Drug discovery is an expensive, long, and complex process, usually with a high degree of uncertainty. In order to improve the efficiency of drug development, effective methods are demanded to screen lead molecules and eliminate toxic compounds in the preclinical pipeline. Drug metabolism is crucial in determining the efficacy and potential side effects, mainly in the liver. Recently, the liver-on-a-chip (LoC) platform based on microfluidic technology has attracted widespread attention. LoC systems can be applied to predict drug metabolism and hepatotoxicity or to investigate PK/PD (pharmacokinetics/pharmacodynamics) performance when combined with other artificial organ-on-chips. This review discusses the liver physiological microenvironment simulated by LoC, especially the cell compositions and roles. We summarize the current methods of constructing LoC and the pharmacological and toxicological application of LoC in preclinical research. In conclusion, we also discussed the limitations of LoC in drug discovery and proposed a direction for improvement, which may provide an agenda for further research. Drug development is a long, costly, and highly uncertain process that usually takes 10–15 years ,3. It isOne of the primary areas of unfavorable medication effects is the liver, which also performs a significant role in drug metabolism. Thus, the liver can play a major part in assessing drug efficiency and safety in the preclinical stage. Consequently, establishing an in vitro liver model reproducing the liver microenvironment is conducive to understanding the preclinical research of drug development. The recently developed liver-on-a-chip (LoC) technology is innovative in managing the liver microenvironment in vitro, which allows the dynamic flow of cell medium over the cell environment with good robustness and reproducibility. The LoC system can also be integrated into the laboratory as preclinical tests to predict in vitro human experiments . MultiplAs the largest internal organ, the liver plays a crucial role in regulating the homeostasis of the internal environment, the anabolism of various substances, and the detoxification of endogenous and exogenous substances, especially in drug metabolism ,28. The Drug metabolism can be divided into oxidation, reduction, hydrolysis, and conjugation. Phase I metabolism includes oxidation, reduction, and hydrolysis, while phase II metabolism includes conjugation. Hepatocytes are rich in various enzymes required for phase I and phase II drug metabolism. Among them, cytochrome P450 (CYP450) enzymes are terminal oxygenases involved in nearly all phase I drug metabolism steps in the liver. CYP450 enzymes have apparent species differences, leading to many differences in metabolic pathways and metabolites of drugs between animals and humans. Polymorphisms are a critical feature of CYP450 and the fundamental reason for individual differences in drug response. In addition, CYP450 can be induced and inhibited; that is to say, drugs or other exogenous chemicals will alter the number and activity of CYP450, which may result in metabolic drug interactions.Hepatocytes, known as parenchymal cells, account for about 60% of liver cells . HepatocOn the micro-scale, the liver is a reticular structure with hepatic lobules as the functional liver unit. Lobules take the hepatic vein as the center and distribute layers of liver plates around. The liver sinusoid is the lacuna between adjacent liver plates with strong permeability. Blood is supplied to each lobule from hepatic arterioles and portal veins C. HepatoAs mentioned above, drug development requires in vitro liver models to investigate drug metabolism and other aspects. Typical models include 2D planar primary hepatocytes ,37, 3D pTraditional 2D culture of hepatocytes is easy to handle with low cost and plays an essential role in drug research, development, and cell biology. However, liver functions cannot be wholly reproduced because most hepatocytes will soon lose internal biochemical clues and cell–cell communication, leading to phenotypic changes. The rapid development of 3D printing liver tissue and constructing liver organoid technologies provides a viable strategy for in vitro liver models; however, they are also limited by insufficient accuracy or lack of spatial structure.With the ability to precisely control the culture environment at the micro-scale, microfluidics-based cell culture technologies have recently captured the most attention. It is assayed robust and replicates the hepatic microenvironment. Moreover, with the recent rise of nanomedicine in the application of vaccines, the LoC system can conduct abundant and accurate research on the toxicity of nanomedicines , making The reliability of the simulation effect of liver models is significantly affected by the source of the cells. Primary human hepatocytes (PHHs), primary animal cells, stem cell-derived hepatocytes, and immortalized liver cell lines are the main cell types used for liver tissue reconstruction in vitro.PHHs with good reproducibility in vitro maintained the metabolic function of the liver, mainly retained the enzyme level consistent with that in vivo, becoming the “gold standard” for drug tests and widely used in drug metabolism and toxicology research ,49,50. IAnimal-based testing has built an essential bridge between in vitro drug research and clinical trials, which is critical in drug safety research. In addition, since research animals are easily accessible commercially, they can be employed as sources of fresh primary cells without the limitation of donor shortage ,56. HoweImmortalized liver cell lines, which can be manipulated with unlimited proliferation by inhibiting cellular senescence ,59, are Hepatocytes derived from stem cells have emerged as a new source of liver cells in recent years . RegardiOverall, the physiological culture conditions of the liver models are strongly influenced by the source and kind of cells employed, such as the characteristics of primary hepatocytes, HepG2, and HepaRG cell lines mentioned above. In addition, many cells require sensitive environments, so rational in vitro liver model systems must provide these specialized environments in culture. Therefore, currently, the researchers turn to microfluidics to effectively control the culture microenvironment.Microfluidics is a downsizing of biological separation and analysis techniques with a high surface-to-volume ratio, automation, and integration ,72. The The initial static culture platforms inspired perfused devices to culture primary hepatocytes in vitro. In the first LoC reported in 2007 , microflThese rich designs and formats all have their strengths and weaknesses. In the experimental design for drug development, the focus should be on selecting the critical parameters needed, simplifying other aspects of the need. It is essential to seek clues from the in vivo liver environment and to be good at incorporating different types of platforms to achieve better results.Preclinical research of drug development refers to the safety and effectiveness testing of new active substances before human trials. The goal is to identify and exclude ineffective, toxic, or unqualified candidate drugs at each stage. In preclinical research, the significance of the LoC platform is to reduce or replace conventional mammalian models and conduct PK/PD prediction and toxicological safety research closer to the natural human environment.Currently, single-organ and multi-organ liver models are employed in drug metabolism research. The single LoC model focuses on the drug ADME  in the only liver. The multi-organ model examines how drugs react when different organs in the body interact with the liver, including how much of a drug is present in various organs and how metabolites affect other organs. The basis for the drug ADME is to improve the survival time and functional activity of cells in the LoC system. The widely accepted markers are albumin synthesis and urea secretion . It has The metabolism of drugs will be affected by inflammation. Severe inflammation will cause liver damage and even endanger life. Sarkar et al.  designedIn addition to predicting drug metabolism at the individual level, variability in the population can also be considered. Tsamandouras et al.  applied The failure of possible therapeutic candidates has been chiefly attributed to the toxicity of drugs and unidentified safety issues. Efficient identification of hepatotoxic compounds during preclinical drug development has important significance for drug development and prevention of liver injury. Prior to the invention of the LoC, primary isolated hepatocytes and immortalized cell lines were used in preclinical drug hepatotoxicity testing . Common The investigation of drug-induced liver injury (DILI) is one of the noteworthy focuses of drug development. Xiao, Rong Rong et al.  chose toAnother significance of LoC is to reduce the use of animal models and drug screening failures caused by physiological differences between species. Jang et al.  performeIntegrating the liver with other organs of humans to form body-on-a-chip can better imitate the real physiological organ networks in vivo and incorporate the organs’ interaction factors into the research of drug ADME. Common combinations include the liver, kidney, intestine, heart, and other organs on a chip .Given the significance of absorption and barrier functions of the small intestine in drug flow in vivo, Kimura et al.  integratThe kidney is the main organ for eliminating drugs. The metabolism of drugs in the kidney promotes the development of drug-targeting tissue distribution systems, and drug-targeting tissue distribution can avoid some side effects of