OXTR gene, is responsible for the signal transduction after binding its ligand, oxytocin. Although this signaling is primarily involved in controlling maternal behavior, it was demonstrated that OXTR also plays a role in the development of the nervous system. Therefore, it is not a surprise that both the ligand and the receptor are involved in the modulation of behaviors, especially those related to sexual, social, and stress-induced activities. As in the case of every regulatory system, any disturbances in the structures or functions of oxytocin and OXTR may lead to the development or modulation of various diseases related to the regulated functions, which in this case include either mental problems  or those related to the functioning of reproductive organs . Nevertheless, OXTR abnormalities are also connected to other diseases, including cancer, cardiac disorders, osteoporosis, and obesity. Recent reports indicated that the changes in the levels of OXTR and the formation of its aggregates may influence the course of some inherited metabolic diseases, such as mucopolysaccharidoses. In this review, the involvement of OXTR dysfunctions and OXTR polymorphisms in the development of different diseases is summarized and discussed. The analysis of published results led us to suggest that changes in OXTR expression and OXTR abundance and activity are not specific to individual diseases, but rather they influence processes  that might modulate the course of various disorders. Moreover, a possible explanation of the discrepancies in the published results of effects of the OXTR gene polymorphisms and methylation on different diseases is proposed.The oxytocin receptor (OXTR), encoded by the  Transmembrane receptors, as structures with the ability to receive a specific type of information from the extracellular environment, are key elements in maintaining cellular homeostasis. The signals received by the receptors initiate cascades of signaling reactions, enabling the cell to adapt to the environmental conditions .The oxytocin receptor (OXTR) and oxytocin itself (OXT) are primarily known for controlling maternal behavior. When the fetus develops, OXTR is mainly formed in the myoepithelial cells of the mammary gland and in the myometrium and endometrium of the uterus at the end of pregnancy. OXT is produced by the neurons of the hypothalamus and transported to the higher centers of the brain and the posterior pituitary gland, from where it enters the peripheral circulation. OXT and OXTR take part in the induction of labor  and the initiation and maintenance of lactation, as well as psychological contact between mother and child. They also modulate sexual, social, and stress-related behaviors ,3. In adq/11 protein. The signal transduction cascades initiated by the OXTR activation involve several pathways, leading to various effects, including (i) the modulation of the voltage-regulated Ca2+ channel and the subsequent activation of the myosin light chain (MLC) kinase, (ii) the stimulation of phospholipase C (PLC) and the activation of protein kinase C (PKC) through the phosphatidylinositol 4,5-bisphosphate (PIP2)–phosphatidylinositol 3 (PI3) pathway, (iii) the activation of the MAP kinase cascade, (iv) cytosolic phospholipase A2 (cPLA2) stimulation, and (v) the activation of the RhoA/Rho-associated protein kinase (ROK) pathway. Therefore, the stimulation of OXTR results in the specific regulation of a battery of genes regulating various cellular and physiological processes. Although early studies reported that OXTR is present mainly in cells occurring in the central nervous system and cells of the mammary gland and uterus during pregnancy [The molecular mechanism of OXTR action has been reviewed recently ; neverthThe disturbances in the levels of OXT or the activity of the OXTR and their consequences for the functioning of cells and the whole organism have been detected in many human diseases . The mosThe role of the elements of the OXT system and its receptor is inherently related to the functioning of the endocrine and reproductive system, taking part in maintaining the functionality of the uterus, inducing labor or lactation . It is tOXTR and the estrogen receptor 1 gene (ESR1) in patients with Mayer-Rokitansky-Küster-Hauser syndrome were performed [OXTR gene were detected, of which one  was classified as non-pathogenic, the other  was a missense mutation, and the third (c-133A > C) was of unknown effect on the function of OXTR as this variant was described for the first time. The authors suggested that the identified variants of the OXTR gene may disrupt the function of the receptor through various yet unexplored molecular mechanisms [DNA sequence analyses of both erformed . This coOXTR expression in two types of affected tissues , immunohistochemical staining showed very high levels of OXTR both in the cytoplasm and nuclei in the epithelial cells of the functional endometrial layer, and in the cytoplasm of epithelial cells of peritoneal endometriotic lesions [OXTR may be enhanced under specific conditions, possibly contributing to pathomechanisms of these reproductive system diseases. Subsequently, a similar study was conducted using tissues with adenomyotic lesions derived from premenopausal women, indicating not only the overexpression of OXTR in adenomyosis-associated myometrium, compared to unaffected myometrium, but also significant morphological changes [When premenopausal women were screened for  lesions . An even lesions . These e changes . TherefoOXTR gene polymorphism studies did not indicate a direct correlation between the presence of any individual polymorphism and preterm birth [OXTR variants were not correlated with the risk of preterm birth [OXTR polymorphisms (rs4686302 and rs237902) have been identified to likely contribute to gestational age-dependent effects on prematurity. Moreover, significant differences in the bindings of the ligand by wild-type OXTR and the products of these two mutant alleles of OXTR were demonstrated in in vitro assays [OXTR and preterm birth is not simple, showing a complexity of the regulation of this physiological process.OXT is critical in inducing and sustaining labor . Thereform birth . Neverthrm birth . Interesrm birth . On the o assays . TherefoOXTR gene has been associated with maternal and paternal affection towards their child [OXTR and maternal care were studied to conclude that the specific OXTR genotype (rs2254298 AG/AA) may be correlated with poor maternal care [As mentioned in ir child . The effir child . Associanal care . Anothernal care . On the nal care .OXTR gene with maternal behavior has been detected when DNA methylation was studied. Namely, hypermethylation of this gene was associated with perinatal depression [OXTR locus in the cells of the placenta; however, cord plasma antidepressant levels were associated with an increased level of the methylation at the OXTR promotor region [OXTR gene were higher in the blood cells of mothers of infants than in no-infant women. Moreover, OXTR mRNA levels were lower in mothers with early trauma and less maternal experience than in the group of mothers who had not experienced trauma [Interestingly, another correlation of the pression . On the r region . DNA metd trauma . Intrigud trauma .OXTR and behavior. When women exposed to childhood maltreatment were tested, the results of genetic analyses suggested that the rs237895 polymorphism influenced the relationship between childhood maltreatment and maternal behavior, as these two features were associated only in studied individuals who did bear the T allele, which caused a high-level expression of the OXTR gene [OXTR polymorphism, rs1042778, was correlated with lower behavioral sensitivity, lower engagement, higher intrusiveness, and more frequent frightened/frightening behavior in mothers [OXTR polymorphisms with maternal behavior were published recently, suggesting the correlations of specific polymorphisms  with perceived maternal care [Recent investigations came back to the problem of genetic polymorphisms in the XTR gene . Another mothers . More renal care , parentanal care .OXTR gene polymorphisms and maternal/parental behavior; however, little information can be provided on the molecular mechanisms of such correlations. On the other hand, some investigators questioned the direct connection between the genetic variants of OXTR and maternal behavior, showing that more advanced studies are required to solve this problem.In summary, there are many reports indicating the associations of the OXTR gene in different parts of the brain and in different organs, have been recently reviewed [Studies on genetic and biochemical bases of mental and personality disorders are especially difficult and complicated due to the enormous complexity of both regulatory processes occurring in the central nervous system and genetic networks involved in these interactions ,32. The reviewed . The synreviewed . Apart freviewed . In factreviewed . TherefoApart from monogenic diseases with evident mental symptoms and changes in the personalities of patients, the connections of genetic and biochemical factors with changed behavior, mental development, and cognitive abilities are often equivocal. Moreover, there are problems with the use of animal models of such diseases since many mental features are specific for humans; thus, non-human models cannot be fully adequate in assessing the specific effects of any factors or agents. Nevertheless, by analyzing genetic polymorphisms in the genes of patients and control individuals it is sometimes possible to find correlations with symptoms of mental disorders and to build hypotheses about the possible mechanisms of specific diseases. Below, we summarize and discuss the results of studies on the potential roles of OXTR in various mental disorders.https://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-asd; (accessed on 5 February 2023)). The features and causes of this disease have been deeply and comprehensively reviewed recently . Theee refs. ,37.OXTR gene in autistic patients from China. An association between autism and two SNPs (rs2254298 and rs53576) was found, providing a basis for suggesting that impaired OXTR function might contribute to the development of the disease [OXTR with autism [OXTR was identified as a candidate gene responsible for autism if present in a mutant form [OXTR with autism spectrum disorder came from a more robust analysis in which 18 SNPs in this gene were tested. The discovery that a five-locus haplotype block, rs237897-rs13316193-rs237889-rs2254298-rs2268494, is considerably associated with autism corroborated the proposal that specific genetic variants of OXTR may be risk factors for this disease [Early evidence for the connection between OXTR and autism came from observations that significant changes in plasma oxytocin OXT levels occur in affected patients. This encouraged researchers to test four single nucleotide polymorphisms (SNPs) in the  disease . Importah autism . The hypant form . Further disease .OXTR appeared