The Effects of Convalescent Plasma Transfusion on Serum Levels of Macrophage-Associated Inflammatory Biomarkers in Patients with Severe COVID-19.

As an antibody-based therapy, plasma therapy has been used as an emergency therapeutic strategy against severe acute respiratory syndrome coronavirus type 2 infection. Due to the critical role of macrophages in coronavirus disease-19 (COVID-19)-associated hyperinflammation, the main objective of this study was to assess the effect of plasma transfusion on the expression levels of the inflammatory biomarkers involved in activation and pulmonary infiltration of macrophages. The target population included 50 severe hospitalized COVID-19 patients who were randomly assigned into 2 groups, including intervention and control. Serum levels of chemokine (C-C motif) ligand (CCL)-2, CCL-3, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were measured by enzyme-linked immunosorbent assay. Moreover, quantitative real-time polymerase chain reaction (PCR) was carried out to assess the relative expression of nuclear factor (NF)-κB1, NF-κB2, nuclear factor erythroid 2 p45-related factor 2 (NRF-2), and thioredoxin-interacting protein genes. Sampling was done at baseline and 72 h after receiving plasma. The intervention group demonstrated significantly lower serum levels of IL-6, TNF-α, and CCL-3. In addition, real-time PCR data analyses showed that the relative expression of NF-κB2 was significantly declined in the patients who received plasma. The use of convalescent plasma probably has a significant inhibitory effect on the cytokines, chemokines, and inflammatory genes related to macrophage activation, which are closely associated with the worsening of clinical outcomes in severe COVID-19.

Evaluation the frequencies of HLA alleles in moderate and severe COVID-19 patients in Iran: A molecular HLA typing study.

Background: Severe acute respiratory syndrome coronavirus 2 was first reported in December 2019 and it has spread globally ever since. The HLA system is crucial in directing anti-viral immunity and recent studies are investigating the possible involvement of the HLA genes on the severity of immune inflammation in different phases of COVID-19. Methods: In this cross-sectional study, peripheral blood-extracted genomic DNAs of 109 COVID-19 patients and 70 healthy controls were genotyped for different alleles of HLA-A, HLA-B, and HLA-DRB1 loci using sequence-specific primer PCR method. Results: The results indicated that frequencies of HLA-DRB1*11:01 and HLA-DRB1*04:03 were significantly higher in severe patients rather than moderates (p: <0.001 and 0.004, respectively). Also, it was observed that HLA-DRB1*04:01 was more frequent in moderate patients and healthy controls (p:0.002). In addition, HLA-B*07:35, and HLA-DRB1*07:01 showed higher frequencies in patients compared with controls (p: 0.031 and 0.003 respectively). Inversely, due to the higher frequencies of HLA-B*51:01 (p:0.027), HLA-DRB1*11:05 (p:0.003), HLA-DRB1*13:05 (p:0.022), and HLA-DRB1*14:01 (p:0.006) in healthy individuals rather than patients, they may be associated with COVID-19 resistance. Conclusion: The results show that, based on the population differences, the type of alleles related to the severity of COVID-19 is different, which should be clarified by designing large-scale studies in order to develop HLA-based treatments and vaccines.

Potential Role of SUMO and SUMOylation in the Pathogenesis of Diabetes Mellitus.

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia and associated with multiple organ systems complications. The incidence and prevalence of diabetes are increasing in an epidemic proportion worldwide. In addition to environmental factors, some epigenetic and post-translational modifications have critical roles in the pathogenesis of diabetes and its complications. Reversible covalent modification such as SUMOylation by SUMO (Small Ubiquitin-like Modifier) has emerged as a new mechanism that affects the dynamic regulation of proteins. In this review, we initially focus on the function of SUMO and SUMOylation. Subsequently, we assess the potential effects of this process in the pathogenesis of type 1 and 2 diabetes mellitus.

Evaluation of miRNA-21-5p and miRNA-10b-5p levels in serum-derived exosomes of breast cancer patients in different grades.

