A clear margin is an important prognostic factor for most solid tumours treated by surgery. Intraoperative fluorescence imaging using exogenous tumour-specificfluorescent agents has shown particular benefit in improving complete resection of tumour tissue. However, signal processing for fluorescence imaging is complex, and fluorescence signal intensity does not always perfectly correlate with tumour location. Raman spectroscopy has the capacity to accurately differentiate between malignant and healthy tissue based on their molecular composition. In Raman spectroscopy, specificity is uniquely high, but signal intensity is weak and Raman measurements are mainly performed in a point-wise manner on microscopic tissue volumes, making whole-field assessment temporally unfeasible. In this review, we describe the state-of-the-art of both optical techniques, paying special attention to the combined intraoperative application of fluorescence imaging and Raman spectroscopy in current clinical research. We demonstrate how these techniques are complementary and address the technical challenges that have traditionally led them to be considered mutually exclusive for clinical implementation. Finally, we present a novel strategy that exploits the optimal characteristics of both modalities to facilitate resection with clear surgical margins. Cancer is the leading cause of premature death in Europe and the USA and one of the most important public health issues worldwide , 2. DepeOver the past two decades, important advances have been made to improve assessment of surgical margins by the introduction of intraoperative imaging techniques. Besides frozen section analysis, several optical methods have been studied to perform intraoperative margin assessment in surgical oncology, including optical coherence tomography (OCT) , photoacIn this review, we describe the state-of-the-art of FLI and RS and include an overview of the advantages and limitations for their use in image-guided cancer surgery. Next, we demonstrate how these two techniques are complementary and how they can overcome each other’s disadvantages and limitations. Finally, we highlight the technical challenges that need to be addressed to implement this novel approach into clinical practice.Intraoperative FLI of tumour tissue requires the systemic administration of a cancer-specific exogenous fluorescent agent that can identify the tumour using a spectrum of targeting strategies, including antibodies, small peptides, and activatable fluorophores –64. The FLI exhibits several favourable characteristics for clinical translation. Preclinical studies have demonstrated low toxicity with high sensitivity and specificity for tumour detection using targeted fluorescent agents , 72, 73.The simultaneous development of clinically available fluorescent agents and intraoperative camera systems over the past decade has now positioned intraoperative FLI as a promising real-time detection modality for surgeons in oncology. Since the first clinical trial of FLI with tumour-specific NIR fluorescent agents , ground-Despite a strong driving force coming from the auspicious results of these trials, there is still a fundamental controversy in the scientific field on how to cope with the complex process of optical imaging. Optical properties of the tissue can attenuate fluorescence signals; light scattering, for example, may cause blurred images. In addition, tumour-to-background ratios are influenced by nonspecific autofluorescence of the surrounding healthy tissues, although this disturbance is lower in the NIR region. Further, fluorescence intensity is further dependent on many factors, such as the concentration and fluorescence quantum yield of the fluorescent agent, the affinity of the fluorescent agent, the abundance of target receptors or epitopes, and the imaging system . InnovatRaman spectroscopy is an optical technique that can be used for real-time characterisation of biological tissue in and ex vivo. A Raman spectrum of tissue is a representation of the molecular composition of that tissue. As cancer alters the molecular composition of tissue, RS can be used for discrimination between tumour and healthy tissue. Contrary to FLI, the technique does not require preparation or staining of the tissue to be analysed, which facilitates clinical application. With the use of optical fibres, many body locations can be assessed in vivo using hand-held RS probes . RS has −1). This region is rich in spectral features, including the biochemical signatures associated with lipids, proteins, nucleic acids (DNA), and blood .Based on these findings, the development of an automated fibre optic needle probe for determination of the water concentration profile across the margins of a resection specimen has been initiated. The needle probe is placed on the resection surface and then driven into the tissue while recording spectra at regular distance intervals along its path. The goal is to measure the distance between resection surface and tumour border in this way, to enable rapid and objective margin assessment without the need for specimen grossing [127The combination of other imaging modalities with selective sampling of suspicious areas by RS as a powerful label-free analytical technique has also been explored , 129. SuIn FLI, the signal originates from the interaction of light with the administrated fluorescent agent binding in the tumour. In RS, however, the signal originates from the interaction of light with the tissue itself, regardless of the specificity of fluorescent agent binding. Owing to the distinctly different physical signal origins of FLI and RS, the provided information is complementary.FLI allows for real-time whole-field imaging of the surgical field, with high signal intensity. However, fluorescence signal intensity is limited by intrinsic optical tissue properties as well as the concentration and fluorescent quantum yield of the fluorescent agent . On the Other than helping to distinguish malignant from healthy tissue (i.e. during excision with tumour-free margins and debulking procedures), FLI has additional advantages for surgical oncology. Due to its ability to scan large surfaces, FLI is a useful tool for identifying additional occult lesions as well as relevant vital structures that require preservation during cancer surgery . FLI hasBesides securing adequate margins and achieving conservative resection during cancer surgery, RS can complement FLI in several other ways. When fluorescent areas are detected in the wound bed or elsewhere in the scanned surface (e.g. abdomen), RS could be the ideal tool to instantly assess this suspect region, thereby confirming or ruling out the presence of occult lesions. For unanticipated intraoperative findings such as the detection of clinically occult peritoneal metastases during colorectal cancer surgery , subsequHowever, laser-induced fluorescence itself can be a limiting factor for Raman measurements. Because fluorescent signals are generally orders of magnitude stronger, obscuring the Raman signal, these techniques were traditionally considered mutually exclusive. Figure Combining FLI with RS indeed requires careful matching of excitation and emission wavelengths of RS and the exogenous fluorescent agents; several groups have studied various approaches to deal with this issue. The excitation of fluorescent labels can be avoided by shifting the wavelength of the Raman laser to a longer wavelength .In a study using phantoms and breast specimens stained with patent blue dye (BD), it was demonstrated that fluorescence induction from surgical pigments could be circumvented by combining a laser with a longer wavelength (785 nm vs. 685 nm) with an indium gallium arsenide (InGaAs) camera capable of measuring the water/total area ratio of the HWVN spectrum . Noting Another study combined fingerprint RS with wide-field AFI spectral imaging for intraoperative margin assessment in breast-conserving surgery . AFI wasWhen it comes to the combination of FLI and RS, 5-aminolevulinic acid (5-ALA) is the most frequently studied fluorescent agent. In 2006, in vivo fingerprint RS was studied on bladder cancer biopsies obtained under the guidance of 5-ALA-induced protoporphyrin IX (PPIX) FLI . AlthougMore recently, ex vivo RS was performed to differentiate glioma from normal brain in the presence of 5-ALA . It was To summarise, several studies showed successful Raman measurements in the presence of fluorescent agents with emission in the visible and NIR-700-nm channel regions. However, to the best of our knowledge, there is no report on performing Raman measurements with the agents in the NIR-800-nm channel (e.g. ICG). ICG is the most widely used fluorescent agent in clinical trials of fluorescence-guided surgery (FGS) , 153. ItA novel HWVN RS system was recently developed to characterise tumour in highly pigmented skin lesions (i.e. melanomas) –157. TheAlthough RS is generally a label-free method, systemic injection of molecular imaging agents for Raman signal enhancement has recently been studied preclinically for margin assessment purposes. By selectively accumulating in the tumour tissue, multi-purpose nanoparticles could be used for FLI while simultaneously enhancing the Raman signal, as well as providing the option of photothermal tumour ablation –160. ThiWhile combining FLI with RS to achieve both whole-field imaging of the surgical field and objective margin verification would be very advantageous, these techniques have traditionally been considered mutually exclusive. Careful matching of RS excitation wavelengths and fluorophore emission wavelengths is required, presenting various technical hurdles. This issue could be solved by quantification of differences in water concentration in the HWVN region. After FLI with tumour-specific fluorescent agents, HWVN RS may be used to assess margin adequacy. In addition, evidence for the utility of RS in the identification of occult lesions and vital structures underlines its potential as an adjunct to FGS in all its basic applications. It is worth mentioning that intraoperative imaging techniques can also be beneficial for other applications, not limited to cancer surgery. These include delineation of targeted borders for precise surgical resections, evaluation of vascular perfusion, and identification of vital structures, such as nerves or ureters . The syn