to be risk factors in different populations, as mentioned previously for Chinese and Caucasian patients with autism [OXTR polymorphisms with autism risk. Therefore, 18 SNPs in this gene were analyzed in samples derived from autism patients living in Ireland, Portugal, and the United Kingdom. Perhaps surprisingly, the results did not support the hypothesis about the role of common polymorphisms in the OXTR gene in the development of autism spectrum disorder, at least in the Caucasian population [OXTR in relation to the ratios of N-acetylaspartate to creatine in the right medial temporal lobe in Japanese patients with autism spectrum disorder suggested again the presence of an association between OXTR variants and neuronal function in the medial temporal lobe, which is affected in autism [OXTR polymorphisms to autism spectrum disorder susceptibility [An interesting observation is that some SNPs in h autism ,39. One h autism . Howeverpulation . A similpulation . On the n autism . These rtibility .OXTR gene variants to the development of autism. This indicated a need for more detailed studies in this area. One such focused and extensive work led to the proposal that social impairment and repetitive behaviors observed in patients with autism spectrum disorder might be associated with polymorphisms in the OXTR 3′UTR [OXTR impacts the reward system connectivity in patients with autism spectrum disorder, as well as in neurotypical controls [OXTR, which were controversial in their connection to the susceptibility to autism rs53576 and rs2254298, were associated with an increased severity of social deficits [OXTR gene revealed more severe phenotypes than those carrying the GG genotype [As indicated above, significant controversies appeared in the interpretation of the results of genetic polymorphism studies on the possible contribution of the TR 3′UTR . Anothercontrols . The studeficits . On the deficits . On the genotype .OXTR gene polymorphisms and autism spectrum disorder, a meta-analysis was performed to assess if there were any connections between the SNPs in this gene and the development of the disease. The results of studies with almost 4000 autistic patients were included in this analysis, which demonstrated significant associations between autism spectrum disorder and the following OXTR SNPs: rs7632287, rs237887, rs2268491, rs2254298 [In the light of the contradictory conclusions drawn on the basis of results from different studies on the s2254298 . It was s2254298 . In facts2254298 .OXTR polymorphisms are not sufficient to conclude about a role for OXTR in the development of autism spectrum disorder [OXTR gene and its product. One of the processes modulating the efficiency of the expression of OXTR is epigenetic modification, especially DNA methylation, which can probably affect the course of autism [OXTR methylation was demonstrated to be associated with an increased neural response within regions of the salience in the brain and with a decreased functional coupling between these regions and attentional control networks during selective social attention [OXTR methylation levels (within intron 1) were detected in autistic patients than in neurotypical subjects [OXTR expression is the MYC-associated zinc finger protein (MAZ), a specific transcription factor. It was demonstrated that the G allele in rs1042778 of OXTR is a determinant for the binding of this transcription factor [OXTR gene. Moreover, significantly changed densities of OXTR in the human basal forebrain and midbrain were reported in the postmortem brain tissue from individuals with autism, relative to the controls [OXTR SNPs  with the brain activity localized to the right supramarginal gyrus was reported in autistic patients [OXTR gene polymorphisms on the brain connectivity have been also shown to be dependent on sex [OXTR gene expression were also evident in the mRNA levels [OXTR gene were specific to females with autism spectrum disorder [All the above presented and discussed results indicated that analyses of disorder ,54. Thusf autism . Indeed,ttention . Moreovesubjects . Anothern factor . Therefocontrols . Interespatients . The efft on sex , indicatA levels . Furtherdisorder .OXTR gene polymorphisms as risk factors for autism. In a very recent robust synthesis of published evidence of candidate genes for autism spectrum disorder, the authors failed to determine the credibility of the evidence for OXTR [OXTR variants to the development of autism, the question about the importance of OXTR in this disease remains still unanswered.In summary, there are many results suggesting that disturbed levels and activities of OXTR may considerably contribute to the development of autism spectrum disorder. However, there are discrepancies in conclusions about roles of the for OXTR . Therefohttps://www.nimh.nih.gov/health/topics/depression; (accessed on 5 February 2023)). The complexity of this disease manifests in a long list of symptoms, with some patients experiencing many of them while others experience only a few. Moreover, the severity of each symptom can be different in each individual patient. Depression is broadly described in the literature with proposals of potential mechanisms and causes so we indicate only a couple of recently published comprehensive review articles as examples [Depression is an extremely broad and complex disorder, defined as a “serious mood disorder with severe symptoms that affect how people feel, think, and handle daily activities, such as sleeping, eating, or working”  different. A decreased level of methylation of the morphism . On the  rs53576 . Yet ano’ allele . As evidractions , prepulsractions , interperactions , hippocaractions , effectsractions ,80, negaractions , trauma-ractions , and worractions . HoweverXTR gene ,86,87,88OXTR gene with the severity of depression, however, no significant association between these two parameters could be found, despite quite a large number (846) of tested patients [OXTR methylation strongly suggested that functions of the oxytocin system, including OXTR-mediated signal transduction, may be involved in the attenuation of the fear response, which can protect against depression [OXTR gene, rather than the gene polymorphisms per se, might facilitate the development of this disease. Such a hypothesis can be supported by the results of studies on chronic stress, which is both the major risk factor for depression and significantly influences OXTR expression [OXTR gene expression, though independently from the DNA methylation status [There were attempts to correlate the level of methylation of the patients . On the pression . Thus, wpression . Indeed,pression , while an status .OXTR gene and resultant abundance of the receptor may also have implications for understanding the roles of OXTR in other diseases. These will be discussed in the next sections of this paper.The above presented conclusion and hypothesis on the crucial role of the level of expression of the https://www.nimh.nih.gov/health/publications/schizophrenia; (assessed on 5 February 2023)). Among the numerous symptoms of this disease, one can distinguish psychotic , negative , and cognitive  ones. The description of this disease is broad, and recent review articles provide a great background for its causes, mechanisms , and treatment possibilities [Schizophrenia is defined as “a serious mental illness that affects how a person thinks, feels, and behaves”  of patients (tested post-mortem), the levels of mRNA of the e vermis . On the  persons . The enhonfirmed . Therefol cortex . Again, OXTR gene were also reported as being associated with schizophrenia. Namely, significantly decreased OXTR methylation was reported in cells from the peripheral whole blood in the patients relative to the controls [OXTR gene [Epigenetic changes in the controls . The precontrols , which, XTR gene , can corConnections of various dysfunctions of OXTR and the oxytocin system with not only autism, depression, and schizophrenia, but also different mental disorders were reported. Here, we will mention studies which might shed further light on the mechanisms by which OXTR may influence the mental development.OXTR gene [OXTR locus, as there are reports demonstrating enhanced DNA modification in the cells of patients with obsessive-compulsive disorder [OXTR [As in the mental disorders discussed above, the role of OXTR in obsessive-compulsive disorder is also controversial. Some results indicated no significant associations between any of several tested SNPs in the XTR gene , while oXTR gene . Anotherdisorder ,106 whiler [OXTR .OXTR methylation in patients suffering from various mental disorders revealed that the level of this modification varies significantly between patients; however, those with extreme levels had lower intelligence quotient (IQ) scores and experienced more social problems than the patients with the methylation efficiency comparable to that in the healthy controls [OXTR gene can influence the antisocial behavior in adolescent boys [Interestingly, recent investigations of controls . Once moent boys , attentient boys , and aggent boys ,112.OXTR gene [OXTR gene was found to be increasing during the prenatal period, while the highest levels of the expression were detected in early childhood. A comprehensive analysis revealed an enrichment in a network of the expression of genes functionally coupled with OXTR in several mental disorders [An especially interesting and inspiring report has been published recently in which human post-mortem brain samples were analyzed for the efficiency of expression of the XTR gene . Brains isorders . That woMucopolysaccharidoses (MPS) are inherited metabolic disorders belonging to lysosomal storage diseases (LSD), which are characterized by the accumulation of partially degraded glycosaminoglycans (GAGs) ,115. DepInterestingly, it appears that the primary GAG storage is only the trigger of subsequent devastating changes, rather than the main or the only cause of the disease . For exaOXTR gene was found to be one of the most affected, indicating a significant up-regulation , as estimated by both RNA-seq and RT-qPCR analyses [Global transcriptomic analyses revealed that the expressions of many genes related to human behavior were dysregulated in all types of MPS . Among tanalyses . This waanalyses ,129. Sucanalyses ,132,133.OXTR expression and the formation of the OXTR-containing aggregates was confirmed in experiments with the agents causing a decrease in GAG storage, like supplementation with either an enzyme allowing efficient degradation of these compounds or a compound impairing their synthesis. In both cases, the levels of OXTR mRNA and OXTR protein, as well as the abundance of OXTR aggregates, decreased significantly [The results of recent molecular studies provided a possible explanation for the OXTR-related modulation of the pathomechanism of MPS. Namely, it was found that OXTR can directly interact with GAGs (stored in MPS cells), forming large aggregates . Such agficantly .OXTR and/or changes in DNA methylation, leading