Metabolites are closely intertwined genotypes that can provide clear information about the final phenotype. The high-throughput analysis platform used to identify candidate metabolites and describe their contributions can help to quickly detect metabolic characteristics from large spectral data, which may lead to peak data preprocessing, statistical analysis and functional interpretation. Developing a comprehensive strategy for discovering and verifying bioactive metabolites can provide a large number of new functional biomarkers, and then more closely reveal their functional changes, which has relevant biological significance for disease diagnosis and prognosis treatment. In 2022, five studies on high-throughput mass spectrometry metabolomics analytical platforms and softwares for identifying metabolites and delineating their contribution were published in Nature Protocols . These sMetabolites are the final downstream products of protein translation and gene transcription or cellular perturbations to the proteome, genome or transcriptome, which serve as potential key links between genotype and environment and can provide a clear image of the final phenotype. Small-molecule metabolites can provide insights into unique metabolic mechanisms and therapeutic targets of diseases, and lead to personalized applications of metabolic phenotypes. Furthermore, metabolite identification or metabolic pathway changes will help to understand the pathophysiology of the disease and assist in determining therapeutic targets. Metabolomes are comprehensively characterized by measuring the small metabolites in cells, biofluids, organs, or other biological systems, and represents the upstream input from the environment and the downstream output from the genome. In particular, due to the huge complexity of metabolome, there is urgency to developed various powerful tools to facilitate spectral data processing and interpretation that help to identify bioactive metabolites. Identification of small molecule metabolite is one of the most important processes in the discovery stage and can be performed by a range of established innovative technologies . TherefoNature Protocols by Horvath et al. developed a LC/MS quantitative analytical platform for liquid chromatography-tandem mass spectrometry metabolomics method for targeting analysis and monitoring the content change of microbially derived short-chain fatty acids and neurotransmitters from the bacterial cultures, organoid cultures and in vivo samples (in vivo and in vitro (media and organoids) models, reveal the contributions of microbes to host neurotransmitters, and dissect the important bidirectional connections, between commensal microbes and host. In this study, the authors demonstrated a systematic approach to reveal how the bacteria regulate the CNS and gut, provide valuable information by determining the specific pathways into the functional mechanisms that specific microbes influence host metabolism -based approaches  to conduct high-resolution mass spectrometry spectra processing, statistical analysis of complex metabolic datasets, and joint-pathway analysis of multi-omics integration (NOREVA to facilitate optimizing the multiclass metabolomic data processing (Kirkwood and colleagues have analyzed lipidome data by the open-source software proaches . Importaegration . It can ocessing . This prMetaboAnalyst includes numerous modules for metabolite enrichment and relevant metabolic pathway analysis with pathophysiological mechanism by establishing the network interaction and visualization map (Taken together, these helpful studies provide the technical advances for identifying active metabolites and greatly broaden the coverage level of metabolites for exploring metabolic altered dimensions of diseases. The described analytical platforms and software tools provide some advantages in the sensitivity, dynamic range, reproducibility, time-saving and throughput for the combination of qualitative and quantitative. Rapid analysis of complex metabolome requires the specialized tools for the preprocessing raw data followed by multivariate statistical analysis, omics data mining and bioinformatics integration and functional interpretation. In this setting, tion map .Despite these tremendous advances, at present, no single analytical method can fulfill the mission of identification of entire metabolome in the large sample sizes. Future works aimed at developing the integrated strategy for enhancing the accuracy of discovering a list of biologically active metabolites with pathological basis of diseases, could provide a large number of the relatively abundant ions and acquire more reliable identifications, and then shed light on the functional changes of small molecule metabolites more closely. Moreover, it should establish multi-cycle training optimization models of experimental and clinical studies to validate the overall prediction performance of particular metabolite bioactivity and relevant biological significance for disease diagnosis and prognostic treatment that are worthy of further exploration. In the future, the integrated use of computational algorithms, artificial intelligence, and big data mining method will improve the precise identification ability of metabolites for resulting optimization and verification.


Theyent role , 4. Its ent role . The incent role , 7. NMSCent role –10. Seveent role , 12.New tools and molecular advances in hyperproliferative skin disorders,” reports manuscripts by several scientists operating in the field, aiming to decipher the complexity of these diseases.Given the high heterogeneity of the HSD conditions, basic and translational research is essential for developing novel therapeutic strategies. The present Research Topic, “Mercurio et al. provide an extensive overview of the role and function of the PI3K/AKT/mTOR molecular axis in the pathogenesis of different HSD. They discuss recent evidence of the involvement of the PI3K/AKT/mTOR pathway in the development and progression of NMSC, enhancing cell proliferation and resistance to apoptosis. In inflammatory skin conditions, such as psoriasis and AD, the pathway shows a dual effect. In psoriatic lesions, the hyperactivation PI3K/AKT pathway could be implicated in regulating the senescent-like phenotype of epidermal keratinocytes, thus promoting a keratinocyte growth arrest. In AD, the pathway is involved in epidermal stratification, cornification, and immune-mediated inflammatory response. Finally, the authors summarize the current and future strategies targeting AKT/mTOR pathway.Xiuli and Honglin reviewed the dysregulation of miRNAs, focusing on two hallmarks of psoriasis: keratinocyte hyperproliferation and T-cells deregulation. They identified the existence of an up and down of miRNAs expressions forming distinct networks that collaborate to promote the development and maintenance of psoriasis by NF-kB, Notch, PTEN/PI3K/KT3, and STAT3 signaling pathways.Among HSD, psoriasis plays a prominent role because of its complexity. Recent evidence shows altered microRNA (miRNA) expression profiles in the psoriasis , 14. CirZhu et al. demonstrated that specific MTHFR SNPs  could be associated with the development of PsA. The authors also explained that the MTX-related hepatotoxicity could depend on particular genotypes. Even though these results are a good starting point, they necessitate further investigation to increase the robustness of their data by increasing the size of the analyzed samples.In the context of psoriasis, a mention should be made of those patients who develop psoriatic arthritis (PsA) after psoriasis or concomitantly with it. Among treatments, methotrexate (MTX) has greater efficacy in patients without arthritis and is less associated with hepatoxicity . TherefoChen et al. discuss recent literature on the role of AGEs in the skin. They highlight the biochemical pathways leading to AGEs formation and accumulation, provide a classification of AGEs found in the skin, and describe endogenous and exogenous sources of AGEs. The authors then summarize the effects of AGEs on the structure and functions of the epidermal and dermal compartments of the skin and the current information on the underlying molecular mechanisms by which AGEs cause damage in different skin layers. Moreover, the review also includes a comparative overview of several novel comprehensive methodologies for measuring the AGEs content in human skin. Finally, the mechanisms of the prevention and inhibition of the formation and accumulation of AGEs are discussed, suggesting that AGEs inhibitors could be of potential therapeutic benefit for treating skin diseases, promoting cutaneous wound healing, and delaying skin aging.Advanced glycation end products (AGEs) accumulate in organs and tissues with aging and are linked to the pathogenesis of a multitude of age-related and chronic inflammatory diseases, such as diabetes, cardiovascular and neurodegenerative diseases, and renal failure , 19. In Quadri et al. provided an update about the most important in vitro and in vivo tools developed for cSCC studies. They explained the use of two-dimensional (2D) cell culture and of the most recently established three-dimensional (3D) cSCC models , emphasizing their contributions to novel drug testing and pharmaceutical development. Moreover, the authors explained the continued necessity of using animal models in cancer research, which compensates for the lack of systemic components of in vitro models. The new zebrafish xenotransplant model allows monitoring tumor metastasis in real time. In the last years, several categories of cSCC-mouse models have been developed, which have been fundamental to understanding new molecular mechanisms underlying cSCC pathogenesis and evaluating drug response in an in vivo setting.cSCC is a complex disease representing the second most common type of skin cancer , 10, 20.In summary, this Research Topic highlights the latest efforts in HSD research, focusing on identifying novel molecular networks, biomarkers, or signaling pathways and developing novel models that allow a better understanding of these skin conditions.All authors contribute to writing the manuscript and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Inflammation is a physiologic process occurring in response to tissue damage. Already in 1863, Virchow , based oMore recently, the term tumor microenvironment (TME) was used to include both cellular and soluble components which surround and infiltrate the tumor mass . The TMEIt progressively became clear