BACKGROUND & OBJECTIVES: Tumor cells have various effects and dominance over other healthy cells. Cancer cells alter the cell program in healthy cells by secreting exosomes containing microRNAs involved in epithelial-mesenchymal transition (EMT). They can migrate to distant organs and establish a pre-metastatic niche. The purpose of this study was to determine the expression of miRNA-21-5p and miRNA-10b-5p, both of which are involved in EMT, in breast cancer-derived exosomes of various grades in order to identify new biomarkers involved in breast cancer progression. METHODS: In this study, a blood sample was taken from 60 patients with grades I, II, or III breast cancer, as well as twenty healthy individuals as a control group. The exosomes were then purified from serum samples, and their relative expression of miRNA-21-5p and miRNA-10b-5p was determined using the real-time PCR method. RESULTS: miRNA-21-5p expression was significantly increased in patients with breast cancer grades I, II, and III compared to the control group (p < 0.01), (p < 0.0001) and (p < 0.0001), respectively, as was miRNA-10b-5p expression in patients with breast cancer grades I, II, and III compared to the control group (p < 0.0001), (p < 0.0001) and (p < 0.0001), respectively. CONCLUSION: Our results show that both microRNAs increase as cells lose their differentiation and become more invasive, which is evidence of cancer progression. Hence, both microRNAs may have the potential to be used alone or in combination with other biomarkers for the diagnosis and prognosis of breast cancer.

The therapeutic efficacy of quercetin in combination with antiviral drugs in hospitalized COVID-19 patients: A randomized controlled trial.

In this study, the therapeutic efficacy of quercetin in combination with remdesivir and favipiravir, were evaluated in severe hospitalized COVID-19 patients. Our main objective was to assess the ability of quercetin for preventing the progression of the disease into critical phase, and reducing the levels of inflammatory markers related to SARS-Cov-2 pathogenesis. Through an open-label clinical trial, 60 severe cases were randomly divided into control and intervention groups. During a 7-day period, patients in the control group received antivirals, i.e., remdesivir or favipiravir, while the intervention group was treated with 1000 mg of quercetin daily in addition to the antiviral drugs. According to the results, taking quercetin was significantly associated with partial earlier discharge and reduced serum levels of ALP, q-CRP, and LDH in the intervention group. Furthermore, although the values were in normal range, the statistical outputs showed significant increase in hemoglobin level and respiratory rate in patients who were taking quercetin. Based on our observations, quercetin is safe and effective in lowering the serum levels of ALP, q-CRP, and LDH as critical markers involved in COVID-19 severity. However, according to the non-significant borderline results in comparing the mortality, the ICU-admission rate, and the duration of ICU-admission, further studies can be helpful to compensate the limitations of our study and clarify the therapeutic potential of quercetin in COVID-19 treatments.

Frequency of virulence-associated genotypes of Helicobacter pylori and their correlation with clinical outcome and histological parameters in infected patients.

Helicobacter pylori (H. pylori) is a gram-negative which can cause several gastroduodenal diseases, including gastritis and peptic ulcer disease (PUD). H. pylori specific genotypes have been related to increased occurrence of gastritis and PUD. The aim of this study was to investigate the clinical relevance of the major virulence factors of H. pylori with clinical outcomes and histological parameters in Iranian patients. Totally, 200 subjects with PUD and gastritis disease who underwent gastroduodenal endoscopy were enrolled in this study. The presence of the cagA, vacA, oipA, babA2, and iceA genes in antral gastric biopsy specimens were determined by polymerase chain reaction (PCR) and the results were compared with clinical outcomes and histological parameters. The frequency of babA2 + , oipA + , vacA s1/m2, and vacA m2 genes was significantly higher in patients with peptic ulcer disease compared with patients with gastritis. In contrast, the frequency of vacA s1/m1 gene was significantly higher in gastritis subjects than PUD subjects. The high-density scores of H. pylori were strongly associated with iceA1 ¯ , babA2 + , and oipA + genes. Additionally, the high polymorphonuclear cell infiltration and high mononuclear cell infiltration scores were strongly associated with the cagA + , iceA1 ¯ , oipA + genes and cagA + , babA2 + , oipA + genes, respectively. Our study indicated that the vacA, babA2, and oipA virulence factors are related to a higher risk of PUD in subjects with H. pylori-infection. Infection with these strains was associated with a more severe gastropathy.

A novel mutation in RFXANK gene and low B cell count in a patient with MHC class II deficiency: a case report.

Recurrence of severe microbial infections results from a primary immunodeficiency disorder known as major histocompatibility complex class II deficiency or bare lymphocyte syndrome type II. Immunologic function is severely impaired due to the absence of MHC class II molecules on the surface of immune cells. Here, we report a 5-year-old boy with a novel homozygous mutation in RFXANK gene that negatively affects the proper expression of MHC class II molecules by antigen presenting cells. The frame shift mutations in RFXANK gene and negative HLA-DR proteins expression on peripheral blood mononuclear cells were identified and confirmed by whole exome sequencing, Sanger sequencing, and flow cytometry. The patient was referred with long-term severe prolonged diarrhea, fever, coughing, and vomiting. Also, antibiotic resistance, normal T cell, and NK cell counts with low B cell count and reduced serum immunoglobulin level were observed. The patient did not give a dramatic response to intravenous immunoglobulin infusion. The significancy of this report is the novelty of mutation and low B cell count which is not commonly expected in such patients. The final diagnosis of BLS type II is based on WES, Sanger sequencing, and flow cytometric evaluation. Moreover, it seems that the only therapeutic choice is hematopoietic stem cell transplantation.

