Our understanding of reactive oxygen species (ROS)—a group of highly reactive chemicals containing oxygen—has changed in the last few years from ROS as just harmful substances to crucial intra- and extracellular messengers as well as important regulators controlling a wide spectrum of signaling pathways. Nevertheless, there are still many uninvestigated points and open questions regarding ROS, especially in pathophysiology. Delicately controlled ROS homeostasis is critical for maintaining normal cell functions and any disruption in the oxidation-antioxidation balance leads to oxidative stress associated with a wide spectrum of human disorders such as chronic inflammation, age-related diseases, and cancers. In health, the intracellular ROS level is tightly controlled by various antioxidants. In contrast, cancer cells have an abnormally high level of ROS due to an increased ROS production and/or impaired ROS detoxification that can damage intracellular macromolecules such as nucleic acids, proteins, and lipids. Elevated ROS production in cancer cells may result from an aberrant metabolic activity, mitochondrial dysfunction, disturbed cellular signaling, oncogene activity, and interaction with tumor infiltrating immune cells.2O2 has the opposite effects on cancer cell proliferation depending on its concentration and cancer type. G. Vilema-Enriquez et al. in their article “Molecular and Cellular Effects of Hydrogen Peroxide on Human Lung Cancer Cells: Potential Therapeutic Implications” review effects of hydrogen peroxide on human lung cancer. The authors discussed effects of H2O2 on migration and invasion, calcium release, and other molecular features of cancer cells. Furthermore, they describe the link between hydrogen peroxide and inflammation. Finally, the authors hypothesize that novel therapeutic approaches against lung cancer may be based on the use of H2O2. Y.-C. Hung et al. in their review “Roles of Reactive Oxygen Species in Anticancer Therapy with Salvia miltiorrhiza Bunge” deal with Danshen as a drug of the traditional Chinese medicine and provide a systematic review of its antioxidant capacity and potential anticancer effects. Moreover, they conclude that based on the existed preclinical data this drug may be pipelined in clinical trials. A research paper by W. Li et al.  deals with hyperglycemia in pancreatic cancer cells. The authors succeeded in finding the link between hyperglycemia and epithelial-mesenchymal transition through the production of hydrogen peroxide. Another research report on breast cancer of D. M. Badr et al. (“The Combination of α-Tocopheryl Succinate and Sodium Selenite on Breast Cancer: A Merit or a Demerit?”) shows in vitro and in vivo that sodium selenite antagonizes effects of α-tocopheryl succinate on apoptosis induction in cancer cells via inhibition of oxidative stress. An intriguing review came from France, authored by M. Assi and A. Rébillard, and was devoted to the problem of cachexia in cancer patients (“The Janus-Faced Role of Antioxidants in Cancer Cachexia: New Insights on the Established Concepts”). As regulators of catabolic pathways ROS are involved in muscle atrophy in cachectic cancer patients, the authors summarize and discuss contradictory data on the effects of antioxidants in such patients.The ultimate purpose of this special issue is to publish high-quality research communications as well as review articles dedicated to the role of ROS in cancer biology, anticancer therapy, and related topics. Five articles published in this special issue are devoted to reactive oxygen species in cancer biology. Presently, it is rather well known that HThe next topic highlighted in this issue is devoted to ROS in tumor immunology. A review by X. Chen et al. (“Reactive Oxygen Species Regulate T Cell Immune Response in the Tumor Microenvironment”) gives readers an overview of ROS in the tumor microenvironment and especially in the tumor-induced immunosuppression. The authors, based on improvement of anticancer T cell response, consider an antioxidant treatment as a promising option for cancer therapy. A. Scala et al. in their research article “Alterations in Red Blood Cell Functionality Induced by an Indole Scaffold Containing a Y-Iminodiketo Moiety: Potential Antiproliferative Conditions” deal with a prediction of the antiproliferative effects of heterocyclic scaffolds, which could be important for development of new therapeutic approaches against cancer.A research article by M. Weniger et al.  considers pancreatitis as a main risk factor for pancreatic cancer. The authors show an unexpected analgesic effect of the new antioxidant SkQ1 during pancreatic inflammation. The last article from this issue deals with the oxidative stress in cancer-prone diseases in pediatric age. S. Perrone et al. in “Oxidative Stress in Cancer-Prone Genetic Diseases in Pediatric Age: The Role of Mitochondrial Dysfunction” review recent literature on such diseases and discuss molecular mechanisms of oxidative stress associated with mitochondrial dysfunction. They conclude that mitochondria-targeted medicines could be applied into the clinics to improve the quality of life of patients with cancer-prone genetic diseases.Summarizing, the wide spectrum of review and research articles presented in this issue provides recent interesting data on ROS in the context of cancer biology and anticancer therapy.Alexandr V. BazhinAlexandr V. BazhinPavel P. PhilippovPavel P. PhilippovSvetlana KarakhanovaSvetlana Karakhanova


Mandibular advancement surgery may positively affect pharyngeal airways and therefore potentially beneficial to obstructive sleep apnea (OSA).To collect evidence from published systematic reviews that have evaluated pharyngeal airway changes related to mandibular advancement with or without maxillary procedures.PubMed, EMBASE, Web of Science, and Cochrane Library were searched without limiting language or timeline. Eligible systematic reviews evaluating changes in pharyngeal airway dimensions and respiratory parameters after mandibular advancement with or without maxillary surgery were identified and included.This overview has included eleven systematic reviews. Maxillomandibular advancement (MMA) increases linear, cross-sectional plane and volumetric measurements of pharyngeal airways significantly (p<0.0001), while reducing the apnea-hypopnea index (AHI) and the respiratory disturbance index (RDI) significantly (p<0.0001). Two systematic reviews included primary studies that have evaluated single-jaw mandibular advancement, but did not discuss their effect onto pharyngeal airways. Based on the included primary studies of those systematic reviews, single-jaw mandibular advancement was reported to significantly increase pharyngeal airway dimensions (p<0.05); however, conclusive long-term results were lacking.MMA increases pharyngeal airway dimensions and is beneficial to patients suffering from OSA. However, more evidence is still needed to draw definite conclusion related to the effect of single-jaw mandibular advancement osteotomies on pharyngeal airways. Pharyngeal airway dimensions are inevitably affected by skeletal jaw movements during orthognathic surgery. Both one-jaw mandibular advancement, 2 and tSurgeons and orthodontists have gained increasing interest in pharyngeal airway evaluation, as it affects patients’ health and quality of life. The effThe aims of this overview were to examine systematic reviews for changes in pharyngeal airway dimensions and/or respiratory parameters related to mandibular advancement osteotomies with or without concomitant maxillary osteotomies, and to critically appraise the quality of the reported systematic reviews.https://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42016046489).The reporting of this systematic review adheres to the Cochrane’s recommendation on overview of systematic reviews and the rd April 2017. There was no search limitation set for publication language or dates. The search results were exported into Endnote X7  and duplicate articles were removed. Next, the title and abstract of all articles were screened for potential eligibility, and the full text of relevant articles was retrieved. Lastly, the reference lists of those relevant articles were manually searched to screen for further relevant articles. Both electronic and manual searches were performed independently by two authors (TSK and RAZ). Disagreement was resolved by discussion with the other authors.The electronic databases PubMed, EMBASE, Web of Science, Scopus and Cochrane Library were searched using the search strategy outlined in This overview has included systematic reviews that have assessed changes of pharyngeal airways related to mandibular advancement osteotomies with or without concomitant maxillary osteotomies. Eligible systematic reviews had to report outcome measures of pharyngeal airway dimensions and their post-surgical changes, i.e. linear, cross-sectional plane or volumetric measurements. Furthermore, data from reviews reporting on respiratory parameter changes have also been evaluated and included.Systematic reviews that have studied specific target group (i.e. edentulous patients and morbidly obese OSA patients), or pharyngeal airways in cleft lip and palate, syndromic or distraction osteogenesis patients have been excluded from this overview.Data from included systematic reviews was extracted independently by two authors  and inserted in pre-tabulated data sheets . Any disagreement related to data extraction was resolved by consensus in discussion with the other authors  to ensure consistency and reliability of extracted data. The data extraction included authors, publication year and title, methods of analyses, number and study design of included studies, sample population ; type of interventions, outcome measures and main findings, follow up period and meta-analyses’ result when available.The methodological quality of the included reviews was assessed independently by TSK and RAZ using the Assessment of Multiple Systematic Reviews (AMSTAR) tool. On the 2 test for heterogeneity (p = 0.1) and the Ι2 measure of inconsistency. A significant heterogeneity was considered when p< 0.1 for χ2 test or when Ι2> 50%. Treatment effects across the studies were combined using the fixed effect model when there was no heterogeneity observed (p> 0.1); in case of heterogeneity observed, the random effect model was applied. Funnel plot was used to assess publication bias, while Egger test for funnel plot asymmetry will be used when more than ten primary studies were included in an analysis[A narrative overview is provided summarizing the data gathered from included systematic reviews. Meta-analyses have been performed whenever possible by pooling the data across different reviews using the software “Review Manager” . The heterogeneity of trial results was assessed with the χ analysis, 24.An electronic search of the databases has generated an overall of 1642 articles. Titles and abstracts of 1211 articles were screened after removing the duplicates. The full texts of 23 relevant articles were retrieved and assessed for their eligibility of inclusion. No other relevant article was found while manually searching the reference lists of those 23 articles. Ultimately, 11 systematic reviews –18 have Two systematic reviews, 16 haveThe AMSTAR tool analysis revealed one systematic reviewwith a hiAlthough a self-declared no conflict of interest was found in eight systematic reviews, 16, 18,Eight out of eleven systematic reviews have analyzed the quality of evidence of their included primary studies. Three reviews, 9, 11 aet al[For the 38 primary studies that have been assessed based on risk of bias or methodology quality, only two were reported as low risk of bias or high methodological quality. Besides, half of them showed a moderate risk of bias or methodological quality. Zaghi et al did not The narrative information from the included systematic reviews is elaborated below. The results of the meta-analyses of included systematic reviews are shown in Although two systematic reviews, 16 inclMeta-analyses of three systematic reviews showed a significant increase of minimum cross-sectional area (CSA), pharynget al[et al[I2 = 0%), the fixed effect model was used. The meta-analysis indicated that MMA with or without genioplasty or genial tubercle advancement (GTA) lead to a significantly increased total pharyngeal volume  after the surgery (p<0.00001). Although there was no statistically significant different (p = 0.62) between the subgroups, MMA with genioplasty or GTA has higher increased total pharyngeal volume (mean = 8.73ml) in comparison with MMA alone  after the surgery. A symmetry funnel plot was noted suggesting a low risk of publication bias ..et al[etion bias et al[et al[et al[et al[Two primary studies reported by Butterfield et al, 43 were al[et al of the a al[et al meta-ana al[et al, 46 incl al[et al were fou al[et alwas eventMeta-analyses of post-MMA data reported by included systematic reviews in this overview revealed a significant reduction of the AHI, 18, Reset al[et al[Two systematic reviews, 18 haveet al reportedHsieh and Liao did not et al[et al[2 nadir (p = 0.04) to be associated with a higher post-MAA OSA cure rate (AHI<5/h).Univariate analysis of Holty et al suggesteet al. These r al[et al who haveThe here presented overview detected significantly reduced AHI after MMA with a relatively high treatment success rate (>85%) in OSA patients. This is comprehensible and in line with consistently increased post-MMA linear, cross-sectional area and volumetric pharyngeal airway measurements. The minimum CSA is one of the most commonly used airway measurements, and hasMandibular advancement with bilateral sagittal split osteotomies (BSSO) is a well-established procedure in the treatment for patients with retrognathic mandible, with concomitant beneficial effect on pharyngeal airways. However,et al[Based on CBCT analysis, Hernandez-Alfaro et alhave repoet al of MMA cet al, 18 withet al, 18 and et alare assocet al and OSA The maximum follow-up period varies across primary studies between 5 weeks to 12 years, with a vast majority of less than 5 years. Therefore, some of these follow-up periods were definitely too short since recurrence of OSA has been reported as late as 10 to 15 years after MMA. A standAround one third of the included systematic reviews have performed electronic search in only one database and therefore posed a significant threat to selection bias. Moreover, none of the included systematic reviews has disclosed the ‘conflict of interest’ status of their included primary studies. Besides, four systematic reviews did not describe the characteristics of their included primary studies. As the quality of systematic reviews is affected directly by the quality of its included primary studies, a thorough investigation and reporting of each included study are mandatory.et al[Publication bias is another critical aspect to be investigated in the systematic reviews. Only two, 18 out et al suspecteThe following shortcomings of this overview have to be highlighted. Most primary studies of the included systematic reviews were of moderate and only a few of high quality, which might have affected the quality of those systematic reviews. Besides, seven of the included systematic reviews–15, 17 hMaxillomandibular advancement (MMA) increases pharyngeal airway dimensions, providing positive post-surgical effects in patients suffering from OSA. However, still more evidence is needed to draw conclusions related to effect of single-jaw mandibular advancement osteotomies on pharyngeal airways.S1 Text(PDF)Click here for additional data file.S2 Text(PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.