that both the phenotype and the number of infiltrating cells are strongly dependent upon specific chemokines secreted within the TME. Thus, chemokines rapidly became among the most extensively characterized molecules involved in the maintenance and progression of tumor-related inflammation .In the five articles included in this Research Topic, different aspects of the most recent lines of research on the field of TME and cancer biology were addressed. The findings are here briefly overviewed with the final aim to provide a stimulating summary of the present knowledge.Huang et al, by performing a Gene-Set-Enrichment-Analysis on a large group of patients with breast cancer, demonstrated that the expression levels of ITK gene  were significantly and positively related to prolonged overall survival. Given that the IL-2-inducible T-cell kinase (ITK) gene regulates T cell signaling and subsequent secretion of several pro-inflammatory cytokines  (By using a similar approach (GSEA),  family)  gene expRuan et al., aimed at reviewing most recent evidences on the role of integrins, cadherins, selectins, and CD44 in endocrine-related cancer. Briefly, an overview of the mechanisms by which altered expression of CAMs lead to remodeling of TME and subsequent development of drug resistance of cancer cells is provided, and their application also to endocrine-related cancer is discussed.Cell adhesion molecules (CAMs) are transmembrane receptor proteins involved in cell-to-cell or cell-to-extracellular matrix binding . CAMs arin vivo and in vitro preclinical studies. However, high toxicity and resistance characterize these agents as reported by clinical trials  secretion within the TME provides beneficial effects in terms of slowing down tumor progression. Vitamin D displays several er cells . Furtherer cells , 16. CopIn conclusion, although a limited number of studies were collected in the present Research Topic, it is clear that the Endocrine Cancer Microenvironment represents a major target for developing novel anti-cancer strategies. Currently available evidences have consistently supported the concept that cancer progression is promoted by the complex interplay between malignant cells and the surrounding environment –19. TumoAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Several data indicate that the success of pharmacological treatment in major depressive disorder (MDD) is still unsatisfactory. The determination of the optimal treatment generally requires multiple trials with different treatments, with the sobering observation that the more treatments tried without success, the less likely a successful outcome, with the result of a long unremitted disease, worse long term prognosis, increased rates of side effects, and important medical, social and economic burden. The reasons for the low response and remission rates are multiple and depend on environmental and biological factors intrinsic to the disease and drug treatments. Pharmacogenetic (PG) tests have the potential to increase efficacy predicting outcome and to reduce antidepressant discontinuation due to side effects. Several studies investigated the utility of PG tests for antidepressants in MDD with interesting but contrasting results. To date most of them are observational studies with no comparator group, and few are randomized controlled trials (RCTs). Several limitations concerning study design, generalization of results, duration of trials, patients group studied, and cost-effectiveness ratio were found, and a number of barriers have been noted in the adoption of PG tests into clinical practice. Despite some preliminary positive results, there is the need for larger and longer‐term RCT studies, with the goal to capture the real impact of PG tests, also with stratified analysis concerning MDD features in terms of severity and antidepressant treatment failures in different ethnicity cohorts.No significant relationships.


Neuroplasticity in Rehabilitation, a Research Topic exploring how the nervous system changes in response to rehabilitative interventions. While the field of human neural interfacing began with the development of bypass devices , botulinum neurotoxin injection , and rapid-reciprocal leg training , to newer techniques like robotic-assisted therapies , biofeedback , and exoskeleton-based walking with trans-spinal stimulation . Similarly, resultant neuroplasticity is measured with a range of classical functional outcome measures  and reflex arc assessments  to newer imaging-based surrogates of brain activation and connectivity such as functional magnetic resonance imaging (fMRI) , diffusion tensor imaging (DTI) , and functional near-infrared spectroscopy (fNIRS). Finally, Proulx et al. round out our topic by providing a thoughtful narrative review on the importance of multimodal sensory feedback in neurorehabilitation strategies, making a case for the importance of intentionally incorporating brain multisensory integration areas during motor learning to improve motor outcomes in stroke.The sheer number of modalities available for rehabilitation and the study of its effects on the human nervous system has rapidly expanded, and this Research Topic represents a sampling of active areas of investigation. Interventions presented here span classical rehabilitation therapies like stepping  repair; instead, it is our persistently incomplete understanding of human CNS organization, regeneration, and plasticity. Because the CNS is such a complex system that functions on physical scales ranging from microscopic/molecular to full human body circuitry and interacts on timescales ranging from near-instantaneous to a lifetime , obtainiHowever, even short of a complete understanding, incremental progress and discoveries are having tangible impacts. For example, we are now seeing unprecedented recovery from spinal cord injury –8, novelAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Radiofrequency energy is a common treatment modality for chronic pain. While there are different forms of radiofrequency-based therapeutics, the common concept is the generation of an electromagnetic field in the applied area, that can result in neuromodulation (pulsed radiofrequency—PRF) or ablation. Our specific focus relates to PRF due to the possibility of modulation that is in accordance with the mechanisms of action of orthobiologics. The proposed mechanism of action of PRF pertaining to pain relief relies on a decrease in pro-inflammatory cytokines, an increase in cytosolic calcium concentration, a general effect on the immune system, and a reduction in the formation of free radical molecules. The primary known properties of orthobiologics constitute the release of growth factors, a stimulus for endogenous repair, analgesia, and improvement of the function of the injured area. In this review, we described the mechanism of action of both treatments and pertinent scientific references to the use of the combination of PRF and orthobiologics. Our hypothesis is a synergic effect with the combination of both techniques which could benefit patients and improve the life quality. Radiofrequency (RF) energy-based procedures, whether conventional, ablative or pulsed, represent a technique commonly performed for chronic pain in a variety of musculoskeletal conditions ,2,3.Pulsed radiofrequency (PRF) is derived from conventional RF with the aim of a less destructive RF-based treatment to be applied to the afferent nerve pathways of injured tissues . PRF creThe changes produced by electrical fields are selective for small unmyelinated and lightly myelinated nerve fibers, producing a motor-sparing effect . HistoloAlthough both techniques have been reported to be effective (pulsed and ablative RF), there are some limitations more related to the ablative RF, such as failure to completely denervate the nerve, disrupt nociceptive sensation, worsening of symptoms due to aberrant neuronal regeneration, neuroma formation, and reduced motor function, neuritis, paresthesia and deafferentation pain syndrome .Some studies demonstrated that the analgesic effect of PRF is not related to thermal effects or to permanent physical neural damage ,12. ThisPreclinical studies have proposed several biological effects of PRF. The mechanisms of action may consist of morphological changes in the inner structures of axons , molecul2+ influx. Once the cell is exposed to high electric fields for a short period, the cell membrane increases its permeability to ions and molecules, a process called electroporation. Accordingly, PRF could be applied to different regions of afferent nervous pathways, so this influx could occur in the same fashion in all aspects of the targeted neuron [In addition, it was hypothesized that PRF could cause neural membrane permeabilization due to a mild electroporation process leading to a Cad neuron .PRF is not limited to targeting afferent nerves, which was observed after the use of intra-articular PRF, and, as a result, it was verified that PRF promotes an analgesic effect. Therefore, it was suggested that PRF could present a local anti-inflammatory effect due to an effect on the immune system, which may ultimately impact the nociceptive process ,23.It was reported that PRF has the ability to decrease levels of interleukin-1 (IL-1), metalloproteinase-3 (MMP-3), and tumor necrosis (TNF-α) in the synovial fluid of severe osteoarthritic (OA) patients. This was demonstrated by the observation of clinical improvements, resulting in better outcomes in comparison to the use of betamethasone. The effect on the immune response could be explained by the inhibition of immune cells and pro-inflammatory cytokines. Therefore, as inflammatory cytokines are regulated, PRF stimulates a greater level of cascade reaction-stop amplification of the inflammatory reaction and avoids the common inflammatory wind-up phenomenon. This may explain the mechanisms of long-term pain mitigation after using PRF . Given iPreclinical studies demonstrated a rapid onset (within 3 h) increase in c-FOS expression, a specific marker for cellular activity, which lasted one week after PRF stimulus. c-FOS inhibition of excitatory C fibers is a possible mechanism involved in analgesia . In vitrPertaining to ultrastructural changes in the sciatic nerve, a preclinical study reported extensive mitochondrial swelling and hyperplasia. Functional recovery of the animals suggests that this mechanism is a compensatory response that helps the recovery and regeneration of lesioned nerve fibers. In the treated animals, it was observed that the