The interaction of inflammasomes and gut microbiota: novel therapeutic insights.

Inflammasomes are complex platforms for the cleavage and release of inactivated IL-1ß and IL-18 cytokines that trigger inflammatory responses against damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). Gut microbiota plays a pivotal role in maintaining gut homeostasis. Inflammasome activation needs to be tightly regulated to limit aberrant activation and bystander damage to the host cells. Several types of inflammasomes, including Node-like receptor protein family (e.g., NLRP1, NLRP3, NLRP6, NLRP12, NLRC4), PYHIN family, and pyrin inflammasomes, interact with gut microbiota to maintain gut homeostasis. This review discusses the current understanding of how inflammasomes and microbiota interact, and how this interaction impacts human health. Additionally, we introduce novel biologics and antagonists, such as inhibitors of IL-1ß and inflammasomes, as therapeutic strategies for treating gastrointestinal disorders when inflammasomes are dysregulated or the composition of gut microbiota changes.

Serum IL-33 Is Elevated in Children with Asthma and Is Associated with Disease Severity.

BACKGROUND: The role of IL-33, a member of the IL-1 family, in airway hyperresponsiveness and asthma has still to be fully understood. OBJECTIVES: This study is aimed at investigating serum IL-33 in children with asthma and its association with asthma severity. METHODS: This age- and sex-matched case-control study comprised 61 children with asthma and 63 healthy controls. The mean age of the participants was 9.21 years (range: 6-14). Serum IL-33 was measured using ELISA and was compared between children with asthma and controls. In addition, the association of serum IL-33 with asthma severity was investigated. RESULTS: The level of serum IL-33 was significantly higher in children with asthma than in controls (15.17 ± 32.3 vs. 0.61 ± 2.16 pg/ml; p = 0.028). It was significantly increased proportionately to asthma severity, namely 9.92 ± 30.26 pg/ml in children with mild asthma, 13.68 ± 29.27 pg/ml in children with moderate asthma and 31.92 ± 41.45 pg/ml in children with severe asthma (p = 0.026). CONCLUSION: Serum IL-33 is increased in children with asthma and is associated with disease severity.

Clues of HLAs, metabolic SNPs, and epigenetic factors in T cell-mediated drug hypersensitivity reactions.

Drug hypersensitivities are common reactions due to immunologic responses. They are of utmost importance because they may generate severe and fatal outcomes. Some drugs may cause Adverse Drug Reactions (ADRs), such as drug hypersensitivity reactions (DHRs), which can occur due to the interaction of intact drugs or their metabolites with Human Leukocyte Antigens (HLAs) and T cell receptors (TCRs). This type develops over a period of 24-72 h after exposure and is classified as type IV of DHRs. Acute generalized exanthematic pustulosis (AGEP), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) are types of Severe Cutaneous Adverse Reactions (SCARs). In this review, we aim to discuss the types of ADRs, the mechanisms involved in their development, and the role of immunogenetic factors, such as HLAs in type IV DHRs, single-nucleotide polymorphisms (SNPs), and some epigenetic modifications, e.g., DNA/histone methylation in a variety of genes and their promoters which may predispose subjects to DHRs. In conclusion, development of promising novel in vitro or in vivo diagnostic and prognostic markers is essential for identifying susceptible subjects or providing treatment protocols to work up patients with drug allergies as personalized medicine.

Assessment of Human Leukocyte Antigen Differences between Smokers with Reinke's Edema and Those with Laryngeal Cancer.

Introduction: The present study aimed to assess human leukocyte antigen (HLA) typing differences between smokers with Reinke's edema and those with laryngeal squamous cell carcinoma (SCC). Materials and Methods: The HLA class I, II alleles were examined in 76 unrelated Iranian patients using low-resolution polymerase chain reaction with the sequence-specific primer (PCR-SSP) method. Results: The frequency of the HLA-A*36 allele and HLA-B*35 was significantly higher in patients with SCC. The frequency of HLA-DRB1*01 alleles in Reinke's edema was significantly higher, as compared to that in others. In the volunteer group, HLA-DRB1*13 and HLA-DRB1*15 were significantly higher. Conclusions: As evidenced by the obtained results, HLA-A*36 was significantly higher in SCC, as compared to that in volunteers and Reinke's edema patients. It can be concluded that being positive for HLA-A*36 increases the chance of SCC by three times. This result should be further investigated in cohort studies conducted on larger samples. Furthermore, HLA-A*24 was significantly higher in the volunteer group, as compared to that in other groups. The HLADRB1*01 was remarkably higher in Reinke's edema, as compared to that in SCC.

Molecular characterization of polymorphisms among Pseudomonas aeruginosa strains isolated from burn patients' wounds.