Alternative splicing of precursor mRNA is an important mechanism that increases transcriptomic and proteomic diversity and also post-transcriptionally regulates mRNA levels. Alternative splicing occurs at high frequency in brain tissues and contributes to every step of nervous system development, including cell-fate decisions, neuronal migration, axon guidance, and synaptogenesis. Genetic manipulation and RNA sequencing have provided insights into the molecular mechanisms underlying the effects of alternative splicing in stem cell self-renewal and neuronal fate specification. Timely expression and perhaps post-translational modification of neuron-specific splicing regulators play important roles in neuronal development. Alternative splicing of many key transcription regulators or epigenetic factors reprograms the transcriptome and hence contributes to stem cell fate determination. During neuronal differentiation, alternative splicing also modulates signaling activity, centriolar dynamics, and metabolic pathways. Moreover, alternative splicing impacts cortical lamination and neuronal development and function. In this review, we focus on recent progress toward understanding the contributions of alternative splicing to neurogenesis and brain development, which has shed light on how splicing defects may cause brain disorders and diseases. Alternative splicing is a crucial step of post-transcriptional gene expression that substantially increases transcriptome diversity and is critical for diverse cellular processes, including cell differentiation and development as well as cell reprogramming and tissue remodeling. Our understanding of the physiological significance and disease implications of alternative splicing has been greatly improved by genetic approaches and RNA deep sequencing. In this review, we focus on alternative splicing in neuronal differentiation from stem/progenitor cells, neuronal migration and functional development of neurons Figure .trans-acting splicing regulators and cis-elements of pre-mRNAs   and muscleblind-like 1 (MBNL1) exhibit switched expression during heart development to regulate splicing of cardiac mRNAs  can be distinguished from neurons in the developing brain  promotes exon 10 inclusion of PTBP2 and thus maintains PTBP2 level in neurons  in NPCs and hence maintains apical progenitors. Genetic mutations that generate aberrant Flna splice isoforms in NPCs are linked to periventricular nodular heterotopia, a neuronal migration disorder. Thus, a better understanding of the mechanisms of neuronal alternative splicing may provide plausible treatment strategies for neuronal disorders.Among neuronal splicing regulators, PTBP1 is exclusively expressed in embryonic stem cells and NPCs, whereas PTBP2 and Rbfox proteins are mainly expressed in neurons. A recent report showed that PTBP1 and Rbfox antagonistically modulate neuronal fate via their roles in regulating alternative exon selection  splice isoforms, i.e., PKM1 and PKM2 in neurons and glial cells, respectively (Zhang et al., PKM1 and PKM2 isoforms result from mutually exclusive exon selection. Selective expression of PKM isoforms is also critical for regulating glucose metabolism in muscle and cancer (Christofk et al., Brain tissues comprise a variety of cell types including neural precursor cells, neurons, and various subtypes of neuroglia. Tantalizing issues remain as to whether and how alternative splicing influences neural fate determination and which splicing regulators are involved (Raj and Blencowe, Reeler mutant mice and mice with spontaneous or targeted mutations of Dab1 or either of the receptors exhibit similar phenotypes characterized by ataxia, tremors, and a reeling gait (D'Arcangelo et al., Dab1 occurs during brain development, resulting in multiple splice isoforms (Gao et al., Dab1 exon 9b/c (Yano et al., Dab1. Differential selection of exons 7 and 8 of Dab1 is also intriguing because these two exons encode a domain containing critical tyrosines that are targets of Reelin-mediated phosphorylation. Moreover, ApoER2 also undergoes alternative splicing. The exon 19-containing domain of ApoER2 is important for synapse formation and function via its interaction with PSD-95 (Beffert et al., ApoER2 and that blocking SRSF1-binding sites using an antisense oligonucleotide has therapeutic potential (Hinrich et al., The mammalian cerebral cortex has a highly organized six-layered structure consisting of a variety of neuron subtypes (Molyneaux et al., Scn9a mRNA increases the SCN9A level (Eom et al., Alternative splicing also regulates neurologic functions such as axon guidance and synaptogenesis. A number of neuronal mRNAs undergo alternative exon selection to generate isoforms in response to neuronal stimulation. Synaptic activity promotes exon 19 inclusion of ApoER2, which then binds Reelin and enhances long-term potentiation (Beffert et al., The combination of various genetic tools and RNA-seq has advanced our knowledge of the impact of alternative splicing on neural development and function. Recently, the use of cell-surface or genetically engineered fluorescent protein markers and fluorescence-activated cell sorting has enabled the isolation of stem/progenitor cells and specific neuronal types (Zhang et al., C-HS, DD, and W-YT: Jointly wrote this review; W-YT: Defined the scope of the review and edited the draft. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


At the cellular and subcellular levels, acid-base balance is achieved by ion exchange.Most physiological processes are sensitive to pH  and regulation of pH within tissues and body fluids represents a fundamental homeostatic process in living organisms. At the organismal level, acid-base balance is achieved by fast respiratory modulations of the partial pressure of CORecently in Current Biology, Jalalvand et al.  describein vitro spinal cord was studied. While mammals regulate arterial blood pH (pHa) at 7.4 at their normal body temperature of 37°C, Jalalvand et al. (a and CSF pH (pHCSF) increase by ~0.015 unit per °C when body temperature decreases in ectothermic vertebrates  upon intense and exhaustive exercise  that interfaces with neuronal membranes. Chesler , the Danish Natural Sciences Research Council (FNU) (TW), the National Institutes of Health- NS091836 to Sherif Elbasiouny (SD), and the National Science Foundation IOS-1257338 (LH) for funding.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.