macrophages contained intracellular cholesterol crystals and necrotic tissue, suggesting that PRF promoted an inflammatory response to clear the lesion area, as an early response to PRF .Up until now, the literature has been trying to elucidate the mechanisms of action underlying the use of PRF. Well-designed randomized controlled and in vitro trials are needed in order to clarify the mechanism of action further for procedures at frequencies and temperatures used in current clinical practice and how they modify central and peripheral components of pain pathways. Additionally, it is important to note that clinical outcomes could be influenced by lesion parameters (sensory and motor stimulation thresholds), lesion duration, electrode position, and local tissue properties .Another possible effect of PRF involves changes in the oxygen molecule. The recombination of oxygen (geminate recombination or cage recombination) competes with the final separation of the radicals (escape reaction with the possibility of forming products different from those of cage recombination). The ratio of the cage to escape reaction yields will critically depend on the rate of spin evolution, which, on the other hand, depends on an external magnetic field .Thus, the reaction kinetics become magnetic field dependent and this could explain the phenomena that result in the PRF mechanism of action. The radical pair mechanism is a plausible way in which weak magnetic field variations can affect chemical reactivity, allowing radical pairs containing substances that can function as chemical/biological magnetic sensors ,29.Regarding the analgesic effects of PRF in nerves and other tissues, we summarized them in This review will focus on PRF and its potential synergistic action with orthobiologics, given that PRF represents a less destructive and more modulatory role, which is in agreement with the mechanisms of the orthobiological substances.Orthobiologics comprise a group of autologous biological materials, including bone grafts, growth factors, cell-signaling proteins, and cell-based therapies, such as platelet rich plasma (PRP), bone marrow- and adipose tissue-derived products, which promote bone, ligament, muscle, and tendon healing . The widAlthough the concept of biologics is not quite new—platelet rich plasma has been used in oral maxillofacial surgery for decades , most adPlatelet rich plasma (PRP) is an autologous product with a platelet concentration above baseline in a small volume of plasma. It is obtained following steps of centrifugation and cell selection . Its effUpon activation, platelets release molecules that bind to the specific receptors on the cell membrane of the target cells, triggering a signaling cascade that activates acute inflammation, with tissue repair as an end product . Among tPRP has been studied to treat a range of musculoskeletal conditions. A recent meta-analysis with 18 studies was published comparing the use of PRP with hyaluronic acid (HA) for the treatment of knee OA. An improvement was noted in the PRP group for the function scores of specific joints. In addition, patients who received PRP also reported significant pain relief . AnotherThe use of PRP for pain management is also a matter of discussion in the literature. Studies that evaluated PRP for the treatment of knee OA reported a significant decrease in the visual analogic scale (VAS) for pain evaluation and WOMAC pain score ,41. A feBone marrow is a rich source of stem and progenitor cells, including hematopoietic cells (HSC) and mesenchymal stem cells (MSC) . HSCs arBone marrow aspirate (BMA) is a rich source of MSCs and HSCs and is also considered a great reservoir of growth factors . BMA canBone marrow aspirate concentrated (BMAC) is a product with anti-inflammatory and immunomodulatory characteristics, capable of potentially augmenting tissue repair as it presents high levels of all cellular and molecular components present in BMA . The effThe efficacy of BMAC has been reported for several musculoskeletal conditions. Centeno et al. studied the effects of BMAC on shoulders with rotator cuff injuries and shoulder osteoarthritis. An improvement in joint function and disability and a decrease in pain were reported with both outcomes reaching statistical significance . With reAdipose tissue (AT) is predominantly composed of mature adipocytes containing lipids, and stromal vascular cells, such as preadipocytes, interstitial cells, endothelial cells, mesenchymal cells and pericytes. In addition, AT presents an extensive system of blood vessels, lymph nodes, and nerves, associated with an extracellular matrix (ECM) composed of collagen types I, III, IV, V, and VI, and other ECM proteins .AT is also recognized as a vital endocrine organ with the ability to secrete adipokines and inflammatory cytokines. Adipokines are represented by adiponectin, leptin, resistin, visfatin; inflammatory cytokines include TNF-α, IL-6 and IL-1 . With thVascular stromal fraction (SVF) is a heterogeneous mixture of cells, including mesenchymal stem cells (AD-MSC), which play important roles in the regenerative context . SeveralIn orthopedics, the use of SVF has been indicated for several conditions. Most of the studies for cartilage regeneration associated SVF with other orthobiologics, such as PRP or HA, and they reported promising results: pain relief, improvement of function, and cartilage regeneration seen in magnetic resonance image (MRI) of patients with OA ,66,67. IData from the literature now consider Brain-derived Neurotrophic Factor (BDNF) a critical factor involved in the anti-hyperalgesic effect mediated by PRF applied in the Dorsal Root Ganglion (DRG) or Spinal Cord. BDNF is a protein of the neurotrophin family. Neurotrophins are a family of growth factors that include, in addition to BDNF, nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin 4/5 (NT-4/5). They were initially described as trophic factors involved in neuronal development, survival, and function ,71. DeveIn summary, data from the literature describe that BDNF outside the nervous system via TrKB receptor activation promotes anti-inflammatory and immunomodulatory effects and triggers events related to tissue repair. However, it is essential to point out that, although the BDNF has less affinity to the p75 receptor, its activation results in a pro-inflammatory and degenerative effect that is crucial to effective regeneration and tissue repair.After the injection of PRP in the injured site, endogenous thrombin or collagen fragments released into the intra-articular space activate platelets . Once acAlthough it is clinically evident that PRP therapy has a potential role in augmenting tissue repair, studies on the mechanisms of action of the proteins released by PRP and their specific role in PRP treatment are still scarce. Indeed, most of the effects attributed to this therapy are based on physiological properties already evidenced by the various proteins present in platelet granules ,93,94. HDespite the lack of studies on the mechanisms of action of PRP, platelets can store large amounts of TGF-β, serotonin, and VEGF ,97. AddiInterestingly, BDNF concentrations in the synovial fluid of patients with osteoarthritis are significantly increased compared to healthy individuals , suggestIn this sense, the association of orthobiologic therapy, in particular PRP, with Pulsed Radiofrequency (PRF) could further reinforce joint tissue repair. However, no evidence in the literature supports this association with neuropathies or other peripheral nervous system injuries.However, with these ideas in mind, we can hypothesize that the modulation in BDNF response provided by the action of PRF, may prevent more exacerbated inflammatory responses occasionally encountered in the use of orthobiologics, and may also provide a gain in the activation of reactive cascades that stimulate neuroplasticity and neural tissue regeneration, also helping to control extracellular glutamate levels, in addition to synergistic effects to the paracrine actions of some orthobiologics in controlling pain and modulating inflammation .In fact, PRF has a better description and defined effect when used on neural structures, the effects in other tissues and joints seem to be promising; however, in the literature we need more high-quality studies. We have some trials, especially for knee osteoarthritis. In 2016, Yuan et al. evaluated 42 patients with knee OA treated with PRF versus corticosteroids. It was verified until 24 weeks that the group that used PRF significantly presented improvement in functional evaluation through WOMAC and pain. In addition, the markers of catabolism  show significantly decreased levels in the group of PRF in comparison to corticosteroids. These results showed superiority in relation to corticosteroid therapy and also the ability to alleviate clinical symptoms and change the catabolic environment in the knee joint [In 2007 Sluijter et al., published an article using PRF for arthrogenic pain in refractory patients. In this case series, the authors described six clinical cases of the cervical facet joint pain, knee joint, sacroiliac joint, radiocarpal joint degeneration, shoulder, and atlantoaxial joint. In general, in the follow-up, all the patients reported good conditions, with mobility and no pain recurrence .Fini et al., reported in a review evaluating some results of experimental and clinical studies suggesting that the use of electromagnetic field stimulation could be a promising chondroprotective therapy for OA joints. In these articles, it was related to an in vivo action on chondrocyte metabolism by enhancing cartilaginous and subchondral bone tissue properties. In addition, clinical studies showed the amelioration of clinical and radiographic observations with the use of pulsed electromagnetic fields .According to the current knowledge, the combination of PRF and orthobiologic therapies can be applied to pain of nociceptive origin from damage to peripheral tissues. There is a lack of evidence about the combination and its possible effects. Michno et al. published an in vitro study using leukocyte-rich PRP (L-PRP) in combination with PRF, and it was observed that PRF was able to activate L-PRP in a similar way that thrombin does. Additionally, the PRF settings used  had no impact on the functional integrity of platelets and leukocytes present in PRP, suggesting the safety of PRF but only for cellular components of PRP and in vitro conditions . Aside fClinical studies are case series publications with a small number of