Immunogenicity of mannan derived from Mycobacterium bovis as a promising adjuvant in vaccine BCG.

Background and Objectives: Lipoarabinomannan is one of the components of the significant structural cell surfaces of mycobacteria and serves as an immunostimulatory factor. TNF-α and IL-12 are two examples of the anti-bacterial inflammatory cytokines that are activated and induced during infection. Materials and Methods: In this study, mannan was extracted and processed, and then Bulb/c female mice were used in three groups, one group was given BCG vaccine, the other group was given BCG vaccine with mannan adjuvant, and a non-injected group was used as a control group. Inflammatory factors interleukin-12, TNF-α, IgG and IgM were measured in mouse serum. Results: The levels of the inflammatory factors interleukin-12 and TNF-α in the serum isolated from mice receiving the BCG vaccine with mannan adjuvant showed a significant difference compared to the group that received only the BCG vaccine and the control group [IL-12] and , with P≤0.05.The examination of the level of IgG immune factors in these three groups revealed a significant difference. The group that received the BCG vaccine with mannan adjuvant showed a marked contrast compared to the group that received only the BCG vaccine and the control group, with P≤0.05. The level of IgM was higher in the group that received the BCG vaccine alone compared to the adjuvant vaccine group and the control group, with P≤0.05. Conclusion: Our results indicated that mice receiving the BCG vaccine with mannan adjuvant had significantly higher serum levels of IL-12, TNF-α, and IgG than the group receiving BCG alone.

Predictive Value Alteration of Laboratory Routine and Ferritin/Transferrin Ratio in Monitoring of COVID-19 Patients.

BACKGROUND: Inflammatory processes activated by rapid viral replication of SARS-CoV-2 can play a key role in the pathogenesis of multiple organ damage and be responsible for the COVID-19 patients' dramatic outcomes and common abnormal laboratory findings. The aim of this study was to assess the correlation between various laboratory biomarkers, ferritin/transferrin ratio (FTR) and receiver operating characteristic (ROC) analysis in monitoring COVID-19 patients. METHODS: This observational study was conducted in three groups: healthy participants, non COVID-19 patients with COVID-19-like clinical signs, and COVID-19 patients (severe and non-severe). Biochemical (CRP, ferritin, transferrin and albumin) and hematological (WBC, lymphocytes) parameters were assessed by automated methods. Moreover, FTR and NLR markers were calculated in the three groups mentioned. Statistical analyses were done using R (version 4.1.0). ROC curve was used to validate the predictive value of parameters. RESULTS: The COVID-19 positive group had significantly higher NEU, CRP, ferritin, FTR values, while it's WBC, absolute counts of lymphocytes and albumin were significantly lower compared to the non-COVID-19 patients (p < 0.001). Serum ferritin and FTR level of the severe group was significantly higher than that of the non-severe group (p = 0.006 and (p = 0.011, respectively). The strongest correlation in all subjects showed between lymphocytopenia and increased NEU (r = -0.99, p < 0.001). The AUC values of WBC (0.95), lymphocytes (0.89), NEU (0.88), and NLR (0.88) were higher than CRP (0.64) or Ferritin (0.81). CONCLUSIONS: We recommend using FTR, WBC, and NLR changes as simple, useful, and inexpensive indicators in early detection of COVID-19 patients.

Genetics of Familial Combined Hyperlipidemia (FCHL) Disorder: An Update.

Familial combined hyperlipidemia (FCHL) is one of the most common familial lipoprotein disorders of the lipoproteins, with a prevalence of 0.5% to 2% in different populations. About 10% of these patients suffer from cardiovascular disease and this number is increased by up to 11.3% in the young survivors of myocardial infarction and by 40% among all the survivors of myocardial infarction. Although initially thought to be that FCHL has an inheritance pattern of monogenic, the disease's etiology is still not fully understood and it appears that FCHL has a complex pattern related to genetic variants, environmental factors, and lifestyles. Two strategies have been used to identify its complex genetic background: candidate gene and the linkage approach, which have yielded an extensive list of genes associated with FCHL with a variable degree of scientific evidence. Until now, more than 30 different genetic variants have been identified related to FCHL. In this study, we aimed to review the individual genes that have been described in FCHL and how these genes and variants can be related to the current concept of metabolic pathways resulting in familial combined hyperlipidemia.

