DNA Methylation and Non-Coding RNAs during Tissue-Injury Associated Pain

While about half of the population experience persistent pain associated with tissue damages during their lifetime, current symptom-based approaches often fail to reduce such pain to a satisfactory level. To provide better patient care, mechanism-based analgesic approaches must be developed, which necessitates a comprehensive understanding of the nociceptive mechanism leading to tissue injury-associated persistent pain. Epigenetic events leading the altered transcription in the nervous system are pivotal in the maintenance of pain in tissue injury. However, the mechanisms through which those events contribute to the persistence of pain are not fully understood. This review provides a summary and critical evaluation of two epigenetic mechanisms, DNA methylation and non-coding RNA expression, on transcriptional modulation in nociceptive pathways during the development of tissue injury-associated pain. We assess the pre-clinical data and their translational implication and evaluate the potential of controlling DNA methylation and non-coding RNA expression as novel analgesic approaches and/or biomarkers of persistent pain.

Special Issue: Anti-Inflammatory Activity of Plant Polyphenols 2.0

Inflammation is a complex process that occurs in response to infections or other tissue damages, such as trauma, wounds, burns, and toxic substances [...]

Meta-Analysis of IBD Gut Samples Gene Expression Identifies Specific Markers of Ileal and Colonic Diseases

Background Inflammatory bowel diseases (IBDs) are characterized by chronic inflammation and tissue damages in limited segments of the digestive tract. Pathogenesis in the tissue and mucosal inflammation probably differs according to disease location. Our aim was to further analyze transcriptomic profiles in different locations of IBD, differentiating ulcerative colitis (UC), colonic Crohn’s disease (CD), ileal CD, and pouchitis, with respect to normal colonic and ileal mucosa. We thus performed a meta-analysis focusing on specific transcriptomic signatures of ileal and colonic diseases. Methods We identified 5 cohorts with available transcriptomic data in ileal or colonic samples from active IBD and non-IBD control samples. The meta-analysis was performed on 1047 samples. In each cohort separately, we compared gene expression in CD ileitis and normal ileum; in CD colitis, UC, and normal colon; and finally in pouchitis and normal ileum. Results We identified specific markers of ileal (FOLH1, CA2) and colonic (REG3A) inflammation and showed that, with disease, some cells from the ileum start to express colonic markers. We confirmed by immunohistochemistry that these markers were specifically present in ileal or colonic diseases. We highlighted that, overall, colonic CD resembles UC and is distinct from ileal CD, which is in turn closer to pouchitis. Conclusions We demonstrated that ileal and colonic diseases exhibit specific signatures, independent of their initial clinical classification. This supports molecular, rather than clinical, disease stratification, and may be used to design drugs specifically targeting ileal or colonic diseases.

IL-20 Cytokines Are Involved in Epithelial Lesions Associated with Virus-Induced COPD Exacerbation in Mice

(1) Background: viral infections are a frequent cause of chronic obstructive pulmonary disease (COPD) exacerbations, which are responsible for disease progression and mortality. Previous reports showed that IL-20 cytokines facilitate bacterial lung infection, but their production and their role in COPD and viral infection has not yet been investigated. (2) Methods: C57BL/6 WT and IL-20 Rb KO mice were chronically exposed to air or cigarette smoke (CS) to mimic COPD. Cytokine production, antiviral response, inflammation and tissue damages were analyzed after PVM infection. (3) Results: CS exposure was associated with an increase in viral burden and antiviral response. PVM infection in CS mice enhanced IFN-γ, inflammation and tissue damage compared to Air mice. PVM infection and CS exposure induced, in an additive manner, IL-20 cytokines expression and the deletion of IL-20 Rb subunit decreased the expression of interferon-stimulated genes and the production of IFN-λ2/3, without an impact on PVM replication. Epithelial cell damages and inflammation were also reduced in IL-20 Rb-/- mice, and this was associated with reduced lung permeability and the maintenance of intercellular junctions. (4) Conclusions: PVM infection and CS exposure additively upregulates the IL-20 pathway, leading to the promotion of epithelial damages. Our data in our model of viral exacerbation of COPD identify IL-20 cytokine as a potential therapeutic target.