patients. In 2021, Jin et al., combined PRF with four PRP injections into the knee joint to treat OA. As result, a reduction in pain, and the recovery of knee joint mobility were observed. The purpose of the combined application of PRF and PRP would be to make full use of the analgesic effect of PRF technology in combination with the repairing effect of PRP, which can maximize the advantages of both treatment methods with minimally invasive techniques. In conclusion, it was verified that the combined application of PRF and PRP can promote the improvement of knee osteoarthritis symptoms and shorten the course of treatment which may restore knee joint function in the shortest time frame, which is an important outcome for patients .The combination of PRF and PRP was also used to treat supraspinatus injury. A case report with four patients used PRP as a single application after the PRF procedure. As a result, the patients reported no significant increase in pain after the procedure. Additionally, the Constant–Murley shoulder score was increased and the range of movement was significantly improved, showing positive results with the combination of both procedures. All these outcomes were maintained for 6 months .RF treatment, especially when ablative, uses heat to coagulate proteins, inactivate nerve endings, and eliminate edema, promoting a better analgesic effect. However, the repairing effect is not better than other conservative treatments. The efficacy of PRP treatment is based on the production of collagen and growth factors, increasing the number of local cells, and providing bioactive particles with powerful repair functions. Therefore, the use of both treatments may significantly augment the improvement of symptoms, and shorten the treatment course, with an improvement in life quality and a faster return to daily activities .Filippiadis et al., published a study using PRF in combination with hyaluronic acid (HA) to treat knee osteoarthritis. Forty-five patients (53 knees) were included with a follow-up period of 12 months. The results showed an initial improvement in the first month in 86.8% of the knees. Pain recurrence during the follow-up period was noticed in 39.1% of the joints that, in the first month, responded well to treatment. Overall mobility was improved in 88.6% of the patients. The combination of PRF with HA seemed to further increase the duration of pain reduction .In Filippiadis’ study, the use of intra-articular injections of HA aimed to provide a viscoelastic supplementation of the joint. As PRF does not promote osteophyte regression or cartilage and meniscus regeneration in patients with substantial bone and cartilage damage, the addition of hyaluronate seemed to be a necessity. In conclusion, the authors described that percutaneous, intra-articular application of PRF combined with HA is an effective and safe technique for the palliative management of chronic pain in patients with knee osteoarthritis. Results seem to be reproducible and long-lasting (1 year), which may require a repeat procedure after this period .A single-blinded randomized clinical trial compared the use of intra-articular injection of PRP with pulsed radiofrequency of the genicular nerves in 200 patients with knee osteoarthritis. As a result, it was reported, that a significant difference in pain relief occurred between the groups as the PRF group showed a lower score than the PRP group .The aesthetic field has also evaluated the combination of PRP with RF. A study published recently compared the effect of three sessions of fractional radiofrequency microneedling alone and in combination with PRP in 20 patients with mild to moderate neck laxity. The authors observed that both groups presented a statistically significant improvement in dermal thickness; however, the difference was not significant when the groups were compared . A pilotWith this review, we hypothesized that the combination of PRF with orthobiologics may have potential benefits due to a faster improvement in pain, neuromodulation, and stimulus to extracellular matrix secretion . This co


Bone marrow or hematopoietic stem cell transplantation (HSCT) is a curative treatment option for hematological malignancies, several non-malignant hematological disorders and severe combined immune deficiencies. However, relapse, graft-versus-host disease (GVHD) and opportunistic infections represent major complications following allogeneic HSCT which compromise the survival and quality-of-life of the recipient, limiting the wider application of this immunotherapy. Basic research has significantly advanced our understanding of the underlying mechanisms of these complications and has led to the development of promising pharmaceutical, immune and cellular therapies. Despite intensive research and development, GVHD, infection and relapse remain significant clinical problems and represent major unmet needs in HSCT.Frontiers In Immunology Research Topic presents the latest insights from preclinical studies of HSCT, highlighting opportunities and challenges, and sheds light on the future of HSCT. The collection is comprised predominantly of review articles which focus on GVHD pathophysiology, regulatory T cell-mediated immune tolerance, antigen presentation, microbiota/metabolite modulation of GVHD, intestinal immunopathology and infectious pulmonary complications, with an emphasis on the biological relevance to the clinic and translational potential.This Teshima and Hill provides a historical overview of major experimental concepts in bone marrow transplantation discovered using murine models and the translation of these findings into clinical practice, highlighting the pivotal insights afforded by murine models.The perspective article by Guo et al. review the biology of Tregs, their role in GVHD and GVL and the challenges related to Treg adoptive cell therapy to treat and/or prevent GVHD. The authors review Treg expansion strategies and discuss new sources of Tregs to address challenges encountered with this therapy. In the review by Ikegawa and Matsuoka, the authors detail the importance of Treg homeostasis post-HSCT and discuss strategies to manipulate this to modulate post-HSCT immunity to treat and/or prevent GVHD.Since the discovery of regulatory T cells (Tregs) by Sakaguchi in 1995, Tregs have been of great interest to researchers studying immune tolerance and regulation after HSCT. In this collection, Ara and Hashimoto review historical and recent advances in our understanding of the cellular and molecular mechanisms of GVHD-induced tissue damage in the gastrointestinal tract, providing important novel insights garnered from mouse models which inform translational potential. With technological advances in genomic/metagenomic sequencing and metabolomics, the ability to study intestinal microorganisms and their secreted molecules in HSCT has rapidly generated new knowledge in the field. In this collection, Fujiwara provides an in-depth review of the intestinal microbiota, metabolite and epithelial cell crosstalk critical in GVHD regulation, highlighting the complex relationships and potential microbiota-based therapeutic strategies.The cardinal feature of GVHD is immune-mediated tissue pathology. Gastrointestinal GVHD is the most challenging to treat and the greatest cause of GVHD-related mortality. In this collection, Zhou and Moore review murine models of infectious pulmonary complications after HSCT  focusing on host-pathogen interactions and the important insights garnered from these studies.Conditioning-induced toxicity, immunosuppressive therapies and alloimmunity permit opportunistic infections post-HSCT, a major cause of morbidity and mortality. Koyama and Hill review the field and discuss recent advances uncovered by the use of antigen-specific murine models of GVHD, providing novel insights for the translational potential of targeting this pathway. Critically, the authors review antigen presentation in xenograft transplantation models used to study GVHD and GVL and discuss the controversies associated with the interpretation of findings from these models.The therapeutic effect of HSCT, mediated by alloimmunity towards malignant cells , is compromised by detrimental alloimmunity towards recipient tissues (GVHD). Antigen presentation is central to these two processes, however the ability to delineate between these remains elusive and is considered the holy grail in HSCT. Song et al. review important mechanistic findings identified using murine models of chronic GVHD which reflect features characteristic of the disease in humans. The authors highlight low P-selectin glycoprotein ligand 1 expressing CD4 T cells as key players in cGVHD pathophysiology. Original research presented by Choi et al. revealed that deletion of the endoplasmic reticulum stress protein, XBP-1, reduced B cell activity and the ability to stimulate allogeneic CD4 T cells via a regulated IRE-1a-dependent decay pathway which led to a reduction in cGVHD. These preclinical findings demonstrate targeting XBP-1 a potentially useful strategy to ameliorate cGVHD.Chronic GVHD continues to be a major clinical problem in HSCT survivors. Shaikh et al. present a detailed description of the development of a murine model of orthotopic mesenteric lymph node transplantation to study immune cell responses and migration in the gastrointestinal tract. The authors determined its utility in a HSCT setting and suggest potential for broader application.Finally, In summary, murine models have proven to be instrumental for advancement of our understanding of the complications that occur following HSCT. As demonstrated in this collection, murine models of HSCT have led to the discovery of new scientific knowledge, permitted established concepts to be challenged and emerging concepts to be explored, enabled the development of new therapeutics and provided important insights that have guided clinical studies. With the development of new ideas, technologies and tools, murine models of HSCT will continue to empower academic research and translation into the clinic in the future.All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Unlike humans, plants do not possess an immune system to protect them from biological, physical and chemical threats, hence they had to develop different strategies to protect themselves from predation and other environmental menaces. (Poly)phenols are secondary plant metabolites able to fulfill this protective role, so why wouldn't they also confer health benefits to humans? Over the last decades, a great body