drugs. Liu et al.  publisheAnother crucial topic that needs to be investigated in drug metabolism studies is drug–drug interactions (DDIs), which occur when the ADME properties of one pharmacological are affected by the concurrent administration of another drug component. In clinical practice, tumor patients are prone to DDI due to their frequent medication use and narrow treatment index of anticancer drugs. Therefore, Lohasz et al.  selectedIn addition to detecting the DDI phenomenon directly, we also seek to comprehend the pharmacokinetics of DDI in detail, developing more practical methods for DDI prediction. Kenta et al.  combinedThe advances described above demonstrate that drug discovery using microfluidic platforms can be more productive than traditional methods. Both single liver-on-a-chip and multi-organs-on-chip models have numerous advantages for the drug metabolism simulation and toxicity test stage of preclinical studies. Compared with 2D culture and static culture, a dynamic 3D culture platform with microfluidic significantly extends the duration of cellular activity in vitro, providing a solid foundation for drug testing. Adding related chemicals increases the activities and drug sensitivity of cells or tissues, sometimes even outperforming newly obtained hepatocytes. The LoC platform is more effective than most in vitro physiological systems at simulating the natural liver environment, leading to an accurate recreation of the results of many previous drug tests ,94,95.In contrast to organoids, microfluidic systems will not change shape over time and have strong repeatability and controllability, making them ideal for large-scale preclinical drug screening and testing . In addiAt present, however, liver chips cannot replace animal models completely. Researchers often use organ chips to reproduce key drug-related events when they observe them in animals. The controllability and reproducibility of liver chips are very useful for studying the details of candidate drug compounds and long-term repeated treatment issues. Although animal models must deal with the cost problem, the complex components and manufacturing technology required by liver chips cannot avoid the cost issue. Complexity limits the large-scale manufacturing of liver chips, increases the cost of operation training, and limits the development of high-throughput automation. Meanwhile, there are also crucial problems in the physiological simulation of liver microarray, such as the cell source being closely related to the physiological relevance of the physiological model. PHHs are still the best choice at present. The microfluidic technology can prolong their active time in vitro, but the donor supplies are limited. The current trend is to replace PHHs with inexpensive, highly differentiating iPSCs ,100,101.In addition, this new technology with complex functions is difficult to match the commonly used microscope imaging methods. Manual positioning and manipulation of organ chips for image acquisition are variable and time-consuming, and the amount of data is limited . NeverthIn the long run, compatibility with laboratories and automatic high-throughput screening are the constant goals of LoC technology in drug development. Currently, the maximum number of organ chips in an MPS device is only 96. The throughput of this scale will inevitably pose obstacles to high-throughput screening when subsequent research is accelerated . Miniatu


Natural Products (NP) are essential for the discovery of novel drugs and products for numerous biotechnological applications. The NP discovery process is expensive and time-consuming, having as major hurdles dereplication (early identification of known compounds) and structure elucidation, particularly the determination of the absolute configuration of metabolites with stereogenic centers. This review comprehensively focuses on recent technological and instrumental advances, highlighting the development of methods that alleviate these obstacles, paving the way for accelerating NP discovery towards biotechnological applications. Herein, we emphasize the most innovative high-throughput tools and methods for advancing bioactivity screening, NP chemical analysis, dereplication, metabolite profiling, metabolomics, genome sequencing and/or genomics approaches, databases, bioinformatics, chemoinformatics, and three-dimensional NP structure elucidation. Natural bioresources are well known for producing secondary metabolites with unique features, highly complex structures, and biochemical properties valuable for human healthcare and well-being, which have inspired industries for numerous biotechnological applications ,2. The uDereplication: racing to speed up the natural products discovery process”  and the hybrid systems combining different types of mass analyzers  have remarkably increased the informative power of the MS detectors  ,89,90. ONP isolation and purification are beyond the scope of this review. Nevertheless, chromatographic techniques are the most commonly used for this purpose, either using normal or reverse-phase silica, depending on the NP polarity, alumina for NP that require neutral pH conditions, or Sephadex for molecular weight-based isolation. It is also very common to perform pre-fractionations by column chromatography, followed by semipreparative or preparative HPLC chromatography.The rapid identification of previously reported compounds, termed as structural dereplication, is a crucial component in NP and MNP chemistry. The taxonomic characterization of the metabolite-producing organisms, the availability of molecular structure data for known metabolites, and the accessibility to metabolite spectrometric and spectroscopic signatures are considered the focal points of structural dereplication . Enabling free, open access to databases will advance new technologies in NP discovery. Increased progress on new computational methodologies for secondary metabolite identification and elucidation will be achieved by enhancing and improving comprehensive databases of known compounds to compare against experimental data . In addim/z or molecules that are exclusive to each strain within a group, supporting automated mass matching to databases such as Antibase pyrano chromene, notoamide I, emindole SB beta-mannoside, and two bromoindole derivatives were proposed as the most promising marine drug-like leads as SARS-CoV-2 Mpro inhibitors [The investigation of MNP as a key resource for the discovery of drugs to mitigate the COVID-19 pandemic is a developing field. Several CADD approaches were explored ,428,429.hibitors .pro inhibitors are shown [In re shown .Molecular docking has been the major structure-based methodology to predict affinities to macromolecular targets, interpret binding modes, and assist in the design of drug leads. Several recent publications illustrate the application of this method to MNP ,425,430,HOMO-LUMO (energy difference between the HOMO and LUMO) were identified, associating the anti-HIV activity of five diterpenes with possible action on the reverse transcriptase allosteric site. Further investigation by molecular docking identified that only dolabelladienetriol  samples, rapid dereplication, and evaluation of preferred cultivation and extraction conditions. Moving forward with rapid and efficient isolation, the discovery of novel specialized metabolites, and the 3D structural elucidation of the metabolite’s chemical scaffolds while minimizing the waste of resources on rediscovering known compounds, more and more chemists are using cutting-edge analytical and computational methods to organize and mine data from enormous data sets to accelerate the discovery of bioactive NP. MN was able to successfully organize extensive collections of MS/MS data as well as sample metadata in a format that was simple to understand for spectral similarity networks. The process of carrying out NP dereplication and metabolic profiling was significantly influenced by the online platform GNPS , especially when combined with MN. The post-genomics era and the development of bioinformatic tools have also had a significant impact on NP research, speeding up the process of dereplication and structure elucidation of secondary metabolites.Starting from the premise that the NR are integrated into their habitat, one should select the best approach and techniques to investigate the NR of interest based on an integrated approach to NP identification using the several technologies that are currently available. The unexpected diversity of the NR metabolome outweighs the complexity of the genome by a considerable margin. We are just starting to put together the necessary computational and experimental tools to understand the metabolome in comparable detail. We anticipate that in the future it will be possible to comprehend the precise connections between NR, their genome and metabolites, absolute structure elucidation, bioactivity, MoA, and immune response.The diversity and pervasiveness of NR have been seen in new ways by modern technology, but these tools have primarily produced outlines that provide insufficient insight into organisms’ functions or community dynamics. Advancing knowledge about organisms’ functions or community dynamics could revolutionize our perception of the world and spark information and innovations in a variety of fields, including the environment, biotechnology, and health. Discovering the relationship between microbiome and NP structure would advance science towards increasing the NP chemical space and solving NR supply shortages for further biotechnological development such as pre-clinical and clinical trials or moving forward from proof of concept in industrial development.