The prevalence of overweightness and obesity has been documented as a major public health issue since it has increased at an alarming rate worldwide. Structured physical exercise programs have been reported as an essential strategy for preventing, managing, and treating obesity, inducing critical improvements in various physiological and psychological markers. However, it is unclear whether Pilates training can elicit positive changes in body composition, physical fitness, cardiometabolic health, and well-being among overweight and obese populations. The purpose of this topical review was to catalog studies investigating the physiological and psychological adaptations to Pilates training in order to identify what outcomes have been assessed, the research methods used, and the results. The inclusion/exclusion criteria were met by 14 published articles involving 582 participants  who were overweight or obese. The present topical review on Pilates training-induced adaptations shows that this widely used exercise type can significantly improve the majority of the selected indicators. These beneficial changes are frequently focused on anthropometric parameters, body composition, glucose, and lipid metabolism, as well as blood pressure in sedentary overweight or obese women. Specialized equipment-based Pilates interventions and trials investigating various mental health indices were limited. Further research is warranted in this area, emphasizing the Pilates training configuration and potential mechanisms behind positive alterations in several psychophysiological markers through large-scale randomized controlled trials with superior methodological quality, implementing long-term interventions in various populations that are overweight and obese. Obesity is a complex chronic disease defined as an excessive body fat accumulation predisposing to impaired metabolic health, which is responsible for developing several obesity-related chronic diseases . The prePhysical exercise has been widely recommended as an essential part of a multicomponent strategy against the obesity epidemic, promoting significant improvements in metabolic health, physical fitness, and well-being in previously inactive overweight and obese individuals ,13,14,15Pilates training is a mind–body exercise form founded by Joseph Pilates during the 1920s . This alThe purpose of this brief review was to abridge the research methods used and the main findings displayed in Pilates-based training studies where selected physiological  and psychological outcomes  were investigated. Such a review article may circulate the main outcomes on psychophysiological adaptations to Pilates training in overweight and obese individuals, aiming to detect research issues, considerations, and gaps in the literature. Given the serious lack of evidence on physiological and psychological responses to Pilates training method, all relevant studies were collected, regardless of their methodology, in order to distribute a wide-ranging viewpoint on the current evidence. The present brief review addressed the general question: ‘What is known from published research about selected psychophysiological responses to numerous Pilates-based training interventions in individuals with overweight and obesity?’The PubMed and MEDLINE databases were used to retrieve relevant articles from inception up to 1 August 2022 after a systematic electronic search by the author (A.B.) and a research assistant (P.B.). The search algorithm used the following terms: overweight, obese, obesity, Pilates. The complete search strategy is provided in the online 2; (2) included studies employed an intervention of various forms of Pilates; and (3) examined at least one of the following physiological and psychological outcomes in humans: body weight, BMI, body fat percentage, lean body mass, waist circumference, blood glucose, lipid profile, blood pressure, cardiorespiratory fitness, muscular strength, muscular endurance, flexibility, balance, functional capacity, adherence, exercise enjoyment, depression, anxiety, and quality of life. All studies were required to be written in English and published in a refereed journal from inception up to 1 August 2022. Studies were considered eligible for inclusion if the following criteria were met: (1) participants were individuals of any age with no diagnosed comorbidities, signs/symptoms of any noncommunicable disease or eating disorders, pregnancy, and with a body mass index (BMI) ≥ 25 kg/mAs for the exclusive criteria, studies were not considered eligible for inclusion if the following criteria were met: (1) studies recruited a mixed sample of individuals with overweightness/obesity and other chronic diseases per intervention arm; (2) articles where the effects of Pilates training intervention cannot be isolated because it was involved as part of a multicomponent exercise intervention ; (3) articles that did not evaluate the selected outcome measures; (4) studies published in languages other than English; and (5) studies that had not undergone full peer review .The author (A.B.) and a research assistant (J.W.) independently screened the titles and abstracts of potentially eligible studies and downloaded the full texts of the remaining articles to assess their eligibility. Any discrepancies between the two assessors were resolved by discussion and consultation with a research fellow (L.T.). EndNote X9  literature management software was used to manage the literature search records. The flow diagram is illustrated in The author (A.B.) and a research assistant (J.W.) independently extracted data using Microsoft Excel. Any disagreements were resolved by consensus. In case of insufficient information, the authors of the included studies were contacted via email for missing values where required. Data extraction included first author, year of publication, country, intervention duration, sample size, participant demographics , study design, Pilates training classification (mat/props or equipment), Pilates training intervention details , and critical psychophysiological outcome measures and findings reported from each eligible study, as shown in The electronic search returned 32 articles. After screening titles, abstracts, and full texts, 14 eligible studies were included in this review . Relevann = 5, 2016–2020: n = 9), and research was conducted in eight countries. There was a total sample of 582 participants  with overweightness or obesity across all studies. One (7%) article reported on the investigation of psychological measures as a primary outcome, and all articles reported on investigations of chronic responses (≥2 weeks) to Pilates training protocols. Training studies lasted from 4 to 24 weeks in duration , with exercise session frequency ranging from three to five times per week, and used quantitative methods. Articles reported on studies that implemented randomized controlled trials  or controlled trials . Articles reported on studies that assigned supervised  or semi-supervised  Pilates training interventions. Articles reported on studies that were conducted in a lab-based  or field-based  environment.Articles were published from 2006 to 2020  were classified as floor-based (matwork with props), and 2 (14%) were classified as specialized equipment-based (Cadillac and Reformer). The authors did not present details of the Pilates interventions considering the prescribed training parameters . The most frequently reported Pilates training protocol was a floor-based protocol . Through a mini review, 14 articles were systematically detected that published psychophysiological outcomes associated with Pilates training in previously inactive, overweight, and obese individuals. The large majority (93%) of eligible studies included in this review examined floor-based forms of Pilates training (matwork with props) in a supervised (86%) and lab-based setting (14%). The finding that 57% (8/14) of the eligible articles were published between 2017 and 2020, while 5 studies (35%) were published in 2020, underlines the novelty of this particular emerging research topic. The present brief review abridged the current literature to support further discussion of the questions, reflections, and gaps that need to be considered in future studies. Overall, Pilates-based training interventions appear to be a beneficial exercise approach for overweight and obese individuals, mostly seeking to improve body composition and physical fitness. As for cardiometabolic and mental health-related indices, no strong evidence was found across all eligible studies investigating these particular adaptations in this cohort. Additionally, the lack of data in all eligible studies regarding adverse events does not help identify how safe and feasible Pilates-based training programs are in a real-world gym setting for this population.Anthropometric parameters and body composition have been the most frequently studied physiological outcomes in the Pilates training literature for overweight and obese individuals. On the other hand, there is currently a scarcity of research to test whether psychological outcomes can be obtained by this population following various Pilates training protocols. However, Pilates training programs have been widely established in the health and fitness industry worldwide ,67. The Given that raised cardiovascular risk factors are common among overweight and obese individuals ,5, an inPilates training is not a type of cardiovascular exercise; however, it may elevate cardiorespiratory fitness levels in previously inactive adults compared to controls . In geneConsidering that psychological health-related disorders are frequently present among individuals with an unhealthy weight ,88,89,90Of particular importance is that the large majority of eligible studies (86%) reported low dropout rates ranging from 0% to 14%. Given that 93% of studies included in this review implemented a supervised Pilates training intervention in a field-based environment, it seems that supervision by qualified instructors may play a key role in adherence to structured exercise. This is an important observation since lack of time has been widely documented as the most critical exercise barrier among adults ,26,27, wThe small number of available trials delivers limited data concerning the efficacy of Pilates training on selected physiological and mostly psychological endpoints in overweight and obese individuals. Overall, the feasibility of Pilates training as a common type of exercise for these populations is still unclear. More rigorous research is needed to detect whether this mind–body exercise strategy can play a valuable role in the exercise programming puzzle adapted for previously inactive individuals with overweightness and obesity. However, from a physiological standpoint, the current evidence supports the viability of Pilates training as an alternative resistance-based exercise approach since it demonstrates positive alterations in several biomarkers in this population. Further research is needed on this topic, emphasizing examining the dose–response relationship of long-term Pilates training interventions (>12 weeks) and cardiometabolic as well as mental health-related indicators for overweightness and obese people in a real-world gym setting. Additionally, the potential mechanisms behind beneficial changes in several psychophysiological health markers should be explored in the future through larger samples and high-quality randomized controlled trials conducted in real-world conditions.Since data considering the efficacy of Pilates training on key psychosocial indices such as anxiety, depression, mood state, quality of life, exercise enjoyment, affect valence, and adherence are currently limited for this population, the outcomes briefly summarized here may lead researchers to study Pilates training-based interventions promoting favorable changes in selected psychophysiological markers in sedentary overweight and obese individuals. Such a mind–body exercise approach may be a useful strategy to determine how to participate the vast majority of the adult population globally in structured and adapted Pilates training programs characterized by supervision, progression, and variety. Moreover, additional randomized controlled trials with an emphasis on attrition and compliance to such an alternative exercise mode are warranted, given that Pilates training has been reported as one of the most popular fitness services among health club/gym/studio members and especially women ,66,67. IThe present topical review has numerous strengths: (i) the rigorous study selection process; (ii) the classification  of Pilates training protocols administered across all studies; (iii) the provision of reasonable suggestions for further research in this popular topic; and (iv) the summary as well as distribution of important research findings regarding the psychophysiological adaptations to Pilates training in the masses affected by overweight or obesity worldwide. However, this study has several limitations that should also be mentioned. Surely, it does not evaluate the quality of current data in the primary research studies, and therefore this mini-review presents a narrative clarification of existing evidence without addressing the synthesis of available data. Such a review study is primarily focused on a variety of study designs and methodologies than a systematic review, which is likely to emphasize a comprehensive analysis of a smaller number of randomized control trials.Pilates training is an alternative resistance-based exercise strategy that induces psychophysiological adaptations associated with improved anthropometric parameters, body composition, and various cardiometabolic-health-related markers, mainly through short-term interventions (4–12 weeks) in overweight and obese individuals. It is worth noting that supervision by qualified instructors may play a key role in serving these populations when performing this mind–body exercise type in real-world conditions. Progressive Pilates training protocols seem to be an efficient and injury-free approach for individuals with unhealthy weight. In summary, evidence that emerged during the past decade suggested that supervised Pilates training protocols can be an efficient, safe, and attractive exercise mode for apparently healthy individuals affected only by overweightness or obesity. However, further randomized controlled trials with superior methodological quality implementing long-term interventions conducted in a free-living environment are warranted to examine the real-world impact of Pilates training on a wide-ranging spectrum of psychophysiological health markers in overweight and obese individuals of all ages. International guidelines on physical activity and exercise ,68,91 sh