of scientific evidence has demonstrated the diverse health benefits exerted by these bioactive compounds on human physiology. (Poly)phenols represent a fantastic preventive treatment opportunity against many pathologies, including neurodegenerative diseases, as they are already present in many plant-based foods we consume, contributing to their color, flavor, bitterness, astringency and oxidative stability, and therefore are safe to prescribe. Phenolic acids and flavonoids are the (poly)phenols the most abundantly found in plant-based food consumed by humans.in vitro, when a particular metabolite is applied at high dose. However, in many cases such high dose isn't achievable with normal food consumption and the bioactivity and bioavailability will differ greatly when used in vivo. Various metabolites with different potency and actions can be formed according to where (which organ or cell type) they are metabolized. Additionally, (poly)phenols can also be extensively transformed by the gut microbiota and results in numerous novel compounds harboring a range of different physiological effects. It is therefore important to take these limitations into account and to use multi-dimensional approaches along with various models  when investigating the health benefits of (poly)phenols, and in this particular context, be aware of 1/ the possibility of a specific polyphenol to access the central nervous system (CNS) and 2/ knowing which metabolite(s) derived from the polyphenol of interest is/are likely to act on the brain microenvironment and target cells.Since (poly)phenols are known to cross phenols on the brain. Experimental results obtained from cell lines, rodents, and human studies measure (poly)phenols' health benefits at the molecular level and show how these mechanisms may translate into behavioral effects.Hepsomali et al. highlighted the significant positive effect of (poly)phenol consumption (various compounds and doses) on accuracy and speed of attention, independently of age and gender. Pontifex et al. studied more specifically the effect of citrus fruits-derived (poly)phenols on various homeostatic and physio-pathologic events occurring in/affecting the CNS such as depression, schizophrenia, stroke, dementia, cellular processes contributing to the maintenance of homeostasis, gut/brain cross-talk, antioxidant, and anti-inflammatory activities. The authors analyzed and summarized the results from in vitro and pre-clinical studies, using isolated compounds or whole fruit or mixture of compounds in a juice, as well as molecular and behavioral studies performed in rodents with dietary supplementation or injections of citrus-derived polyphenols to demonstrate that hesperidin, hesperetin, naringenin, naringin, and kaempferol consistently exert beneficial effects on the CNS-dependent parameters studied.Accuracy and speed of attention analyzes represent a good measurement of some of the function of a healthy brain. In their meta-analysis of the results from 18 of the most recent randomized controlled trials, . While the molecular mechanisms of this protective effect remain to be further investigated, it would be interesting to see whether this preventive effect translates into better cognitive outcomes as well.Tg4510 is a mutant mouse model of Alzheimer's disease which spontaneously develops TAU pathology, one of the hallmarks of the neurodegenerative disease in which the hyperphosphorylation of TAU protein leads to its aggregation and propagation, contributing to neuronal dysfunction and ultimately neuronal death. The oral administration of relatively high dose of the flavonoid epicatechin for 3 weeks in older mutant mice was able to prevent the development of TAU pathology in this murine model Corral-Jara et al. explored a possible molecular mechanism underlying the neuroprotective actions of this flavanol, at the level of the vasculature composing the anatomical and physiological barrier between the blood and the brain. To replicate the physiopathological conditions of neurodegenerative diseases, inflammatory stress was mimicked using TNF-a in the culture medium of brain endothelial cells. After treatment of the cells with 5-(4'-Hydroxyphenyl)-γ-valerolactone-3'-sulfate and 5-(4'-Hydroxyphenyl)-γ-valerolactone-3'-O-glucuronide, the two major products of gut microbiota catabolism of epicatechin, the authors investigated the multi-omics responses. Study of gene expression, micro-RNAs, non-coding RNAs and proteins revealed that microbiome-derived metabolites of epicatechin modulate the expression of genes and proteins regulating cellular processes such as adhesion, cytoskeleton organization, cell permeability and therefore could be involved in the maintenance of BBB integrity. Despite these results needing to be confirmed in vivo, this study explores the gut/brain axis in a new and original way: the action of metabolites from the gut microbiota on BBB function and unravels an unexplored until recently an original mechanism by which flavonoids could exert their well-known neuroprotective effects.Epicatechin has also known beneficial effects on cognitive functions and has the potential to prevent neurodegenerative disorders. Grewia asiatica, a popular native berry of Pakistan represents a very promising plant to treat and/or prevent various pathologies linked to oxidative stress and inflammation. The authors of the study showed that the berry contains various (poly)phenols including phenolic compounds, anthocyanins and flavonoids. Following 28 days of Grewia asiatica consumption in drinking water, the rats were subjected to diverse behavioral tests well-recognized to detect, quantify and analyze depression, anxiety, learning and memory. Interestingly, the rats treated with the highest doses of Grewia asiatica displayed low anxiety levels, similar to diazepam-treated animals, low depressive behavior similar to fluoxetine-treated animals and better learning and memory scores, counteracting the deleterious effect of scopolamine administration. Biochemical analysis of rat brains revealed that consumption of Grewia asiatica resulted in higher oxidative stress resistance indicated by elevated levels of superoxide dismutase and glutathione peroxidase and a reduction of malondialdehyde production. This effect was further paralleled by a beneficial modulation of the cholinergic system as indicated by reduced levels of acetylcholinesterase .Otostegia Limbata, a Lamiaceae plant, is commonly used as an active compound to potentially treat epilepsy. As many other (poly)phenol rich plants, O. Limbata demonstrated antioxidant  andanti-inflammatory properties (reduced expression of P-NFkB and P-TNFa in the brain) potentially responsible for the anti-convulsant effect observed in mice model of epilepsy .The methanolic extract of We previously highlighted the necessity to study all the metabolites of each food-derived (poly)phenol and their by-product from microbiota, within various biological models, to better characterize the molecular action of these compounds in physiological conditions. And more specifically, when focusing on the brain, it's important to be able to answer the following questions: 1/ Which metabolite and at what dose does it cross the BBB 2/ Is the metabolite transformed during the uptake process 3/ Can brain cells metabolize (poly)phenolic compounds?In conclusion, we need to investigate the specific molecular mechanisms for each (poly)phenol, their derivates and how they could potentially be metabolized in endothelial cells and diverse brain cells , and then what would be the action of the resulting metabolites? Importantly the BBB isn't the only site of access to the brain for circulating molecules, circumventricular organs (CVO), highly vascularized structures located around the third and fourth ventricles and characterized by the lack of a classic BBB architecture, deserved to be studied along with the tanycytes, the main cellular component of the modified barrier around the CVOs (Langlet et al., EB wrote the manuscript. EB, DV, and PL edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Taste perception is crucial for the critical evaluation of food constituents in human and other vertebrates. The five basic taste qualities salty, sour, sweet, umami (in humans mainly the taste of L-glutamic acid) and bitter provide important information on the energy content, the concentration of electrolytes and the presence of potentially harmful components in food items. Detection of the various taste stimuli is facilitated by specialized receptor proteins that are expressed in taste buds distributed on the tongue and the oral cavity. Whereas, salty and sour receptors represent ion channels, the receptors for sweet, umami and bitter belong to the G protein-coupled receptor superfamily. In particular, the G protein-coupled taste receptors have been located in a growing number of tissues outside the oral cavity, where they mediate important processes. This article will provide a brief introduction into the human taste perception, the corresponding receptive molecules and their signal transduction. Then, we will focus on taste receptors in the gastrointestinal tract, which participate in a variety of processes including the regulation of metabolic functions, hunger/satiety regulation as well as in digestion and pathogen defense reactions. These important non-gustatory functions suggest that complex selective forces have contributed to shape taste receptors during evolution. The concerted action of vision, olfaction, mechanoreception, and gustation enables humans to differentiate nutritionally valuable food items from inedible or even potentially harmful ones. The final gatekeeper is our sense of taste, which provides a rapid analysis of the relevant food-borne chemicals in the oral cavity prior to ingestion. To facilitate the detection of nutritionally relevant molecules among countless food constituents, the oral cavity is equipped with sensors for the five basic taste qualities salty, sour, sweet, umami (in humans mainly the taste of L-glutamic acid) and bitter . The senTAS1R (taste 1 receptor) genes code for heteromers that assemble the predominant umami taste receptor, TAS1R1/TAS1R3  and frequent implications in taste-related signaling events . The firQuite a number of physiological roles have been assigned to taste receptor-mediated signaling in the GI tract. However, not all physiological responses triggered by tastants must occur via the activation of taste receptors, in fact, in many cases where taste receptors are implicated in