Impairment of T cells' antiviral and anti-inflammation immunities may be critical to death from COVID-19

Clarifying dominant factors determining the immune heterogeneity from non-survivors to survivors is crucial for developing therapeutics and vaccines against COVID-19. The main difficulty is quantitatively analysing the multi-level clinical data, including viral dynamics, immune response and tissue damages. Here, we adopt a top-down modelling approach to quantify key functional aspects and their dynamical interplay in the battle between the virus and the immune system, yielding an accurate description of real-time clinical data involving hundreds of patients for the first time. The quantification of antiviral responses gives that, compared to antibodies, T cells play a more dominant role in virus clearance, especially for mild patients (96.5%). Moreover, the anti-inflammatory responses, namely the cytokine inhibition and tissue repair rates, also positively correlate with T cell number and are significantly suppressed in non-survivors. Simulations show that the lack of T cells can lead to more significant inflammation, proposing an explanation for the monotonic increase of COVID-19 mortality with age and higher mortality for males. We propose that T cells play a crucial role in the immunity against COVID-19, which provides a new direction–improvement of T cell number for advancing current prevention and treatment.

Programmed Cell Death Pathways in the Pathogenesis of Idiopathic Inflammatory Myopathies

Idiopathic inflammatory myopathy (IIM) is a heterogeneous group of acquired, autoimmune muscle diseases characterized by muscle inflammation and extramuscular involvements. Present literatures have revealed that dysregulated cell death in combination with impaired elimination of dead cells contribute to the release of autoantigens, damage-associated molecular patterns (DAMPs) and inflammatory cytokines, and result in immune responses and tissue damages in autoimmune diseases, including IIMs. This review summarizes the roles of various forms of programmed cell death pathways in the pathogenesis of IIMs and provides evidence for potential therapeutic targets.

Accidents in agriculture involving muscle skeletal system in children. Analysis based on hospitalization in the Paediatric Orthopaedics and Rehabilitation Department University Children’s Hospital in 2010-2019

Introduction. Accidents in agriculture involving children happen every year. They are attributable to a lack of safety and low awareness of caretakers, who oftentimes don’t pay enough attention to the little ones. Injuries in agriculture involve mainly falls from great heights: ladders, trailers, tractors; crushing by various types of agricultural machinery; partial or complete amputations within the regions of upper and lower limbs: amputations of feet or fingers. Those cases often include multi-tissue damages, which means that in addition to bone fractures, there might also occur other concurrent injuries like interstitial infections, crushing, neurovascular damages, or soft tissue damage. Material and Methods. In the years 2010-2019 there were 207 patients hospitalized in the Paediatric Orthopaedics and Rehabilitation Department of University Children’s Hospital in Lublin due to accidents in agriculture. Patients who suffered bone injuries, either caused by falling from heights or falling from agricultural machines, constitute the majority of the total 207 cases. The second case in terms of frequency, were the children whose limbs got stuck, or struck, by moving parts of agricultural machines and devices, which resulted in amputations at different levels. The third group consisted of patients crushed by agricultural machines or livestock. Results. The following data indicate a gradual decrease in the number of children requiring hospitalization. Between 2010 and 2019 there was a year-onyear decrease of 38.4%. Conclusions. After the analysis of causes and mechanisms of the injuries mentioned before, we conclude that the vast of these accidents could have been avoided if the caretakers looked after children with due attention, and the children were not allowed in the vicinity of currently functioning agricultural machines.