Despite the numerous epidemiological studies demonstrating the health benefits of physical activity and the increased risk of chronic diseases associated with physical inactivity, a significant portion of the global population remains physically inactive –4. The mThe aim of this Research Topic is to gather and disseminate new knowledge pertaining to the impact of physical (in) activity on major non-communicable diseases across all age groups, ranging from childhood to old age. The 10 studies that have emerged as a result of this Research Topic, comprising six cross-sectional studies, one case-control study, and three review articles, offer readers a unique opportunity to expand their knowledge in this field. The findings presented in these studies are expected to advance our understanding of the relationship between physical activity and non-communicable diseases, thus contributing to the development of effective strategies to prevent and manage these diseases. By focusing on a range of age groups, these studies provide a comprehensive view of the impact of physical activity on health outcomes across the lifespan, offering valuable insights into the potential benefits of physical activity promotion programs for individuals of all ages.Fu et al. investigated the effects of functional training, lasting 12 weeks, on children's gross motor skills, physical fitness, and sensory integration. The results of this study showed a significant improvement in all three areas, highlighting the benefits of functional training for children's physical development. The second study by Yin et al. examined the effects of physical activity combined with extra ciliary-muscle training, lasting 16 weeks, on children's kinetic visual acuity and uncorrected distance visual acuity. The results showed that the combination of physical activity and extra ciliary-muscle training improved both visual acuity measures, indicating the potential benefits of this intervention for children's vision. The third study by Patti et al. assessed the effects of physical exercise continuity during the COVID-19 pandemic on strength performance in children. The results indicated that consistent physical exercise during the pandemic period resulted in higher strength performance in both the Handgrip test and the Countermovement Jump test. Overall, these studies provide important insights into the benefits of physical activity for children's physical development, particularly in the areas of gross motor skills, physical fitness, sensory integration, vision, and strength performance.The majority of the studies conducted in this Research Topic primarily focused on adults. However, to establish a comprehensive understanding of the impact of physical (in)activity on non-communicable diseases, it is crucial to also investigate its effects on the youngest population, i.e., children. This Research Topic included three studies that examined the effects of physical activity on children aged 5–17 years. These studies, consisting of two cross-sectional studies and one case-control study, evaluated the benefits of physical activity on gross motor skills, physical fitness, sensory integration, kinetic visual acuity, uncorrected distance visual acuity, and strength performance. The first study by Mao et al.). Another study reported that greater participation in mass sports increased the likelihood of prosocial behavior , while a third study found that increased physical activity could prevent hypertension . The remaining two studies, which were review articles, aimed to determine the potential of physical activity in suppressing the negative effects of sedentary behavior on cardiovascular disease and obesity epidemics . The results of these studies suggest that physical activity can reduce the risk of cardiovascular disease and improve indicators associated with it. Furthermore, alternative workstations, such as standing or walking workstations, seated pedals, and gymnastic balls, may be useful in combating the obesity epidemic.The following five studies investigated the effect of physical activity on a sample of adults aged 18–60 years. The first three studies, which were cross-sectional in design, examined the impact of physical activity on various health outcomes, all concluding that physical activity has a positive effect. One study found that physical activity could reduce the incidence of kidney stones in diabetes patients with a high body mass index (BMI), despite high BMI being a risk factor for kidney stones .An additional study in this Research Topic focused on both adults and older adult individuals. It was a systematic review study that examined a clinical population with participants ranging from 48 to 75 years of age. The study concluded that physical exercise interventions may improve, or at least not worsen, cognitive performance in patients undergoing hemodialysis .The last study was a cross-sectional study that examined individuals in the older adult age group (65–85 years). The study aimed to investigate the combined impact of smoking and physical activity on mortality rates in older adult patients diagnosed with hypertension. The study's results suggest that the combination of smoking and physical inactivity may have a synergistic effect on the risk of premature death, emphasizing the critical need to enhance behavioral factors and advocate for a comprehensive healthy lifestyle in older adult patients with hypertension (This particular Research Topic contains 10 articles that support well-established evidence regarding the positive effects of regular physical activity on health outcomes . In addiBM and SA drafted the Editorial. SP, SH, and DS revised and approved the final version. All authors contributed to the article and approved the submitted version.