to the dysregulated expression of the OXTR gene, but also because of the interactions of this receptor with other compounds and formation of inactive aggregates, lowering its actual activity. Second, the deposition of protein complexes in MPS cells, which impairs the autophagy process and leads to further cellular dysfunctions, concerns not only amyloids  that arOXTR gene were associated with an increased risk of Barrett’s esophagus, a premalignant condition, and esophageal adenocarcinoma [OXTR gene were found in patients with hepatocellular carcinoma; however, these changes, though statistically significant in the association analyses, occurred in only 3% of affected individuals [The involvement of OXTR in cancer development was suggested several times. SNPs in the arcinoma . Alternaividuals .OXTR mRNA were correlated with the occurrence of other cancers. Namely, the expression of this gene was up to 10-fold up-regulated in pancreatic cancer cells [OXTR gene expression was reported recently in breast cancer relative to the non-cancer tissue [OXTR in a mouse model [Increased levels of er cells , and incer cells . Moreoveer cells . On the r tissue ,141. In se model .OXTR was proposed for prognostic purposes in different cancers. Namely, OXTR-derived mRNA levels were significantly increased in malignant mesothelioma cells, and the higher expression efficiency correlated with the poor prognosis [OXTR was among genes whose changed expressions were classified as potential prognostic markers of lower-grade glioma [OXTR mRNA were suggested as an indicator of the poor prognosis of colon adenocarcinoma [OXTR expression was also characteristic for oral squamous cell carcinoma [Interestingly, the use of data related to rognosis . The OXTe glioma ,145. Thearcinoma  and coloarcinoma . Finallyarcinoma .OXTR gene rather than SNPs themselves result in the effective modulation of the disease course. Again, this appears to be a common feature of many diseases, rather than being restricted to individual disorder(s).Generally, the results of studies on the involvement of OXTR changes in cancer corroborate the conclusions presented in OXTR gene polymorphism and cardiovascular risk factors [OXTR genotype and cardiovascular disease was corroborated in studies, indicating that the rs2268498 SNP in the OXTR gene is not a risk factor for hypertension [No significant associations were found between the  factors . Such a rtension . Neverthrtension , vasculartension , and carrtension .A comprehensive review of OXTR in vascular functions and stroke has been published recently , where tOXTR gene. Therefore, it was concluded that the pathogenesis of cardiovascular diseases can be significantly influenced by the dysregulation of OXT production and OXTR expression, especially in such disorders as ischemia, hypoxia, inflammatory disturbances, pain, and stress conditions [In another recent comprehensive review on the role of OXT and OXTR in cardiovascular diseases , it was nditions . Becausenditions .OXTR gene were reported in obese persons relative to control ones [OXTR methylation was significantly lower in the obese group with binge eating disorder; however, this correlation occurred only in males, not in females [OXTR gene, and thus the abundance of OXTR, can be significantly modulated by external factors, such as viral infections [Other diseases might also be modulated by the functions and dysfunctions of OXTR. For example, the signal transduction pathway initiated by this receptor regulates the osteoblast/adipocyte balance . Studiesrol ones . The eff females . It is afections  and inflfections . TherefoOXTR gene was impaired and the OXTR gene region was hypermethylated in the blood cells of patients suffering from Williams syndrome relative to healthy controls [OXTR gene on the development of symptoms of Williams syndrome. They suggested that a better understanding of the role of OXTR in this disease should facilitate the development of an efficient treatment for patients. Together with the studies discussed in Interestingly, apart from the effects of OXTR dysfunction on the pathomechanism of mucopolysaccharidoses . They are presented schematically in OXTR gene, methylation efficiency of this gene, and/or changes in the levels of OXTR mRNA with occurrence of selected symptoms or diagnosed disorders. The picture is even more complicated because exactly the same SNPs have been reported to affect different diseases. Nevertheless, this fact led us to propose the hypothesis that the effects of OXTR are not specific to individual diseases but rather that they can affect common processes which might, in turn, modulate the course of different disorders. Intriguingly, there are many examples of contradictory results published by different authors which demonstrated either significant associations of specific OXTR SNPs with particular diseases or a complete lack of correlations in studies on the same SNPs in the same diseases. Such confusions concern also OXTR methylation. Moreover, considerable differences were reported between sexes and between different tissues. However, we propose that the ostensible paradox of contradictory results obtained by various research groups might be explained in such a way that similar variabilities in OXTR polymorphisms or DNA methylation may occur in both patients suffering from different diseases  and healthy controls; however, the effects of specific SNPs or levels of methylation can be significantly more pronounced in affected persons due to their influence on ongoing pathological processes and enhancement of symptoms. The same disturbances in OXTR-mediated regulations might be masked in healthy persons due to fully functional other control processes. This can be especially pronounced in the effective controlling of emotions and behaviors which are otherwise disturbed in people with mental disorders. Therefore, depending on the compositions of investigated groups , the manifestations of (sometimes subtle) differences in symptoms related to OXTR functions might be more or less pronounced  and significantly affect the results of statistical analyses of the influence of the OXTR status on the investigated disorders.However, the molecular mechanisms by which OXTR affects these diseases are mostly unknown. Our knowledge in this matter is based predominantly on the associations between various polymorphisms of the OXTR gene, rather than the presence of its specific polymorphic variant, may considerably influence the signal transduction process mediated by OXTR, and then, all cellular and further organismal changes related to the activities of a battery of genes controlled by this molecular signaling. Such a scenario is compatible with the results of mechanistic investigations which are, unfortunately, still relatively scarce. As presented in this review, one of few molecular mechanisms of the effects of OXTR malfunctions in human diseases was reported in studies on mucopolysaccharidoses. In this case, elevated levels of OXTR, resulting from enhanced transcription of the OXTR gene, do not correspond with its higher activity, due to the direct interactions with accumulated glycosaminoglycans (stored in large amounts in this disease), which cause the formation of aggregates, leading to the inactivation of the receptor and the impairment of the signal transduction process. Definitely, an understanding of the molecular details of the mechanisms of OXTR-dependent changes in other diseases is necessary to fully assess the affected processes and to enable us to predict the effects of various changes in OXTR on the development of specific symptoms of different diseases. Then, the development of effective therapies targeting OXTR may be potentially efficient in the future.We also emphasize that the efficiency of expression of the


Cardiovascular disease, particularly coronary artery disease, is the leading cause of death in humans worldwide. Coronary heart disease caused by chemotherapy affects the prognosis and survival of patients with tumors. The most effective chemotherapeutic drugs for cancer include proteasome inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, 5-fluorouracil, and anthracyclines. Animal models and clinical trials have consistently shown that chemotherapy is closely associated with coronary events and can cause serious adverse cardiovascular events. Adverse cardiovascular events after chemotherapy can affect the clinical outcome, treatment, and prognosis of patients with tumors. In recent years, with the development of new chemotherapeutic drugs, new discoveries have been made about the effects of drugs used for chemotherapy on cardiovascular disease and its related mechanisms, such as inflammation. This review article summarizes the effects of chemotherapeutic drugs on coronary artery disease and its related mechanisms to guide efforts in reducing cardiovascular adverse events during tumor chemotherapy, preventing the development of coronary heart disease, and designing new prevention and treatment strategies for cardiotoxicity caused by clinical tumor chemotherapy. The efficacy and safety of drugs are always a public concern. Optimal drugs, including those used for chemotherapy, are expected to have good therapeutic effects and minimal adverse effects. With significant advances in the treatment of cancer, the survival rates of patients have increased and their outcomes have improved. However, many chemotherapeutic drugs have cardiotoxic effects that can lead to important health problems such as cardiovascular disease. Commonly used chemotherapeutic drugs include proteasome inhibitors, tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and anthracyclines. These drugs are among the most effective treatments for tumors and are widely used in clinical practice with proven efficacy. However, their use is often limited by their toxicity to the cardiovascular system. Notably, some anticancer drugs can cause coronary atherosclerotic heart disease. Atherosclerotic lesions of the coronary arteries can lead to vascular cavity stenosis or obstruction, resulting in myocardial ischemia, hypoxia, or necrosis. Coronary atherosclerotic heart disease is associated with high incidence and mortality rates. Studies have shown that pediatric cancer survivors who have undergone chemotherapy have considerably high rates of stroke and coronary artery disease and an 8.2 times higher cardiac mortality than expected . One stuThis review article provides an overview of the relationship between some chemotherapeutic agents and coronary atherosclerosis and summarizes the effects of some chemotherapeutic drugs on coronary events. In addition, the mechanism of the effect of chemotherapeutic agents on the formation of coronary atherosclerotic plaques and the management of patients are explored to lay a foundation for the safety of tumor therapy and, to a certain extent, elucidate the occurrence of cardiovascular adverse events during tumor treatment. The purpose of this review is to guide efforts in reducing the occurrence of