that are localized near nerve endings . SeveralG37R mice, which are a model for slow-onset amyotrophic lateral sclerosis. In normal physiological conditions, PSCs detect synaptic activity due to an increase in intracellular Ca2+ concentration. SOD1G37R mice have abnormally enhanced intracellular Ca2+ concentrations, even before the onset of denervation  have an average lifespan of 1–3 months , extensiCrePax7  are found in ganglia  of the peripheral nervous system (PNS)  study has permitted the analysis of the molecular profiles of these cells in various physiological processes, including the development of somatosensory dorsal root ganglia and auditory spiral ganglia , in indidult DRG . DespiteEnteric glial cells (EGCs) comprise a large population of peripheral glia of the enteric nervous system (ENS), that are part of ganglionated myenteric and submucosal plexus  and extra ganglionic spaces, within the intestinal mucosa and muscle layers . These cDhh, Mal, and Mpz can distinguish two cell types that express similar TFs  are a separate population of adult SCs, that lose contact with and demyelinate the distal stump after axonal injury. These cells undergo reprogramming that involves the upregulation of several genes and activation of multiple transcriptional mechanisms. For instance, rSCs are known to upregulate c-Jun, mitogen-activated protein kinase (MAPK) pathway, Sonic Hedgehog (Shh) pathway, secrete trophic factors that support the survival of damaged neurons, and promote axonal regrowth . This prCreERT2/+; R26-lsl–TdTomato mice  are poorly understood. Some of the questions that need to be answered include: (1) What causes a cell to detach from a nerve and undergo differentiation? (2) Do the transforming signals arrive from peripheral nerves  on which glia are located? (3) Could they possibly arise from the internal heterogeneity of SCPs, from neighboring tissues, or all of the above? A second aspect that need to be studied is the application of the multipotency of SCPs in clinical scenarios. Disturbances in the migration and directed differentiation mechanisms of SCPs can result in a wide range of disorders associated with lack of sufficient cells required for proper functioning. This further leads to abnormalities in the development of tissues/organs, including the parasympathetic ganglia and their innervations, neurogenesis of the enteric system, adrenal glands, skeletal structures, teeth, and pigmentation. For instance, more than 20 types of autonomic dysfunctions currently known, cause symptoms including heartburn, intestinal gas, flatulence, diarrhea, constipation, colitis, dry mouth, cardiac disorders, dysuria, and sexual dysfunction. The mechanisms that underlie these disorders have not been elucidated, but may possibly involve SCPs and their ability to differentiate into autonomic neurons. The immense potencies of different glia types in adults are just beginning to be discovered. Cells of several peripheral glia types have been found to be capable of differentiating into neurons under both normal and pathological conditions, participating in perineural invasion, and playing important roles in carcinogenesis, apart from their involvement in axon regeneration.AS, DA, NB, MV, LM, and VD planned the study, and wrote the manuscript. MV and LM participated in data acquisition. VD supervised the study. All authors read and approved the final version 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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