Interleukin-22 and intestinal homeostasis: Protective or destructive?

Interleukin (IL)-22 is a member of IL-10 family cytokines with various immunologic functions. As its name implies, IL-22 is known to be secreted mainly by Th22 cells, a recently discovered lineage of CD4+ T cells. Also, Th17, Th1, natural killer cells, γδT cells, and innate immune cells along with some nonlymphoid cells have been confirmed as secondary cellular sources of IL-22. Different cell types such as bronchial and intestinal epithelial cells, keratinocytes, hepatocytes, dermal fibroblasts, and tubular epithelial cells are affected by IL-22. Both pathologic and protective roles have been attributed to IL-22 in maintaining gut homeostasis and inflammation. According to the latest fast-growing investigations, IL-22 is significantly involved in various pathologies including allergic diseases, infection, autoimmunity, and cancer development. Regulating gut immune responses, barrier integrity, and inflammation is dependent on a diverse complex of cytokines and mediators which are secreted by mucosal immune cells. Several investigations have been designed to recognize the role of IL-22 in gastrointestinal immunity. This article tries to discuss the latest knowledge on this issue and clarify the potential of IL-22 to be used in the future therapeutic approaches of intestinal disorders including inflammatory bowel diseases and colon cancer.

The role of protein SUMOylation in rheumatoid arthritis.

Small ubiquitin-like modifier (SUMO) proteins, as a subgroup of post-translational modifiers, act to change the function of proteins. Through their interactions with different targets, immune pathways, and the responses they elicit, can be affected by these SUMO conjugations. Thus, both a change to protein function and involvement in immune pathways has the potential to promote an efficient immune response to either a pathogenic challenge, or the development of an imbalance that could lead to an autoimmune-based disease. Also, a variety of changes such as mutations and polymorphisms can interfere with common functions of these modifications and move an effective immune response in the direction of an autoimmune disease. The present review discusses the general characteristics of SUMO proteins and focuses on their involvement in rheumatoid arthritis as an autoimmune disease.

The Role of Inflammatory Cytokines in Creating T Cell Exhaustion in Cancer.

Secreted inflammatory cytokines are considered as critical mediators in the tumor microenvironment. Cancer cells play a significant role in the differentiation of effector T cells to exhausted T cells through mediator production. Effector T cells that undergo tumor microenvironment become terminally differentiated into exhausted T cells. These changes create an opportunity for tumorigenesis and invasion of cancer cells. Despite having some characteristics of effector T cells, the exhausted T cells lose their antitumor properties. In this article, the phenotypes and function of exhausted T cells were reviewed and the expression pattern of inflammatory cytokines in tumor tissues and peripheral blood of cancer patients were described. Additionally, the effects of inflammatory cytokines on intracellular factors and signals of T lymphocyte cells were explained. In conclusion, the authors referred to probable approaches that could be used to improve the antitumor activity of T cells and intervention into T cell exhaustion.

The regulatory role of Nrf2 in antioxidants phase2 enzymes and IL-17A expression in patients with ulcerative colitis.

BACKGROUND: Reactive oxygen species (ROS) is one of the pathogenic factors responsible for intestinal injury in Ulcerative colitis (UC). Nuclear factor erythroid-2 related factor 2 (Nrf2) plays a critical role against ROS factors to conserve epithelial integrity. This study aimed to localize Nrf2 and IL-17A protein in the inflamed mucosa of patients with ulcerative colitis. The gene expression of Nrf2 was also correlated with GST-A4 and PRDX1. MATERIALS AND METHODS: A total of 20 patients and 20 healthy controls with definite UC based on the clinical criteria were enrolled for this study. The expression pattern of Nrf2 and IL-17A protein was compared in inflamed and non-inflamed colonic biopsies by immunohistochemical staining. Nrf2, GST-A4 and PRDX1 gene expression were determined by real-time polymerase chain reaction (RT-PCR). RESULTS: In inflamed colonic biopsies, an increased level of Nrf2 protein factor was detected in epithelial cells. Conversely, IL-17A protein was presented more in mononuclear cells in mucosa and lamina propria regions. A significant increase of Nrf2, GST-A4 gene expression was observed in both mild and severe patients with ulcerative colitis. GST-A4 gene expression indicated a high exponential rate in logistic regression. CONCLUSION: Oxidative stress in inflamed colonic tissue can induce Nrf2 gene expression. The performance of Nrf2 transcription factor may lead to the induction of GST-A4 and PRDX1. IL-17A is less detected in intestinal inflammation, presenting Nrf2 factor. The present findings suggest that Nrf2 function in the gut plays a role in arresting both inflammatory response and oxidative damages of UC.