Anterior shoulder instability has been successfully managed arthroscopically over the past two decades with refined “anatomic” reconstruction procedures involving the use of anchors for the repositioning and re-tensioning of the antero-inferior capsuloligamentous complex, in an effort to recreate its “bumper effect”.Research and online content related to arthroscopic treatment of shoulder instability was reviewed and their results compared.The short- and mid-term results of this technique have been very satisfactory. The greatest number of recent reports suggests that long-term results (>5 years follow-up) remain rather satisfactory, especially in the absence of significant glenoid bone loss (>20-25%). In these studies recurrent instability, in the form of either dislocation or subluxation, ranges from 5.1 to over 20%, clinical scores, more than 5 years after the index procedure, remain good or excellent in >80% of patient population as do patient satisfaction and return to previous level of activities.As regards arthroscopic non-anatomic bony procedures (Latarjet or Bristow procedures) performed in revision cases or in the presence of >20-25% bone loss of the anteroinferior aspect of the glenoid, recent reports suggest that their long-term results are very satisfactory both in terms of re-dislocation rates and patient satisfaction.It appears that even “lege artis” performance of arthroscopic reconstruction decelerates but does not obliterate the degenerative procedure of dislocation arthropathy. The presence and grade of arthritic changes correlate with the number of dislocations sustained prior to the arthroscopic intervention, the number of anchors used and the age at initial dislocation and surgery. However, the clinical significance of radiologically evident dislocation arthropathy is debatable. Despite prompt reduction and immobilisation for a reasonable but not excessive period of time before further rehabilitation, it can often lead to recurrent shoulder instability -3. It apet al. , Porcell [et al.  and Yian [et al.  have sug [et al. , 8.A Bankart lesion or various Bankart-variants appear to be the “essential lesion” in most instability cases and is most usually amenable to “anatomic” procedures that aim to reconstruct and recreate the anatomy of the antero-inferior capsule-ligamentous complex. Over the past 10 years refined arthroscopic reconstruction techniques involving the use of suture anchors have been developed and offer very satisfactory short- and mid-term outcomes that are comparable to classic open techniques. On the other hand, “non-anatomic” procedures such as the Latarjet or Bristow coracoid transfer or other “bone-block” procedures are being used all the more often to address patients with a combination of osseous and ligamentous injuries. These procedures have recently been performed arthroscopically by a number of experienced surgeons, with a very promising outcome -12. In t1 & 2). Therefore, only studies reporting on the long-term outcome following arthroscopic stabilisation with the use of anchors will be analysed in this review. Both metal and bio-absorbable anchors have been used very successfully in the treatment of shoulder instability, neither one providing superior clinical outcomes. However, the visibility of the drill holes was significantly greater after using poly-L-lactic acid polymer implants [Initial clinical studies on the long-term clinical outcome (>5-year mean patient follow-up time) following arthroscopic Bankart procedures describe the clinical outcome in patient series where techniques involving the use of tacks and trans-glenoid sutures were employed and report relatively high re-dislocation rates  and haveimplants .et al. [Kim et al.  report oRhee and colleagues  on the oUnlike Rhee and colleagues  Larain aCastagna and colleagues in 2010  analysedet al. in 2007 [Porcellini  in 2007  reportedPlath and colleagues  in a veret al. [Van der Linde et al.  report aet al.  for failet al. . It alsoArthroscopic or open techniques involving bone block procedures or coracoid transfer techniques are used more and more often in both revision and primary instability surgery, especially in the presence of >20-25% bone loss of the anteroinferior aspect of the glenoid , 22. Recet al. [et al. have also reported a low recurrence of instability (4 out of 68 shoulders- 5.9%) in their long term results study of open Latarjet procedure [Schmid et al.  have reprocedure .et al. [Dumont et al.  have repet al. in 1983, who introduced the term “dislocation arthropathy” for this pathology and classified it radiologically [et al. [Arthritic changes in the shoulder joint following shoulder dislocation were first described by Samilson ogically . The cla [et al.  and cons [et al. .No such evidence was available concerning the long term effect of arthroscopic anatomic procedures on the prevalence and evolution of dislocation arthropathy until recently, when a number of publications have demonstrated that the long-term incidence of moderate and severe dislocation arthropathy is similar to that reported following open anatomic procedures , 19, 28.et al. reviewed the long term results of 68 shoulders treated with the Latarjet procedure. One fourth of the patients  showed progression of arthritis [3).Mizuno rthritis . This perthritis  and the It appears that initial joint trauma sustained during anterior shoulder dislocation has long-term biologic effects on the shoulder joint cartilage and the joint physiology in general. Avoiding numerous pre-operative dislocations appears to prevent to some extent the occurrence and severity of post-operative dislocation arthropathy . One shoAnterior first time shoulder dislocation has significant short and long term effects on the shoulder joint. It can lead to anterior instability, loss of function and dislocation arthropathy. Open or arthroscopic anatomic procedures in the absence of severe glenoid bone loss provide good to excellent long term results even for the high demand athlete. Long term results of non-anatomic procedures in the presence of significant glenoid bone loss have been reported as satisfactory. Shoulders with a history of anterior dislocation are very likely to eventually develop some grade of arthritis even when they are treated surgically, however the presence of arthritis does not correlate with functional scores.


Stem Cells International set out to publish a special issue focused on the “Ex Vivo and In Vivo Stem Cell-Based Tissue Engineering Strategies for Their Use in Regenerative Medicine.” This special issue resulted in a collection of nine outstanding articles which include two reviews and seven original studies made by recognized researchers from seven countries across Europe, Asia, South America, and North America.Tissue engineering is an emergent discipline focused on the generation of bioartificial tissue-like substitutes through the combination of biomaterials, cells, and growth factors. In this context, stem cell-based strategies have made substantial contributions in the field. Researchers worldwide have demonstrated that stem cells have an extraordinary capability to differentiate into different cell lineages, promote tissue regeneration, release a wide range of growth factors, and modulate the host immune response. Based on the current impact of tissue engineering and stem cells in medicine, Concerning the review articles, M. Cimino et al. contributed with a complete review entitled “Xeno-Free Strategies for Safe Human Mesenchymal Stem/Stromal Cell Expansion: Supplements and Coatings,” where authors suggest that culture/expansion of human mesenchymal stem cells under xeno-free conditions is still needed to improve their clinical translation. The review made by A. Owczarczyk-Saczonek et al. discussed “The Use of Adipose-Derived Stem Cells in Selected Skin Diseases ,” highlighting that these stem cells are promising alternatives to generate new engineered or stem cell-based strategies to treat skin diseases.in vivo studies were published in this special issue. On the one hand, M. Mata et al. published the article entitled “In Vivo Articular Cartilage Regeneration Using Human Dental Pulp Stem Cells Cultured in an Alginate Scaffold: A Preliminary Study” in which they demonstrated, through different histological approaches, that human dental pulp stem cells have a positive impact on the regeneration of articular cartilage in rabbits. On the other hand, V. Chapman et al. demonstrated that late passage marrow-derived mesenchymal stem cells were more efficient than early passage cells in the treatment of osteoarthritis on their article entitled “Therapeutic Benefit for Late, but Not Early, Passage Mesenchymal Stem Cells on Pain Behaviour in an Animal Model of Osteoarthritis.” These articles provide new evidence related to the usefulness of stem cells in cartilage tissue engineering.In the field of cartilage tissue engineering, two interesting Cryptomphalus aspersa's eggs induced the differentiation of adipose stem cells to myofibroblast on their study entitled “High Sensitivity of Human Adipose Stem Cells to Differentiate into Myofibroblasts in the Presence of C. aspersa Egg Extract.” In another interesting ex vivo approach, E. Oliveira et al. on their article “Influence of Different ECM-Like Hydrogels on Neurite Outgrowth Induced by Adipose Tissue-Derived Stem Cells” demonstrated the synergetic effect of the correct combination of biomaterials and adipose stem cells to increase the neurite outgrowth from DRG explants. In these articles, the usefulness and versatility of adipose stem cells in tissue engineering were well demonstrated.Currently, adipose-derived mesenchymal stem cells are considered one of the most promising mesenchymal stem cells by several and well-supported reasons. Within this special issue, N. Garcia-Honduvilla et al. demonstrated that a natural extract purified from in vivo approach, M. Garrido et al. demonstrate the potential clinical application of amniotic membrane in digestive surgery on their article “Transplantation of Human Amniotic Membrane over the Liver Surface Reduces Hepatic Fibrosis in a Cholestatic Model in Young Rats.” These three articles highlight the potential clinical usefulness of extraembryonic-derived cells and scaffolds in tissue engineering.Extraembryonic tissues are an important source of stem cells and natural scaffolds. In this regard, G. P. Liao et al. successfully repaired diaphragmatic defects in rats by using decellularized rat diaphragm containing human amniotic fluid-derived stem cells on their article entitled “Tissue Engineering to Repair Diaphragmatic Defect in a Rat Model.” In addition, in order to solve the problem associated to the expansion of epithelial cells, S. M. Nam et al. investigated the use two stem cells sources as feeder cells of corneal epithelial cells on their article entitled “Ex Vivo Expansion of Human Limbal Epithelial Cells Using Human Placenta-Derived and Umbilical Cord-Derived Mesenchymal Stem Cells.” In an Finally, in these nine articles, authors rigorously discussed and demonstrated the high versatility of different kinds of stem cells to differentiate, promote tissue healing, modulate host immune response, and serve as feeder platform for the ex vivo expansion of differentiated cells. In conclusion, the articles published in this special issue provide new tissue engineered-based strategies and scientific evidence that support the potential clinical usefulness of stem cells in regenerative medicine.Víctor CarrielStefano GeunaMiguel Alaminos


ICC) is the second most common primary hepatic malignancy with poor prognosis. Despite improvements in its diagnosis and therapy, the prognosis for ICC patients remains poor. An improved understanding of ICC pathogenesis and consequential identification of novel therapeutic targets would improve the prognosis of ICC patients. MicroRNAs (miRNAs) are a class of highly conserved, endogenous, small non‐coding RNA molecules of 18–23 nucleotides in length, which regulate gene expression through complementary base‐pairing with target messenger RNAs and subsequent gene silencing. Several studies have shown deregulated expression of miRNAs in ICC cell lines and tissues, in which these miRNAs play important roles in ICC apoptosis, cell proliferation, invasion, migration and metastasis. In this review, we illustrate the potential role of miRNA in the pathogenesis of ICC and explore the possibilities of using miRNAs as prognostic and diagnostic markers, as well as therapeutic targets in ICC.Intrahepatic cholangiocarcinoma ( Intrahepatic cholangiocarcinoma (ICC) originating from cholangiocytes is the second most common primary tumour of the liver MicroRNAs (miRNAs) belong to a new class of small non‐coding, endogenous RNAs comprising 18–23 nucleotides that negatively regulate gene expression through inducing mRNA degradation or repressing translation by annealing with the complementary sites in 3′‐untranslated regions (3′‐UTRs) of target mRNAs via exportin‐5 Previous data showed that miRNA synthesis and maturation consists of a stepwise process that is compartmentalized between the nucleus and the cytoplasm et al. using 27 ICC tissues, 10 normal cholangiocyte samples and 8 normal liver tissues Deregulated miRNAs in ICC were listed in Table Further study on miRNAs expression profiling identified a number of significantly deregulated miRNAs in two ICC cell lines (HuCCT1 and MEC) as compared with a normal intrahepatic biliary epithelial cell line (HIBEpiC) et al. Oishi et al. Plieskatt et al. Wang et al. Karakatsanis et al. Recently, Zhang et al. Plieskatt via derepressing or suppressing important signalling mediators along specific signalling pathways pertinent to cancer development.A number of aberrantly expressed miRNAs have been reported to function as tumour suppressors or oncogenes in ICC Table  via dereet al. Hu et al. Wang et al. in vitro and impaired tumour growth in vivo. Furthermore, PTPN14 and PTEN were identified as direct and functional targets of miR‐21. High expression levels of miR‐21 were closely related to adverse clinical features, diminished survival and poor prognosis in ICC patients.Wang The biological functions and/or prognostic significance of two down‐regulated miRNAs, namely miR‐204 and miR‐320, have been studied in details et al. Twist, and decreased E‐cadherin levels by directly targeting the Twist gene. Oishi et al. Li et al. in vitro and reduced the protein levels of SMYD3 and downstream target genes . Knockdown of SMYD3 inhibited cell migration and invasion resembling that of miR‐124 overexpression.Hepatitis C virus core protein (HCVc) plays an important role in the development of ICC. Zeng et al. Iwaki et al. Qiu et al. Li et al.Bernuzzi The dismal prognosis and aggressive progression associated with ICC have led researchers and clinicians to explore new avenues of potential treatment for ICC patients The authors declare no conflict of interest.