In all living organisms, extracellular signals are translated into specific responses through signal transduction processes. Research with fungal experimental systems has contributed substantially to uncovering the components participating in these processes, such as signaling molecules, receptors, kinases, phosphatases and second messengers. Different signal transduction pathways interact at various cellular levels and form networks that enable the integration of multiple signals for coordinated cellular responses. Such responses include changes in gene transcription, RNA translation and modification, and protein post-translational and conformational states. Most importantly, these processes are dependent on their cellular locations. These molecular events trigger a variety of fungal cellular reactions and developmental processes, including DNA damage response, cell cycle arrest and progression, pathogenic and symbiotic interactions, asexual and sexual propagation, primary and secondary metabolism, stress adaptation, autophagy, and apoptosis.This special issue includes different research papers and reviews that study the role of signaling molecules, G proteins and receptors, signaling pathways, and multi-subunit complexes allowing the interaction between different signaling pathways, and thus connect upstream regulators and downstream targets. These contributions will promote our understanding of the molecular mechanisms controlling both development and cellular processes in diverse fungal systems .Ganoderma lucidum. They suggest that rebuilding redox homeostasis increases cysteine and proline levels, thus reducing cadmium accumulation. Inositol phosphate signaling is the subject of an article by Murry and coworkers [Schizophyllum commune, they found that altered inositol signaling is involved in tolerance towards metals, such as cesium and zinc, and increased tolerance towards cadmium, which is associated with induced expression of kinases and repression of phosphatases within the inositol cycle. These authors provide a model of how inositol signaling is governed by Ras, G-protein-coupled receptors, and cAMP, and elucidate their different roles in development.Although there is unambiguous evidence that signaling molecules play an essential role in a broad variety of fungal cellular pathways, less is known about the identity of those regulating fungal development. Eight articles contribute to our current knowledge about the molecular players that participate in initiating cellular differentiation. Abdalmegeed et al.  provide oworkers . StudyinMagnaporthe oryzae showed that the molecular mechanisms of fludioxonil action and the perception of osmotic stress are different. In their study, Herrero-de-Dios and co-workers [Candida albicans. In addition to this, a Hog1 mutant strain showed that Hog1 is involved in lipid homeostasis. The authors propose that lipid metabolism contributes to the sensitivity to osmotic stress.Four articles investigated the effect of osmotic stress on sensing. The relationship between external osmotic stress sensing and the fungicidal activity of phenylpyrrole fludioxonil was the subject of a study by Bersching and Jacob . Essenti-workers  showed tMagnaporthe oryzae and addressed the question of how a single gene for a phosphotransfer protein may generate several isoforms to contribute to a multistep phospho-relay system. Their study indicates that alternative splicing is a promising mechanism to generate signal diversity in multistep phospho-relay systems. The HOG pathway is also the subject of a study by Plemenitaš [Hortaea werneckii and the obligate halophilic fungus Wallemia ichthyophaga with the salt-sensitive yeast S. cerevisiae. The author found important structural differences in the HOG pathway components. In conclusion, novel mechanisms of adaptation were driven by changes in salt concentration. In filamentous fungi, the high-osmolarity glycerol (HOG) signaling pathway is present as a multistep phospho-relay system. Bühring et al.  investigemenitaš . Changes2O2, are involved in the signaling of all living organisms and are implicated in a variety of biological processes [2O2 in the ascomycete Aspergillus nidulans. They found that H2O2 affects the phosphorylation of critical regulatory nodes of phosphoinositide, MAPK and TOR signaling, as well as the phosphorylation of multiple proteins involved in diverse developmental processes.Reactive oxygen species (ROS), such as Hrocesses . Carrascrocesses  used a gUstilago maydis and its plant host maize. They investigated extracellular vesicle-associated mRNAs secreted by the maize smut pathogen. Using isolated vesicles, they show by RNA-seq analysis that several mRNAs are enriched and upregulated during infection, and may thus participate in the interaction between the pathogen and host plant.Signaling molecules play a central role in the interspecies or even interkingdom communication of all living organisms. Kwon et al.  are inteSchizosaccharomyces japonicus. Interestingly, strains isolated from diverse host Drosophila species showed a high frequency of sexual sporulation, even under nitrogen-abundant conditions. The authors suggest that their ecological and evolutionary study provides a basis for understanding the sporulation mechanism.Two articles provide quite different experimental systems to understand signal transduction pathways. Groth, Schunke and coworkers  used a fAspergillus fumigatus, lacking a gene for a Gβ-like protein. They showed by organ-specific transcriptional analysis that the Gβ-like protein is essential for completing sexual development. Further roles are associated with phagocytosis by alveolar macrophages, biosynthesis of the cell wall, and oxidative stress responses. A similar experimental approach was used by Tang and coworkers [Botrytis cinerea, which causes gray mold disease in crops. A deletion strain lacking the G protein β subunit gene shows significantly reduced transcription of genes involved in cAMP signaling. From their results the authors conclude that the Gβ protein controls development and virulence through both the cAMP and MAPK signaling pathways.Classical paradigms show that G-protein-coupled receptors (GPCRs) transduce signaling through G proteins. For example, they act as molecular switches in the transduction of intracellular signaling . Since toworkers , on the Aspergillus nidulans. Gene knock-out experiments and fluorescence microscopy data provide evidence for a Golgi-localized TRP-like protein that performs an important function in conidiation, cell wall integration and cellular calcium equilibrium.Transient receptor potential (TRP) proteins are thought to constitute transmembrane ion channels with highly diverse permeation and gating properties. Wang et al.  characteSchizophyllum commune, but the function of other pheromone receptor-like genes has not yet been described. Wirth et al. [S. cerevisiae Ste3a-factor receptor. The data from transcriptome expression analysis and overexpression experiments provide evidence that these genes play a functional role in vegetative growth, possibly by determining growth direction.Pheromone receptor genes are involved in sexual mating of the tetrapolar basidiomycete h et al.  characteAspergillus nidulans. Analyses of the expansion of different families of TFs indicate that the duplication of TFs has an impact at the species level, and the author concludes that the expansion of Zn2Cys6 TFs is mainly due to dispersed duplication events.Signaling pathways activate or silence DNA sequence-specific regulators, such as transcription factors (TFs), which have been intensively studied in members of the Saccharomycotina. In this context, Extebeste  providesThe initial characterization of diverse signaling pathways considered them as linear pathways that do not interact with each other. However, depending on certain physiological conditions, these pathways may enable crosstalk between each other, probably to increase the range of specific cellular responses without increasing the number of components constituting a pathway. The following articles investigated the interplay between two signaling cascades in diverse fungal systems by comparing the phenotypes of signaling-component mutants.Verticillium dahlia. They constructed mutants related to the pheromone response MAPK pathway, or the endoplasmic reticulum-associated unfolded protein response (UPR), both affecting fungal growth, resting structure development, and virulence of the pathogen. The similar phenotypes of signaling-component mutants implied that an interplay exists between UPR and pheromone response MAPK signaling. Similarly, the interplay between two signaling pathways was studied by Moreno-Ruiz et al. [Trichoderma atroviride, a mycoparasitic fungus. The comparative analysis of mutants lacking genes for components of the above-mentioned signaling pathways showed that they are essential for establishing fully functional mycoparasitism.Starke et al.  investigz et al.  They invThe integration of components of several pathways is facilitated by multi-subunit complexes that allow crosstalk between upstream and downstream effectors of the complex . A well-Podospora anserina. For example, the stability of mitochondrial DNA affects lifespan, as does the mitochondrial level of reactive oxygen species (ROS), which has to be balanced since ROS, at low abundance, are essential signaling molecules, but at higher levels cause damage to all kinds of biomolecules. However, when the abundance of ROS passes critical limits, different pathways are induced to cope with the resulting impairments. One of these processes is the degradation of damaged, or excess mitochondria via mitophagy.Mitophagy, the selective vacuolar/lysosomal degradation of mitochondria, is also involved in the aging process, basically occurring in all living beings. The molecular networks that affect this biological process are associated with mitochondria and pathways involved in the biogenesis and quality control of these organelles . The revImproving our understanding of signal transduction networks will require scientific work by many investigators, and I hope that this special issue contributes to this effort. I very much appreciate receiving the articles and reviews from each of the authors, making this special issue possible. Furthermore, I am grateful to the “Journal of Fungi” to have this opportunity to gather articles from the fungal community presenting remarkable work that advances our understanding of “Signal Transductions in Fungi”.