GI tastant sensing additional research is warranted. Among the best investigated processes elicited by tastants in the GI tract are peptide hormone secretions from various enteroendocrine cell types. One of these hormones is the incretin hormone GLP-1 (glucagon-like peptide-1) which is produced by enteroendocrine L cells. The cells express both TAS1R subunits, namely TAS1R2 and TAS1R3, constituting the functional sweet taste receptor as well as the canonical taste signaling elements. Challenging the cells with sweet compounds results in the acute release of GLP-1 and the subsequent insulin secretion from pancreatic beta-cells leading to a reduction of blood sugar levels and, in case of chronic stimulation, an elevated absorptive capacity of intestinal enterocytes via the upregulation of the transport molecule SGLT-1 , 58. AlsCompared to enteroendocrine cells, intestinal brush cells seems to play a very different role, the defense of pathogenic organisms –68 Figu. In factAfter the discovery of taste receptors outside the oral cavity, the research field of extra-oral taste receptors practically exploded. Taste receptors were found in an increasing number of tissues and were associated with numerous roles. Whereas, some of the most optimistic appraisals had to be corrected, other proposed opportunities solidified over the years resulting in realistic research goals such as the use of bitter compounds as asthma medication or compounds to improve metabolic functions.One research gap that exists since the discovery of non-gustatory taste receptors and the subsequent investigations of their physiological roles is the firm association of taste stimuli with specific cellular functions and the unambiguous involvement of the corresponding taste receptors in this process. Moreover, many observations of physiological effects in tastant-responsive GI cells were rather broadly assigned to specific cell types, which may underestimate diversity with regard to taste receptor expression and function. Another gap comes from the observation that a large number of animals exhibit taste receptor pseudogenizations, which usually correlates well with their nutrition, however, it has so far not been investigated how these animals compensate for the loss of those receptors and their function in extra-oral tissues.In summary, research on taste receptor functions outside the gustatory system has become a topic of great interest with future prospects ranging from more healthy nutrition to even using tastants and/or their derivatives for medicinal treatments.The manuscript was written together by MB and TL. All authors contributed to the article and approved the submitted version.The authors declare that this study received funding from Soremartec Italia S.R.L. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Reproduction of different tissues using scaffolds and materials is a major element in regenerative medicine. The regeneration of whole organs with decellularized extracellular matrix (dECM) has remained a goal despite the use of these materials for different purposes. Recently, decellularization techniques have been widely used in producing scaffolds that are appropriate for regenerating damaged organs and may be able to overcome the shortage of donor organs. Decellularized ECM offers several advantages over synthetic compounds, including the preserved natural microenvironment features. Different decellularization methods have been developed, each of which is appropriate for removing cells from specific tissues under certain conditions. A variety of methods have been advanced for evaluating the decellularization process in terms of cell removal efficiency, tissue ultrastructure preservation, toxicity, biocompatibility, biodegradability, and mechanical resistance in order to enhance the efficacy of decellularization methods. Modification techniques improve the characteristics of decellularized scaffolds, making them available for the regeneration of damaged tissues. Moreover, modification of scaffolds makes them appropriate options for drug delivery, disease modeling, and improving stem cells growth and proliferation. However, considering different challenges in the way of decellularization methods and application of decellularized scaffolds, this field is constantly developing and progressively moving forward. This review has outlined recent decellularization and sterilization strategies, evaluation tests for efficient decellularization, materials processing, application, and challenges and future outlooks of decellularization in regenerative medicine and tissue engineering. Tissue engineering, as a division of regenerative medicine, combines engineering and biological science in order to reproduce tissues and organs that can help to overcome the lack of enough donor organs . Tissue Scaffolds could be made up of natural tissues harvested from animal or human sources or being constructed using synthetic biomaterials. Natural scaffolds represent biological characteristics that better fit the regular tissue microenvironment, promoting appropriate cellular interactions, biocompatibility, and degradability. Decellularization is the process of eliminating cells and their components  from the extracellular matrix (ECM) to yield a natural matrix with saved mechanical integrity. It has been demonstrated that decellularized extracellular matrix (dECM) is a suitable type of natural scaffold for tissue engineering since the ECM plays a crucial role in tissue development .2 concentration) of the matrix differ from one tissue to another based on the tissue function and its residing cells that secrete ECM components , and polysaccharides . The commponents . Fibroblmponents .So far, a wide variety of decellularization methods have been studied and developed . Since aThe application of dECM as wound healing products and surgical mesh devices has been reported . In addiSeveral decellularization techniques have been developed to date to reconstruct different types of living organs. The main principle in all methods is removing cellular material and leaving the ECM ultrastructure unchanged in the tissue. Decellularization techniques differ in terms of applied materials (reagent combinations) and the routes used to deliver the main reagent, namely vascular, airway, or both .Generally, tissue decellularization methods are classified into three main groups: chemical methods, such as alkaline/acid, detergents, and alcohols; physical methods, such as electroporation, pressurization, freeze/thaw; biological methods, such as enzymes  Badylak. SeveralIonic detergents act by solubilizing DNA and cell membrane and tend to denature the proteins, thus decreasing collagen integrity. Ionic detergents are powerful in removing glycosaminoglycans (GAGs) and growth factors, therefore destroying ECM rigidity and function. Sodium dodecyl sulfate (SDS), sodium deoxycholate (SD), and Triton X-200 are ionic detergents that have been used in decellularization . AlshaikNon-ionic detergents, such as Triton X-100, can strongly break lipid-lipid and lipid-protein bonds, but they are less effective on protein-protein interaction. Although they maintain the ultrastructure of the decellularized tissue and preserve the growth factors, they are less effective in removing cellular materials than SDS. The Triton X-100 is not appropriate for tissues where GAGs and lipids are important parts. Accordingly, the effectiveness of non-ionic detergents depends on the tissue undergoing the decellularization process .Zwitterionic detergents have the properties of both ionic and non-ionic detergents. They have shown better cell removal than non-ionic detergents and improved preservation of the ECM ultrastructure than ionic detergents . ZwitterEthylene glycol tetraacetic acid (EGTA) and ethylenediaminetetraacetic acid (EDTA) are used as chelating agents in organ decellularization through binding to divalent metal cations at the cell adhesion site of ECM. This binding was found to dissociate the cell from the remaining ECM. Due to their ability to damage cells, Cytotoxic agents could be used in the decellularization process . Reyna eSolutions with extreme pH were indicated to be effective in the decellularization process. Alkaline substances including sodium sulfide, ammonium hydroxide, calcium hydroxide, and sodium hydroxide were suggested as commonly used in organ decellularization processes. It has been shown that increasing the PH of CHAPS during decellularization increases the effectiveness of cell and protein removal. Bases could eliminate growth factors and disrupt the mechanical structure of the scaffold .in vitro and in vivo recellularization. Peracetic acid (PAA) can also be used as a decellularizing agent; however, it is mostly used as a sterilizing agent and has an unsuitable impact on decellularization. Kao and colleagues , and nucleases  are used in the decellularization process. Trypsin breaks peptides containing Lys and Arg, and in extended exposure, it may damage the ECM structure . DispaseThe freeze-thaw cycle is being done by fluctuation between freezing temperature (−80c°) and biological temperature. The freeze-thaw cycle disrupts the cell membranes and cell lysis via the formation of intracellular crystals. It has been demonstrated that this method considerably keeps the structure of the ECM but does not effectively remove the remnant cellular debris; thus, further detergents are needed after the freeze-thaw cycle. Multiple freeze-thaw cycles can be used in the decellularization process, whereas they could deteriorate the ECM structure .The agitation in conjunction with immersion leads to cell lysis, but it is mostly used with chemical reagents to enhance the exposure of the ECM to the detergents and to augment the decellularization process. Agitation could be applied in the decellularization of the thin tissues, including the small intestine and bladder. In addition, the use of agitation and immersion in the decellularization of the tracheal tissue has been reported. The time of the protocol and intensity of agitation depends on the thickness of the tissue. Agitation may cause cell lysis before exposure to the detergents; thus, deteriorating the structure of the ECM. Furthermore, pressure could promote accessibility of the detergents to the ECM, hence decreasing the time of the decellularization process. Also, it can improve the removal of cellular remnant materials. The pressure leads to minimal changes in ECM structure, even less than agitation . Sonicat2 , and membrane-associated molecules  