The present study seeks to determine potential associations between viral infections and neuropsychiatric diseases. To address this issue, we investigated the peptide commonalities between viruses that have been related to psychiatric and neurological disorders—such as rubella, human immunodeficiency virus, and herpesviruses—and human distal-less homeobox (DLX) proteins expressed in developing brain—namely, DLX1, DLX2, DLX5, and DLX6. Peptide matching analyses revealed a high degree of pentapeptide sharing. From an immunological perspective, this overlap is relevant because pentapeptides are endowed with immunogenicity and antigenicity—that is, they are immune determinants. Moreover, infection-induced immune cross-reactions might have functional, spatial, and temporal implications related to the functions and expression patterns of DLX1 and DLX5 in the fetal and adult human brain. In sum, our data support the hypothesis that viral infections may be linked to neuropsychiatric diseases through autoimmune cross-reactions caused by molecular mimicry between viral proteins and brain-specific DLX self-antigens. Infections, neuropsychiatric diseases, and language disorders are often concomitant pathological events that can have early etiological roots in fetal life and then become apparent in any stage across the life span of the individual, from the postnatal period to the late age  family—namely DLX1, DLX2, DLX5, and DLX6—that have been thoroughly investigated in numerous studies on neurodevelopment. Indeed, the four TFs are expressed during early fetal neurodevelopment , where DLX proteins may be expressed , DLX2 , DLX5 , and DLX6  were dissected into pentapeptides offset by one aa residue: MTMTT, TMTTM, MTTMP, and so forth. Then, each of the resulting pentapeptides was analyzed for matches to a sample library of 25 viral proteomes using the Protein Information Resource (PIR) match program (https://research.bioinformatics.udel.edu/peptidematch/batchpeptidematch.jsp)  was used as a control neural protein. Glutamate decarboxylases 1  and 2  were additionally investigated as DLX-related proteins.The primary amino acid (aa) sequences of human DXL1 : Borna disease virus ; Epstein-Barr virus ; Hendra virus ; Hepatitis B virus genotype C subtype ayr ; Hepatitis C virus genotype 1a ; Human cytomegalovirus ; Human herpesvirus 1 ; Human herpesvirus 2 ; Human herpesvirus 6A ; Human herpesvirus 6B ; Human immunodeficiency virus type 1 group M subtype A ; Human parvovirus B19 ; Influenza A virus, H5N5 ; Influenza A virus, H1N1 ; Influenza A virus, H7N7 ; Influenza B virus ; Influenza C virus ; Measles virus ; Rotavirus A ; Rotavirus C ; Rotavirus X ; Rubella virus ; Vaccinia virus ; Varicella-zoster virus ; and Zika virus .www.iedb.org) resource   and 4.4% of the DLX2 peptide sharing ;the extent of the peptide sharing is independent of the virus protein length. For example, Rubella virus  and the eleven times longer HHV3  share exactly the same number of pentapeptides—namely, three—with DLX1 protein;quantitatively, the extent of the peptide sharing is unexpectedly high compared to the mathematical expected value of the pentapeptide sharing between the five neural proteins and the 25 viral proteomes. The expected value can be calculated as follows: given two protein entities  and assuming that all aa occur with the same frequency, the expected probability for the two entities to share a pentapeptide is expressed by the formulam is the number of pentapeptides present in the DLX1 protein ; n is the number of pentapeptides present in the set formed by the 25 viral proteomes , and N is the number of all possible pentapeptides. Since each residue can be any of 20 aa, then N is 205 . Developing the equation, the expected pentapeptide sharing between DLX1 and the 25 viral proteomes is equal to 1,02668314453125e-5 or, practically, zero.where: www.immuneepitope.org; Vita et al., n < 12.The pentapeptide matching between viral and neural proteins illustrated in Table A comparative analysis of DLX expression in fetal and adult neurogenic areas of the human brain was conducted using the online database and resources of the Allen Institute for Brain Science (Lein et al., On the whole, Figure Actually, few data are available on DLX protein expression in humans. Rakic and Zecevic  studied https://www.proteinatlas.org/on DLX1 and DLX5 protein expression in the adult human brain. The data are shown in Figure Such experimental results obtained in human fetal developing brain are flanked by data collected from the Human Protein Atlas (www.proteinatlas.org; Uhlén et al., In essence, we found a vast and unexpected peptide sharing between DLX proteins and numerous infectious agents that constellate human life, from prenatal time to adulthood. The peptide platform defined in Table In this context, different immunological pathogenic mechanisms might be theoretically account for the neuronal damage according to the type of immune response, i.e., humoral vs. cell-mediated, and the timing of infection-induce maternal immune activation in relationship to the expression patterns of DLX proteins in the fetus (see Figure On the other hand, a cell-mediated mechanism could also theoretically be implied in the cross-reactive immune-mediated subclinical damage of the fetal nervous systems, since memory T-cell trafficking between mother and fetus is also a well-known phenomenon (Jeanty et al., Based on data from Figure Functionally, infection-induced immune cross-reactions would affect two TFs that, according to numerous studies, are implicated in crucial functions and fundamental processes during neurodevelopment and adult neurogenesis, and are potentially relevant to language competence and other higher cognitive functions see Box ;Spatially, infection-induced immune cross-reactions would damage brain structures where adult neurogenesis occurs and that are involved in the neural circuitry of language and memory, and in cognitive and emotional functions (Ming and Song, Temporally, infection-induced immune cross-reactions suggest a two-hit model that, depending on the DLX protein expression profiles, comprehends targets allocated in two time-windows in the life of an individual with a subclinical damage in fetal life and clinical onset in adulthood.Box 1DLX1:regulates the development of the ventral forebrain, craniofacial patterning, and the early diencephalic subdivision (Eisenstat et al., regulates neurite maturation and migration (Cobos et al., regulates the fate switch between cortical and striatal interneurons: cells that ordinarily would become cortical interneurons transform toward a subtype of GABAergic striatal interneurons, thus reducing glutamatergic input to the hippocampus (McKinsey et al., its loss leads to subtype-specific loss of inhibitory interneurons with a reduction in inhibitory currents and generalized seizures in mice (Cobos et al., contributes to promote cortical interneuron migration from the basal forebrain by direct repression of the semaphorin receptor neuropilin-2 (Le et al., when altered, might be related to Mowat-Wilson syndrome (McKinsey et al., is downregulated or altered in autism spectrum disorders (ASD; Liu et al., has low thalamic expression in psychosis (Kromkamp et al., has been proposed as a language-associated protein (Boeckx and Benítez-Burraco, DLX5:promotes neuronal differentiation in SVZ (Shu et al., its loss leads to defective neuronogenesis (Perera et al., contributes to convert fibroblasts into induced GABAergic interneurons (Colasante et al., regulates development of peripheral and central components of the olfactory system (Long et al., is a candidate genes for autism (Nakashima et al., is involved in Rett syndrome (Itaba-Matsumoto et al., participates to the regulation of the expression of the glutamic acid decarboxylases (Stühmer et al., its loss preferentially reduces the number of mature parvalbumin- interneurons (Wang et al., in vivo, the possibility of obtaining animal models of neuropsychiatric disorders by immunizing pregnant animals with DLX proteins could be examined. Moreover, analyses of sera from human patients with neuropsychiatric diseases, for example schizophrenia, are warranted to measure immunoreactivity against the peptides shared between viruses and DLX proteins. Possibly, the results of these joint basic and clinical in vivo approaches might also help design new therapeutic approaches in neuropsychiatry.In synthesis, the present study confirms previous reports (Kanduc et al., All 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.