Motor neuron diseases (MNDs) include a broad group of diseases in which neurodegeneration mainly affects upper and/or lower motor neurons (MNs). Although the involvement of specific MNs, symptoms, age of onset, and progression differ in MNDs, the main pathogenic mechanism common to most MNDs is represented by proteostasis alteration and proteotoxicity. This pathomechanism may be directly related to mutations in genes encoding proteins involved in the protein quality control system, particularly the autophagy-lysosomal pathway (ALP). Alternatively, proteostasis alteration can be caused by aberrant proteins that tend to misfold and to aggregate, two related processes that, over time, cannot be properly handled by the ALP. Here, we summarize the main ALP features, focusing on different routes utilized to deliver substrates to the lysosome and how the various ALP pathways intersect with the intracellular trafficking of membranes and vesicles. Next, we provide an overview of the mutated genes that have been found associated with MNDs, how these gene products are involved in different steps of ALP and related processes. Finally, we discuss how autophagy can be considered a valid therapeutic target for MNDs treatment focusing on traditional autophagy modulators and on emerging approaches to overcome their limitations. Motor neuron diseases (MNDs) are a large class of neurodegenerative diseases (NDs) primarily affecting neurons that control the skeletal muscle fibers. These neurons comprise upper motor neurons (MNs) localized in the motor cortex and lower MNs localized in the bulbar regions or in the anterior horns of the spinal cord. Other cell types surrounding  or connecting to  MNs may contribute to disease onset and progression, and ultimately to paralysis and death of the patients. These neural systems are governed by a complex architecture, thus various MN types are differentially and selectively involved in these disorders, leading to multifaceted clinical manifestations that considerably vary among affected individuals.To simplify, MNDs can be roughly classified into three major categories that reflect both the clinical signs and the type of MNs affected: (i) with lower MNs involvement , spinobulbar muscular atrophy (SBMA or Kennedy's disease), progressive muscular atrophy (PMA), pseudobulbar palsy (in the bulbar region), monomelic amyotrophy (MMA), lethal congenital contracture syndrome (LCCS), etc.), (ii) with upper MNs involvement  and hereditary spastic paraplegias (HSP), etc.), and (iii) with combined upper and lower MNs involvement , etc.) . OverallNo cure is available for most of these MNDs. Only for specific forms of SMA some highly innovative genetic approaches have recently proved to be therapeutically efficient .The molecular bases of these MNDs may considerably differ and, while specific inherited  forms are characterized by mutations in genes encoding proteins involved in a variety of intracellular and extracellular biological functions, some MNDs occur in a sporadic manner, making it very difficult to determine the causes of MN loss. Nevertheless, sporadic forms often display a dysregulation of the same proteins that have been identified mutated in familial forms of MNDs  . IntriguThe term ‘autophagy' refers to various cellular processes involved in proteins or organelles clearance via the lysosomal system. Autophagy eliminates unused, excessive, and/or defective macromolecules (either endogenous or exogenous) and recycles their components for other biosynthetic pathways . AutophaAutophagy is a complex system, in which the delivery of cargoes to lysosomes for degradation follows different routes named (i) macroautophagy , (ii) microautophagy, and (iii) chaperone-mediated autophagy (CMA).Macroautophagy implies that cargoes are sequestered by ‘omegasomes' released by the endoplasmic reticulum (ER) or other membranous compartments . Omegasomes release double-membrane structures to enclose substrates generating the autophagosomes. This process is tightly regulated and controlled by the autophagy-related proteins (named ATGs) which orchestrate autophagosome assembly, trafficking, and fusion to lysosomes ,12. The In diseases characterized by the presence of misfolded proteins prone to aggregate (including MNDs), aggrephagy may utilize a specific form of cargo delivery to the microtubule organization center (MTOC), where aggresomes are assembled . This roRegarding mammalian microautophagy, cargoes are specifically engulfed into lysosomes via the intervention of late endosomes. Protein recognition can be achieved either ‘in bulk' or  selectively thanks to a KFERQ-like motif in the target protein which is recognized by the constitutive form of HSPAs/HSP70s, the heat shock cognate 70 (HSPA8/HSC70) . In micrAs mentioned above, in the past two decades, it emerged that many mutant genes causative of specific MND forms encode proteins differentially involved in the regulatory steps of autophagy.SPG) genes, encode proteins that are key regulators of the endolysosomal system and autophagy. An autosomal dominant form of HSP is caused by a mutation of the SPG42 gene encoding a protein involved in ER membrane transport, bone morphogenetic protein (BMP) signaling and autophagy [SPG11, encoding spatacsin), in endosomal trafficking , in vesicle formation and trafficking , in Golgi apparatus-multivesicular bodies (MVB) dynamics , and lysosomal targeting to autophagosomes , or in membrane trafficking and mitochondrial function  [Indeed, by merely looking at the many different HSP forms, several mutated genes, called Spastic ParapleGia   , the DCTN1 and KIF5A  and kinesin family member 5A, involved in the autophago-lysosome fusion process and, for dynein/dynactin, in the routing of the CASA complex to the MTOC), VCP , SQSTM1/p62 and OPTN , TBK1 , FIG4 P2) into phosphatidylinositol-3-phosphate (PI(3)P) on endosomal membranes, a process relevant for endosomal transport and autophagy), and others.Even more complex is the autophagy involvement in ALS ,11,84. AANXA11, encoding annexin A11; in endocytosis (and RNA metabolism), like ATXN2, encoding ataxin 2; in sorting of endosomal cargo proteins, like CHMP2B, encoding the charged MVB protein 2B, a component of the ESCRT complex III; in vesicle trafficking from the ER-membrane, like VAPB, encoding VAMP associated protein B/C)  or to BAG1 (for proteasome degradation) [UBQLN2 or CCNF , even if it is still unclear whether the autophagic response may compensate the altered proteasome pathway.Moreover, several mutant genes encode proteins not directly involved in autophagy, but related to mechanisms that facilitate the process , like ein B/C) . Also, tadation) . Autophahttps://alsod.ac.uk/)) has tried to correlate how the variants are linked to ALS, even when evidence is weak.The impact of some of the mutations/variants reported above on ALS onset and progression is debated. A recent database  [It should be underlined that mutations in some of the genes associated to HSP and ALS may also be responsible for the appearance of PLS  . SimilarEven in the case of SMA, the causative survival MN (SMN1) protein  has been found involved in endocytosis and autophagy  altering its capability to properly fold, (ii) enhancing its hydrophobicity, (iii) affecting highly disordered domains, or (iv) altering its interaction with partners, etc. These mechanisms are not mutually exclusive and often increase the propensity of the mutant proteins to clamp together, forming aggregate structures of diverse nature: liquid–liquid droplets or fluid condensates, solid-like aggregates or densely packed insoluble protein inclusions, etc., based on their mechanism of formation and/or their stage of maturation. As a function of their biochemical state, aggregates can be dissolved or further processed to be cleared from cells via autophagy. However, aggregated proteins may impair the autophagic flux, causing severe consequences to the PQC system, with the degradative capability of affected neurons (or surrounding cells affected in MNDs) being overwhelmed. Indeed, this is the case of SBMA, caused by the transcription factor androgen receptor (AR) carrying an elongated polyglutamine tract (ARpolyQ) in its N-terminus. Soon after its translation, the polyQ is masked by specific chaperones , that are released upon AR-binding with its natural androgenic ligands. These molecules activate the AR, allowing conformational changes that unmask the polyQ, causing ARpolyQ aggregation and impairment of the autophagic process . DespiteBased on what reported above, autophagy activation may represent a valuable therapeutic approach for MNDs, but this approach has to be carefully evaluated considering the specific alteration present in each clinical form studied.For example, in case of insufficient autophagy , it might be useful to stimulate the remaining functional wild type allele, or ‘redundant' factors to restore autophagy. Unfortunately, autophagy and its regulation may considerably differ in the various cell types affected in MNDs  making it difficult to identify the proper therapeutic agent for each MND form .In general, drugs stimulating autophagy are relatively poorly specific. This is the case of the mammalian target of rapamycin (mTOR) inhibitor rapamycin, tested in MND animal models  and undeOther autophagy inducers, like trehalose and the more stable derivatives melibiose and lactulose, appear to be more promising, since their molecular mechanism of action is more selective and impacts directly on the autophagy master regulator transcription factor EB (TFEB) ,142–146.In the case of some MND forms in which autophagy is already enhanced in response to the overload of aberrant aggregation-prone proteins, generic autophagy activators may not be effective treatments. Instead, the pharmacological targeting of factors specifically acting on misfolded protein recognition and delivery to autophagy will represent a valid therapeutic strategy. The drug colchicine has these properties since it has been identified as a potent activator of the human HSPB8 promoter in MNs. Its capability to enhance HSPB8 expression was correlated with an increased CASA-mediated removal of ALS-associated proteins (TDP-43 and its disease associated fragments) in ALS cell and fly models . A doublIn conclusion, autophagy is an essential cellular process that maintains proteostasis in neurons and other cell types typically affected in MNDs. Its role in MNDs is extremely complex as both its dysregulation and its insufficient or excessive activity play multiple roles in the appearance and/or progression of different forms of MNDs and other NDs. Moreover, it is still unclear why this relatively conserved mechanism among the various cell types of the human body associates to so many different pathological conditions. Since these diseases are characterized by the selective vulnerability of different neuronal populations, other modifier factors might differentially contribute to exacerbate or attenuate, respectively, the deleterious or protective activities of autophagy in each neuronal type. Therefore, the identification of a proper target to be tackled by drugs capable of modulating the autophagic pathways is still challenging. However, it is emerging that approaches aimed to facilitate an already activated autophagy (e.g. those acting on the selective delivery of misfolded proteins to the autophago-lysosomes for their clearance) will provide more tailored treatments to counteract the neurotoxicity of aggregation-prone proteins in a wide variety of MNDs linked to defective response to proteotoxic stimuli.MNDs comprise several untreatable neurodegenerative diseases characterized by the loss of neurons controlling voluntary movements. Several MND forms are associated to alteration of the main degradative systems, particularly the ALP.Several genes found causative of MNDs are involved in the regulation of the various forms of autophagy. Other genes code proteins that perturb proteostasis in neurons indirectly altering autophagy.Different compounds have been developed to stimulate and/or facilitate the ALP, some have already been successfully tested in animal models of MNDs and may be utilized soon for advanced clinical trials in MND patients.