One of the common challenges in oral surgery is dealing with patients who are taking oral anticoagulant/antiaggregant drugs. Several local hemostatic agents have been proposed as an alternative to conventional suturing. Among these, autologous platelet concentrates (APCs) have been widely used to decrease the risk of hemorrhage after dental extraction. Nevertheless, there is a lack of consensus regarding the superiority of any one specific hemostatic agent over the others. This systematic review is aimed at evaluating the effectiveness of APCs as hemostatic agents after tooth extraction in patients on anticoagulant therapy. A literature search was conducted of articles published before March 2023 on PubMed, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL). Studies on the use of APCs in patients undergoing dental extractions and being treated with anticoagulant drugs were included. Only randomized, controlled trials (RCTs) published up to March 2023 were included; the outcomes assessed were the time to hemostasis, the presence of post-operative bleeding and pain, and the effectiveness of wound healing. The risk of bias for each RCT was assessed by using the ‘risk of bias’ tool (RoB 1.0). The research revealed 6 RCTs. The findings indicated that patients on anticoagulant therapy who received APCs without discontinuing their medication experienced a decreased post-operative bleeding, a shorter hemostasis time, reduced pain, and accelerated wound healing. However, due to the high/unclear risk of bias of the studies included, no definitive conclusions can be drawn on the superiority of APCs as hemostatic agents over other similar products. Additional studies are required to validate these findings. Hemostasis is the result of a set of well-regulated cellular and biochemical processes that maintain the blood in a liquid state in normal vessels and induce hemostatic clot formation after the occurrence of vascular damage. A congenital or iatrogenic  deficiency in coagulation can be a serious risk in surgery.Over the years, the population affected by cardiovascular diseases has been increasing. Antithrombotic drugs (antiplatelet and anticoagulant drugs) are commonly prescribed for the long-term prevention of arterial or venous thromboembolism (VTE) in cases of mechanical heart valves, atrial fibrillation, deep vein thrombosis, pulmonary embolism, coronary stents, and other clinical conditions with an increased thromboembolic risk .In oral surgery, the treatment of patients on antithrombotic drugs is one of the most frequently encountered challenges. These patients are at a varying risk of thromboembolism and intra- and post-operative bleeding, depending on the pharmacodynamic characteristics of the anticoagulant drugs and on the type of surgical intervention .If a patient treated with an oral anticoagulant must undergo invasive diagnostic or surgical procedures, the decision on how to manage the anticoagulant treatment requires a careful balancing act between the bleeding risk of the diagnostic/surgical procedure and the thrombotic risk resulting from any possible discontinuation of the anticoagulant.There are many discrepancies relating to any interruption or modification of antithrombotic therapy in patients with cardiovascular disease. According to several clinicians, antiplatelet therapy should be stopped for patients with stable angina and stroke before dental extractions . HoweverAccording to Appendix 3 of the Italian Drug Agency (AIFA) Note 97 and to the latest 2021 recommendations of the practical guide of the European Heart Rhythm Association (EHRA) ,6, if a Today, thanks to the introduction of new oral anticoagulant drugs NOACs  with their short half-life, more rapid onset and offset, fewer drug interactions, and the absence of any need for international normalized ratio (INR) assessment, this “bridging therapy” is no longer necessary . The EHRIn patients undergoing low-risk hemorrhagic procedures where good local hemostasis is possible, the 2021 EHRA guidelines suggest that the NOAC should not be discontinued, taking advantage of the period of minimal drug action before assuming the next dose . Resumption of the NOAC is recommended 6–8 h after completion of the procedure .Although many authors clearly indicate that the risk of bleeding is less even when multiple dental extractions must be performed at the same session ,9,10 andDuring the past few years, the use of autologous platelet concentrates (APCs) in achieving an adequate post-operative hemostasis in patients with coagulation disorders has aroused great interest in the literature. APCs are blood products used in several medical and dental fields to increase the soft and hard tissue healing rate ,29. TheySeveral studies have shown that their use in post-extraction sockets without any modification of oral anticoagulant therapy leads to great results in the prevention of post-operative bleeding, i.e., a higher quality and more rapid post-operative tissue healing ,37,38,39Hence, the aim of this systematic review has been to evaluate the results of RCTs, comparing the hemostatic effect of APCs following dental extraction in patients assuming anticoagulant/antiaggregant medication with other hemostatic agents or when only suturing is performed. This review was compiled following the PRISMA  guidelines  for imprIn accordance with the PICO statement, this systematic review is aimed at answering the question “Does the use of APCs following dental extractions (Intervention/exposure) reduce the time to hemostasis (Outcome) in patients who are on anticoagulant/antiaggregant medication (Population)?” Other types of hemostatic agents and natural healing by blood clotting are considered as the Comparison/Control.The primary outcome variable was the time to hemostasis. The secondary outcomes were the presence of post-operative bleeding, wound healing and biological complications .The protocol was registered on the PROSPERO National Institute of Health Research Database (CRD42021258587).Three electronic databases ) were explored up to 31 March 2023 using a combination of keywords and MeSH terms according to the database rules . A manuaAfter title and abstract screening, the articles were selected for full-text reading. Whenever differences in the judgment of the eligibility of the title and abstract occurred, full texts were included for the final assessment.In order to identify unpublished or discontinued studies, all authors of the selected studies were contacted and the bibliographies of all the selected studies and relevant reviews were checked.Disagreements between the two investigators were solved through discussion; if needed, a third operator (GS) was contacted for a final decision.The data were independently extracted by two authors (RG and AA) using a pre-determined extraction form. Any disagreements were solved by discussion. All the authors were contacted to clarify information or identify missing information and, where no agreement was reached, the data were excluded until further clarification was possible. The following data were extracted: author, publication year, country of origin, total number of subjects included, participant data (age and gender), type of therapy, type of intervention, APC specifications, control groups, follow-up, outcomes evaluated, results and conclusions.www.cochrane-handbook.org, accessed on 27 February 2019]. It is a two-part tool, addressing six specific domains . Each domain includes one specific entry in a “risk of bias” table. Within each entry, the first part of the tool involves describing what was reported to have happened in the study. The second part involves assigning a judgment relating to the risk of bias for that entry. This is achieved by answering a pre-specified question about the adequacy of the study in relation to the entry, such that a judgment of “Yes” indicates a low risk of bias, “No” indicates a high risk of bias and “Unclear” indicates an unclear or unknown risk of bias.The risk of bias assessment was conducted using the risk of bias tool (RoB 1.0), the recommended approach for assessing the risk of bias in studies included in Cochrane reviews  (A) Low risk of bias  if all the criteria were met.(B) Unclear risk of bias (plausible bias that raises some doubt about the results) if one or more key domains had an unclear risk of bias.(C) High risk of bias (plausible bias that seriously weakens confidence in the results) if one or more criteria were not met.The methodological quality of the RCTs included was independently assessed by two reviewers (MDC and AA) as a stage of the data extraction process. In any case in which the study to be assessed had one or more review authors in the author list, it was independently evaluated only by those review authors not involved in the trials. After considering possible additional information provided by the authors of the trials, the studies were grouped into the following categories. It was assumed that the risk of bias was the same for all outcomes and each study was assessed as follows:Two review authors  independently assessed the certainty of the evidence for the outcomes  according to the GRADE approach  , which cThe data extracted from the six RCTs are summarized in According to Sakar et al. , who anaBrancaccio et al. , using tSarkar and Brancaccio ,46 also The final risk of bias assessment is summarized in The certainty of evidence for the main comparison  was classified as low for time to hemostasis which represents that APCs may make little or no difference compared to control. On the contrary, the certainty of evidence for the main comparison was classified as moderate for post-operative bleeding, pain, and wound healing, which indicates that the likelihood that the effect of APCs will be substantially different compared to the control is moderate. There was a downgrade in the levels of evidence due to the methodological quality of the studies, the different types of APCs analyzed, and the small sample size. The aim of this paper has been to review systematically the evidence concerning the hemostatic effectiveness of APCs following dental extraction in patients taking anticoagulant/antiaggregant medication without discontinuing the therapy.The findings indicate that these patients experienced a decreased post-operative bleeding, shorter time to achieve hemostasis, reduced pain and accelerated wound healing.Cross-linked fibrin clot formation is essential to avoid hemorrhages. The tridimensional fibrin network allows for a clotting stability in the last phase of the coagulation process by ensuring the regeneration of injured tissues ,49. In fLocal hemostats are sterile medical devices, which can be derived from plants (polysaccharides and cellulose derivatives), animals (collagen and gelatins), or minerals . The mechanism of action is chemical and/or mechanical. Hemostats promote platelet aggregation on the surface, creating a substrate for the coagulation cascade. To date, several hemostatic agents used in oral and periodontal