Intensified Th9 Response is Associated with the Immunopathogenesis of Active Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disorder of the large intestine histologically characterized by indistinct sustained inflammatory responses. Genetical susceptibility and environmental factors' effects play the roles in disease occurrence and it can be life threatening if remains untreated. It seems that intensification of inflammatory responses in this condition is not restricted to a specific cell line of T lymphocytes. Our aim was to determine the number of T helper 9 (Th9) cells in inflamed colonic biopsies of UC patients. We also correlated it with interleukin (IL)-9 protein level in addition to certain genes expressions associated with Th9 phenotype. METHODS: Expression of CD4 and IL-9 were evaluated by immunohistochemical staining. Enzyme linked immunosorbent assay (ELISA) was performed to determine the colonic expression of IL-9 protein and finally mRNA expressions of interferon regulatory factor 4 (Irf4), Smad2, and Smad3 were measured by real-time polymerase chain reaction (RT-PCR) as critical transcription factors of Th9 differentiation. RESULTS: Number of Th9 cells was significantly increased in inflamed samples as compared with normal tissues. Also quantitative measurement of IL-9 by ELISA and mRNA expressions of Irf4, Smad2, and Smad3 showed notable correlative enhancements in patient's samples. CONCLUSION: Function and number of Th9 cells are up-regulated in the inflamed mucosa of UC patients as with the protein secretion of IL-9 and mRNA expressions of Irf4, Smad2, and Smad3, so Th9 cells and IL-9 may become remarkable therapeutic targets for IBD treatment in the future.

The expression analysis of Fra-1 gene and IL-11 protein in Iranian patients with ulcerative colitis.

BACKGROUND: Fra-1 (fosl1) belongs to the activator protein1 (AP-1) family inducing IL-11 expression in oxidative stress condition. IL-11 plays a pivotal role in protecting epithelial barriers integrity. In this study, we investigated the Fra-1 gene expression in the inflamed mucosa of patients with ulcerative colitis (UC) as well as its relation to IL-11 expression. MATERIALS AND METHODS: We enrolled 20 patients and 20 healthy controls with definite UC based on the clinical criteria. Fra-1 gene expression in inflamed and non-inflamed colonic biopsies was determined by real-time polymerase chain reaction (RT-PCR). The IL-11 protein concentration was measured by Enzyme-Linked Immunosorbent Assay (ELISA) method. Pearson correlation was applied to calculate the relation between Fra-1 and IL-11. RESULTS: An increased level of Fra-1 gene expression was observed in patients with mild ulcerative colitis. The protein concentration of IL-11 was also increased in mild UC patients. Conversely, a significant decrease of IL-11 protein level was detected in severe UC patients compared to control group. CONCLUSION: Oxidative stress in inflamed intestinal biopsies can induce fra-1 gene expression. Our findings suggest that Fra-1 transcription factor leads to the production of IL-11 protein in UC patients.

Th9 Cells: Probable players in ulcerative colitis pathogenesis.

T lymphocytes represent an important part of adaptive immune system undertaking different functions to regulate immune responses. CD4+ T cells are the most important activator cells in inflammatory conditions. Depending on the type of induced cells and inflamed sites, expression and activity of different subtypes of helper T cells are changed. Recent studies have confirmed the existence of a new subset of helper T lymphocytes called Th9. Naive T cells can differentiate into Th9 subtypes if they are exposed simultaneously by interleukin (IL) 4 and transforming growth factor ß and also secondary activation of a complicated network of transcription factors such as interferon regulatory factor 4 (IRF4) and Smads which are essential for adequate induction of this phenotype. Th9 cells specifically produce interleukin 9 and their probable roles in promoting intestinal inflammation are being investigated in human subjects and experimental models of ulcerative colitis (UC). Recently, infiltration of Th9 cells, overexpression of IL-9, and certain genes associated with Th9 differentiation have been demonstrated in inflammatory microenvironment of UC. Intestinal oversecretion of IL-9 protein is likely to break down epithelial barriers and compromise tolerance to certain commensal microorganisms which leads to inflammation. Th9 pathogenicity has not yet been adequately explored in UC and they are far from being considered as inflammatory cells in this milieu, therefore precise understanding the role of these newly identified cells in particular their potential role in gut pathogenesis may enable us to develop novel therapeutic approaches for inflammatory bowel disease. So, this article tries to discuss the latest knowledge on the above-mentioned field.