Kinetic models of metabolism are crucial to understand the inner workings of cell metabolism. By taking into account enzyme regulation, detailed kinetic models can provide accurate predictions of metabolic fluxes. Comprehensive consideration of kinetic regulation requires highly parameterized non-linear models, which are challenging to build and fit using available modelling tools. Here, we present a computational package implementing the GRASP framework for building detailed kinetic models of cellular metabolism. By defining the mechanisms of enzyme regulation and a reference state described by reaction fluxes and their corresponding Gibbs free energy ranges, GRASP can efficiently sample an arbitrarily large population of thermodynamically feasible kinetic models. If additional experimental data are available , these can be integrated to generate models that closely reproduce these observations using an approximate Bayesian computation fitting framework. Within the same framework, model selection tasks can be readily performed.github.com/biosustain/GRASP.GRASP is implemented as an open-source package in the MATLAB environment. The software runs in Windows, macOS and Linux, is documented (graspk.readthedocs.io) and unit-tested. GRASP is freely available at Bioinformatics Advances online. GRASP makes also use of the Bioinformatics, Optimization and Parallel Computing Toolboxes from MATLAB, albeit the latter is not strictly necessary for single-core computations. External dependencies can be avoided if the user chooses linear and nonlinear optimization solvers included in MATLAB, although additional alternatives are also supported [Gurobi ] for LP a posteriori analysis (The main three steps to building a kinetic model population are (i) input preparation, (ii) parameter simulation and fitting and (iii) The second step samples a population of feasible kinetic models according to the chosen simulation mode. GRASP currently supports two sampling modes: (i) prior sampling at the reference state (GRASP) and (ii) ABC-rejection sampling consistent with various experimental conditions (rejection). The latter mode can also be employed for simultaneously performing model selection, enabling for example the identification of allosteric interactions supported by the data .The final step consists of the quantitative analysis of the model population (ensemble). This population is encoded as a MATLAB structure, which can be readily used to perform MCA, as well as time-course simulations using GRASP functions. In addition, the user can export individual models to SBML format. To increase the usability of GRASP and facilitate the visualization of MCA and simulation results, an additional Python package was developed along with illustrative Jupyter notebooks, which are available in the GRASP repository.In order to illustrate the use and capabilities of GRASP for building and analysing kinetic models of metabolism, we prepared a demonstration of its performance in a complex system and perform MCA on the resulting ensemble . A step-Pseudomonas putida , and the pyruvate–malate axis in the TCA cycle .The GRASP framework implementation enables the construction and simulation of thermodynamically feasible and detailed kinetic models of cellular metabolism. To the best of our knowledge, this is the first open-source well-documented MATLAB package of its type that enables building, analysing and sharing detailed kinetic models consistent with thermodynamic and experimental data. By enabling the prediction of metabolic fluxes and control coefficients from kinetic models, we expect GRASP to improve the understanding of biologically relevant reactions and pathways, which are often under complex metabolic regulation. For this task, GRASP provides a robust computational suite that can be further expanded as more advanced kinetic modelling tools become available, particularly for parameter sampling and fitting. Community contributions will not only be welcome, but they will be critical to increase current computational capabilities.This work was supported by the Novo Nordisk Foundation [NNF14OC0009473 and NNF20CC0035580]; ANID through Fondecyt de Iniciación [11190871 to P.A.S.]; and a Copenhagen Bioscience PhD fellowship .Conflict of Interest: none declared.vbac066_Supplementary_DataClick here for additional data file.


Mycobacterium tuberculosis (Mtb), to many distinct classes of antimicrobials. This review will focus on the major gaps in our understanding of intrinsic drug resistance in Mtb and how functional and chemical-genetics can help close those gaps. A better understanding of intrinsic drug resistance will help lay the foundation for strategies to disarm and circumvent these mechanisms to develop more potent antitubercular therapies.Tuberculosis (TB) is among the most difficult infections to treat, requiring several months of multidrug therapy to produce a durable cure. The reasons necessitating long treatment times are complex and multifactorial. However, one major difficulty of treating TB is the resistance of the infecting bacterium,  Mycobacterium tuberculosis (Mtb) infection is notoriously difficult to treat. Standard treatment regimens for drug sensitive tuberculosis (TB) typically last for 6 months and involve combination therapy with 2-4 antibiotics, depending on the stage of treatment , a 23S rRNA methyltransferase that protects the ribosome from macrolide, lincosamide, and streptogramin binding (erm(37) does not have a known role in bacterial growth, virulence, or stress tolerance and likely evolved to protect ancestral, soil-dwelling actinobacteria against ribosome-targeting natural products produced by themselves or their neighbors eighbors . In otheeighbors . For exaeighbors .katG are the primary mechanism by which INH resistance emerges (rpoB)  . Althougs (rpoB) . Such los (rpoB)  but muchThis review will first briefly outline existing methods used to define intrinsic drug resistance mechanisms in Mtb. We will then review our current understanding and knowledge gaps of intrinsic drug resistance in Mtb and highlight how functional and chemical-genetics  can helpChemical-genetic studies have been a pillar of biology for decades. This vast body of literature covers studies of species from all three domains of life and serves as a rich resource for understanding basic biology as well as informing drug discovery efforts . Broadlyin vitro non-essential genes as mutants for in vitro essential genes are lost during library construction. Despite the strong GC bias in the Mtb genome, the overwhelming majority of Mtb genes are sufficiently susceptible to transposition for this technique to work efficiently at genome scale , the sspB adapter is expressed and the corresponding protein is degraded  has been used by several labs, including our own, to perform targeted transcriptional inhibition of essential and non-essential genes . This teIt has long been appreciated that mycobacteria have a high level of intrinsic resistance to a diverse set of antibiotics . This phvia porin-like proteins  regimen for drug sensitive TB. It has previously been suggested that ethambutol mainly serves as a “safety net” to prevent the emergence of rifampicin and isoniazid resistant TB   has been shown to be active against several drugs including bedaquiline and clofazimine . Express(Rv0678) . Loss of TB drug . Interesaquiline . The preaquiline . Tap expsistance . Thus, eMost validated or putative efflux pumps in Mtb are poorly characterized, but it is likely that efflux pumps beyond MmpS5/L5 and Tap contribute to intrinsic drug resistance in Mtb . An in-dIn designing these experiments, it will be important to carefully curate the list of predicted efflux pumps. For example, several ABC proteins have been annotated as efflux pumps even though these proteins lack transmembrane helices . Two sucGiven the role of drug efflux in intrinsic and acquired Mtb drug resistance, there has been considerable interest in developing efflux pump inhibitors (EPIs) to potentiate TB drug regimens. Numerous small molecule EPIs, including both natural products and synthetic compounds, have been described . Many ofUltimately, while non-specific EPIs may have clinical value, specific and selective EPIs could help augment TB treatment. However, substantial advances in our understanding of efflux pump specificity and structure may be required to identify such compounds. Until then, more generic EPIs, especially those that have stand-alone antitubercular activity, may be of utility for TB treatment .An intrepid compound has traversed the mycobacterial envelope, avoided efflux, and is ready to engage its target. What next? Once again, Mtb is well-equipped with numerous cytosolic mechanisms of intrinsic drug resistance. Once again, Mtb is well-equipped with numerous cytosolic mechanisms of intrinsic drug resistance . Not surwhiB7 pathway. WhiB7 is a transcription factor that senses translational stalling which can be triggered by ribosome stress during drug treatment, host-derived stressors, and poorly characterized metabolic changes (whiB7 expression is low due to upstream ORF (uORF)-mediated transcription attenuation  (erm(37), a ribosomal RNA methyltransferase which modifies the macrolide binding site on the 23S rRNA to prevent drug binding (target modification)   . Anotherication) . Moreove rescue) . This WhCompared to the hundreds of genes which contribute to intrinsic resistance by regulating cell envelope processes , there awhiB7-mediated expression of erm(37)  or alteration of a specific molecular target, in some cases it may be the result of a specific intrinsic resistance factor. This is the case with macrolides which are ineffective against Mtb due to  erm(37) . In instinst Mtb . Using twhiB7, there are several documented loss-of-function mutations in the mmpS5/L5 efflux pump  since these represent some of the most attractive drug targets. Essential genes that impart intrinsic drug resistance could be prioritized for target-based drug discovery in order to form synergistic drug combinations where both compounds have individual activity but work more efficiently in combination. One such target is the mycobacterial superoxide dismutase (sodA), an essential oxygen radical quenching enzyme. Our previous work identified that knockdown of sodA sensitizes Mtb to several different classes of drugs  or sustained mutations that result in its hyperactivitity, there can be a pronounced change in drug sensitivity with a clear genetic basis , an NIH/NIAID New Innovator Award , and a shared NIH TB research unit grant 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.