malignant cardiac events caused by chemotherapeutic drugs, prolonging the survival rates, and improving the prognosis of patients.2 dose of anthracyclines 2–60 months before the study. Established measures of endothelial diastolic function, such as brachial artery reactivity, were significantly different between patients who received at least 300 mg/m2 anthracyclines and control patients , Adriamycin liposomes, and daunorubicin, are widely used in the treatment of various malignant tumors, and clinical trials of these drugs began in the 1960s. The cardiotoxic effects of anthracyclines were first identified by Machado et al.  in a clipatients . Brachiapatients . Anthracpatients . Duncan patients  also demed by 1% . As dysled by 1%  evaluateed by 1% . In anoted by 1% . After ced by 1% . A recened by 1% .ICIs, such as PD-1, PDL-1, and CTLA-4, have been used to treat various types of cancer. In recent years, diverse studies on the relationship between immunosuppressants and coronary atherosclerosis have been published. In a single-center clinical study, Drobni et al.  preliminTKIs are a class of compounds that inhibit the activity of tyrosine kinases. These drugs are used to treat CML, non-small-cell lung cancer, renal cell carcinoma, and other cancers. Imatinib, a first-generation representative TKI, has transformed the treatment of CML; however, its safety has been a topic of discussion. The most common adverse reactions to imatinib include edema, gastrointestinal reactions, and cutaneous adverse reactions . The posProteasome inhibitors, including bortezomib, carfilzomib, and ixazomib, are commonly used in the treatment of MM . The mos5-FU is a fluoride of the pyrimidine class that is commonly used in the treatment of malignancies such as colon, rectal, and gastric cancers. 5-FU can cause mild gastrointestinal symptoms, severe neutropenia, life-threatening cardiovascular events, and other adverse reactions. Early studies have identified the effects of 5-FU on the coronary arteries, and knowledge about its cardiovascular toxicity and adverse effects on the coronary arteries has improved with advances in treatments. The incidence of cardiovascular toxicity caused by 5-FU ranges from 2% to 18% , 52. AnoAlthough the mechanism of anthracycline cardiotoxicity has been widely discussed, no specific mechanism has been established to date. Anthracyclines influence endothelial cells, and endothelial cell dysfunction leads to reduced vasodilation and is believed to be an early event in atherosclerosis and other cardiovascular diseases. Impaired endothelium-dependent vasodilation is also observed in patients without risk factors for atherosclerosis , 63. SeaIn recent years, the number of studies on the cardiovascular toxicity of ICIs has gradually increased. Although the complete pathogenesis of cardiovascular toxicity has not been clarified, ICIs have been found to play an important role in the development of atherosclerosis and the regulation of the coronary arteries. Bu et al.  studied DDR-1 gene knockout is associated with increased plaque formation in a mouse model of atherosclerosis  or an endothelium-independent mechanism (primary smooth muscle dysfunction)  and is aChemotherapeutic drugs have shown strong efficacy in the treatment of tumors, thereby considerably improving the survival rate of patients. However, the associated cardiotoxicity has limited the use of these drugs. Studies have shown that the long-term treatment outcomes of breast cancer survivors are largely dependent on atherosclerotic changes. Cardiovascular death is an important concern for older women with early breast cancer . In recein vivo imaging studies need to be conducted in the future. We hope that the resulting additional knowledge will help reduce the occurrence of acute cardiovascular events and improve the survival rate of patients with cancer. The intersection between the treatment of cardiovascular diseases and the treatment of cancer also creates opportunities and challenges for the development of new drugs.In the development of drugs for tumor treatment, from anthracyclines in the past to proteasome inhibitors in recent years, excellent therapeutic effects have been achieved, improving not only the survival rate but also the quality of life of patients. Although ample evidence suggests that treatment with oncologic drugs is associated with the development of coronary atherosclerosis, the mechanisms by which some drugs cause atherosclerosis have not been elucidated. This may be due to the insufficient number of clinical trial indicators and the lack of basic experimental research data. A comprehensive understanding of the relationship between the use of chemotherapeutic drugs and the formation of coronary atherosclerotic plaques can facilitate the development of relevant treatment strategies based on pathogenesis and timely preventive interventions. Therefore, further pathophysiologic experiments, clinical studies, and FZ and XZ designed the framework and direction of the manuscript. YL and YS wrote the manuscript. YZ and DC collected literature and designed the tables. WW supervised the writing of the manuscript and revised the manuscript. All authors approved the final manuscript.


Sarcopenia and frailty represent two burdensome conditions, contributing to a broad spectrum of adverse outcomes. The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force met virtually in September 2021 to discuss the challenges in the development of drugs for sarcopenia and frailty. Lifestyle interventions are the current mainstay of treatment options in the prevention and management of both conditions. However, pharmacological agents are needed for people who do not respond to lifestyle modifications, for those who are unable to adhere, or for whom such interventions are inaccessible/unfeasible. Preliminary results of ongoing trials were presented and discussed. Several pharmacological candidates are currently under clinical evaluation with promising early results, but none have been approved for either frailty or sarcopenia. The COVID-19 pandemic has reshaped how clinical trials are conducted, in particular by enhancing the usefulness of remote technologies and assessments/interventions. Sarcopenia and frailty are two major age-related conditions. Sarcopenia, first described by Irwin Rosenberg in 1988  and inflammaging  are indicated as key determinants . FurtherSignificant research efforts have contributed to our understanding of frailty and sarcopenia. The two conditions have been frequently explored as simultaneously acting, and physical function impairment is often a common feature of both conditions. To date, no pharmacological treatment has yet been approved for either frailty or sarcopenia. Recommendations for the prevention and treatment of frailty and sarcopenia are thus still mainly based on lifestyle interventions, such as nutrition and physical exercise.The lack of treatment options stems in part from the paradigm of standalone/single diseases traditionally adopted in medicine. This paradigm is inadequate for many older people, who often present with high level of clinical complexity due to the simultaneous presence of multiple interacting chronic conditions that often exist in syndromic constellations. Unfortunately, this suboptimal clinical paradigm of addressing single disease condition has also been largely mirrored in the process of drug development for older persons . Indeed,In 2012, the first International Conference on Frailty and Sarcopenia Research (ICFSR) took place in Toulouse, France. In parallel with the conference, an ICFSR Task Force was created to discuss specific aspects of frailty and/ or sarcopenia stemming from the most recent (often still unpublished research) with the final aim of providing updated recommendations. The ICFSR Task Force includes an international panel of Key Opinion Leaders in clinical and basic research, representatives from the pharmaceutical and nutritional industries, and members of non-profit organizations. As it has regularly occurred in previous ICFSR meetings, the Task Force gathered on September 28, 2021, to focus on the specific challenges of developing drugs for frailty and sarcopenia. The present report summarizes the presentations and discussions.Conventional medicine is often inadequate for managing the complex medical needs of frail older people, frequently resulting in misdiagnosis and mistreatment. Furthermore, the biomedical model of disease becomes progressively less clinically relevant as people age, whereas his/her functions and reserves assume greater importance in ensuring healthy aging. In this context, special interest has been devoted over the past years to the sarcopenia and frailty conditions, focused on the skeletal muscle health and the physical functioning of the individual, respectively. Sarcopenia and frailty often coexist and overlap in the common feature of physical impairment . SarcopeTo provide an operationalization of physical frailty and sarcopenia (PF&S) as an objectively measurable condition;To identify a specific target population of older adults at risk of adverse outcomes with unmet medical needs;To evaluate the effectiveness of a multicomponent intervention in the prevention of mobility disability;To identify and validate biomarkers  for the condition of PF&S.Following on that experience, the Innovative Medicines Initiative (IMI) funded the “Sarcopenia and Physical Frailty in Older People: Multi-component Treatment Strategies” (SPRINTT) project , with thThe SPRINTT consortium was initially focused during the first months of activity at theoretically framing the perimeter of PF&S, paying special attention to the requirements of the regulatory agencies for the approval of novel clinical conditions . In factThe SPRINTT study included 1,566 people aged 70 years and older, across 16 sites in 11 European countries. The main eligibility criteria were an SPPB score between 3 and 9, the ability to complete the 400-m walk test within 15 minutes, and the presence of low appendicular lean mass.Participants were randomized to a multi-component intervention  versus a healthy aging lifestyle education program. The primary outcome of interest for the SPRINTT trial was the incident mobility disability, defined as the onset of inability to complete the 400-m walk test . The maiThe SPRINTT project was completed at the end of 2020 and the results  have been finalized and will soon be published. An example of design of a randomized controlled trial on physical frailty and sarcopenia stemming from the SPRINTT experience is provided in The discovery of growth/differentiation factor-8 (GDF-8), also known as myostatin, as an inhibitor of skeletal muscle growth, has led to high expectations in the scientific community. The mutation of the myostatin gene in mice was initially associated with a substantial increase in muscle mass . SubsequSince then, various approaches have been used in this field . In partThe first lesson from the myostatin inhibitors comes from the animal models. In 