is a crucial way to ensure the effectiveness of the decellularization model. On the other hand, the ideal decellularization method should conserve biochemical and mechanical properties with the lowest toxicity rate for the subsequent recellularizing phase to occur. Various evaluation tests and assessments have been introduced to appraise the different characteristics of the dECM .Despite the fact that gross inspection alone is not an entirely reliable evaluation method, it is the first step in the evaluation of the decellularized scaffold, which should be followed by more accurate assessments. Different studies use macroscopic imaging analysis as one of the first assessment steps to determine the level of transparency of dECM compared to native tissue . MoreoveVarious tests assay the effectiveness of the decellularization method. Complete removal of antigens and nucleic acids, along with other cellular components, ensures the biocompatibility of the scaffold. The dECM must be implanted without host immune response activation and graft rejection or the formation of vascular thrombosis. Besides, transgenic transmission has been reported by retained DNA in genetically engineered tissue implantation . Crapo eDNA quantification using immunofluorescence, electrophoresis, or polymerase chain reaction is also of great use . Of notePreservation of 3 dimensional (3D) architecture and structure of the scaffold can be evaluated using different assessments, such as electron microscope . A scannin vivo use, it is crucial to investigate the cellular interaction of cells with the decellularized scaffold. In other words, the damaging effects of the decellularization method or agent on the scaffolds should be assessed ex vivo to guarantee the clinical efficacy of the dECM. In this regard, the initial step is to quantify the remaining chemicals after washing and sterilizing. Decellularizing and sterilizing agents are cytotoxic and prevent efficient recellularization. The threshold for chemicals cytotoxic concentration, such as SDS has been investigated  . Atomic Based on the purpose of the study and future function of the grafted dECM, researchers evaluate various components and characteristics of their acellular scaffold. Proteomic analysis of the dECM can precisely show and compare the proteome of the ECM before and after decellularization treatment. Proteomic evaluation can be exerted by different techniques, such as nano liquid chromatography and tandem mass spectrometry, and is used to assess the complete protein profile of the ECM, including remaining enzymes and growth factors . Computein vitro procedures, including cell seeding. Processing the scaffolds enhance their ability in successful grafting and function  using the electrospinning method resulted in increased biomechanical endurance. Electrospinning provides an efficient method to combine natural and synthetic materials to achieve hybrid scaffolds that resemble native tissue with biomimetic architecture and enhanced biomechanical properties .Combining the decellularized scaffolds with other molecules, including biomaterials, drugs, and growth factors may help modify the characteristics of the decellularized scaffolds. The methods for designing combined scaffolds include solvent casting and particulate leaching, lyophilization (freeze-drying), thermal-induced phase separation (TIPS), gas foaming, rapid prototyping, stereolithography, fused deposition modeling, selective laser sintering, 3D printing, bioprinting, cross-linking, and electrospinning .It was demonstrated that decellularized omentum scaffolds coated with gold (Au) nanoparticles (NP) could provide proper electrical conductivity and characteristics. Hence after seeding cardiac cells, the AuNP-decellularized scaffold can cause higher contraction force, decrease the excitability threshold, and increase the calcium channels currents. Also, silver (Ag) NPs show proangiogenic properties and enhance the biocompatibility of the scaffolds . When moIn order to achieve improved cytocompatibility, mechanical properties, and biological function of decellularized scaffolds without inflammatory reactions, the surface modification could be done via various methods and biomaterials . It is din vitro or in vivo cell seeding. In situ tissue regeneration takes advantage of the recipient’s body’s regenerative capabilities and biological supply. Therefore, cell seeding of the scaffold prior to transplantation is not always necessary, but adding the bioactive molecules would reinforce the regeneration process  derived from the patient’s somatic cells. One of the most important things to keep in mind is to utilize an adequate amount of the appropriate cell type. This factor varies in different tissues and organs and should be considered to reduce the risk of teratoma formation or immune response induction . Various decellularized scaffolds from animal and human sources have been used clinically, mainly for wound healing and surgical mesh devices, albeit their application is still limited, and further studies are needed to make decellularized scaffolds commercially available treatment of disease  are among the unsolved challenges regarding the clinical translation of the decellularized scaffolds (Despite favorable characteristics of the decellularized scaffolds for implementation in clinical practice, there are some constraints and challenges in their application. Determining the suitable tissue, decellularization and sterilization method selection, optimizing the efficacy of these techniques, dECM quality assessment, modification of acellular scaffolds caffolds  (Zhang ecaffolds .in vivo (The decellularization method is selected based on the type of tissue and its characteristics. Developing cell removal techniques with lower toxic agents or productions, in addition to enhancing sterilizing techniques, would be beneficial. Apart from that, unlike most synthetic scaffolds , purifiein vivo .Various evaluation tests have already been established to ensure that cellular compounds have been cleared from the dECM during the decellularization treatment, while the chemical and biomechanical properties remain intact and the residual detergent is removed from the decellularized tissue, as the remaining detergents may cause cell toxicity in the scaffold . Each tiApplication of naturally-derived ECM is restricted owing to limited animal sources that are free of by-products and contaminants, while synthetic scaffolds are available in ample amounts . PolymerAlthough the aforementioned strategies have been effective to a large extent in the decellularization process, there are still many hindrances in the endless road of dECM engineering. Despite all progress in this field, further investigations are needed to overcome challenges regarding the clinical application of decellularized biomaterials and the ultimate goal of whole organ transplantation.


Androgen Receptor (AR) gene, resulting in expanded glutamine tract in the AR protein. Polyglutamine (polyQ) expansion renders the mutant AR protein toxic, resulting in the formation of mutant protein aggregates and cell death. This classifies SBMA as one of the nine known polyQ diseases. Like other polyQ disorders, the expansion of the polyQ tract in the AR protein is the main genetic cause of the disease; however, multiple other mechanisms besides the polyQ tract expansion also contribute to the SBMA disease pathophysiology. Posttranslational modifications (PTMs), including phosphorylation, acetylation, methylation, ubiquitination, and SUMOylation are a category of mechanisms by which the functionality of AR has been found to be significantly modulated and can alter the neurotoxicity of SBMA. This review summarizes the different PTMs and their effects in regulating the AR function and discusses their pathogenic or protective roles in context of SBMA. This review also includes the therapeutic approaches that target the PTMs of AR in an effort to reduce the mutant AR-mediated toxicity in SBMA.Spinal and Bulbar Muscular Atrophy (SBMA) is an X-linked adult-onset progressive neuromuscular disease that affects the spinal and bulbar motor neurons and skeletal muscles. SBMA is caused by expansion of polymorphic CAG trinucleotide repeats in the  These forms of modifications are required to regulate proteome homeostasis, biological pathways, or other cellular functions , allow the genome to drastically increase its ability to produce proteins that can meet the demand of life. Both these mechanisms allow the cell to produce multiple different functional proteins from a single gene. Alternative splicing accomplishes this through modification of pre-mRNA constructs, producing differently spliced mRNAs that are then translated to different mature proteins. In contrast, PTMs are chemical modifications that are added to the mature proteins to change or modify their function. PTMs involve addition of acetyl, methyl, phosphate groups, or ubiquitin molecules unctions . Dysreguunctions , includiunctions . PolyQ dunctions . This grunctions .Androgen Receptor (AR) gene  gene   gene . The loche males . The heas of age  with a ss of age . The diss of age .in vivo and in vitro models have been developed that recapitulate many aspects of SBMA phenotypes  models have also been developed and used to study the SBMA pathology  in humans (The n humans . Its seqn humans . AR is an humans . Structun humans . The amin humans . The DNAn humans . A flexin humans . The nucn humans . The nucn humans .In the absence of ligands such as testosterone or dihydrotestosterone (DHT), AR exists as a complex with the heat-shock proteins (HSPs), such as HSP90 and HSP70, within the cytoplasm. However, when the ligand is present, AR protein binds the ligand, resulting in a conformational change in the AR structure that promotes dissociation from HSPs and allows it to translocate into the nucleus . Within Posttranslational modifications are biochemical modifications that add or remove specific chemical groups, such as acetyl, methyl, phosphate, or ubiquitin, to specific proteins that change the properties of those target proteins. PTMs help expand the potential of a protein to carry out cellular functions beyond its functional capacity . Aberranin vivo and in vitro models - and carboxyl (C)-terminal interdomain (N/C) interaction is known as one of the potential mechanisms that contributes to SBMA pathogenesis . The potin vitro  (Drosophila homolog of NLK (nmo in flies) reversed the severe retinal degeneration phenotypes in the trAR112Q SBMA fly model (A