C), into its disease-associated isoform PrPSc. Besides the aggregation and deposition of misfolded PrPSc, prion diseases are characterized by spongiform lesions and the activation of astrocytes and microglia. Microglia are the innate immune cells of the brain. Activated microglia and astrocytes represent a common pathological feature in neurodegenerative disorders. The role of activated microglia has already been studied in prion disease mouse models; however, it is still not fully clear how they contribute to disease progression. Moreover, the role of microglia in human prion diseases has not been thoroughly investigated thus far, and specific molecular pathways are still undetermined. Here, we review the current knowledge on the different roles of microglia in prion pathophysiology. We discuss microglia markers that are also dysregulated in other neurodegenerative diseases including microglia homeostasis markers. Data on murine and human brain tissues show that microglia are highly dysregulated in prion diseases. We highlight here that the loss of homeostatic markers may especially stand out.Prion diseases are neurodegenerative diseases that affect humans and animals. They are always fatal and, to date, no treatment exists. The hallmark of prion disease pathophysiology is the misfolding of an endogenous protein, the cellular prion protein (PrP PRNP) . S. S97]. S CHI3L1) B . Mo CHI3L1)  [97]. MiSc are diverse in murine models of prion disease, the heterogeneity of PrPSc deposition patterns is higher in human prion diseases and comprises synaptic, perivacuolar, plaque-like, kuru-plaque, florid-plaque, punctuate, perineuronal, and intraneuronal patterns, which might occur side-by-side or even overlapping in the same patient [As already determined in the murine models in more detail (see above), the regional differences in inflammation-associated expression changes are also beginning to be investigated and described in the frontal cortex and cerebellum of patients with sCJD . Neurona patient ,120. If A more systematic investigation including different brain regions and a set of different techniques will certainly provide a better picture about region-dependent microglial (and astrocytic) signature shifts and their respective pathophysiological consequences in the future.Sc, whereas prolonged pro-inflammatory signaling and increased proliferation at later disease stages are harmful and accelerate neuronal decay. Thus, potential future therapeutic interventions targeting microglia in prion diseases certainly need to be thoroughly timed, dosed, and balanced. Although prion diseases, in several pathomechanistic regards, can be considered as a “prototype” for neurodegenerative diseases characterized by protein misfolding, we and others have shown that microglia are exceptionally highly dysregulated in murine and human prion diseases. They display an upregulation of activation markers that might be distinct from those in AD. Moreover, in our recent experiments, the extensive loss of the homeostatic signature in prion diseases stands out remarkably [Microglia are dysregulated in neurodegenerative diseases. However, it is still not clear how microglia contribute to disease pathophysiology in detail: Is it the gain of detrimental proinflammatory functions? Or is it rather the loss of protective homeostatic support towards neuronal and other brain cell types? Or could it be a combination of both? The current data support the hypothesis that microglia activation at an early disease phase is beneficial and contributes to the removal of PrPmarkably ,73,97. W


A medical condition known as alcohol use disorder (AUD) is defined as an impaired capacity to reduce or regulate alcohol consumption despite negative social, occupational, or health effects. According to studies, habitual drinkers experience a reduction in their capacity to process new information, gain new skills, and formulate plans. Studies indexed in PubMed, PubMed Central, Google Scholar, ResearchGate, and ScienceDirect, published from 2012 to 2022, were identified through the search terms “alcohol use disorder” and “executive function.” A total of 2242 abstracts were identified through the initial search terms. Full texts were reviewed for 61 articles, out of which nine articles met the criteria for inclusion. This systematic review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The current systematic review primarily focuses on the following issues: clinical neuropsychological tests of executive dysfunction, specific brain regions most affected by alcohol neurotoxic effects, and alcohol-related dementia. This review concluded that chronic alcohol dependence syndrome causes impairments in several cognitive function domains. Study shows frontal lobe damage is caused by chronic alcohol consumption. A faulty interaction among large-scale networks underlies patients' executive dysfunction in AUD, which is suggested by changes in prefrontal white-matter pathways. The goal of this systematic review is to improve the ability to recognize alcoholics who are particularly at risk of functional impairments to tailor therapeutic therapy to maximize the chance of maintaining abstinence and neuropsychology concerning this complex disease. Alcohol use disorder (AUD) is a relapsing chronic brain disease marked by excessive alcohol consumption despite negative consequences . With alA higher-order cognitive concept known as executive functioning (EF) is engaged in the self-regulation of goal-directed behavior . It descLong-term studies have shown that cognitive deficits in several areas, such as visuospatial processing, memory, and EF, are related to AUD. About half of AUD patients have cognitive deficiencies, which can have a substantial impact on their treatment compliance and day-to-day functioning, with EF playing a critical part in this process . CognitiAlcohol use disorder and its causesAccording to Koob and colleagues, the addiction cycle has three stages: the binge and intoxication stage, the withdrawal stage, and the fixation and anticipation stage. The reward system is initially hyperactive during the binge and intoxication stages, particularly the ventral tegmentum and the nucleus accumbens, and after prolonged alcohol consumption, a homeostatic change to hypoactivation takes place. Focus is placed on decreased feelings of reward for traditional stimuli and increases in negative affect during withdrawal and negative affect. Changes in the functioning of the striatum, extended amygdala, and insula accompany these psychological events. Finally, the third stage is impacted by stress, results in greater disinhibition, obsession with reward anticipation, including desire, and raises the chance of relapse .In each stage of the addiction process, including drug acquisition, escalation/dysregulation, abstinence, and relapse, the decisional and cognitive components of impulsivity are crucial . Its useThe advancement of neuroscience has made it possible to conceptualize addiction as a chronic brain illness that includes a variety of elements, including sociocultural, genetic, and even neurodevelopmental characteristics . AwareneThe National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the World Health Organization (WHO) have separated alcohol usage into five categories. These categories include (1) long-term abstinence from alcohol (LA); (2) binge drinking (BD), which is defined as consuming a large amount of alcohol in a short period (within two hours on one occasion) without any intention of stopping ; (3) long-term damaging alcohol consumption (LD), which is defined as exceeding the safe drinking dosage advised by the WHO, with alcohol intake of three to four drinks for females and four to five drinks for males; (4) long-term low dose drinking (LDD), which involves consuming no more than two drinks of alcohol per day for both sexes; (5) long-term heavy drinking (HD), which involves consuming more than five drinks per day of alcohol, regardless of sex .Changes in neuroanatomyDespite widespread agreement on the effects of alcohol on cognitive function, various hypotheses about the underlying neurocognitive mechanisms have been advanced. Chronic alcohol consumption affects the connections as well as the morphology of the brain. The diencephalic, hippocampus, and frontal regions are most affected by widespread patterns of macro and micro-structural alterations . The proAnalysis of resting-state brain activity, or the intrinsic level of neural function involving spontaneous slow fluctuations of the blood-oxygenation-level-dependent (BOLD) signal, may provide pertinent information. This method reveals functionally connected and temporally coherent networks that overlap with those linked to sensory, cognitive, or motor performance, even without external stimulation. This equivalence suggests that the neurophysiological processes underlying individual differences in cognitive functioning have a baseline activity in resting-state networks .According to imaging studies, those who suffer from executive dysfunction and alcohol dependency have less gray matter (GM) in their prefrontal cortex ,13. The Clinical neuropsychological tests of executive dysfunctionTo find cognitive abnormalities in AUD patients, cognitive screens that assess cognitive function are performed . The tesThe Wisconsin Card Sorting Test (WCST) measures "set-shifting," or the capacity to show flexibility in the face of shifting reinforcement schedules. Utilizing environmental feedback to shift cognitive sets, strategic planning, organized searching, directing behavior toward achieving a goal, and modulating impulsive responding are just a few examples of "frontal" lobe functions that the WCST assesses. The executive function uses WCST as a gauge, due to its reported sensitivity to frontal lobe dysfunction ,14,15.Using single-photon emission computed tomography (SPECT), functional neuroimaging studies have found that chronic alcoholics have decreased cerebral perfusion in the frontal regions . Two imaThe WHO coined the phrase "less alcohol, the better" to encourage young adults to drink less and avoid the repercussions that come with it . This seMethods and materialsAccording to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, this systematic review was carried out, with studies that met the review criteria being assessed and included in the study .Databases and Search StrategyA methodical search was carried out using PubMed, PubMed Central, and Google Scholar. The field search used in the process was selected based on the keywords used in the previous literature and through Medical Subject Headings (MESH), depending on the database used. Table Google Sheets 2022 was used to group every reference to eliminate duplication. The full-text papers were then retrieved after the records were first examined based on the titles and abstracts, and any irrelevant studies were omitted.Inclusion and Exclusion CriteriaTo determine the executive dysfunction in AUD patients who were diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and were at least 16 years old and under 60 years old, a systematic review was done. Electronic databases PubMed, PubMed Central, Google Scholar, ScienceDirect, and Cochrane Library were searched for English language papers published during the previous 10 years containing free full-text articles to find pertinent literature. The studies chosen were cross-sectional, case-control, cohort, systematic reviews, meta-analyses, literature reviews, and randomized control trials. Articles written in other languages or ones that were published earlier than 2012 were not included.Data ExtractionIndependent reviews of the literature were done by two authors, who resolved any differences about inclusion through conversations and consensus. After reviewing the titles, the abstracts were examined to see whether the titles matched the criteria for inclusion. Abstracts that met the criteria for inclusion were read in full, and