We are aware of concepts of osmotic and oncotic pressure in clinical physiology. Per Starling's law, the freely movable ions do not significantly contribute to the retention of vascular volume, or the maintenance of interstitial fluid pressure  was predicted for a long time (Stiernet et al., In the beta cells of the pancreas, the insulin granules are not freely soluble molecules in the cytosol but rather exists as packaged vesicles. Electron micrographs of beta cells and physiological experiments have revealed that these insulin granules undergo regulated exocytosis to a glucose load, rather than random secretion Dean, . PotassiRecently, it has been suggested that the exocytosis involving insulin granules resembles remarkable similarity to the pattern of inhibitory enteric neuromuscular neurotransmission (Chaudhury, −/− mice, the number and appearances of secretory granules in islet β-cells of knockout mice were normal (Sakamoto et al., The SLC17A9 channel transports ATP within the insulin containing dense core vesicles (Sawada et al., Type II diabetes mellitus is characterized by progressive exhaustion of the beta cells of the pancreas (Butler et al., In this commentary, we advance the hypothesis that SLC17A9 dysfunction may contribute to the ongoing inefficacy of insulin exocytosis, leading to progressive diabetes. The lack of entry of ATP through a dysfunctional SLC17A9 (Sakamoto et al., What causes SLC17A9 dysfunction is not clear. Interestingly, SLC17A9 is gated by ATP itself (Sawada et al., There have been recent advances of novel markers that can tag synaptic proteins, especially those acting on the membranes. PET imaging may detect these global aspects of neurotransmission (Finnema et al., ArC, conceptualized and development of manuscript, drafted manuscript. CD, major intellectual contribution. VD, major intellectual contribution. CM, important discussion. NS, important discussion. WM, important discussion and conceptualizations. RR, important discussion. AM, important discussion, manuscript recheck. AdR, important discussion and prospects. All authors read and approved final version of manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Helicobacter pylori-mediated inflammation has been implicated in gastric cancer in many previously established studies, and Fusobacterium nucleatum presence has been observed with greater intensity in colorectal cancer patients. Despite ambiguity in the exact mechanism, infection-mediated inflammation may have a link to cancer development through an accumulation of potentially mutagenic DNA damage in surrounding cells. The multiple DNA repair pathways such as base excision, nucleotide excision, and mismatch repair that are employed by cells are vital in the abatement of accumulated mutations that can lead to carcinogenesis. For this reason, understanding the role of DNA repair as an important cellular mechanism in combatting the development of cancer will be essential to characterizing the effect of infection on DNA repair proteins and to identifying early cancer biomarkers that may be targeted for cancer therapies and treatments.Pathogenic and commensal microbes induce various levels of inflammation and metabolic disease in the host. Inflammation caused by infection leads to increased production of reactive oxygen species (ROS) and subsequent oxidative DNA damage. These in turn cause further inflammation and exacerbation of DNA damage, and pose a risk for cancer development.  The significance of cancer as a disease that affects a large percentage of the world population is undeniable. It is one of the leading causes of death worldwide and according to World Health Organization, it causes 8–9 million deaths/year. In the United States alone, it is projected that 39.6% of the population will have some type of cancer during their life. Consequently, there are enormous expenditures in the field of cancer care. The expenditures for cancer care in the United States were nearly $125 billion in 2010 and could reach $156 billion in 2020; as mentioned in the website of National Cancer Institute. Infection and infection-associated inflammation is the major threat of cancer. Chronic inflammation from infection causes abnormal immune response, obesity, DNA damage and cancer. The best example is the inflammatory bowel disease where Ulcerative colitis and Crohn's disease develop colon cancer.Helicobacter pylori (gastric cancers), hepatitis B and C viruses (hepatic cancers), and Fusobacterium (Colon cancer). The detailed list of microbes that have been researched in relation to their effect on certain DNA repair proteins are added in the Table In 1863, Rudolf Virchow was the first scientist to link inflammation with cancer. He mentioned that the origin of cancer was at sites of chronic inflammation and a group of irritants with tissue injury causes cell proliferation  of innate immune system . The inflammatory cytokines have been reported to generate ROS and reactive nitrogen intermediates (RNI) using NADPH oxidase in phagocytic cells and epithelial cells  directly induces DNA damage. The versatility of different ROS is reflected in the wide array of DNA damage that they can cause. In general, the hydroxyl molecule (OH−) is the most damaging form of ROS, but other forms like the oxygen molecule (O2), RO2, and RO are also capable of different types of damage. For instance, while OH− can react with all of the bases and the deoxyribose backbone of DNA, O2 preferentially targets guanine residues  that inflict damage on the host DNA such as DNA strand breaks that may affect tumor suppressors or oncogenes . The MMR, BER, and NER pathways respond to specific lesions in DNA residues. DSBs are particularly dangerous lesion and are repaired by two principal pathways: NHEJ pathway functions in all phases of the cell cycle, while the high-fidelity HR pathway requires a template for repair and utilizes available sister chromatids during the S and G2 phases of the cell cycle.Nucleotide excision repair, or NER, is a versatile repair pathway that recognizes bulky adducts and general base lesions that cause a distortion of the double-helix structure of DNA. The major sources of these types of DNA damage are ultraviolet radiation and various types of genotoxic chemicals  and transcription-coupled repair (TC-NER) pathways. In GG-NER, DNA damage is removed from the whole genome while TC-NER is primarily involved in repairing the damage on the coding strand of actively transcribed genes  is now considered a specialized sub-pathway of BER. They share several common proteins including APE1, Polβ, LIGIIIα, along with the nick sensor poly (ADP-ribose) polymerase 1 (PARP1) and the scaffold protein X-ray cross-complementation group 1 (XRCC1) . On the other hand, the mammalian bifunctional DNA glycosylases have an associated AP lyase activity generating 3′dRP  or 3′-P (NEIL1 and 2) and 5′-P. The DNA polymerase then fills in the gap using the template DNA strand and finally, DNA ligase seals the nick by completing the repair of the DNA duplex , RAD50, and NBS1 recruits ATM (ataxia telangiectasia mutated), generates DNA breaks followed by phosphorylation of histone H2AX (generating γH2AX) that amplifies the damage signal  and generate DSBs that ultimately progress to gastro-intestinal cancer  and Colibactin. Cdt is present in There are multiple mechanisms for bacterial infections to induce cancer, and we focused gastric cancer and colon cancer here. Further studies in this arena will give more in depth insight to the mechanisms of association between specific bacterial infections and cancers, but in the next section we will discuss the well-known and characterized bacterial-infection associated cancers especially through the lens of ROS induced DNA damage and alteration of DNA repair pathways.Chlamydia pneumonia and Mycobacterium tuberculosis  and failure in these bring DNA damage/mutation and genomic instability. Microbial infection is one of the major reasons of the failure of DDRs.Microbes such as bacteria, virus and parasites are able to activate or alter various signaling pathways that may lead to either activation of oncogenes or down-regulation of tumor suppressor genes in a contribution to cancer progression   is able to bind E-cadherin to induce greater β-catenin release and ultimately activate WNT signaling, which is oncogenic  and outer inflammatory protein A (OipA) are involved in epidermal growth factor receptor activation which leads to PI3K-AKT signaling and ultimately activates β-catenin , the major pathway that repairs small-scale mutations such as single base pair mismatches, is inhibited (Kim et al., H. pylori infection. Additional MMR proteins MLH1, MSH3, MSH6, PMS1, and PMS2 have also been shown to be down-regulated upon H. pylori infection of gastric cell lines AGS and BG (Machado et al., H. pylori infection are supposed to be repaired by the BER pathway in a normally functioning cell. In a cell infected with H. pylori, there is decreased expression of vital BER proteins. APE-1, an AP endonuclease, and YB-1, an early-stage repair protein of BER, are down-regulated upon H. pylori infection (Machado et al., H. pylori infection. Reduced expression of OGG1 allows for accumulation of abasic sites that would not be repaired by the other DNA repair pathways and lead to carcinogenic mutation-build up and cellular transformation (Kidane et al., An accumulation of DNA damage caused by chronic inflammation and resulting ROS has the potential to induce cellular transformation. In a normally functioning cell, the multiple DNA repair pathways are able to curb the accumulation of DNA mutations by addressing the damage as it occurs. In a cell infected by H. pylori induced gastric cancer has been. Certain pathogenic species such as enterotoxigenic Bacteroides fragilis and Escherichia coli strain NC101 have been linked to colitis-associated colon cancer (Wu et al., The association between bacterial infection and colon cancer has not been elucidated to the extent that Fusobacterium nucleatum in abundance in colorectal tumor tissues (Kostic et al., F. nucleatum is a gram-negative microbe more often associated with the oral cavity. However, the bacterial species have been identified in the early stages of cancer in colorectal adenomas as well as carcinoma samples (McCoy et al., F. nucleatum to mice was shown to speed up colonic tumorigenesis and induce a pro-inflammatory state through NF-κB signaling (Kostic et al., F. nucleatum has also been positively correlated with mortality linked to colorectal cancer, meaning that greater abundance of the bacteria more likely resulted in mortality due to the cancer (Mima et al., F. nucleatum is a causative agent in colorectal carcinogenesis, but the preliminary studies have indicated the involvement of bacteria in the induction of cancer (Ray, One area of interest in this field is the presence of cer Ray, .F. nucleatum is a very invasive bacterial species due to its ability to adhere well to mucous surfaces (McCoy et al., F. nucleatum can therefore act similar to H. pylori and adhere to host cell surfaces to alter cellular pathways with its bacterial proteins. Once F. nucleatum adheres to host cells, bacterial FadA adhesin binds E-cadherin to activate β-catenin signaling to increase cell growth and proliferation as well as to regulate inflammatory response of the cell (Rubinstein et al., F. nucleatum has also been found to activate TLR4 and ultimately lead to NF-κB activation (Yang et al., F. nucleatum to a pro-inflammatory state (Kostic et al., F. nucleatum in the colon (Rubinstein et al., F. nucleatum contributing to carcinogenesis and tumorigenesis by inducing genetic mutations as a result of prolonged inflammation and potentially the down-regulation of various DNA repair pathways, similar to what occurs in H. pylori-mediated inflammation leading to gastric cancer.In the oral cavity, H. pylori and Fusobacterium, Salmonella typhi infection has been associated with the development of gallbladder cancer (Mager, Other bacteria associated cancers: Other that r Mager, . All othHelicobacter pylori infection correlated to a lower risk for esophageal cancer development (de Martel et al., Streptococcus pyogenes and Serratia marcescens in the late 1800's to induce an initial fever followed by treatment for many different types of cancers (de Martel et al., Salmonella enterica serovar Typhi reduced tumor growth and enhanced survival in mice (Vendrell et al., Mycobacterium bovis, is used clinically for the treatment of high-risk urinary bladder cancer (Kucerova and Cervinkova, While a number of bacterial infections have been shown to increase the potential for carcinogenesis, recent developments in the field have provided evidence for a positive role of certain bacteria and toxins in cancer prevention and therapy Mager, . For exaH. pylori, Hepatitis B and C virus, and Human papilloma virus (Mantovani et al., F. nucleatum and colorectal cancer, on the functionality of the various DNA repair pathways, can lead to novel identification of various markers for early cancer detection as well as more effective therapies and treatments that can combat the loss in DNA repair function in host cells.About 20% of the global cancer burden is linked to infectious agents including, but not limited to, All authors listed, have made 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.