2002, Bogdanovic et al.  showed tSubsequently, Attie et al.  reportedThe inhibition of myostatin through the above-mentioned mechanisms has been described as generally safe and tolerable. Commonly reported adverse events tend to include muscle symptoms , gastrointestinal symptoms , acne/rash, local skin reactions to subcutaneous injection administration, transient increase of pancreatic enzymes, fatigue, and myalgia.It should not be overlooked the role played by the age-related body composition changes, responsible for an increase in visceral abdominal fat and fat infiltration of the muscle, leading to the induction of myocytic apoptosis –25. IntrIn summary, findings from animal models do not always translate to humans, and early proof-of-concept studies do not always replicate in larger-scale studies. A direct action promoting the muscle mass increase does not necessarily translate into a parallel improvement of strength or function. Patient heterogeneity and comorbidities likely present confounding issues in this regards that may impose limited response potential to PF&S therapies. Thus, discerning which groups of patients that may be responders will be essential to advancing therapeutic candidates; and just as importantly, understanding why others may be poor-responders. Indeed, these lessons will shape future generations of drugs developed to prevent or reverse muscle wasting, which still represents an unmet clinical need.The development of novel therapeutic strategies against frailty and sarcopenia is highly active. Of note, some of these approaches include drugs commonly prescribed for other conditions. Among the ongoing studies testing interventions against frailty, a phase IIB RCT  exploring the effects of Lomecel-B, an allogeneic bone marrow-derived product featuring mesenchymal signaling cells (MSCs) formulation, was presented . The majThe COVID-19 pandemic has drastically modified the clinical routine and introduced significant challenges in research . During The COVID-19 pandemic imposed significant impediments in the enrollment of clinical trial participants. It was not uncommon for studies to have been stopped, or some new initiatives upheld/suspended by either the sponsors or the regional lockdowns . It was Physical function measures are frequently used as primary and secondary outcomes in the assessment of older people living with frailty and sarcopenia in both research and clinical practice –42. The Category 1: procedures that are not aerosol-generating, and result in only a marginal increase in minute ventilation . These types of tests are associated with only a minimal increase in the risk of infection;Category 2: tests that are aerosol-generating and are associated with a marked increase in minute ventilation .Storer et al.  have pubStorer et al. propose a steped approach to maximize safety during the physical function assessments. The first step is aimed at evaluating the benefit to risk ratio of the study procedures. Accordingly, if assessments are included as exploratory outcomes, it may be prudent to consider postponing or even eliminating them. On the other hand, if the assessments are identified as primary or important secondary outcomes, it should be determined whether the test belongs in Category 1 or 2. Safety procedures for Category 1 tests include the optimal use of personal protective equipment, frequent sanitization of surfaces, decluttering of the lab, and maintenance of sufficient distancing . For Category 2 procedures, in addition to all the Category 1 preventive strategies, the optimization of ventilation in the laboratory and the use of HEPA filters may be needed.As mentioned above, the COVID-19 pandemic incentivized the application of remote sensing technologies for some outcome assessments and study procedures. However, it should be noted that the results of the remote assessments may be quite different from the standard ones performed in a clinical research unit. In a recent study, Hale et al.  measuredThe COVID-19 pandemic has reshaped how clinical trials were conducted, also requiring the implementation of procedures to enable the remote administration of visits and tests. To support the validity of these adaptations, the standardization of the remote procedures  is needed. When assessing study participants, the direct and indirect impacts of the pandemic should be considered for potential changes on their biological, clinical, and social characteristics.Over the last decades, increased research efforts have been devoted to frailty and sarcopenia. This has helped pave the way for clinical exploration of pharmacological and lifestyle interventions, and several promising agents are in the pipeline and currently being explored. It is agreed that measures of physical function are critical in this context. Nutritional and exercise interventions remain the first-line approach in the management of older people with frailty and sarcopenia. However, new drug candidates may find an ideal positioning, particularly among non-responders to lifestyle modifications or those not able to participate because of biological, clinical, and/or social factors. Finally, the importance of combining pharmaceutical and exercise interventions should not be overlooked in its potential. The simultaneous adoption of independent strategies targeting the quantitative and qualitative dimensions of the sarcopenia phenomenon may generate beneficial synergies. This approach may even become a requirement for proving the effectiveness of the pharmaceutical intervention.


Arthropod vectors play a significant role in the propagation, maintenance, spread, and transmission of pathogens. Their diversity, abundance, and almost ubiquitous presence across ecosystems signify that arthropod vectors are key drivers of disease across the world, causing huge socio-economic losses due to morbidity, mortality, and loss in livestock productivity, resulting in sustained poverty and food insecurity, especially in low- and middle-income countries (LMICs).This Research Topic invited novel contributions of the latest research regarding key advancements in the field of vector-borne animal disease. Four articles from researchers across the globe  were accepted. The research focus of the accepted articles included the Aino virus in Korea, Corridor disease in Kenya, tick-borne diseases in Guam, and Rift Valley fever (RVF) in Cameroon.Yeh and Ga investigated the Aino virus seroprevalence within wild and farmed cervids, across the Republic of Korea. They identified that both populations were exposed to the endemic virus. The authors suggest that these results highlight the need for closer monitoring of Aino virus infections in both farmed and wild cervids and that the results may help in developing future epidemiological studies of Aino virus infection.Aino virus is a midge-transmitted Orthobunyavirus that can cause significant skeletal and neurological abnormalities in foetal ruminants exposed to the virus during gestation. Cook et al. evaluated the clinical progression of Corridor disease (CD) in naturally infected cattle. As with the more extensively characterised disease, East Coast fever (ECF), the CD is also caused by the apicomplexan protozoan parasite Theileria parva. However, unlike ECF, which is caused by the cattle-derived parasite, the CD is a fatal disease caused by the exposure of cattle to buffalo-derived T. parva. The authors identified key signs in the progression of the clinical disease that may provide indicators for early diagnosis and the basis for future effective treatment interventions.In Kenya, Weaver et al. investigated the prevalence of ticks and tick-borne diseases in dogs, cats, and wild pigs on the Pacific Island of Guam. In this wide-ranging molecular and serological study, the group identified the presence of four tick species, including a Haemophysalis sp. that had not been recognised on the island and a high prevalence of tick-borne pathogens, particularly in dogs. From their studies, the authors suggested that the prevalence of ticks and tick-borne pathogen exposure in dogs makes them good sentinels.Ticks are a significant vector for a range of infections that have a global impact on human and animal health. Bronsvoort et al. investigated the seroprevalence of antibodies to the RVF virus (RVFV) in cattle. RVF is a zoonotic viral disease caused by the mosquito-transmitted RVFV that can cause abortion in livestock, which can act as a useful sentinel for human epidemics. While clinical RVF epidemics in East Africa are often sporadically associated with flooding events, the findings of this study suggest that in absence of apparent clinical disease and evidence of a widely circulating virus, a more stable endemic epidemiological pattern may exist in Cameroon.In Cameroon, Cook et al. and Yeh and Ga). The vector-borne disease can result in catastrophic losses to smallholder livestock keepers in LMICs, highlighting the need for better diagnostic approaches, epidemiological understanding of reservoirs, and improved control measures. Currently, available control measures, such as acaricide treatments for ticks, need to be applied frequently (at least weekly), which can be costly and limited by the development of resistance  and parasites with zoonotic potential . There are two key drivers of disease emergence that may result in changes in vector distribution and patterns of disease in a reservoir and susceptible hosts, climate change, and travel/migration. The current SARS-CoV-2 pandemic and the spread of African swine fever to Asia have highlighted the potential of human and livestock pathogens to rapidly extend their geographical range. Bronsvoort et al. highlighted that transhumance may play a role in disease spread and Weaver et al. suggested that sentinels may indicate a (re)emerging threat. It is necessary to understand the current and changing distribution of vectors and their impact on animal and human health to prepare for potential emerging disease threats.The pathogens under study also include emerging viruses . This demonstrates the global ubiquity of vector-borne pathogens at the wildlife-livestock interface and highlights the diversity of hosts and pathogens. A One Health approach to understanding the epidemiology and clinical significance of vector-borne disease is required as evidenced by the multiple disciplines of the authors, including biologists, entomologists, immunologists, microbiologists, parasitologists, veterinarians, and virologists, of these articles. In addition, an interdisciplinary approach to controlling vector-borne diseases is required, and future work may focus on novel control methods in vectors and reservoirs.The editors are convinced that the readers will find this Research Topic stimulating and that the information may generate novel areas for future research in vector-borne animal disease.EAJC, NW, ML, and VO assisted with the conception, preparation, and writing and editing of the manuscript. EAJC provided the image for 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.