research that still met the criteria for inclusion underwent data extraction. Table ResultsThere were 2242 potentially related titles found in the database search. Using EndNote , 37 duplicates were identified and eliminated. When the titles and abstracts of these records were scrutinized using this review's PICO  elements and eligibility standards, only 86 papers remained. These articles were located, and each one underwent a quality evaluation. The PRISMA flow diagram and the search procedure utilized in this investigation are shown in Figure The systematic review included nine studies assessed as having high quality. Table DiscussionThe concept of executive function needs to be deconstructed to comprehend the relative contribution of different cognitive executive processes to higher-order cognitive abilities like decision-making in AUD. Due to the complexity of these functions and the use of various tasks to evaluate various constellations of component processes, studies have found severe variability in executive function impairment. The majority of standard tasks used to evaluate executive functioning are multidimensional and involve several different processes that make up executive function .Clinical Neuropsychological Tests of Executive DysfunctionDay et al. (2015) provided detailed descriptions of the tasks . Table 4Other TestsEmotion face expression (EFE): Given the significance of facial expressions in interpersonal and social interactions, several studies use modifications of EFE tasks to examine the accuracy of emotion processing. EFE exercises frequently demand participants to assess the kind and/or severity of the emotions depicted on facial stimuli .Near transfer tests included the rotation span (RTS), the reading span (RDS), and the auditory consonant trigram (ACT). A letter is shown to participants in the RTS task either in the right direction or in a mirror-reversed way. After the letter has been rotated to one of eight different angles, participants are asked to choose whether the letter is facing the proper or mirror-reversed direction when turned upright. Participants see a short or long arrow pointing in one of the eight directions after making their decision. The participants are then instructed to click on the arrows that were displayed in the proper sequence after a series of judgments and arrows. After every set of trials, participants are asked to recollect the consonant strings, much like in the other near-transfer tasks. Each task  requires the subject to remember information while executing secondary distracting tasks, which taps the attentional-control mechanisms of the central executive of white matter (WM) capability .The running letter span (RLS), running spatial span (RSS), and keep track (KT) activities are used to evaluate the minor transfer effects of training on working memory capacity. A series of letters are presented one after another in the RLS challenge (two letters per second). Participants must memorize a set size (the number of letters they must remember) prior to the presentation and recollect the most recent set size (n) in the proper serial position. For instance, participants might get seven letters after being instructed to recall the prior five delivered letters. Set sizes ranged from three to nine, with each trial comprising two trials .Specific Brain Regions Most Affected by Alcohol Neurotoxic EffectsConceptualization, programming, and mental flexibility, which were more adversely affected by chronic alcohol consumption, have been connected to the operation of the medial, dorsolateral, and posterior regions of the prefrontal cortex . A PET sA study done by Fama et al. on alcohol dependents and controls showed that precentral frontal and hippocampal sizes were smaller in AUD than in controls, and they had worse scores on all memory tests. The orbital, superior, and inferior frontal volumes, and lifetime alcohol consumption, were independent predictors of episodic memory in AUD. A two-fold dissociation was used to establish selectivity; it showed that inferior frontal volumes predicted visual but not verbal memory, whereas orbital frontal volumes predicted both. Furthermore, orbital frontal volumes predicted verbal memory in AUD + drug addiction history, whereas superior frontal volumes predicted verbal memory in AUD alone ,25. VBM The mesocorticolimbic pathways: Subcortical  and cortical  components showed a broad pattern of GM loss in patients. An impairment of this route has been proposed to underlie the development and maintenance of addiction, via negative reinforcement, based on fMRI evidence for its role in adaptive behavioral learning. The primary nodes of the so-called "salience network," the dorsal anterior cingulate cortex (dACC) and insular cortex, also exhibited GM atrophy . The ideA study done by Crespi et al. used whole-brain voxel-wise analyses of diffuse tensor imaging measurements to assess WM microstructural deterioration and its relationship with fundamental executive dysfunction in AUD patients compared with healthy controls. It found a consistent pattern of WM microstructural deterioration in all the investigated diffusivity indices . It was Studies using neuroimaging techniques to uncover the brain correlates of EF deficiencies may be better able to detect minute changes in EF than studies using solely traditional EF tests. Therefore, neuroimaging research may help us better understand how subtle EF deficits and alcohol use behaviors are related. It may also help us spot people who are at risk of developing AUDs . The froNeurophysiological Correlates of Alcohol Use DisorderAn increasing body of research indicates that people with AUD who have just quit drinking have poor emotional facial expression (EFE) processing. Anger processing was more severely impacted than other emotions, and it was linked to interpersonal issues such as being too reliant, passive, and accommodating. The lack of sufficient data in this area highlights the necessity for in-depth research on emotion processing and its practical applications . These cUnderstanding individual variability in EF is essential for an understanding of the causes, effects, and treatment of AUDs . For insLarge-scale cognitive impairments are linked to alcohol dependence, especially for executive functions. These deficits are still present even after decades of abstinence, significantly affecting patients' day-to-day functioning and risk of relapse . The natChronic alcoholism impairs neuropsychological functions, which may hinder clinical treatment effectiveness  and potentially obstruct efforts to enable other higher-order abilities like successful interpersonal and social interactions, non-risky decision-making, and awareness of cognitive and behavioral dysfunctions  . Drug acA review done by Zilverstand et al. (2018) showed persistent associations between alcohol and other drug use and activation levels of the reward and executive networks, with reward network activation being positively correlated with alcohol (and any other drug of abuse investigated) and recruitment of the executive network being negatively correlated, which were linked to increased addiction severity and inability to remain abstinent .Long-term alcohol use significantly impairs conceptualizing, programming, inhibitory control, and general executive function. Poor executive functioning was correlated with more extended periods of alcohol use and dependency . Of indiAlcohol-Related DementiaAdditionally, it is clear that some alcoholics exhibit clinically significant neurocognitive impairment but do not fully fit the bill for Wernicke-Korsakoff syndrome (WKS) or other distinct alcohol-related neurological disorders (like Marchiafava-Bignami disorder). Alcohol-related dementia (ARD) has been suggested as a diagnosis for those who are more impaired within this group, although there has been some debate over this. Although ARD is described as having a more gradual global decline in cognition than WKS, the choice of name has drawn criticism because, unlike most dementias, the disorder does not worsen with abstinence .In place of other diagnostic nomenclature, the term "alcohol-related brain damage" (ARBD) has recently been adopted to describe a spectrum of neurocognitive impairment that includes both WKS and ARD. By acknowledging the varied effects of chronic alcoholism and its contributing factors, this emerging conceptualization may offer a more practical nosological approach  . There iLimitationsOur research has some limitations. We only selected articles in the English language and published articles; several research studies we chose had tiny sample sizes and could not accurately represent the population as a whole. We only included research published after 2012; however, some earlier studies may contain crucial findings. The results of the studies using MRI scans would have contributed to a better knowledge of the damaged areas, the volume of the brain, and connections. This study will aid future researchers by providing clarification and opening up new avenues for investigating the elements of executive dysfunction in AUD.Alcohol-dependent individuals have serious memory and executive function problems in several areas, and decisional and cognitive impulsivity, problem-solving, inhibition, and self-regulation are affected. Long-term alcohol use is closely linked to cognitive function degradation, but greater education offers protective benefits, especially for executive skills. Therefore, regular cognitive testing as part of an alcohol treatment program may help identify and monitor the development of these changes as well as for cognitive rehabilitation and psychosocial reintegration of alcohol dependents. Improved treatment results continue to be a major public health priority because of the enormous amount of suffering and expense associated with alcohol addiction problems. A promising method that could promote treatment compliance and lessen problematic alcohol consumption is cognitive rehabilitation, particularly in the crucial and complex domain of executive functioning. The conclusions discussed above need to be supported by more studies, and neuropsychology research for cognitive deficiencies has to be prioritized.


Discontinuity in child and adolescent mental health services (CAMHS) and adult mental health services (AMHS) constitutes an important challenge in mental health care. In the last decade, efforts have been made to better define the transitioning population and build consensual models for CAMHS-AMHS’ transition.We aim to present our protocol and transition consultation results on the scope of published literature.Description of protocol and casuistic of 18 months’ transition consultation at Centro Hospitalar Barreiro-Montijo. The literature found on PubMed was published from 2008 to 2020 and was reviewed using the keywords: transition, CAMHS, AMHS, adolescent, mental health service, young people. Articles with full text available written in English and French were selected. The included clinical studies focused on populations with neurodevelopmental disorders, psychotic disorders, non-suicidal self-harm and suicidal attempts.Forty-four articles were included, published from 2008 to 2020. 4 articles were excluded on basis of language and diagnosis criteria (eating disorders). Twelve were reviews, 24 were clinical studies and 4 were opinion articles. There are cultural and referral issues that explain the loss of patients in this transition gap. Individuals with history of severe mental illness were more frequently referred than those with neurodevelopmental disorders. Optimal transition is defined as adequate transition planning with a flexible age cut-off and continuity of care following transition.For the vast majority of service users, transition from CAMHS to AMHS is poorly planned, executed and experienced. Improving transition models is essential to the patients autonomy’ promotion and a stronger adult mental health.