In this mini-review we discuss the biological characteristics of studied material  and its handling  which influence results of histochemical staining with “classical” fluorochromes. Future perspectives of ROS and RNS imaging with newly designed probes are briefly outlined.Developmental transitions and stress reactions in both eukaryotes and prokaryotes are tightly linked with fast and localized modifications in concentrations of reactive oxygen and nitrogen species (ROS and RNS). Fluorescent microscopic analyses are widely applied to detect localized production of ROS and RNS  Quite recently, peroxynitrite (formed upon NO reaction with superoxide anion) was shown as a positive regulator of plant cell signaling by tyrosine nitration in proteins  are generated and scavenged over the whole life span of all known types of aerobic organisms. In plants and fungi production of ROS, together with reactive nitrogen species (RNS), has been linked with almost all developmental processes from germination through reproduction until cell death Asada, . ROS andArabidopsis research. Cell-permeable fluorescence-based probes were subsequently introduced to detect tiny real-time changes in ROS and RNS levels within relevant cellular compartments, e.g., DCF DA and DHDCF DA for detection of ROS , proper sample washing, keeping constant time of staining/scanning within a set of experiments, using optimal pH and turgor pressure can contribute to obtaining of correct results. Still it should be emphasized that histochemical staining and subsequent microscopic detection cannot be used for accurate ROS/RNS quantification but the combinations of several different analytical methods can give more reliable estimation of their intracellular levels  for hydrogen peroxide , hydatodes (at leaf edge), or nectaria (in flowers) can enhance the introduction of fluorochromes into the living tissues of above-ground plant organs. The fluorochromes uptake in multicellular organs can thus be enhanced by increased external or decreased internal pressure, e.g., by syringe or vacuum infiltration, respectively (Figure Optimization of staining procedures for different photosynthetic and fungal organisms in our laboratory showed that results of ROS/RNS imaging in multicellular biological matrices are significantly influenced by the feasibility of material infiltration with the applied probes Figure . Currenty Figure . Moreovey Figure  but sevey Figure .in vivo patterns of ROS and RNS abundance within plant organs and meristems. Newly synthesized probes with increased specificity and improved photostability have been reported, such as Aarhus Sensor Green preferable to SOSG for singlet oxygen (Pedersen et al., Arabidopsis, both on cultured cells and on leaves (Ledoux et al., 2O2 endogenously produced in living macrophages (Yuan et al., Recognized drawbacks of commercially available fluorescence probes for ROS and RNS detection initiated a quest for improved tools to measure more accurately the differential 2O2 with good selectivity based on intramolecular charge transfer (Chen et al., in vitro. However, the “classical fluorescent probes” based mainly on diaminofluorescein derivatives, still represent important tools to study ROS and RNS in plant science (Nie et al., 2O2, peroxalate esters, and fluorescent dyes as published for in vivo imaging of H2O2 in mouse model (Lee et al., Fluorescein derivatives have become replaced in animal ROS and RNS research by more specific molecular probes based on nanoparticles or redox-sensitive fluorescent proteins (for review see Guo et al., in vivo monitoring. The situation resembles a “population bottle-neck”; only a reduced number of protocols are applicable to ROS and RNS microscopy in plant and fungal models and thus these few remain fixed in routine practice for a substantial period. With increasing knowledge on the importance of localized and tiny intracellular redox fluctuations the quantitative and spatio-temporal analysis of ROS and RNS levels in plant and fungal cells is still highly challenging.Although, a plethora of ROS and RNS sensing molecules have been designed, just a part of them has been confirmed experimentally to be suitable for ROS and RNS MS prepared manuscript based on long-lasting discussions and joint experiments with LL, it was approved and widely discussed by both authors.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.


One rationale for the frequent use of MgSO4 in critical care is the high incidence of hypomagnesaemia in intensive care unit (ICU) patients. Correction of hypomagnesaemia along with the neuroprotective properties of MgSO4 has generated a wide application for MgSO4 in ICU.Magnesium (Mg) has been developed as a drug with various clinical uses. Mg is a key cation in physiological processes, and the homeostasis of this cation is crucial for the normal function of body organs. Magnesium sulfate (MgSO Magnesium (Mg) is one of the most abundant cations in the body, and is also a drug with numerous clinical applications. The body usually contains up to 28 g of Mg . Most ovia regulating intracellular calcium availability . Magnesani, 2011). Calciuani, 2011; Noronhaani, 2011). Influx and efflux of Mg plays an important role in different transcellular transports . MagnesOne of the key reasons for the wide use of Mg in critical care is the high prevalence of hypomagnesaemia in ICU patients  reduction of intestinal absorption of Mg, (2) increased loss of Mgbyrenal route, and (3) compartmental redistribution . The moIntravenous Mg supplementation rapidly increases serum Mg level following long-term use of PPIs and subsequent hypomagnesaemia. PPIs affect intestinal epithelial cell locally. Oral Mg is not effective in PPI's induced hypomagnesaemia. Discontinuation of PPI use will resultsin quick normalization of serum Mg levels , post-renal transplantation and drug-induced Mg wasting  are reasons for renal Mg loss . These Numerous roles for magnesium in critical care medicine have been suggested . Defici4) was used to prevent eclamptic seizures in Germany . Magnesal., 1985). MgSO4 hak, 2002; Ignatavhak, 2002). A numbhak, 2002; Gonzalehak, 2002). Hypomahak, 2002). MgSO4 ard, 1925; Pritchaard, 1925), and coNumerous mechanisms of action have been suggested for magnesium including 1) vasodilatory action, (2) blood-brain barrier (BBB) protection, (3) reduction of cerebral edema, and (4) central anticonvulsant action .4 as a treatment option for patients who are resistant to standard therapy , agonists of β2-receptors, inhaled ipratropium bromide, corticosteroids, anticholinergic drugs and general managements . Researal., 2008; Gontijoal., 2008; Jones aal., 2008; Kew et al., 2008). Life-tal., 2000; Daengsual., 2000; Griffital., 2000; Kew et al., 2000; Kokturkal., 2000; Rowe, 2al., 2000; Rowe anal., 2000; Rower eal., 2000; Singh eal., 2000).+-Ca2+ pumps), (2) muscle relaxation , (3) reduction of inflammatory mediators (inhibition of degranulation of mast cells and T-cells stabilization), (4) depression of the irritability of muscle fibers, and (5) inhibition of prostacyclin and nitric oxide synthesis. These mechanisms lead to a reduction in the severity of asthma  reduction of intracellular calcium level .4 is used via intravenous and inhalation routes for the management of acute asthma  and peak expiratory flow rate (PEFR) were assessed in different clinical trials . Use ofal., 2000; Daengsual., 2000; Griffital., 2000; Kew et al., 2000; Kokturkal., 2000; Rowe, 2al., 2000; Rowe anal., 2000; Rower eal., 2000; Singh eal., 2000). In somnes, 2008). Unlikeal., 2000, 1996[29al., 2000; Porter al., 2000; Scarfonal., 2000). The imal., 2002; Boonyaval., 2002; Devi etal., 2002; Gallegoal., 2002; Green aal., 2002; Hughes al., 2002; Mahajanal., 2002; Silvermal., 2002; Tiffanyal., 2002). In chial., 2013; Liu et al., 2013). Up to al., 2013; Devi etal., 2013; Green aal., 2013; Singh eal., 2013; Tiffanyal., 2013). Howeveal., 2006; Gallegoal., 2006; Gandia al., 2006; Hill etal., 2006; Hughes al., 2006; Kokturkal., 2006; Mangat al., 2006; Nanninial., 2006; Nanninial., 2006; Rolla eal., 2006; Zandsteal., 2006). Respiral., 2006; Gandia al., 2006; Hill etal., 2006; Mangat al., 2006; Nanninial., 2006; Nanninial., 2006; Rolla eal., 2006; Zandsteal., 2006). In oneal., 2013). In 201al., 2016). In chial., 2016). Adversott, 2008). 4 has been well documented to be beneficial in the management of nervous system injuries especially in the ICU. These injuries include stroke, aneurysmal subarachnoid hemorrhage (ASAH), and traumatic brain injuries . 4 in ASAH in the last two decades  velocity and Glasgow Outcome Scale (GOS). The findings showed better outcome in patients with ASAH 90 days post-hemorrhage, but they did not find a significant difference in GOS between the control and treatment groups . Differal., 2002). Also, al., 2002) showed ues (2005) revealeal., 2006). High dal., 2008). MgSO4 al., 2013; Chen anal., 2013; Westermal., 2013). Despital., 2009; Wong etal., 2009). Friedlal., 2009) reporte4 24 hours post-stroke shows a significant decrease in the infarct volume based on the findings of MRI . Saver al., 2009). In theal., 2002). Singh al., 2002) showed al., 2013). It wasal., 2006). Concural., 2012; Zhu et al., 2012).4 on biomarkers in different neuropathies has been assessed in several studies . MgSO4 al., 2012). The inal., 2012; Mirrahial., 2012). The deal., 2012). S100B al., 2012; Lamers al., 2012). Increaal., 2012; Mizukosal., 2012). Increaal., 2012). 4 decreases inflammatory biomarkers such as nitric oxide, prostaglandin E2, interleukin 1β and tumor necrosis factor-α . Concural., 2013; Ovbiageal., 2013).TBI is an important health problem with high a mortality and morbidity rate . StudieNumerous studies have reported that Mg plays an important role in the prevention and treatment of central nervous system (CNS) injuries. Magnesium protects neurons from ischemic injuries and supports neuronal survival following TBI with different mechanisms such as: (1) blocking NMDA channels, (2) inhibition of presynaptic excitatory neurotransmitters, (3) inhibition of voltage-gated calcium channels, and (4) potentiation of presynaptic adenosine. Moreover, Mg can relax vascular smooth muscles and enhance cerebral blood flow. Serum total and ionized Mg levels are reduced after head injuries  .4 in diffuse axonal injury has been shown by Zhao et al. . The inal. (2016). The pral. (2016). The moal. (2016). 4 cannot improve the strength of respiratory muscles in the critically ill patients under mechanical ventilation . Serum al., 1993). The noal., 1993).4 is an important drug in the ICU. MgSO4 can increase brain tissue oxygenation index by 34 % after cerebral artery occlusion . As staal., 2005). Electrolyte imbalance following hypomagnesaemia has been reported by researchers in the ICU , coronary artery bypass surgery and heart valve surgeries . Kaplanal., 2003). Concural., 2012). In subal., 2012). Adminial., 2013).4 as a neuroprotective agent, current evidence suggests that MgSO4 is an important part of the management of ICU patients (Table 14 therapy in the ICU, serum Mg levels should be checked on a daily basis.Despite the controversial views on the effects of MgSOs Table 1. (RefereThe authors have no competing interests to declare.