subsequent study found that AR S81 phosphorylation contributes to SBMA phenotypes . Nemo-lirylation . To checrAR112Q) . Loss ofly model . The trAly model . Taken tly model .in vitro, in a manner that potentially involves inhibition of CDK2  was found to suppress the polyQ-AR induced neurodegeneration phenotypes in the fly eye  in the wild-type AR, resulted in delayed nuclear localization , a SUMO-1 activating enzyme, was found to worsen the polyQ-AR mediated degeneration in SBMA fly model  bind to the target proteins and play crucial roles in multiple cellular functions, including neuronal development and differentiation , DNA damly model ; howeveractivity , indicat(in vivo . In this(in vivo . In thes(in vivo . Taken tCurrently, there are no known cures for SBMA. Available treatment strategies provide only limited improvement, underscoring the need for development of more effective therapeutic options for the patients. There have been several approaches used to modify SBMA pathogenesis, including lowering the levels of androgens such as DHT , modulatin vitro and in vivo (in vitro models of SBMA, treatment of forskolin reduced phosphorylation of polyQ-AR at S96 and decreased polyQ-AR aggregation (The role of phosphorylation as PTM in modulating the polyQ-AR mediated toxicity has shown great potential. A study reported that CDK2 phosphorylates polyQ-AR at S96 site . This CD in vivo . Similar in vivo . In in vregation . Taken tin vitro studies, IGF-1 was found to enhance clearance of AR aggregates through the ubiquitin-proteasome system in a mechanism mediated by phosphorylation of AR by Akt (in vivo (Previous studies have clearly shown the toxic effect of polyQ-AR in skeletal muscles in SBMA . Thus, tR by Akt . Overexp(in vivo . Similar(in vivo . Taking (in vivo .in vivo and in vitro models. An in-depth understanding of the exact roles of PTMs on AR in SBMA context may help in developing more efficient and reliable therapeutics for the SBMA patients in the future.The results obtained from the clinical trials further raised questions on whether targeting the PTMs can be utilized in potential therapeutics to treat SBMA. The safety and efficiency of therapeutics utilizing this mechanism and their performance in the clinical trials are still major concerns. Thus, it is important that the therapeutic candidates are extensively tested and validated for their therapeutic potential in in vivo and in vitro models that accurately model all aspects of the disease may also aid in more effective translation of findings to therapeutic options for the patients. Gaining detailed insights in these aspects may help discern the gaps in terms of regulatory mechanisms that are involved in SBMA pathogenesis and may aid in the detection of novel biomarkers, drug candidates, or effective and reliable therapeutics to treat SBMA.Since the genetic underpinnings of SBMA were identified over 30 years ago, our understanding of the molecular and cellular mechanisms underlying SBMA pathogenesis has advanced substantially. Multiple mechanisms have been implicated in SBMA pathogenesis, including structural alterations in AR, transcriptional dysregulation, altered protein-protein interactions, and formation of toxic polyQ-AR fragments and AR aggregation. PTMs of AR have been of particular research interest, as dysfunction of PTM regulation is implicated in AR dysfunction and subsequent SBMA pathology, and manipulation of specific AR PTM sites have shown potential in modulating SBMA pathogenesis as effective therapeutic strategies. Although our understanding of diverse PTM sites of AR, as well as the functional impact of manipulating these sites, has advanced substantially, the translation of these findings to viable therapeutic options for SBMA patients has achieved limited success only. Absence of effective methods to detect the novel and precise PTM sites may serve as a major limitation factor in this aspect. The advancements in genomic and proteomic techniques may help in identification and use of more accurate methods that may facilitate detection of novel and accurate PTM sites that are difficult to access and have yet remained to be discovered. Besides the PTMs discussed in this review, the roles of additional PTMs in AR biology and SBMA disease are the potential areas that may provide more insights in disease pathogenesis and thus needs to be explored. It is also imperative to understand the effect of interactions of PTMs at protein level in regulating AR function to understand the complexity of the disease better. Furthermore, the development of NG and JL developed the concept. NG, LN, and VO were involved in writing, reviewing, and editing the manuscript. FH and KL were involved in preparation of figures, tables, and editing the manuscript. JL was involved in reviewing, editing, and providing comments on the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Therefore, this Research Topic aims to collect research related to in vitro and/or in vivo studies on the antioxidant, anti-inflammatory, and antitumoral activities of polyphenols from plant and food matrices and, particularly, the relationship between their chemical composition and structure and their biological activity in target cells and tissues.An emerging trend in food science is the link between food and health. Consumer concerns center around what is in their food, and especially how it can promote wellbeing. Thus, nowadays, food is considered not only a source of energy but also an affordable way to prevent future diseases . ChronicDe Santis et al. described the anti-inflammatory abilities of extra virgin olive oil (EVOO) in obese children. The authors validated their previous in vitro data, in an ex vivo study on peripheral blood mononuclear cells (PBMCs) from obese children. Specifically, the study reported on the ability of EVOO extract to reduce the pro-inflammatory CD14+CD16+ monocytes, and the secreted CCL2 and CCL4 chemokines involved in the recruitment of inflammatory cells. Moreover, the molecular profile of EVOO treated-PBMCs from obese children was significantly modulated in terms of metabolic and inflammatory pathways. Importantly, a good correlation between the chemical profile of EVOO and its biological modulations in terms of anti-inflammatory activity was highlighted. Khoo et al. investigated the protective effects of the Chinese-origin red pitaya peel and pulp extracts in terms of antioxidative properties, lipid-reducing capacity, and cytotoxicity. Betanin, total betacyanins, total anthocyanins, and the DPPH index of both red pitaya pulp and peel extracts were analyzed. The authors demonstrated a higher content of total betacyanins and total anthocyanins in the pitaya peel extract than in the pulp extract, even if for the former a lower DPPH was reported. Biological studies were used to demonstrate the in vitro efficacy of the antioxidant and lipid-reducing effects, and the low cytotoxicity of the pitaya extracts. The paper by Mehmood et al. focused on the inhibitory mechanism of certain phenols toward the xanthine oxidase (XO) enzymes whose overactivity is directly linked to an excess of uric acid leading to hyperuricemia (HUA), gout, and many other diseases. The authors applied in vitro, atomic force microscopy, 1H NMR analysis, and different computational methods to assess the inhibitory potential of eight structurally diverse phenols. The results showed the high variability of the selected phenols in inhibiting XO depending on the phenol considered. The computational methods revealed that phenols can bind to the surrounding amino acids of XO at the molybdenum site. Rasouli et al. reviewed the current trends in the application of polyphenols (PPs) to alleviate aflatoxins (AFs) toxicity. The emergence of AFs has raised food safety issues as AFs can cause damage to the liver, kidney, and gastrointestinal organs, and the development of cancer for long-term exposure. The authors first reviewed factors influencing AFs occurrence, frequency, and world distribution, and the association between AFs and the pathogenesis of human chronic diseases. Then, they reported how PPs-rich extracts are promising AFs detoxifying products with heterogeneous biological activities. PPs can be used for the decontamination of AFs either in human/animal bodies or production/storage sites. The manuscript by Su et al. investigated the metabolic and molecular regulation mechanisms of chlorogenic acids (CGAs). The authors evaluated the composition and content of three forms of CGAs in mature fruits of 205 peach cultivars. The content of CGAs during the growth and development showed a trend of rising first and then decreasing in all peach cultivars studied. Moreover, the contents of quinic acid, shikimic acid, p-coumaroyl quinic acid, and caffeoyl shikimic acid all showed similar patterns to that of CGAs, indicating they could be involved in the accumulation of CGA during the growth. In addition, eight structural genes and 15 regulatory genes revealed that the expression levels of two Pp4CL, two PpCYP98A, and four PpHCT genes were positively correlated with the content of CGA, indicating that these may be key genes for CGA biosynthesis. Finally, Izuegbuna provided an overview of the possible use of polyphenols in the management of cancer blood diseases. The author especially described how polyphenols are involved in intracellular pathways by the phosphatidylinositol 3-kinase/protein kinase B way or in the PI3K/Akt/mTOR pathway, which is involved in every step of carcinogenesis as well as in the response to chemotherapy. In addition, the author detailed the effects of the polyphenols in the different steps of the cell cycle , displaying how they can be used as immunomodulatory agents in combination with some established therapies to attenuate the kynurenine pathway or enhance cellular immunity in hematological malignancies. Furthermore, clinical studies of the last 10–15 years herein reported, point out that polyphenols play an active role in clinical response and hematological malignancies management, suggesting their possible use in combination with chemotherapy or maintenance therapy.The paper by In conclusion, the papers published in this Reaserch Topic clearly show that many aspects must still be clarified and understood in the fascinating world of polyphenols and their human health benefits.PC wrote the introduction and the conclusion. SD, SB, and DF wrote the central part with comments on the cited papers and references. All authors contributed to the article and approved the submitted version.