SC-derived or -inspired strategies as a putative surrogate for conventional cell therapy are thus gaining momentum. In this article, we review current knowledge on the patho-mechanistic roles of ECM components in common vascular disorders and the prospects of developing adult SC based/inspired therapies to modulate the vascular tissue environment and reinstate vessel homeostasis in these disorders.The extracellular matrix (ECM) represents a complex and dynamic framework for cells, characterized by tissue-specific biophysical, mechanical, and biochemical properties. ECM components in vascular tissues provide structural support to vascular cells and modulate their function through interaction with specific cell-surface receptors. ECM–cell interactions, together with neurotransmitters, cytokines, hormones and mechanical forces imposed by blood flow, modulate the structural organization of the vascular wall. Changes in the ECM microenvironment, as in post-injury degradation or remodeling, lead to both altered tissue function and exacerbation of vascular pathologies. Regeneration and repair of the ECM are thus critical toward reinstating vascular homeostasis. The self-renewal and transdifferentiating potential of stem cells (SCs) into other cell lineages represents a potentially useful approach in regenerative medicine, and SC-based approaches hold great promise in the development of novel therapeutics toward ECM repair. Certain adult SCs, including mesenchymal stem cells (MSCs), possess a broader plasticity and differentiation potential, and thus represent a viable option for SC-based therapeutics. However, there are significant challenges to SC therapies including, but not limited to cell processing and scaleup, quality control, phenotypic integrity in a disease milieu  The structural and functional homeostasis of mammalian organs is maintained by support provided by their connective tissue components comprising of a three-dimensional network of cells and ECM , 2. The The walls of healthy blood vessels exhibit a lamellar structure, with the concentric layers variably containing endothelial cells (EC), smooth muscle cells (SMC), and fibroblasts distributed in a layer-specific ECM milieu . Medium-The ECM secreted by vascular cell types  allows the vessel wall to adapt to mechanical forces encountered. The mechanical and viscoelastic properties of the vessel wall  are mostly imparted by 3 main structural ECM components: elastic fibers, collagen fibers, and large aggregating PGs  Figure .Elastin is the chief protein constituent of elastic fibers, and accounts for ~90% of its composition by mass , 16. ElaIn the aorta, elastin is predominantly produced by medial SMCs, though adventitial fibroblasts and ECs also exhibit limited elastogenic capacity. The process of elastic fiber neo-assembly is initiated during fetal development, and this serves as counterbalance to the mechanical forces acting on the forming vascular conduits, to enable their elastic recoil. Repeated stretch and relaxation cycles allow the tropoelastin monomers to polymerize through a process termed as coacervation . TropoelTropoelastin molecules are rich in hydrophobic amino acid residues and are amenable to robust crosslinking. Thus, fully polymerized mature elastin is practically insoluble in aqueous environments, metabolically inert, and extremely resistant to thermal and chemical onslaught , 17. ForDeregulation of vascular SMCs impairs their ability to switch between a differentiated phenotype  and dedifferentiated phenotype . Differentiated vascular SMCs exhibit high levels of contractile gene expression and demonstrate low levels of proliferation, migration and ECM synthesis, while the dedifferentiated state is often linked to increased rates of proliferation, migration and production of ECM . Upon invia positive feedback  and their inhibitors , with increased levels of the former, can also lead to the same adverse remodeling outcomes . In the feedback .Collagen is one among the major structural components of the ECM that provide integrity and stability to the vascular wall . Collagevia LOX and LOX–like proteins and small leucine-rich proteoglycans (SLRPs) contain collagen-binding domains. This allows the formation of a protein coat on the surface of the fibrils and further protects them from protease degradation  that provide structural/biomechanical functions. Non-fibrillar collagens (type IV and VI), which form part of the basement membrane, are involved in anchoring and organizing fibrillar collagens and have cytoprotective roles . Collageradation . The intradation .PGs composed of protein cores that are decorated with glycosaminoglycan (GAG) side chains . GAGs arPGs are extremely diverse in size, shape and chemistry, and their structure is based on their core proteins, location, and GAG composition. PG content in ECM of normal vascular tissue is low, however this dramatically increases in almost all stages of vascular diseases. PGs accumulate largely in lesions of the vasculature that are prone to disease initiation and are frequently coincident with early phases of atherosclerotic lesion formation through the retention of cholesterol-rich lipoproteins . PGs areThe vascular ECM is critical to maintain vascular wall integrity, to impart tensile strength, viscoelasticity, elastic recoil and compressibility to the vessel wall. The ECM also plays a key role in regulating the phenotype and cellular fate of vascular cell types, through the distinct properties of its different constituents , 5, 7. EArterial stiffness, also referred as arteriosclerosis, is one of the earliest clinically detectable manifestations of impaired vascular ECM remodeling . AlteredArterial stiffness increases with advancing age and is associated with a higher risk of developing hypertension . HoweverAS is a common cause of coronary artery disease and stroke and is a leading cause of morbidity and mortality worldwide . AS refeRecent studies have indicated the role of PGs and GAGs in orchestrating AS progression . AccordiIn AS, ECM remodeling is considered a critical step in development and progression of the condition, the dynamic interactions between the multitude of cell types and molecular mechanisms involved in regulating the matrix remodeling process are still not fully understood . In AS, Aortic aneurysms involve progressive enlargement or bulging of the aorta that has the propensity to expand and rupture . The mosAAAs are localized, focal dilatations of the abdominal aorta, the segment between the renal bifurcation and iliac bifurcation . An aortECM degradation in AAAs occurs due to a chronic imbalance between elastolytic proteases (MMP2 and MMP9), generated by pro-inflammatory macrophages infiltrating the injured aorta wall, and their natural inhibitors, the TIMPs. SMCs in the healthy adult vascular wall are of contractile phenotype and are intrinsically deficient in their capacity for elastin synthesis and have impaired ability to assemble mature elastic fibers . FurtherThe decrease in total aortal elastin content in the vessel wall due to chronically upregulated proteolytic activity is compensated by the cellular deposition of collagen in response to enhanced flow-induced stresses encountered by SMCs in the thinning vessel wall. While adult cells, more so, diseased vascular cells, are intrinsically deficient in their ability to generate elastic matrix, and have impaired ability to assemble mature elastic fibers, vascular SMCs and fibroblasts readily and exuberantly regenerate collagen . This coThoracic aneurysms are classified as aortic root or ascending aortic aneurysms . The comTAADs typically demonstrate a classical Mendelian inheritance with high or complete penetrance. This possibly suggest the contribution of a single gene defect in the progression of TAADs. TAADs can be further classified into syndromic presentations that demonstrate characteristics of a systemic connective tissue disorder , and non-syndromic presentations . MFS is a typical heritable autosomal-dominant disorder caused by mutations in a structural glycoprotein fibrillin 1, which is a major component of the microfibrils critical to elastic fiber assembly . These mSCs represent a unique population of undifferentiated cells which are capable of extensively differentiating into different tissue and cell types . They arSCs are classified broadly based on origin as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult SCs . ESCs arin vivo and initiate revascularization of the ischemic cardiac tissue through differentiation and generation of new specialized cells  cells from non-regulatory cells and also suppressed the proliferation of NK cells in Apolipoprotein E (−/−) (ApoE−/−) mice AS model  reducing pro-inflammatory responses, (b) promoting anti-inflammatory environment, and (c) mitigating monocyte recruitment to the lesion site.Undifferentiated MSCs have the capacity to modulate and reduce inflammation and can alter immune cell components within AS plaques to alleviate inflammation . The proAS model . The ince region . These rvia the Akt/eNOS pathway by upregulating IL8 and Macrophage Inflammatory Protein (MIP)-2 in ApoE−/− mice  due to reduction in very-low-density-lipoproteins (VLDLs) levels  levels . OverallMSCs have the potential to treat advanced AS plaque lesions through the regeneration of the inner endothelial lining and collagen fiber formation in the vessel wall , 95. MSCCurrent strategy of using MSCs as a therapeutic option for AS treatment involves their use as a post-injury treatment approach, exploring the immunomodulatory properties and plaque stabilization effect of MSCs –81. GiveAAA pathophysiology is driven mainly by the progressive degradation and loss of ECM structures in the aorta wall, a process driven by the chronic inflammatory milieu in the tissue , 49. Thein vivo studies on male angiotensin II (Ang II) infused ApoE−/− mice demonstrated that MSC implantation via laparotomy was effective in downregulating the expression of MMPs, IL-6, Monocyte Chemoattractant Protein-1 (MCP-1), and TNF-α, and also in upregulating Insulin-like Growth Factor-1 (IGF-1) and TIMP-1. Since laparotomy for localized cell delivery to the AAA wall was invasive, BM-MSCs were delivered via the intravenous (I.V.) route into an AngII-induced AAA mouse model  are used to broadly describe distinct sub-types of extracellular secretions comprised of small bilayer lipid membrane vesicles –134. EVsIn a study by Feng et al. EVs (exosomes) obtained from iPSC-MSC were used as treatment option for aging-associated arterial stiffness and hypertension . I.V. adSC-derived exosomes can regulate the incidence and progression of AS and could overcome the limitations associated with conventional AS treatment strategies. MSC-derived exosomes are reported to have an anti-atherosclerotic role , whereas−/− mice model and greatly reduced the infiltration of macrophages into the plaques, suggesting their anti-atherosclerotic effect. Exosomes were also effective in inducing macrophage polarization toward M2 phenotype via up-regulation of miR-let7  and reduced AS plaque area . The results from this study suggest that MSC-CM moderates AAA growth by potentially regulating macrophage polarization and through immunomodulation  in cytokine-injured cultures of SMCs isolated from the elastase injury induced rat AAAs  Figure . Apart fin vivo, and (f) challenges to their localized delivery to the site of tissue repair  ethical issues concerning use of ESCs, (b) potential tumorigenesis, (c) immune rejection, (d) quality control in sourcing and scale up issues, (e) their uncertain phenotypic state and fate e repair . Even wie repair , 151. MSe repair . These de repair . Lack ofe repair . To overEfforts should be also made to capitalize the paracrine signaling pathways, as an effort to develop a cell-free approach for regenerative therapeutics. While exosomes promise unparalleled advantages over cell-based therapy , their fAnother limitation in studying in chronic immunometabolic vascular diseases is the fact that most of these diseases evolve in humans over a period through the involvement of several organs and immune cell type . Animal Changes in the vascular ECM microenvironment is pervasive across a wide spectrum of vascular disorders. In many instances, these changes have been shown to drive the progressive pathophysiology of these disorders through signaling feedback. Our comprehensive understanding of the dynamic interplay between altered ECM state and dysregulation of vascular cell signaling provides new insight that might guide toward development of new treatment approaches to either prevent or to actively regress these vascular pathophysiologies.via secretion of growth factors have demonstrated efficacy not only in prevention of diseases but also in the regression of damaged vascular tissues. This synergistic immunoregulatory effect combined with matrix regenerative abilities of SC-based and inspired products may help in developing novel therapeutic strategies for preventing and treating vascular disorders. The clinical translation of these therapeutic strategies is however conditional on progress in addressing key challenges associated with the clinical translation of SC technology.Recent advancement in SC technologies have brought MSCs to progress closer to clinical applications for disease therapy and tissue reconstruction, even though challenges might seem daunting. The immunomodulatory effect of SCs at vascular injury sites, followed by ECM regenerative effect induced SS and AR conceptualized and wrote the manuscript. SDah, SDay, SB, and JY helped in the collection of literature and critically discussed the content. All authors reviewed the manuscript before submission and have read and agreed to the publication of the manuscript.The AR lab has been funded by the following agencies in the USA for the following projects: National Institutes of Health (NHLBI), HL 139662-01. Title: Matrix Regenerative Nanotherapeutics for Abdominal Aortic Aneurysm Repair. National Science Foundation, CBET 1926939, Collaborative Research: Design and development of a multifunctional nanoplatform for augmented elastic matrix repair. American Heart Association, 19TPA34890029, Matrix regenerative siRNA nanotherapeutics for small aneurysm repair. Discretionary funds from Lehigh University usable to cover publishing costs.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.