surgery have been studied in the literature, in particular, oxidized regenerated cellulose ; resorbaNowadays, the development of APC technologies offers simplified and optimized products of an autologous origin without any production costs. APCs form a natural fibrin matrix, which acts as a scaffold at the wound site. The fibrin matrix helps to stabilize the clotting, promote platelet adhesion, and provide a physical barrier to prevent further bleeding. Moreover, APCs contain a large quantity of platelet growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), and vascular endothelial growth factor (VEGF), and cytokines, which stimulate the healing process, promote tissue regeneration, enhance the formation of new blood vessels and reduce post-operative pain ,37,62.APCs exhibit variations in the polymerization and final fibrin architecture, which may influence the strength and the growth factor trapping/release potential of the clotting with diverse effects on the process of hemostasis. For example, during the PRF preparation, the polymerization of fibrinogen into fibrin occurs slowly, naturally and progressively in the presence of physiological thrombin, resulting in a strong natural fibrin meshwork, composed of a tetra molecular structure. On the contrary, for PRP products, bilateral junctions of the fibrin fibrillae are provoked by a drastic activation and polymerization, for example, with high thrombin concentrations, which leads to a dense network of monofibers, similar to a fibrin glue .The recent literature has indicated that there is no significant difference in post-extraction bleeding among patients on an uninterrupted therapy with various antiplatelet/anticoagulant medications. DOACs, as well as single or dual-antiplatelet medications, showed the same incidence of post-operative bleeding and determined an acceptable rate of controllable post-operative bleeding after a simple tooth extraction . TherefoIn fact, the RCTs included in this review showed that continuing the therapy was linked to a post-operative bleeding which did not cause any serious adverse complications and was easily managed using hemostatic agents and instructions given to the patients.While the included studies are valuable randomized, controlled trials (RCTs), which are widely regarded as the gold standard for clinical trials, it is important to note that a meta-analysis, which combines numerical results from multiple similar studies, was not conducted. This omission was due to the heterogeneity observed in the data collected from the selected studies, such as variations in the patient populations, treatment protocols, number of extractions, and patient comorbidities. In fact, the included RCTs considered different types of control groups using various hemostatic agents, such as hemostatic sponges and tranexamic acid  or chitoAnother factor which affected the heterogeneity of the studies and the assessment of both the primary and secondary outcomes is the number of teeth extracted. In Brancaccio et al.  and GiudFurthermore, it must be taken into account that patient factors, such as the presence of comorbidities and vicious habits, may influence post-operative bleeding and wound healing . Only BrFurthermore, it is critical to highlight that the most recent oral anticoagulants  were not considered in the selected studies. This deficiency makes it problematic to assess the effective role of APCs in patients assuming NOACs, even if their effectiveness could be hypothesized through a better management of these drugs compared to dicoumarol.In conclusion, we advise caution when interpreting the findings of the present systematic review, taking into consideration the above-mentioned limitations.The findings indicate that patients on anticoagulant therapy who received APCs without discontinuing their medication experienced decreased post-operative bleeding, shorter time to achieve hemostasis, reduced pain, and accelerated wound healing. However, due to the high/unclear risk of bias of the included studies, no definitive conclusions can be drawn on the superiority of APCs as hemostatic agents over other forms of medication and no valid clinical guidelines for the use of APCs as a hemostatic agent can be proposed. For this reason, an additional aim of this paper is to raise awareness in the scientific community to encourage researchers to explore the role of the APCs, also in patients taking NOACs, and to perform further studies which could provide more homogeneous results qualitatively and quantitatively which might be comparable and subject to meta-analysis.


Chronic pain is the leading cause of disability in industrialized countries and its prevalence increases throughout adulthood. The aim of this Research Topic is to explore the different factors influencing its development and maintenance across the lifespan. The articles included in this collection range from basic to clinical research, including practical applications to improve current assessment instruments and self-management practices. This collection of articles is comprised of three types of manuscripts  focusing on the following subtopics of chronic pain: (1) factors affecting quality of life in fibromyalgia (2) alteration in electrophysiological indices of pain expectation in fibromyalgia, (3) assessment and treatment of kinesiophobia in musculoskeletal pain conditions, and (4) proprioceptive acuity is core for back awareness in chronic low back pain.Fernandez-Feijoo et al. that performed both linear and logistic regression analysis of these symptoms and other less explored factors that may also predict QoL, such as lifestyle  and multi-medication . They also compared subgroups created based on lifestyle and medication patterns. The results of this study have relevant clinical implications for improving QoL of patients with FM. The symptoms which most significantly predicted QoL (explaining 49% of the variance) were depression and anxiety. Medication and smoking also predicted lower QoL (explaining 14% of the variance). Moreover, patients who exercised regularly had improved QoL compared to patients who did not (regardless of the severity of FM). Overall, these results highlight the importance of increasing self-management practices focused on improving mood, but also sleep quality, reducing medication and tobacco use, and promoting a balanced diet and regular exercise.Fibromyalgia (FM) is characterized by the presence of chronic and widespread musculoskeletal pain, and other symptoms , which cause a high negative impact on quality of life (QoL). This Research Topic includes a study by Barjola et al. recorded event-related potentials (ERPs) during an S1-S2 (or cue-target) paradigm, consisting of the presentation of an image (triangle or square) that predicted the occurrence of a (painful or non-painful) laser stimulation,_to explore the temporal dynamics of anticipatory attention to pain processing (or pain expectancy). Although no statistically significant differences were found in behavioral data , an abnormal pattern of pain expectancy , and an enhanced amplitude of the P2 component related to increased stimulation intensity but not related to pain predictive cues) were observed in FM participants compared to healthy controls. The results of this study also have practical implications, as a better understanding of neural correlates of pain processing and modulation allows for the development of more effective coping strategies to improve QoL of chronic pain patients.Among cognitive alterations in FM, attentional biases or hypervigilance to pain leads patients to anticipate or interpret pain as a threat, promoting inadequate coping strategies (such as escape and avoidance behaviors). Therefore, these cognitive alterations seem to contribute to the origin, exacerbation and maintenance of increased pain perception and may even be involved in the severity of FM symptoms. From a basic research perspective, Bordeleau et al. about the assessment and treatment of kinesiophobia is highly relevant to evidence-based clinical practice. According to their results, the Tampa Scale of Kinesiophobia (TSK) is the most used tool for measuring kinesiophobia, but the Fear-Avoidance Components Scale (FACS), which is only starting to be used, seems to be the most suitable tool to date to assess the multiple components of fear of movement. The authors also point out that physical exercise is a key component of non-pharmacological interventions for musculoskeletal pain and that high levels of kinesiophobia may compromise its adherence.The fear-avoidance model of pain describes how negative and catastrophizing beliefs about pain could lead to a vicious cycle of fear, activity avoidance, and resultant disuse and distress. In line with this, when a painful event is perceived as threatening, it can lead to catastrophizing thoughts . This fear of movement, or kinesiophobia, is common in patients with chronic pain, and is associated with increased pain intensity and disability. The knowledge gained from the scoping review by García-Dopico et al. presents a further analysis of the face/content validity of the Spanish version of the FREBAQ (FreBAQ-S), based on questions regarding the completeness, comprehensibility, time-to-complete adequacy, and time spent completing this questionnaire, in a large sample of CLBP patients and healthy controls. The authors also explored additional variables involved in back awareness suggested by the participants, categorized into four classes: neglect-like symptoms , proprioceptive acuity , trunk shape and size, and psychological variables . Their results showed that CLBP participants spent significantly more time on completing the questionnaire than controls, but no differences were found between groups regarding the time-to-complete adequacy. Regarding the back awareness-related variables, CLBP patients made more suggestions than healthy controls , most of them related to proprioceptive acuity.Patients with chronic low back pain (CLBP) can present with different sensorimotor abnormalities, including body image disturbances . Consequently, an increasing number of studies focuses on altered back awareness as a potential contributor to CLBP and a target for treatment. The Fremantle Back Awareness Questionnaire (FREBAQ) is a validated and reliable tool to assess back-specific altered body perception in patients with CLBP. The study developed by In conclusion, this Research Topic aims to enhance our understanding of the multifaceted nature of chronic pain and its impact on individuals across the lifespan. The diverse range of topics covered provides valuable new insights for researchers, clinicians, and individuals living with chronic pain, offering opportunities to develop more effective interventions and improve quality of life for those affected by chronic pain conditions.CS redacted the first draft of the manuscript. All authors reviewed and improved the manuscript. All authors contributed to the article and approved the submitted version.