Editorial on the Research TopicHomeostasis and Allostasis of Thyroid FunctionA basic understanding of thyroid control involving pituitary thyrotropin (TSH) has become a cornerstone for the contemporary diagnosis of thyroid disorders. However, long-held simplistic interpretations of the classical feedback concept fall short of the elusive goal of a universally applicable and reliable diagnostic test. Diagnostic ambiguities may arise from the dynamic nature of thyroid homeostasis. Concentrations of TSH and T3 are governed by circadian  and, addConsequently, the clinical care of thyroid patients faces major challenges, foremost ill-defined reference ranges for TSH and thyroid hormones (THs), and persistently poor quality of life in a substantial subset of treated hypothyroid patients . Divergestability through change by modifying setpoints and parameters of feedback control  provides an overview of homeostatic mechanisms in the light of recent research. The classical “short feedback” structure (Astwood-Hoskins loop) (A review article by the editors (ns loop)  is now cns loop) , 18, thens loop) –23.Hoermann et al.; .Newly identified non-classical processing structures add to the complexity of the control system. They explain both pulsatile thyrotropin release and significant deviations from a log-linear relationship between FT4 and TSH concentrations . In  et al.; , therebyrelational stability [Hoermann et al.; .The novel clinical concepts feed back to theory. ” models –35, demoLeow, extending implications to antithyroid treatment and LT4 substitution.Interpretation of thyroid function tests can be severely affected by homeostatic time constants resulting in hysteresis effects , as reviAlthough sensitive for primary hypothyroidism, TSH measurement has low specificity and is unable to detect dysfunctions of central origin. Isolated TSH measurements may be misleading in certain physiological  and alloDietrich et al.) for novel diagnostic approaches based on mathematical modeling, such as functional thyroid reserve capacity and step-up deiodinase activity. These calculated parameters deliver estimates for “hidden” structure parameters of thyroid homeostasis and provide early indicators of thyroid failure. Reconstructing the individual equilibrium point  of thyroid homeostasis is facilitated by new tools and may prove useful as a personal target for L-T4 dosage titration , e.g., for therapy of stroke or in long-lasting space flights. Based on its pleiotropic effects they question if 3-T1AM can be a safe cryogenic drug. Some of the inconsistencies in reported serum concentrations may result from plasma protein binding, potential role of gut microbiota in the formation of thyronamines from iodothyronines or conversion of 3-T1AM to 3-iodothyroacetic acid (3-TA1), a possible major mediator of thyronaminergic signaling .The traditional view of pituitary–thyroid feedback control holding T4 plasma concentration constant close to a fixed set point  has beenHoermann et al.).Deeper insights in the physiology of thyroid function and its homeostatic control warrant a rethinking of diagnostic practice. The old paradigm employing TSH in the center of diagnostic work-up has to be replaced by a relational concept, where TSH is interlocked with FT4 and FT3, and multivariable distributions represent homeostatic equilibria , 30. ThiJD, JM, and RH wrote some of the papers in this Research Topic and participated as guest editors for manuscripts, where they were not coauthors themselves. All authors listed have made a substantial, direct, and intellectual contribution to this editorial and approved it for publication.JD received funding and personal fees by Sanofi-Henning, Hexal AG, Bristol-Myers Squibb, and Pfizer and is co-owner of the intellectual property rights for the patent “System and Method for Deriving Parameters for Homeostatic Feedback Control of an Individual” . All other authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.


We recently elucidated several misperceptions in a field related to toxin/antitoxin (TA) systems, persister cell biology  field, born of controversy, is plagued by several prevailing misperceptions. For example, some TA systems stabilize plasmids and other genomic regions; however, the evidence of post-segregational killing by toxins of TA systems is weak. In addition, the evidence is weak for cell death via TA systems like MazF/MazE and weak for TA systems mediating death in phage exclusion systems. Although many aspects of the biological roles of TA systems remain enigmatic, there are now some clear, confirmed TA functions: (i) phage inhibition, (ii) plasmid maintenance, (iii) stress response (including regulation of loci distinct from the TA pair itself), (iv) biofilm formation, and (v) persistence. Therefore, this opinion piece aims to challenge the oft-repeated claims of cell killing related to TA systems with the goal of emphasizing their primary biological role: constraining metabolism in a reversible manner. Hence, their roles in their five confirmed functions all stem from their ability to rapidly and reversibly reduce metabolic activity.Historically, TA systems were deemed cytosolic (not secreted); hence, TA system toxins were considered primarily to affect the metabolism of the host that produced the TA system rather than as serving as a weapon against other cells, such as colicins , regardless of the gene order. In addition, we prefer naming the antitoxin with four letters ending with an “A” , where possible, to more readily identify the antitoxin.How TA systems are classified is also evolving and is based on the mechanisms by with antitoxins mask toxin activity. There are six well-established systems , was discovered in 1983, and was shown to maintain a mini-F plasmid , that also stabilized a plasmid (R1) , and R1 plasmids  have a copy number of 6  are also suspect. For example, although roughly 80% of vegetative Myxococcus xanthus cells undergo PCD during nutrient-limiting development , it was claimed that MazF mediated this killing  has been proposed as a quorum-sensing element for E. coli type I TA system Hok/Sok inhibits T4 phage propagation  was an “antitoxin” .Even this year it has been written that “the biological roles of many TA modules still remain elusive”  eliminating nearly all mRMA via toxin MqsR cleaving 5′-GCU sites and (ii) reducing ATP via toxin GhoT  and thereby reduces the translation of the RpoS transcript (Hu et al., S. aureus, the SavS/SavR TA system silences the virulence genes hla and efb by binding their promoters (Wen et al., This role of antitoxins controlling more than their own promoter was confirmed by antitoxin DinJ of the In addition, the TisB/IstR-1 type I TA system has been shown to have the physiological role of producing persister cells when the cell is stressed by ciprofloxacin (Dörr et al., mqsRA is not governed by conditional cooperativity (Brown et al., E. coli YafQ/DinJ TA system (Ruangprasert et al., Yersinia pestis HicA3/HicB3 TA system (Bibi-Triki et al., Proteus vulgaris HigB-HigA TA system (Schureck et al., It is frequently indicated that conditional cooperativity is the prevalent form of type II TA system regulation (Harms et al., Charles Darwin emphasized the importance of natural selection for beneficial mutations; i.e., changes that lead to improved reproduction will become dominant Darwin, . For bacTW conceived and wrote the manuscript. SS helped write the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Evidence from experimental and clinical studies have shown that oxidative/nitrosative stress and inflammation associated with metabolic disorders such as obesity, hypertension, and diabetes conduce to left ventricular hypertrophy, fibrosis, diastolic dysfunction, heart failure, and ischemia/reperfusion damage , 2.κB, are shown. Information in this issue also includes findings on the relationship between ROS and the activation/maturation of dendritic cells (DCs) that might trigger cardiovascular and metabolic pathologies.In this special issue, original researches on the causative effect of oxidative stress and inflammation on pathologies such as mitral valve prolapse (MVP), arteriosclerosis, hypertension, and ischemia/reperfusion (IR) injury are presented. Also, the evidence of the effect of NLRP3-inflammasome and reactive oxygen species (ROS) production by Ca2+ overload on mitochondrial function, along with the demonstration of the regulatory properties of MG132, demetoxicurcumin, and lycopene on signaling pathways that activate either nuclear factor E2-related factor 2 (Nrf2) or NFThe strong association between osteoprotegerin (OPG) levels and oxidative stress status in patients affected by MVP with severe regurgitation opens its possible use as a serum marker of this pathology according to P. Songia et al. On the other hand, R. Mastrocola et al. demonstrate that the inhibition of NLP3-inflammasome reduces IR injury by activating prosurvival RISK pathway and preserving mitochondrial function. This is interesting and is related to the article presented by Y. Oropeza-Alamazán et al., which demonstrates that silencing of MCU decreases ROS production and mitochondrial dysfunction induced by Ca2+ overload in reperfusion injury.Pharmacological regulation of oxidative stress and inflammation is also included in this special issue. Y. Li et al. demonstrated that the downregulation of cyclooxygenase (COX-2) by demethoxycurcumin (DMC) favors nitric oxide (NO) production via e-NOS activation, preventing endothelial dysfunction, whereas L. Kong et al. demonstrated that MG132 administration inhibits Nrf2 and IkB proteolysis via the proteasome, preventing endothelial dysfunction associated with cardiovascular disease in animals with diabetic nephropathy. The antioxidant and anti-inflammatory properties of lycopene are shown to be related with the downregulation of Rho-associated kinases and the activation of key factor expression in the study described by Y. He et al., who propose that this compound might by a potentially effective method for transplant arteriosclerosis in clinical organ transplantation. Finally, J. Stein et al. show that Nox2-derivated oxidative stress and PKC activation play relevant roles in DCs activation and the atherothrombotic processes that might impinge on cardiovascular and metabolic pathologies.We hope that the research articles included in this issue contribute to the understanding of mechanisms related to the development of cardiovascular diseases and increase the possibility to find novel specific markers and the proposal of new potential therapeutic treatment with the use of new drugs that regulated pathway risk related with the trigger of cardiovascular disease.