The Efficacy of Silver-Based Electrospun Antimicrobial Dressing in Accelerating the Regeneration of Partial Thickness Burn Wounds Using a Porcine Model

(1) Background: Wounds with damages to the subcutaneous are difficult to regenerate because of the tissue damages and complications such as bacterial infection. (2) Methods: In this study, we created burn wounds on pigs and investigated the efficacy of three biomaterials: polycaprolactone-gelatin-silver membrane (PCLGelAg) and two commercial burn dressings, Aquacel® Ag and UrgoTulTM silver sulfadiazine. In vitro long-term antibacterial property and in vivo wound healing performance were investigated. Agar diffusion assays were employed to evaluate bacterial inhibition at different time intervals. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and time-kill assays were used to compare antibacterial strength among samples. Second-degree burn wounds in the pig model were designed to evaluate the efficiency of all dressings in supporting the wound healing process. (3) Results: The results showed that PCLGelAg membrane was the most effective in killing both Gram-positive and Gram-negative bacteria bacteria with the lowest MBC value. All three dressings (PCLGelAg, Aquacel, and UrgoTul) exhibited bactericidal effect during the first 24 h, supported wound healing as well as prevented infection and inflammation. (4) Conclusions: The results suggest that the PCLGelAg membrane is a practical solution for the treatment of severe burn injury and other infection-related skin complications.

Quercetin against MCF7 and CAL51 breast cancer cell lines: apoptosis, gene expression and cytotoxicity of nano-quercetin

Aims: To evaluate the anti breast-cancer activity, biocompatibility and toxicity of poly(d,l)-lactic- co-glycolic acid (PLGA)-encapsulated quercetin nanoparticles (Q-PLGA-NPs). Materials & methods: Quercetin was nano-encapsulated by an emulsion–diffusion process, and the nanoparticles were fully characterized through Fourier transform infrared spectroscopy, x-ray diffractions, FESEM and zeta-sizer analysis. Activity against CAL51 and MCF7 cell lines were assessed by DNA fragmentation assays, fluorescence microscopy, and acridine-orange, and propidium-iodide double-stainings. Biocompatibility towards red blood cells and toxicity towards mice were also explored. Results: The Q-PLGA-NPs exhibited apoptotic activity against the cell lines. The murine in vivo studies showed no significant alterations in the liver and kidney's functional biomarkers, and no apparent abnormalities, or tissue damages were observed in the histological images of the liver, spleen, lungs, heart and kidneys. Conclusion: The study established the preliminary in vitro efficacy and in vivo safety of Q-PLGA-NPs as a potential anti-breast cancer formulation.

Immune Functional Capability Dynamics Determine Disease Outcomes as in Cancer, Heart Diseases, COVID-19, Etc.

Having proved flaws in using clinical trials to study weak factors, we want to investigate how life factors affect health and diseases. In this study, we show that cancer, heart disease and infectious diseases are inherently preventable and curable. We would like to find how life factors revolving around environment, emotion, activity, disease agents, diets, behaviors, etc. affect disease outcomes. We expand the scope of the immune functions to include functions for removing garbage and repairing tissue damages, and then identify six classes of health properties for evaluating the immune system’s actual functional capabilities. In this model, personal ability to resist infection depends on the immune system’s current functional capabilities, and the ability to resolve existing diseases depends on the immune system’s actual functional capabilities integrated over a relevant time. We show how each life factor affects the immune system’s current functional capabilities by examining its effects on any of the six classes of properties. Many seemingly irrelevant factors can affect disease outcomes because they share biological resources for removing garbage, repairing tissue damages and maintaining all vital functions. Thus, we found that rational strategies for conquering diseases are identifying disease causes, avoiding exposure to disease agents, detoxifying toxic substances, and using seemingly-irrelevant life factors to boost real-time immune functional capabilities and vital organ functions. All chronic diseases including personal resistance to SARS-CoV-2 are influenced by N and M factors, where N represents the number of factors related to disease causes, and M represents the number of factors that influence the immune functional capacities and organ capacities. Most of N factors are pollutants while most of M factors are created social practices that are formed after industrial revolution. It is time to address toxic substances and examine health-ruining social practices in education, employment, business, litigation, promotion, etc. which is responsible for switching on human stress hormones for months and years, with predictable adverse effects on human health.