Now, as the Editorial for the second volume of this Research Topic is released (early March 2023), the same search returns 13,121 studies, 4,170 of which are active. To give an idea of what those numbers represent, when the same database is queried using the string “HSCs OR hematopoietic stem cells OR hemopoietic stem cells”, it returns 6,096 studies, 1,701 of them active. In spite of the impressive number of clinical trials using MSCs, the use of these cells in the clinic has not become established as a routine yet, which calls for further investigation of their biological properties.Currently, mesenchymal stromal cells (MSCs), which are often still referred to as mesenchymal stem cells, are among the most used cells in clinical trials. When the Editorial for the first edition of this Research Topic was written (mid-January 2021), a search at in vitro or in vivo studies. Consequently, suggested subjects for submitted manuscripts included a) novel features of MSCs from different tissues; b) molecular aspects of MSC differentiation; c) Processes for the enhancement of MSC differentiation and expansion in culture; d) identification of MSCs, or cells that can give rise to them, in situ; e) acellular MSC-derived products such as extracellular vesicles; f) immunomodulatory properties of MSCs; and g) molecular interactions between MSCs and other cell types in vitro or in vivo. This Research Topic received 12 manuscripts. Seven of these manuscripts were accepted; four of these were original research reports, and three were reviews. Short descriptions of the papers that make up this Research Topic are provided below.The aim of the second volume of this Research Topic was to provide a venue for high quality research articles and reviews that update the current knowledge on the biology of MSCs, including mechanisms that can affect their role in cell therapy and tissue engineering. Manuscripts submitted to this Research Topic were expected to contain information that can be used to better understand how MSCs behave, and how they exert their therapeutic properties, whether such information comes from Ceccarelli et al. examined the effects of 5-azacytidine, a demethylating agent, on proliferation, clonogenicity, migration and adipogenic potential of human adipose-derived MSCs (ASCs), and observed that this agent impairs cell proliferation and stimulates adipogenic differentiation; further experiments suggested that treatment of ASCs with 5-azacytidine impaired phosphorylation of Akt and ERK and that this could be responsible for reduced cell proliferation and migration. In addition, inhibition of the Wnt pathway could be involved in the enhanced adipogenic differentiation observed. Behm et al. studied the effect of 25-hydroxyvitamin D3, the major metabolite of vitamin D3 in the blood, on human periodontal ligament-derived MSCs; they found that this molecule diminishes the ability of MSCs treated with interleukin-1 beta to suppress the proliferation of CD4+ T cells, but does not have the same effect in the presence of tumor necrosis factor. Findings by Gaggi et al. suggested that human amniotic fluid-derived MSCs could generate motoneurons-like cells. Briefly, the authors induced differentiation by exposing the cells to a sequence of SMAD, ALK2, GSK3, and gamma secretase inhibitors in combination with neurotrophic factors, ascorbic acid and retinoic acid and assessed the resulting changes in gene expression. Moreover, they assessed the formation of neuromuscular junctions and the ability of the differentiated cells to induce skeletal muscle contraction. Overall, the results suggest that amniotic fluid-derived MSCs could differentiate into functional motoneuron-like cells in vitro. If validated in vivo, these finding could have implications for future translational work focus of conditions affecting motoneurons, such as amyotrophic lateral sclerosis (ALS). Umrath et al. studied the effects of corticosteroids on jaw periosteum-derived MSCs. More specifically, they focused on the impact of dexamethasone on the osteogenesis, extracellular matrix (ECM), and secretion of pro-osteogenic factors by MSCs. They demonstrated that osteogenic differentiation of MSCs isolated from the jaw periosteum does not depend on the exposure to dexamethasone if the cells are cultivated in a medium supplemented by human platelet lysate. In addition, they confirmed earlier findings that suggest that dexamethasone affects not only global gene expression but also the ECM, and the profile of the secretome. As dexamethasone is known to cause severe side effects, new dexamethasone-free protocols for osteogenic differentiation of MSCs are important for developing MSC-based therapies for bone fractures and conditions such as osteoporosis.Chetty et al. reviewed the compartments of umbilical cord tissue from which MSCs can be obtained, and discussed the properties of these MSC populations. Koga et al. reviewed roles of extracellular vesicles produced by MSCs on tissue repair and regeneration, and how therapies based on MSC-derived exosomes could be advantageous to treat various conditions. Marson et al. provided insights into the in vivo nature of MSCs, reviewing existing evidence on the behavior of pericytes as MSCs. A perivascular location would be conducive to rapid action after injury, favoring wound healing through the action of pro-regenerative macrophages. This opens a venue to explore the use of MSCs and their extracellular vesicles, or activated pericytes at sites of injury, for regenerative medicine strategies through non-classical mechanisms, by promoting an M2-like profile in tissue–resident macrophages. Further, the authors discuss the advantages of using MSC-derived acellular products such as exosomes for the induction of an immunomodulatory and wound-healing profile.