When considering what makes us human, the development of the neocortex, the seat of our higher cognitive abilities, is of central importance. Throughout this complex developmental process, neocortical stem and progenitor cells (NSPCs) exert a priming role in determining neocortical tissue fate, through a series of cellular and molecular events. In this Perspective article, we address five questions of relevance for potentially human-specific aspects of NSPCs, (i) Are there human-specific NSPC subtypes? (ii) What is the functional significance of the known temporal differences in NSPC dynamics between human and other great apes? (iii) Are there functional interactions between the human-specific genes preferentially expressed in NSPCs? (iv) Do humans amplify certain metabolic pathways for NSPC proliferation? and finally (v) Have differences evolved during human evolution, notably between modern humans and Neandertals, that affect the performance of key genes operating in NSPCs? We discuss potential implications inherent to these questions, and suggest experimental approaches on how to answer them, hoping to provide incentives to further understand key issues of human cortical development. In light of our own research experience, we focus on neocortical stem and progenitor cells (NSPCs) and discuss noteworthy human-specific aspects pertaining to these cells. We include both, (i) human-specific aspects that are qualitative in nature, such as the appearance of human-specific genes during evolution that induce NSPC proliferation; and (ii) human-specific aspects that are quantitative in nature, such as temporal differences in NSPC dynamics between humans and other hominids, i.e., non-human great apes. We define “human-specific” aspects as those found in present-day (”modern”) humans as well as in archaic, extinct humans such as Neandertals and Denisovans. In contrast, we define “modern human-specific” aspects as those found only in present-day humans, that is, features that arose after the divergence of the ancestors of modern humans from those of Neandertals and Denisovans. In discussing human-specific and modern human-specific aspects of NSPCs, we highlight arising questions and suggest approaches on how to answer them.In this Perspective article, we discuss several key questions in the field of The primary criterion for the classification of the various types of NSPCs in the developing neocortex is the germinal zone where the cell body of a given NSPC type resides, and hence where it undergoes mitosis . This isThe various NSPC types residing in the secondary germinal zone, the subventricular zone (SVZ), are collectively referred to as basal progenitors (BPs). This term reflects the fact that, with regard to the above-mentioned apical-basal polarity axis of the developing cortical wall, the cell bodies of BPs are located basally to those of APs. BPs include (i) basal radial glia , and (ii) basal intermediate progenitors (bIPs). In contrast to APs, none of the BPs contact the ventricle. Their centrosomes—like their cell bodies—are not tethered to the apical side but are instead located in the SVZ, and hence undergo mitosis there .A secondary criterion to distinguish between the various types of APs and BPs is their morphology, specifically the presence, number, orientation and structure of cell extensions, i.e., cell processes. Thus, among the APs, both NECs and the canonical aRG extend a radial process that contacts the basal lamina; in the case of the aRG, this basal process passes through the SVZ, intermediate zone and cortical plate and exhibits a distinct molecular composition. In contrast, the so-called truncated aRG and the aIPs extend a radial process in the basal direction that does not contact the basal lamina. These radial processes of the various AP types persist throughout their cell cycle, including mitosis .Among the BPs, bRG characteristically extend a basal process  and/or an apically directed process; both types of processes are typically also observed at mitosis. In contrast, bIPs lack such radial processes but are multipolar in interphase, i.e., extend short processes in various directions, and retract these processes during mitosis .An additional criterion to distinguish between the various types of APs and BPs is the nature of their progeny. Among the APs, mitotic NECs and aRG give rise to other NSPCs , whereas aIPs give rise to neurons. Similarly, among the BPs, diverse functional subtypes of bRG and bIPs can be distinguished, depending on whether their progeny consists of BPs, neurons, or both .Application of these criteria, when comparing the NSPCs of various mammals, has revealed major changes in the relative abundance of the various NSPC types that also apply to human evolution. First, when compared to the embryonic neocortex of the mouse, a canonical lissencephalic model system, the fetal neocortex of the gyrencephalic human exhibits a dramatic increase in the ratio of BPs over APs. Second, there is a huge increase in the ratio of bRG over bIPs . HoweverFrom these data, the key challenge emerges to compare the cellular and molecular features of human NSPCs with those of our closest non-extinct relatives, the non-human great apes . A huge ITGB8) and insulin receptor (INSR). The key challenge here will be to determine whether or not such gene expression differences translate into unique, human-specific physiological features of the NSPCs concerned and, if so, whether they could suffice to justify the existence of potential human-specific NSPC subtypes.How, then, should a search for the potential existence of human-specific NSPC subtypes be conducted? We find that a molecular and a cellular approach, alone or in combination, are most promising. As to a molecular approach, single-cell transcriptomics as performed in the above-mentioned study  and expaAs to a cellular approach, in addition to light microscopy techniques, the advent of the serial block face scanning electron microscopy (SBF-SEM) technology  would alIn sum, while the evidence obtained so far from organoid studies suggests that the principal types of NSPCs are conserved between humans and non-human great apes, the search for potential human-specific, or even modern human-specific, NSPC subtypes remains a crucial challenge. Despite the limitations of brain organoids, it appears worthwhile to concentrate future research efforts on comparative studies of the less-explored SVZ of human vs. non-human great apes. Such studies should focus on morphological differences as well as the potential impact of human-specific genes and/or differences in the expression patterns of genes common to all hominids.As mentioned above, we previously reported a prolongation by 50% of the metaphase during the mitosis of human organoid APs compared to chimpanzee and orang-utan . This huGiven that metaphase is the last phase of mitosis where chromosomes prepare for segregation, a longer metaphase may have a role in ensuring that all chromosomes are ready for accurate segregation . This prmore than humans, yet experience a shorter AP metaphase. Also, despite mice having just 4 chromosomes (≈9%) less than humans (2N = 42), mouse APs have a metaphase that is around 60% shorter  gene family , an intermediate in the TCA cycle . In a recently proposed concept, referred to as the “three-quarter TCA cycle concept”  whether the increase in the proliferative capacity of BPs in the course of the evolutionary expansion of the human neocortex involves yet additional metabolic pathways, besides glycolysis ending at lactate and glutaminolysis, and whether these may operate synergistically with the former two; and (ii) whether humans amplify the activity of any of these pathways compared to chimpanzees. The findings that inolysis  suggestsThe human-specific NSPC features discussed so far have probably been shared not only among present-day humans, but also with other closely related archaic hominins, because the genomic underpinnings of those features have also been found in extinct archaic humans, such as Neandertals and Denisovans. These genomic underpinnings, while being important stepping stones, are, however, insufficient to arrive at the full genomic and physiological constitution of present-day humans as compared to extinct archaic humans.Ancient DNA sequencing and bioinformatics studies have uncovered catalogues of differences between archaic and modern humans . Both coRecent efforts to study the physiological relevance of such differences for brain development have focused on the potential physiological consequences of single amino acid differences. For example, human organoids with the ancestral amino acid variant of splicing regulator NOVA1  were reported to be smaller and have more cell death, to have a more uneven external surface, and to have gene expression differences in synaptic and glutamatergic markers compared to those with the modern human variant . HoweverAn intriguing question that arises is whether such single amino acid differences act indeed in isolated fashion, or if they may potentially act together with others in complex cellular structures and pathways. It is interesting to note that many of these differences can be classified by gene ontology as having functions in common pathways. One example of several amino acid differences between archaic and modern humans acting in the same process could be those found in proteins with functions in the microtubule cytoskeleton and the mitotic spindle . More spIt is intriguing that such a relatively high number of amino acid substitutions is associated with one cellular structure. In this context, two key functions of the kinetochore are the anchoring of chromosomes to kinetochore microtubules for segregation to the daughter cells, and being a crucial site for the assembly and signaling of the spindle assembly checkpoint . InteresFurther studies that convert all modern human-specific amino acid variants potentially involved in one process to the ancestral versions  will therefore be key to explore potential common functions. Studies in appropriate model systems that also perform the converse changes, from the ancestral to the modern human variant  will be equally important to corroborate and obtain a more complete picture, especially since potential phenotypes of extinct species cannot be tested in native tissue.The five questions addressed in this Perspective article concern features of NSPCs which, from our research experience, seem to be of particular relevance to gain further insight into human-specific, and even modern human-specific, aspects of neurogenesis in the developing neocortex. Thus, while the choice of these five questions likely reflects personal bias, we hope that the potential implications inherent to these questions, and the experimental approaches suggested to answer them, will serve as incentives for future efforts to understand key issues of human cortical development. The focus on NSPCs presented here is surely just one facet of this complex developmental process. Thus, topics not addressed in this Perspective article, such as neuronal migration and maturation, synaptogenesis, neuronal circuit formation, gliogenesis, developmental plasticity, and interactions with the environment, are clearly equally essential for trying to obtain a reasonably complete picture of the series of developmental events that contribute in a crucial way to what makes us human.Both authors contributed equally to writing and revising the manuscript and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Peripheral and central sensitizations of the trigeminal nervous system are the main mechanisms to promote the development and maintenance of chronic orofacial pain characterized by allodynia, hyperalgesia, and ectopic pain after trigeminal nerve injury or inflammation. Although the pathomechanisms of chronic orofacial pain are complex and not well known, sufficient clinical and preclinical evidence supports the contribution of the N-methyl-D-aspartate receptors  to the trigeminal nociceptive signal processing pathway under various pathological conditions. NMDARs not only have been implicated as a potential mediator of pain-related neuroplasticity in the peripheral nervous system (PNS) but also mediate excitatory synaptic transmission and synaptic plasticity in the central nervous system (CNS). In this review, we focus on the pivotal roles and mechanisms of NMDARs in the trigeminal nervous system under orofacial neuropathic and inflammatory pain. In particular, we summarize the types, components, and distribution of NMDARs in the trigeminal nervous system. Besides, we discuss the regulatory roles of neuron-nonneuronal cell/neuron-neuron communication mediated by NMDARs in the peripheral mechanisms of chronic orofacial pain following neuropathic injury and inflammation. Furthermore, we review the functional roles and mechanisms of NMDARs in the ascending and descending circuits under orofacial neuropathic and inflammatory pain conditions, which contribute to the central sensitization. These findings are not only relevant to understanding the underlying mechanisms, but also shed new light on the targeted therapy of chronic orofacial pain. Orofacial pain comprises multiple pain conditions of dentoalveolar, myofascial, temporomandibular joint (TMJ), musculoskeletal, neurovascular, and neuropathic origin affecting the oral, face, head, and neck areas  have been proved to be associated with abnormalities in the peripheral nervous system (PNS) and central nervous system (CNS), resulting in neuronal excitation and chronic pain manifestations  AND (chronic pain OR neuropathic pain OR chronic inflammatory pain) AND  in Title/Abstract.via three-order neurons  or NR3 (NR3A-B) subunits], which together form a central ion channel pore  for channel activation, which can distinguish them from other glutamate ionotropic receptors , spinal cord, brainstem, hippocampus, cerebellum, cortex, etc.  is a scaffold protein that can cause a series of downstream molecular events that can cause pain by interacting with NMDARs  and SpVc. The intracisternal administration of NR2A or NR2B subunit antagonists inhibits the nociceptive behavior produced by the injection of formalin into the vibrissa pads of rats  layer, and granule cell layer, which are mainly involved in molecular layer interneurons (MLIs), PC, granule cell (GC), and Golgi cell  is downregulated, whereas the expression of the NR1 subunit is upregulated in the SpVc of WKY rats with genetically predisposed depressive behavior. Intracisternal administration of 6-chloromelatonin  improves depressive behavior as well as mechanical hyperalgesia in WKY rats by preventing the upregulation of NR1 expression  for the treatment of neuropathic pain in clinical trials by meta-analysis. Their results demonstrate that no conclusions can yet be made about the efficacy of NMDAR antagonists on neuropathic pain, as positive and negative outcomes on pain relief are found. In addition, adverse events  are also reported in the clinical trials for suppressing the physiological functions of NMDARs , the Department of Science and Technology of Sichuan Province , and the China Postdoctoral Science Foundation (Grant Number: 2020M683329).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.