Pseudomonas aeruginosa is one of the most common reasons for nosocomial infections. Given the high morbidity and mortality, as well as the cost of management, particularly in developing countries, burn injuries are considered important health concerns. Owing to the increased rate of resistance against antibiotics, this study aimed to isolate Pseudomonas aeruginosa strains from burn patient's wounds by analyzing antibiotic susceptibility and genetic profiling. In this regard, we explored the relationship between the nucleotide sequence and antibiotic susceptibility. In this cross-sectional study, 107 isolates of P. aeruginosa were collected from a major burn center in Tehran, Iran. The isolates were characterized with standard biochemical tests and examined by applying the Disk Diffusion method to find the patterns of sensitivity, and their genetic relationship was revealed by RAPD-PCR method. According to the antibiogram results, most of the isolates were resistant to 3 or more antibiotics tested and the most sensitivity was related to the Colistin antibiotic. RAPD-PCR method revealed a high polymorphism among P. aeruginosa isolates in Tehran. There was no significant association between the genotype groups and antibiotic susceptibility profiles. We evaluated the pattern of resistance to pathogenic organisms and identified multi-drug resistant organisms. Currently, Colistin antibiotic is the most suitable treatment option for burned patients. RAPD-PCR is a genotyping method with high efficiency for typing and categorizing different isolates of MDR-P. aeruginosa.

Comparison of WBC, ESR, CRP and PCT serum levels in septic and non-septic burn cases.

Diagnosis of sepsis is difficult, particularly in cases of burn where signs of sepsis may be present in the absence of a real infection. This study compared serum levels of procalcitonin (PCT), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cell (WBC) among 60 burned people with and without infection, in order to assess the value of the information for diagnosis of sepsis. A significantly higher PCT level was observed in the septic group compared to those without sepsis (8.45+/-7.8 vs. 0.5+/-1.0, respectively, p<0.001); no significant differences were found in CRP or WBC levels, neutrophil count or ESR. The area under the receiver operating characteristics curve in the diagnosis of sepsis was 0.97 for PCT (p<0.001) with sensitivity of 100% and specificity of 89.3%. Non-survivors had a mean PCT level significantly higher than that of survivors. Thus the serum PCT level was a highly efficient laboratory parameter for the diagnosis of severe infectious complications after burn, but WBC, neutrophil, ESR and CRP levels were of little value.

Immunoprotective role of indoleamine 2,3-dioxygenase in engraftment of allogenic skin substitute in wound healing.

Delayed wound healing can significantly impact survival of patients who suffer from severe thermal injury. In general, the use of a wound coverage, particularly with those of bilayer skin substitute, would be ideal to promote healing and prevent infection and fluid loss. Although the use of an autologous skin substitute is desirable, its preparation is time consuming and its immediate availability is impossible. To overcome this difficulty, the authors have previously demonstrated that the expression of indoleamine 2,3 dioxygenase (IDO) could function as a local immune suppressive factor in protecting allogenic fibroblasts and keratinocytes without using any immunosuppressive medication in a wound healing animal model. IDO, which is naturally expressed in the placenta by trophoblast cells during pregnancy, plays an essential role in maternal tolerance toward the fetus. The potent and selective local immunosuppressive function of IDO makes this enzyme a very promising tool for engineering a nonrejectable skin allograft. Here, the authors reviewed and discussed how the expression of IDO by the primary cells of our skin substitute can serve as a source of IDO enzyme activity and generate a tryptophan-deficient environment. Under this condition, only skin cells but not immune cells (CD4(+) and CD8(+) cells) would survive and protect engraftment of this engineered and shelf-ready skin substitute to be used not only as wound coverage but also as a rich source of wound healing promoting factors. Therefore, this review summarizes the body of work on immunoprotective role of IDO in engraftment of allogenic skin substitute in wound healing, which has recently been reported by the authors' research group and others.

Electrospun chitosan-gelatin nanofiberous scaffold: fabrication and in vitro evaluation.