Recently, Mikheil Gogiashvili and colleagues from TU-Dortmund have published a study about the metabolomics heterogeneity of breast cancer . The ba1H NMR are still relatively rare in breast cancer. Therefore, the present study of Gogiashvili and colleagues represents an important milestone in this field of research. Currently, the majority of prognostic studies with cancer patients has been performed based on mRNA (Grinberg et al., 2017; 20159]9]; March


Studies in behavioral economics have shown that social punishment can explain why genetically unrelated individuals are often able to maintain high levels of socially beneficial cooperation  and parties that are financially unaffected (“third parties” —TPP)  and mentalizing  brain regions in TPP (Baumgartner et al., Pioneering behavioral studies have showed that strong emotions trigger the willingness to punish norm violators (Hirshleifer, Recently, Krueger and Hoffman  reviewedInterestingly, these three networks partially overlap with those underlying the detection of norm violations in other social contexts. There is a growing cognitive neuroscience literature on a neural mechanism that detects when individual behavior or beliefs differ from those of others (for reviews, see Izuma, However, amygdala activity was reported only in SPP and TPP studies (Buckholtz et al., Interestingly, TPJ activity during TPP is paralleled by an initial deactivation of the DLPFC (Buckholtz et al., These recent findings raise intriguing and testable questions for future research, e.g., in the use non-invasive brain stimulation to further verify fMRI findings. There is evidence suggesting that transcranial current stimulation could effectively modulate within- and between-network interactions. For example, transcranial alternating current stimulation induced oscillatory desynchronization between the medial frontal and parietal cortices and, therefore, affected value-based decisions but not closely matched perceptual decisions (Polanía et al., All authors listed have made 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.


The IL-23/IL-23R is critical for pathogenic inflammatory Th17 cell differentiation. Experimental data in murine models of arthritis, colitis and encephalomyelitis corroborate these findings. This manuscript reviews the current knowledge on the effects of sodium chloride on innate and adaptive immunity. We also performed a systematic literature review for clinical studies examining the relationships between salt consumption and the development or the activity/severity of the most common IMDs mediated by the IL-23/Th17 pathway, i.e., rheumatoid arthritis (RA), multiple sclerosis (MS), and Crohn's disease (CD). Nine studies were found, 4 in RA, 4 in MS and 1 in CD. An association was found between developments of anti-citrullinated protein antibody (ACPA) positive RA in smokers and salt intake, but these results were not confirmed in another study. For MS, no association was observed in pediatric subjects while in adult patients, a link was found between salt intake and disease activity. However, this result was not confirmed in another study. These conflicting results highlight the fact that further evaluation in human IMDs is required. Moreover, physicians need to develop clinical trials with diet interventions to evaluate the impact of low salt intake on disease activity/severity of IMDs.Immune mediated diseases (IMDs) are complex chronic inflammatory diseases involving genetic and environmental factors. Salt intake has been proposed as a diet factor that can influence the immune response. Indeed, experimental data report the influence of sodium chloride on the differentiation of naive CD4 Immune-mediated diseases (IMDs) are complex chronic inflammatory disorders involving the contribution of different predisposing factors. Indeed, both specific genetic backgrounds and environmental factors participate in their pathogenesis. Environmental factors have been implicated according to the prevalence of these diseases in certain countries or geographical areas, and/or through exposure of the population to local factors, but lifestyle habits as well as diet are also involved. The most common IMDs are type I diabetes, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), psoriasis, multiple sclerosis (MS), and inflammatory bowel diseases, such as Crohn's disease (CD). Contributing environmental factors are specific for each IMD, and for instance, smoking is a well identified factor for the development of RA or CD, while ultraviolet exposure is involved in SLE. The influence of diet has long been suspected as a contributing pathogenic factor for IMD. For instance, a Mediterranean diet is thought to influence the occurrence of RA  immune cells. For instance, sodium chloride favored the polarization of pathogenic CD4+ T cells toward a T helper 17 (Th17) phenotype , and especially ILC3 cells, and mucosal-associated invariant T (MAIT) cells  transcription factor . IL-23 has the capacity to induce and maintain the expression of SGK1 in Th17 cells. Using protein-protein interaction analysis from a large database, FOXO1 was identified as a transcriptional factor that had a downstream role in the expression of SGK1. SGK1 promoted phosphorylation of FOXO1, which led to reduced FOXO1 activity and increased IL23r mRNA expression and induction of RORγt, a major regulator of Th17 differentiation  when cultured in a hypertonic milieu  has also been reported in normal subjects who have a high salt diet . Finally in a case-control study, sodium intake as evaluated by 24 h urinary sodium excretion was found to be increased in a small cohort of patients with early RA  in the colon (Aguiar et al., IL-10 deficient mice that were exposed to a high-salt diet developed also a more severe spontaneous colitis (Tubbs et al., Normal intestinal lamina propria mononuclear cells—extracted from macroscopically and microscopically unaffected colonic samples of 9 patients undergoing resection for cancer colon- express high quantities of IL-17A, IL-23R, TNF-α, and RORγt when exposed to increasing concentrations of sodium chloride (Monteleone et al., One study examined the relationship between salt consumption and CD (Khalili et al., + T cells markedly infiltrated the central nervous system (Kleinewietfeld et al., In EAE, mice that were fed with a high salt diet developed more severe disease. High salt consumption also accelerated the onset of disease. In this setting, IL-17A expressing CD4Our literature search found 4 papers analysing the effect of dietary salt in MS, namely 2 in adult patients and 2 others in pediatric subjects (Farez et al., We found neither experimental nor clinical data examining the relationship between salt consumption and psoriasis.via IL-23R promotion. Indeed, the studies by Wu et al. and Kleinewietfeld et al. both reported that an increased salt concentration promotes Th17 differentiation by SGK1 involvement (Capon et al., Sodium is an essential nutrient for the organism and is a major physiologic player. The description of its role as an environmental factor in inflammation, and especially in IMDs comes from several reports Arora, . Indeed,Lactobacillus murinus. Treatment of mice with L. murinus prevented salt-induced aggravation of actively-induced EAE by modulating Th17 cells. A moderate high-salt intervention in a pilot study in humans reduced intestinal survival of Lactobacillus spp. and increased Th17 cells. These results indicate that high salt intake is connected to the gut-immune axis (Wilck et al., One question is the consequence of a high salt diet on the blood or lymph node compartments. Indeed, besides the hypertonic and vasopressive effects on blood pressure, a high salt diet does not induce a high concentration in the blood or lymph nodes (van der Meer and Netea, Besides sodium chloride, are other salt components involved in the induction of the Th17 lymphocyte subset? For instance, potassium has been reported to be a protective cation for CD (Khalili et al., SGK1 gene polymorphism is another genetic background that merits investigation, despite negative findings in RA (Jiang et al., Despite strong experimental reports, clinical studies did not report consensual results. Indeed, clinical evidence for the relationships between sodium consumption and development and/or activity/severity of IMDs is limited. Three studies reported such a link in the setting of RA (Sundström et al., The influence of the environment on the development and clinical expression of IMDs is an exciting and challenging issue. The role of sodium chloride in IMDs such as RA, CD, psoriasis and MS is a relevant question for the pathogenesis of these diseases but also for the management of patients. Current experimental data strongly support a link between salt intake and Th17 differentiation. However, the specific influence of dietary salt intake on the expression of IMDs in humans is still not demonstrated, and requires further studies, especially clinical trials with nutritional interventions aimed at comparing low vs. high salt diets. The interaction between salt and other environmental factors, as well as the genetic background, is a promising avenue for further research, in order to improve our understanding of the specific role of sodium chloride in the pathogenesis of IMDs.ET, MB, CV, and PS analyzed and discussed the literature and conceived the outline of the manuscript. ET and PS wrote the manuscript. All authors reviewed the manuscript and provided critical discussion and input.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.


Moreover, we measured the concentration of reduced and oxidized ascorbate and glutathione that are involved in ROS detoxification together with phenolics, anthocyanins and tocopherols. Among antioxidant enzymes, we analyzed the activities of ascorbate peroxidase , and the soluble and bound forms of polyphenol oxidase  and guaiacol peroxidase . The data reported in this paper are related to the research article “Metabolic characterization and antioxidant activity in sweet cherry (Prunus avium L.) Campania accessions”, authored by Mirto et al. (2018) In this article, we reported the original data obtained by the study of metabolites and enzymes involved in sweet cherry antioxidant system. We measured hydrogen peroxide (H Specifications TableValue of the data•The data show the antioxidant metabolites and enzyme activities measured in sweet cherries fruits.•The data highlight the differences among the different sweet cherries Campania accessions.•The data are useful to identify the accessions more suitable for long-term storage.1Selecting fruit accessions rich in antioxidant can help delaying fruit senescence and better preserving its characteristics during postharvest. To this aim, we investigated antioxidant metabolites level and antioxidant enzyme activities in forty-three accessions of sweet cherry fruits from Campania region 2O2), as well as malondialdehyde (MDA) of sweet cherry fruit accessions. MDA is considered a useful index of general lipid peroxidation and a biomarker for oxidative stress In 2 (PPO) or H2O2 (POD), and their subsequent, polymerization to melanin. This phenomenon known as enzymatic browning, that occurs during fruit storage In 2To identify the accessions which better resist to oxidative stress and, therefore, are more suitable for the long-term storage, sweet cherry fruits of forty-three accessions from Campania region were harvested and collected at commercial maturity, in the regional experimental farm “Improsta”, Eboli Campania, Italy . One additional commercial accession (Bigarreaux) and two commercial cultivars (Del Monte and Ferrovia) were used as reference. The data were obtained by biological triplicates, each one constituted by twenty fruits from five plants, analyzed separately. The fleshy part of fruits was cut, frozen in liquid nitrogen, and powdered -1. Hydrogen peroxide (H2O2) malondialdehyde (MDA) were assayed according to Woodrow et al. Reduced and oxidized ascorbate (AsA+DHA) and reduced and total (reduced plus oxidized) glutathione (GSH) were extracted and evaluated as described in Annunziata et al. o-tolidine, used as substrate. PPO analysis was performed using catechol as substrate. Ascorbate peroxidase  was extracted and assayed according to Hediye Sekmen et al. Enzyme activity analyses were performed by spectrophotometer assays. Polyphenol oxidase  and guaiacol peroxidase  were simultaneously extracted by a two-step extraction protocol, that allowed the separation of both soluble and membrane bound isoforms