In recent years, heavy metals-induced soil pollution has increased due to the widespread usage of chromium (Cr) in chemical industries. The release of Cr into the environment has reached its peak causing hazardous environmental pollution. Heavy metal-induced soil pollution is one of the most important abiotic stress affecting the dynamic stages of plant growth and development. In severe cases, it can kill the plants and their derivatives and thereby pose a potential threat to human food safety. The chromium ion effect on plants varies and depends upon its severity range. It mainly impacts the numerous regular activities of the plant's life cycle, by hindering the germination of plant seeds, inhibiting the growth of hypocotyl and epicotyl parts of the plants, as well as damaging the chloroplast cell structures. In this review article, we tried to summarize the possible effects of chromium-induced stress on plant growth, developmental physiology, biochemistry, and molecular regulation and provided the important theoretical basis for selecting remedial plants in chromium-induced contaminated soils, breeding of low toxicity tolerant varieties, and analyzing the mechanism of plant resistance mechanisms in response to heavy metal stress. Numerous studies have reported that high concentrations of Cr−1, which far exceeds the allowable maximum chromium threshold concentration of 2 mg L−1    has no apparent effect on germination potential, and when the chromium treatment concentration is >25 mg L−1, the seeds only germinated without root , and root accumulation of chromium reached 2,600 μg·g−1 in radish (Brassica campestris) treated with 1 mg L−1 chromium for 21 days and root length was reduced by 80% , and white clover (Trifolium repens), as well as resulted in yellow and necrotic root tips and root cuttings  was significantly higher than that of trivalent chromium . Turner and Rust  and other plants , with increasing treatment concentrations, the color of duckweed leaves gradually turned yellow, and the content of chlorophyll and carotenoids decreased significantly  and found that combinations of heavy metals treated differently in chromium concentrations changed relative conductivity. According to the area analysis of the orthogonal experiment, chromium has the strongest effect on membrane permeability.The selective permeability of the cell membrane can prevent the inflow and outflow of extracellular substances, make the intracellular environment relatively stable, and ensure that the biochemical reactions required for life can proceed in an orderly manner. When plants are poisoned by heavy metals, these harmful metal ions damage cell membranes and their selective permeability, thereby greatly increasing permeability, causing membrane lipid peroxidation, and affecting the normal growth and development of plants. Relative conductivity and malondialdehyde are the two most commonly used indicators to measure cell membrane damage among which, malondialdehyde, as the final product of membrane lipid peroxidation, can indirectly assess the damage of plant cell membranes. Draper and Hadley  found thn and Yu  found thBrassica napus) produced large black plastoglobules (PG) and increased the volume and number of starch granules (SG) under chromium stress. The chloroplast ruptured and the thylakoid membrane was also damaged after the dwarf bean (Phaseolus vulgaris) was treated with chromium; the chloroplasts in the first leaf cells showed more basal granules and the number of thylakoids decreased compared to the control. A large central nucleus appeared in the third leaf cells, which were smaller vacuoles  was treated with different concentrations of chromium, it was found that the activities of SOD, CAT, and APX in roots and leaves first increased and later decreased   first showed a trend of decreasing  in plants would be in dynamic balance; but when exposed to chromium stress, the cellular redox balance is disrupted, and the ROS level in plants increases significantly, which induces hyperoxia affects the production of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX), which are used to resist the toxic effects of heavy metals, which in turn affect plant growth. The antioxidant enzyme systems of different plants react differently to chromium stress , Jain et al. (MT) gene was found to increase significantly in stem and leaf under chromium stress. It is consistent with previous reports that MT protein can bind metals and detoxify excess metal ions , which could effectively reduce the content of hexavalent chromium in tobacco plants. In addition, when the rat glucocorticoid receptor gene (GR receptor) was transferred to tobacco, the amount of chromium absorbed by the plants was significantly reduced , adenine phosphoribosyl transferase, and other enzyme proteins. In barley (Hordeum vulgare) and grapes (Brassica napus), hexavalent chromium increased chitinase activity H to a variety of substrates, including hexavalent chromium. This enzyme is specifically induced by chromate and cannot be produced under salinity and oxidative stress.However, the role of metal-specific chitinase may help explain the mechanism of chromium detoxification in plants. Bukhari et al.  found thPlant-chelating peptides  are a type of heavy metal chelating proteins that are widely distributed in plants. Catalyzing heavy metal-induced glutathione synthesis Zenk, , after cLemna minor) also promoted the absorption of chromium ions by rice .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.


A distorted body image appears to be a significant factor predisposing an individual to developing anorexia nervosa and its maintaining. Anorexia nervosa presents with the highest mortality rate among all mental disorders.The aim of the research work was to assess the distorted body image in women diagnosed with anorexia nervosa, as well as to analyse the impact of the severity of the symptomatology of eating disorders, level of depression and anxiety on the distorted body image.A total of 105 people participated in the study. The clinical group consisted of 36 women diagnosed with anorexia nervosa, while the group of healthy women consisted of 69 participants. Patients completed several psychological and clinical measures such as: EAT-26, BSQ-34, BIDQ, BDD-YBOCS, CDRS, CESDR, and STAI.Between group comparisons were performed using nonparametric the Mann-Whitney U test. Results revealed statistically significantly greater distorted body image perception in anorexia group. Women diagnosed with anorexia nervosa showed significantly higher levels both depression and anxiety compared to the healthy controls. Based on correlation analyses, it was shown that there are statistically significant relationships between the body image variable and eating disorders, depression, and anxiety (state and trait).To deepen the problem of distorted body image, further research is required on etiopathogenesis and dynamics of body image in relation to body mass index and illness chronicity.No significant relationships.