In this study, chitosan and gelatin solutions were blended at five different ratios. Samples were fed into electrospinning apparatus to produce non-woven nanofibrous mats. Scanning electron microscopy (SEM) showed that the low-viscosity sample with 30% chitosan and 70% gelatin (sample 30/70) formed the least amount of beads and droplets and yielded fibers with the highest morphological uniformity. To examine the effect of processing parameters on fibers morphology and nanofibers diameter, flow rate, voltage and distance between needle to the collector were changed in the sample 30/70. SEM revealed that high voltages (25 kV) and flow rates (1.5 ml·h⁻¹) decrease the uniformity of fibers and lead to bead and droplet formation. It has also shown that the distance between the tip and the collector have no significant effect on fibers' structure. The values of 15 kV (voltage), 0.2 ml·h⁻¹ (flow rate) and the fixed distance of 15 cm were identified as the optimal electrospinning conditions, which produce fibers with a mean diameter of 180±20 nm. Fourier transform infrared (FTIR) experiment revealed an increase in N-H bending and decrease in C-O stretching vibration in both chitosan and gelatin at 1060 and 1148 cm⁻¹. The in vitro biocompatibility tests performed with human skin fibroblasts showed excellent cell proliferation (MTT assay) and attachment (SEM) on these scaffolds confirming its highly acceptable biological properties.

Imipenem-resistant Pseudomonas aeruginosa strains carry metallo-beta-lactamase gene bla(VIM) in a level I Iranian burn hospital.

INTRODUCTION: In this study, we aimed to determine the distribution of bla(VIM) and bla(IMP) transferable genes in Pseudomonas aeruginosa isolates from infected burn wounds in an Iranian level I burn care center. These genes confer imipenem resistance and increase the mortality rate of burn patients. METHODS: P. aeruginosa isolates from burn patients were tested for antibiotic susceptibility with Kirby-Bauer disk diffusion method and for production of metallo-beta-lactamase (MBL) by EDTA disk method. DNA was purified from isolates with positive MBL results and underwent PCR for detection of bla(VIM) and bla(IMP) genes. RESULTS: MBL was produced by 23 imipenem-resistant isolates and bla(VIM) gene was detected in all of these isolates. None of the isolates carried bla(IMP) gene. Mortality rate of infection with MBL-producing Pseudomonas strains was 82.6% in this hospital while the mortality rate for non-MBL-producing Pseudomonas was 22.7%. CONCLUSION: We found that all MBL-producing isolates in this hospital carry bla(VIM) gene. This result is similar to the previous Iranian study and emphasizes the importance of VIM family of MBLs in Iran. Timely identification of these strains and strict isolation methods can prevent spread of this transferable gene to other Gram-negative bacteria and prevent the subsequent outbreak of high mortality.

The immunoregulatory function of indoleamine 2, 3 dioxygenase and its application in allotransplantation.

Indolemine 2, 3-dioxygenase (IDO) is a cytosolic monomeric hemoprotein enzyme that catalyses tryptophan, the least available essential amino acid in the human body, to N-formylkynurenine, which in turn rapidly degrades to give kynurenine. IDO is expressed in different tissues, especially and prominently in some subsets of antigen presenting cells (APCs) of lymphoid organs and also in the placenta of human and other mammals. Expression of IDO by certain dendritic cells, monocytes and macrophages has a regulatory effect on T cells probably by providing a tryptophan-deficient microenvironment and/or accumulation of toxic metabolites of tryptophan. This immunomodulatory function of IDO plays an essential role in different physiological and pathological states. IDO was shown to prevent rejection of the fetus during pregnancy, possibly by inhibiting alloreactive T cells. Moreover, IDO expression in APCs was suggested to control autoreactive immune responses. In this review we discuss the molecular and biological characteristics of IDO and its function in immune system as well as the potential application of this enzyme in improving the outcome of allogeneic transplantation as a local immunosuppressive factor.

Investigation on mitochondrial tRNA(Leu/Lys), NDI and ATPase 6/8 in Iranian multiple sclerosis patients.

As with chromosomal DNA, the mitochondrial DNA (mtDNA) can contain mutations that are highly pathogenic . In fact, many diseases of the central nervous system are known to be caused by mutations in mtDNA. Dysfunction of the mitochondrial Respiratory Chain (RC) has been shown in patients with neurological disease including Alzheimer's disease (AD), Parkinson's disease (PD) and Multiple sclerosis (MS). MS is a demyelinating disease of central nervous system characterized by morphological hallmarks of inflammation, demyelination and axonal loss. Considering this importance, we decided to investigate several highly mutative parts of mtDNA for point mutations as MT-LTI (tRNA(Leucine1(UUA/G))), MT-NDI (NADH Dehydrogenase subunit 1), MT-COII (Cytochrome c oxidase subunit II), MT-TK (tRNA(Lysine)), MT-ATP8 (ATP synthase subunit F0 8) and MT-ATP6 (ATP synthase subunit F0 6) in 20 Iranian MS patients and 80 age-matched control subjects by PCR and automated DNA sequencing to evaluate any probable point mutations. Our results revealed that 15 (75%) out of 20 MS patients had point mutations. Some of point mutations were newly found in this study. This study suggested that point mutation occurred in mtDNA might be involved in pathogenesis of MS.