Thawing permafrost is a serious and worrisome threat to the environment, because it releases trapped heavy metals and greenhouse gasses. Thawing permafrost is also a health threat because, in addition to releasing these noxious gasses, thawing permafrostmay free novel and undiscovered antibiotic-resistant bacteria, viruses, fungi and parasites among a plethora of dormant pathogens. Our immune system is ill-prepared to counter these challenges, and will require significant adaptation, or allostasis, which canbe subsumed under the generic term of permafrost immunity. Since most of the most gravely threatening pathogens released by thawing permafrost are likely to penetrate the organism through the oral cavity, permafrost immunity may first be identified in the oralmucosa. Ever since the onset of the Industrial Revolution in the 1850s, our planet has suffered a mounting onslaught of pollution, which has progressively altered the fundamental cleanliness of its air, water and soil, and favored the rise of new and ancient healththreats [Global warming also causes melting of glaciers and eternal snows at higher altitudes, and the release of large sheets of polar ice into the oceans. On land, extended areas of permafrost are thawing . PermafrCertain of these pathogens may be serious public health threats, including ancient lethal variants of Yersinia pestis, the plague-causing bacterium, influenza virus , and anthrax-9. FragmGroundbreaking and improved DNA sequencing technologies allow a glimpse into ancient DNA of pathogens long entrapped in permafrost. Bacteria, viruses, and fungi, including from periodontal and more generally oral pathogens, can be recovered from thawingpermafrost, and their genomes compared to their extant counterparts. Permafrost microbial history is furthermore enriched by ancient pathogens extracted from specimens of mummified bones and dental pulp released from thawing permafrost.Yersinia pestis, Bartonella quintana, Salmonella enterica serovar Typhi, Salmonella enterica serovar Paratyphi C, Mycobacterium leprae, Mycobacterium tuberculosis, Rickettsia prowazeki, Staphylococcusaureus, and Borrelia recurrentis, to Bartonella henselae, and at least one virus of the Anelloviridae family can be recovered from ancient permafrost dental pulp specimens [A recent review identified at least ten bacteria, from pecimens .Taken t(2017 words) Immunity is best defined as the physiological system that protects from pathogens that could otherwise be harmful or even lethal. Immunity is proffered by the immune system, the set of finely concerted and integrated biochemical and cellularprocesses and regulated events and pathways, which act together in perfect orchestrated unison. Immune processes and events can be either adaptive and specific in nature, or innate and largely nonspecific. Permafrost immunity encompasses both the native andadaptive immune responses to pathogens released by thawing permafrost.As one principal aspect of the physiological processes that regulate and restore health following illnesses and infectious diseases, immunity is itself driven to homeostasis. Physical, psycho-emotional, and physio-pathological stress drive a loss inhomeostasis with potentially profound sequelae, which can involve significant immune suppression and impairment. The natural process of recovering homeostasis is termed allostasis , which eThere are two distinct types of allostatic threats: that which is a temporary and reversible load, and that which is de facto - a chronic, constant, irreversible, or even consistently growing overload. As much as it is possible to attain allostasis,stability through change of state, to reversible and temporary allostatic threats , allostasis to irreversible chronic threats is realistically and factually unreachable , 15. ForIn the context of immunity, immune allostasis is critical for maintaining a strong and efficient resistance against pathogens , as wellAllostasis and allostatic load are foundational to the science of psychoneuroimmunology, the study of the intertwined interdependence among psychosocial and psychoemotional behaviors and cognitive responses, the central and peripheral nervous regulation ofendocrine signals, and cellular and humoral immune surveillance processes. More generally, the existence of bidirectional communication pathways between the brain and the immune system and the implications of this network for perceived allostastic loaddifferential  dictate and determine anti-viral, anti-bacterial and anti-tumor immune efficiency  to an exIn an ever-magnifying set of environmental threats, some perceived by the organism as reversible while others as chronic and consistently rising, the specific pattern of psychobiological labor each individual organism undergoes to regain a balanced stateof homeostasis in response to climate change and global warming can be defined as the allostasiome . The allCertain viruses, which we considered limited to the tropics, have aggressively invaded higher latitudes engendering dangerous pandemics  and epidemics of concern . While they do notoriginate from the thawing permafrost per se, these pathogens exemplify the broad nature of the threat to the immune system resulting from climate change and global warming. It is possible and even likely that the novel and ancient pathogens released themelting permafrost over the next decades will challenge immune surveillance mechanisms to an even greater extent. Case in point, challenge by the SARS-CoV2 virus leads to immune suppression across a variety of domains, from an increase in the absolutenumber and relative percentage of T cells that express manifested programmed cell death marker-1  and the T cell immunoglobulin and mucin domain 3 (Tim-3), and which together are markers of "exhausted" T cells ,to dereVarious permafrost viruses and bacteria have been identified at different geographical locations (Table 1 - see PDF). In brief, and to highlight those listed in the table, in Stordalen Mire, the subarctic region in northernmost Sweden, about 5 miles east ofthe town of Abisko close to Lake Torneträsk, the discontinuous permafrost evinces a large 25ha palsas area; that is, an area that consists of relatively tall peat mounds up to 12 m high and 150 m in diameter with a permanently frozen peat and mineral soil core.The active palsas permafrost of the Stordalen Mire has revealed the presence of Variola virus of the 170-250 kb DNA Orthopoxvirus genus. This genus consists of two principal families, of which the Poxviridae is the largest and causes pox-related pathologies. The Variola virus was thought to have been eradicated globally by 1977 through the use of Vaccinia virus vaccine. The current rise in Monkeypox virus infection worldwide, and the emergenceof permafrost Variola virus, however, is important threats to human health worldwide. The discovery of a know Orthopoxvirus in the Sweden permafrost, came to confirm earlier reports of another pox virus, the novel Alaskapox virus, uncovered in the thawingpermafrost of the Fairbanks North Star Borough. The Alaskapox virus led to human fatalities .The active palsas permafrost of the Stordalen Mire also revealed the presence of tailed bacteriophages, the group I virus of double stranded DNA Order of Caudovirales that includes the Myoviridae, the family of the Podoviridae. While representatives of theCaudovirales Order share similarities, such as being lytic to the bacteria they bind to, they also have characteristically distinctive features. Case in point, Podoviridae duplicate cytoplasmically, while Myroviridae are typically directly lytic. In general,the representatives of the Order of Caudoviradae are considered potential candidates for therapy against bacterial diseases, and thus may be considered beneficial rather than threats to human health.In the lowlands of northeastern Siberia, the Kolyma River was historically frozen to depths of several meters for close to 250 days yearly. Recent measurements show a thinner ice sheet 4-6 months of the year, indicating thawing permafrost along the Riverbanks. The ancient amoebae-infecting giant double-stranded circular DNA virus, Pithovirus sibericum, emerged from the Kolyma ice, as well as the spherical group I double stranded DNA Mollivirus sibericum. While neither is apparently harmful to humans, thelatter may be considered a threat since it, and other members of its family, can be potentially noxious to human health because of their ability to sequester the host's ribosomal proteins in its vision.In the Yamalo-Nenets autonomous Region of Okrig in Russian Siberia, in the northern polar Ural (about 70°N and 70°E), the permafrost of the arctic tundra and taiga have released alarming levels of what is commonly known to cause anthrax, a lethalbacterial infection brought about by the spores released by the Gram-positive 3-5 µm long rod-shaped Bacillus anthracis. Due to its high level of risk to human health, an aggressive program of vaccine development against B. anthracis has been deployed,leading to the development of the Anthrax vaccine adsorbed (AVA), directed to protect against cutaneous and inhalation anthrax. In most instances, however, the Anthrax