What is the effect of our gut microbial flora on brain? Does the gut microbiome have any role in the causation of psychiatric and neurodegenerative diseases? Does the effect of gut microbiota traverse the gut-brain axis? Questions like these have captured the interest and imagination of the scientific community for quite some time now. Research in the quest for answers to these questions, to unravel the potential role of the microbiota inhabiting the gut in controlling brain functions, has progressed manifold over the last two decades. Although the possibility of microbiome as a key susceptibility factor for neurological disorders viz. Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, and autism spectrum disorder has bolstered by an increase in the clinical and preclinical evidence, the field is still in its infancy. Given the fact that the diversity of the gut microbiota is affected by various factors including the diet and exercise, the interpretation of such data becomes all the more difficult. Also, such studies have been mostly conducted on animal models, so there is a need for randomized controlled trials in human subjects, corroborated by longitudinal studies, to establish if modulating the gut microbiota can unravel novel therapeutic interventions. Exploring the genomic, metagenomic and metabolomic data from clinical subjects with psychiatric and neurological diseases can prove to be a helpful guide in individual treatment selection. Gut microbiome is the total genetic pool of the microbiota inhabiting the human gut. The number of microbes in the gut exceeds 10karyotes . Gut mickaryotes . The colkaryotes . A numbekaryotes . Howeverkaryotes . The gutThe taxonomic and functional classification of the gut microbiota is essential to understanding the gut microbiome and its possible effects. Of late, the metagenomic shotgun sequencing-based studies have been instrumental in unraveling the composition and dynamics of the gut microbiota. The application of specific bioinformatics tools, in addition to advancements in next-generation sequencing (NGS) technology, has revolutionized the field of gut microbiomics . SequencThese technologies provide a deeper understanding of the biological properties of gut microbiota and their potential to affect the physiology of the host. Given the fact that most of the microbes in nature are inaccessible as they are unculturable, there is a need to explore culture-independent methods, i.e., metagenomics, metatranscriptomics, microbiomics and metabolomics, to unravel the taxonomy, functional potential, and physiological roles of the unculturable microbes inhabiting the gut.In this review, we discuss in detail the involvement of gut microbiota in the onset of several neuropsychiatric and neurodegenerative disorders and the scientific progression in this domain.The story about the first documented report of the possible connection between the gut and the brain dates back to the 19th century when the United States Army surgeon William Beaumont was treating a Canadian fur-trader Alexis St. Martin who was accidentally shot at close range. The findings of the study in the course of the treatment opened a window of opportunity, though serendipitous, to take forward the study of physiology of digestion and gut . The autA perturbation in the gut microbiota composition (dysbiosis) leads to the signals being sent to the brain that subsequently manifest as enhanced cellular degeneration, low-grade inflammation, increased oxidative stress, and perturbed energy metabolism , contribvia vagus and enteric nerves. On the other hand, the endocrine, neuroimmuno- and neuroendocrine signaling pathways function through systemic circulation. Tryptophan metabolites, vagal nerve, and microbial metabolites such as peptidoglycan or short-chain fatty acids (SCFAs) act as the key routes of communication between the brain and the enteric microbiota , serotonin, glutamine, and γ-Aminobutyric acid (GABA) . The guttococcus , GABA isbacillus , acetylcaromyces . The bloaromyces . There aaromyces . In addiaromyces . SerotonThe monoaminergic systems within the brain have been the most sought-after target for treating the common psychiatric disorders and this has been the most effective pharmacological therapy dating back to the 1950s. Over the past decade or so, the microbiota-gut-brain axis has begun to emerge as a key player in regulating the stress response and maintaining the brain health. So there is a paradigm shift from the traditional modes of pharmacological therapies into the new era of “microbial omics.” The fields of genomics, metagenomics, transcriptomics, microbiomics, metabolomics and proteomics have greatly changed the way we look at things now. The main reason for the gut microbiota to have emerged as such an exciting area in neurological sciences is the advancement in next generation sequencing and metabolomics technologies . ReductiDepression, a stress-related disorder, is one of the most common neuropsychiatric diseases having multifactorial etiology. This worrisome disease has profound influence on the personality of the patient with considerable social consequences. Depression is manifested as the dysregulation of hypothalamic–pituitary–adrenal (HPA) axis which is the most commonly found abnormality in patients with depression and is manifested as elevated levels of corticotropin releasing factor (CRF) and cortisol . AdditioGut microbiota exerts a major influence on both the factors involved in depression, i.e., HPA axis as well as the immune system, bolstering the idea that there is a strong connection between the stress response and the gut microbiota . In theiGerm-free animals differ widely from conventional animals in their behavioral patterns. GF mice display learning and memory impairment, reduced anxiety level, cognitive deficits, as well as impaired social behavior . Figure Bifidobacterium longum and B. breve was able to reduce anxiety in an anxious strain of mouse  as an intervention strategy in depression, the supplementation of gut microbiota viz. of mouse . Thus, mDepression and anxiety usually go hand-in-hand, and the studies involving the microbiota-gut-brain axis in depression generally include measures of anxiety and vice versa. The main clinical manifestation in anxiety disorder are persistent and significant tension and restlessness. It has a global incidence of 3–25%, and the incidence in chronic diseases, such as cardiocerebrovascular disease, irritable bowel disease (IBD), cancer is 1.4–70%  leaving Schizophrenia (SCZ) is a complex neuropsychological disorder associated with disordered thought and behavior, delusions, relapsing episodes of psychosis, and hallucinations, thus impairing daily function and social interaction. It is compounded by the interaction of genetic vulnerability with pre- and postnatal environmental factors . The advN-methyl-D-aspartate (NMDA) receptors. These molecules have a vital role in cognitive function, retention of memory, and other functions of brain  and of brain . BDNF anof brain . The rolof brain  wherein Alkaliphilus oremlandii, Enterococcus faecium, Cronobacter sakazakii/turicensis, and Lactobacillus fermentum. These facultative anaerobes are rare in the gut of a healthy individual. The study also indicated a close association between the gut and the oral microbiota in SCZ as the bacteria inhabiting the oral cavity, such as Bifidobacterium dentium, Dialister invisus, Lactobacillus oris, Streptococcus salivarius, Veillonella atypica, and Veillonella dispar were found to be more abundant in SCZ patients as compared to healthy controls (HCs).Autism spectrum disorder is a neuropsychiatric disorder that is characterized by impaired social communications and interactions, stereotyped behaviors, and cognitive inabilities . The terClostridia and Desulfovibrio genera, and a decreased abundance of the beneficial Bifidobacterium  of a standardized microbial cocktail to autistic children in improving the behavioral and GI symptoms . LeveragBipolar disorder is a serious neuropsychological illness defined by intense changes in mood that include emotional highs (mania or hypomania) and lows (depression) and is hypothesized to be associated with influence of the gut microbiota . PatientFaecalibacterium, a prevalent gut microbe, as compared to HCs. Lower levels of Faecalibacterium are associated with medical conditions such as IBD , impulsivity, hyperactivity, and cognitive impairment . With a d to HCs . The modhildhood , reflectAlzheimer’s disease is the most common, irreversible and chronic brain disorder in which progressive degeneration of neurons leads to cognitive decline and impairments in the memory, mostly in the elderly . It is tBorrelia burgdorferi, Porphyromonas gingivalis, etc. , but often shifts into secondary progressive MS (SPMS). The characteristics of the gut microbiome in different stages of MS revealed that the gut microbiome is differentially altered in these different stages. In particular, reduced SCFA biosynthesis in RRMS and elevated oxidative level in SPMS were characteristic of MS . MS-induermansia . In a di studies . More woAkkermansia muciniphila and Acinetobacter calcoaceticus have been found to be present in fecal samples from MS patients in a relatively higher abundance  was found to considerably alleviate the anxiety-like behavior in an autistic mice , indole, 3-methylindole, etc. (365–370). These catabolites have been demonstrated to affect the health of the host by exerting anti-inflammatory effects and possibly by modulating the gut microbiome . Studies on evaluating the effects of probiotics have been mostly focused on animal models where they have revealed to be beneficial for neurological disorders such as AD and ASD, and have led to improvement in the cognitive outcomes of these animal models  defines prebiotics as “a substrate that is selectively utilized by host microbes conferring a health benefit.” Prebiotics, as an alternative to probiotics, can be used to regulate the gut microbiota and, therefore, affect the health of the GI tract .Lactobacilli and Bifidobacteria, however, only a few studies have evaluated their beneficial impacts on gut microbiota in humans. Prebiotics such as FOS and GOS have been demonstrated to have anxiolytic and anti-depressant impacts, and capability of reversing the chronic stress effects , and non-digestible Fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), and trans-galacto-oligosaccharides (TOS) . The pre effects . Ghanizabundance . The aboOne of the most active areas of research in deciphering the possible treatment of brain disorders is the study of the role of diet on brain functioning. Several dietary components viz. Omega-3 fatty acids , curcumin, flavonoids, B-vitamins, saturated fats, Vitamin D, Calcium, Selenium, Zinc, Choline, etc., have been found to effect cognitive abilities .Omega-3 fatty acids–rich diet has been demonstrated to be involved in strengthening cognitive processing in humans  and up-rLactobacillus and Bifidobacterium species on dietary fiber interventions, particularly fructans and GOS.Like Omega-3 fatty acids, research has demonstrated that other nutrients viz. curcumin, flavonoids, selenium, zinc, vitamins, etc., are vital for cellular processes and molecular systems that are essential for maintaining cognitive function . This raAlthough these studies demonstrate effects of diet on the brain functions, more research is needed to determine the underlying mechanisms of action of diets and the conditions for therapeutic applications in human diseases.Hippocrates is believed to have said: “let thy food be thy medicine and thy medicine be thy food” . After dThe connection between gut-brain axis and gut microbiota has been rendered to substantial research over the last 10 years or so. The gut microbiota is believed to be critical for the normal development and maintenance of functions of the brain. Further, there is accruing evidence from studies on animal models as well as clinical subjects involving the modulations in gut microbiota in a plethora of neurological, psychiatric, and neurodegenerative disorders . HoweverThere is a pressing need for large and longitudinal clinical trials to establish that the alterations in the gut microbiota profile are fundamental to the pathophysiology of such disorders. There seems to be a shift from microbiota-gut-brain axis to diet-microbiota-gut-brain axis as there is growing evidence that diet plays a pivotal role in shaping the diversity of the gut. So more studies in the future should be carried out in order to establish the therapeutic potential of diet-based modulations of gut microbiota and it might prove to be the conduit for future personalized-medicine approaches.YB wrote whole review manuscript. AK conceived idea and guided and checked draft manuscript. Both authors contributed to the article and approved the submitted version.