vaccine AVA is, at this time, restricted for preventive use only in at-risk adults prior toanticipated exposure. It is timely and critical to approve generalized utilization of the vaccine for use after exposure as well. Post-exposure to the infectious agent, the only effective intervention remains at this time treatment for anthrax with β-lactamantibiotics  . PenicilIn the Siberian permafrost along the Unga-Baga-Olonso stream  near the city of Olyokminsk, Siberia, were found emerging along the active permafrost several pathogens among whichthe Gram-negative, oxidase- and catalase-positive Achromobacter insolitus of the Alcaligenaceae family typically pathogenic to humans, the rod-shaped metabacillus, Bacillus idriensis of the Gram-positive, heterotrophic Bacillaceae family that also cause diseaseof varying degree of severity in humans, and of the heterotrophic, Brevundimonas aurantiaca, a Gram-negative, non-fermenting, aerobic bacillus of the Caulobacteraceae family, which is rarely, if ever, recovered from clinical samples despite causing bacterimiaof diverse severity . In addiTo be clear, this list is neither complete not exhaustive. It simply seeks to exemplify the variety of viral and bacterial pathogens emerging from thawing planetary permafrost. The permafrost microbiotome - the uncovered ever evolving in complexitymicrobiology, virology, bacteriology and parasitology of the thawing permafrost-evinces the prevalence of deterministic or purely stochastic processes that can hypothetically predict whether we will continue to be well-suited to survive and to thrive inchanging environmental conditions that accompany permafrost thaw. The predictive model can be conceived as an expansion of the AI approach we proposed to describe viral immune surveillance , becauseIn brief, it is possible and even likely that novel and ancient pathogens released from thawing permafrost could even more seriously perturb immune regulatory mechanisms and the immune allostasiome in general. It follows that together; these alterationswill define and characterize a new cadre of immunity, identifiable as permafrost immunity. To ensure our survival, our immune system facing permafrost-released pathogens will be challenged to favor one over another biochemical pathway and molecular process,one over another lymphocyte population, or one over another cytokine profile. Immune surveillance processes will have to adapt to optimize the neutralization of permafrost pathogens, an allostatic adaptation of immunity that is referred to as"permafrost immunity". Pathogens often first enter our organism through the nasal and the oral cavity. Therefore, it should be expected that the first of signs and symptoms of permafrost pathogens will be evinced at those anatomical sites. It follows thatpermafrost immunity will become evident the soonest in the mucosal immune compartment of the oral cavity and upper respiratory track.As global warming and climate change prevail, glaciers on our planet's highest peaks and polar, peri-polar and sub-polar permafrosts are melting. As this process unfolds, noxious greenhouse gases, such as methane and carbon dioxide are released, rising globaltemperatures. In turn, novel and ancient pathogens, from viruses to bacteria and other parasites are freed from the eternal ice. Our immune system is increasingly called to mount efficient defenses against these biological threats, and to attain new states ofhomeostatic balance. These allostatic changes include certain immune cell populations and their function and cytokine profiles. The physiological adaptation of the immune system to the demands of permafrost pathogens discussed in this paper as permafrostimmunity is akin conceptually to the "molding" of immunity, the modulation of mucosal and systemic immunity by the intestinal mycobiome in health and disease . Permafr


Editorial on the Research TopicMicroRNAs: Clinical biomarkers for atrial fibrillationAtrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the world, constituting a major risk factor for ischemic stroke (fivefold), death (twofold), and long-term incapacity, with a crucial impact on both health and economic health systems. AF has serious clinical implications on patients’ quality of life, with morbidity from ischemic stroke and heart failure and mortality. Early detection of AF decreases the risk of morbidity and mortality of the patients. Thus, early identification of markers of the disease and response to therapy are valuable to improve disease prevention and patient outcomes.Small non-coding oligonucleotides, such as microRNAs (miRNAs), are major regulators of gene expression, constituting an important epigenetic mechanism underlying cardiovascular diseases. MiRNAs are expressed in cardiomyocytes, fibroblasts, endothelial cells, and vascular smooth muscle cells, and their regulation has been associated with the pathophysiology of cardiovascular diseases, such as cardiac remodeling and fibrosis, apoptosis, inflammation, proliferation, angiogenesis, and metabolism modulation. Altered expression of miRNAs in the cardiovascular system (both in tissues and circulating) is associated with disorders such as AF, heart failure, atherosclerosis, and other cardiomyopathies. Circulating miRNAs are considered excellent biomarkers in clinical practice. They are obtained with minimal invasive techniques and are secreted by necrotic or living cells. Their profile may be altered in pathophysiological conditions. Moreover, different studies have shown a correlation between miRNA profiles in the cardiac tissue and blood (plasma or serum), opening the possibility of using circulating miRNAs as biomarkers of cardiovascular diseases even in subclinical phases. Using miRNAs as biomarkers may play a crucial role in patient prognosis, namely, by improving risk algorithms in AF, constituting an asset for the management of health system resources.This Research Topic is focused on the discussion of the use of miRNAs not only as markers of AF diagnosis and prognosis but also as tools for designing novel therapeutic strategies against AF and subsequent development of comorbidities.Wei F et al. investigated the potential role of the competitive endogenous RNA-mediated network in AF. Microarray data of circRNA, miRNA, and mRNA from the Gene Expression Omnibus database were used. To select the differentially expressed circRNAs (DECs), these authors used the RobustRankAggreg method, followed by circRNA–miRNA–mRNA-mediated network generation resorting to CircInteractome and miRWalk databases. The resulting circRNA–miRNA–mRNA-mediated network included two circRNAs, four miRNAs, and 83 genes. hsa_circ_0070391 expression levels were found to correlate with left atrial fibrosis in persistent AF and associated with AF prognosis following radiofrequency catheter ablation . Therefore, this paper advocates in favor of circRNAs as the new biomarkers of atrial fibrosis and AF prognosis.An original article by Dong Y et al. aimed to summarize the role of non-coding RNAs in cardiac fibrosis associated with different cardiovascular pathologies, including therein AF, while clarifying the diagnostic and therapeutic potential of non-coding RNAs in cardiac fibrosis .Atrial fibrosis plays an important role in the onset and development of AF that contribute to structural and electrical conduction abnormalities . Non-codRizal A et al. focused on the study of the correlation between the expression of miRNAs and the development of AF and on the elaboration of the role of genetic factors in the diagnosis of AF. To carry out the bibliographic search, online scientific databases were used, such as Cochrane, ProQuest, PubMed, and Web of Science, using keywords associated with the relationship between miRNAs and AF. The meta-analysis revealed a substantial connection between dysregulation of miR-425-5p expression and AF that showed its potential role as a biomarker .A systematic review by de los Reyes-García AM et al. summarized the association of specific plasma miRNAs with the development of MACE in AF. At a mechanistic level, miRNAs have been suggested to participate in the development of MACE in AF patients through dysregulation of immunothrombosis. In fact, miRNAs can regulate a formation of neutrophil extracellular traps, which are a key element in the establishment and evolution of thrombotic events . In general, authors detailed the use of miRNAs as both biomarkers and therapeutic targets against thromboinflammatory processes, thereby predicting and preventing the occurrence of MACE in AF.Despite the fact that prophylactic anticoagulation has been shown to have valuable benefits in avoiding comorbidities, patients with AF still experience major adverse cardiovascular events (MACE). Therefore, in recent decades, research focused on the identification of useful biomarkers in risk prevention. A mini review by In conclusion, although the promising results are obtained in a large number of studies, miRNAs are not yet used as biomarkers of AF in clinical practice. This Research Topic highlights the role that miRNA and other non-coding RNAs play and their promising use as diagnostic or therapeutic tools in the management of AF.