Association between serum inflammatory parameters and the disease severity in COVID-19 patients.

OBJECTIVE: Most patients infected with the novel coronavirus (SARS-CoV-2), as the causative agent of COVID-19 disease, show mild symptoms, but some of them develop severe illness. The purpose of this study was to analyze the blood markers of COVID-19 patients and to investigate the correlation between serum inflammatory cytokines and the disease severity. METHODS: In this prospective cross-sectional study, 50 patients with COVID-19 and 20 patients without COVID-19 were enrolled. According to ICU admission criteria, patients were divided into two groups of non-severe and severe. Differences in the serum levels of C-reactive protein (CRP), IL-6, and TNF-α, as well as erythrocyte sedimentation rate (ESR), lymphocytes (LYM) count, and neutrophils (NEU) count between the two groups were determined and analyzed. RESULTS: Out of the 50 patients with COVID-19, 14 were diagnosed as severe cases. There was no significant difference between the two groups of COVID-19 patients in terms of gender and age. Blood tests of COVID-19 patients showed a significant decrease and increase in NEU and LYM counts, respectively. There were significant differences in the serum levels of IL-6, TNF-α, and CRP between the severe and non-severe groups, which were higher in the severe group. Also, there was a significant correlation between the disease severity and CRP with ESR (r = 0.79), CRP with IL-6 (r = 0.74), LYM with NEU (r = -0.97), and ESR with TNF-α (r = 0.7). CONCLUSION: The findings of this study, as the first study in Iran, suggest that the levels of IL-6, TNF-α, ESR, and CRP could be used to predict the severity of COVID-19 disease.

Neutrophil to lymphocyte ratio and C-reactive protein level as prognostic markers in mild versus severe COVID-19 patients.

AIM: This research aimed to investigate neutrophil-to-lymphocyte ratio (NLR) with C-reactive protein to identify potential clinical predictors and analyze differences among severe and non-severe COVID-19 patients. BACKGROUND: NLR and CRP are established markers that reflect systemic inflammatory, and these parameters alter in patients with novel coronavirus (SARS-CoV-2) pneumonia (COVID-19). METHODS: A population of patients with COVID-19 referred to Loghman Hospital in Tehran was analyzed. The baseline data of laboratory examinations, including NLR and CRP levels, was collected. Pearson analysis was used to assess the independent relationship between the NLR with disease severity and CRP levels. RESULTS: COVID-19 cases comprised 14 (20%) patients with severe disease and 56 (80%) with non-severe infection. The mean values of WBC, NEU, LYM, and NLR of the severe patients were significantly higher than those of the non-severe patients. Forty-six patients (65.7%) had NLR >1, and the remaining patients had NLR <1. Plasma CRP levels were higher in severe cases than in non-severe cases, and this difference was significant. The results showed that NLR was positively correlated with CRP levels (R=0.23) and negatively correlated with WBC (R=-0.38). CRP (AUC = 0.97, 95% CI: 0.95-0.99) and NLR (AUC = 0.87, 95% CI: 0.81-0.93) had very good accuracy in predicting the severity of COVID-19 disease. CONCLUSION: The findings of this study indicated that the integration of NLR and CRP may lead to improved predictions and is recommended as a valuable early marker to assess prognosis and evaluate the severity of clinical symptoms in COVID-19 patients.

Nanomicellar-curcumin exerts its therapeutic effects via affecting angiogenesis, apoptosis, and T cells in a mouse model of melanoma lung metastasis.

BACKGROUND: Curcumin is a natural phytochemical polyphenol with significant anti-cancer effects and negligible side effects. In this study, the therapeutic capacity of nanomicellar-curcumin for treating lung metastasis was evaluated in an immunocompetent mouse model of metastatic melanoma. MARTIALS AND METHODS: Two doses of nanomicellar-curcumin (i.e. 10 and 20 µM) were used to induce cytotoxicity in 3 melanoma cell lines. A total of 60 mice were allocated to 20 mice in each of three groups (10 for survival and 10 for assays). Groups were no treatment control, PBS control, nanomicellar-curcumin 20 mg/kg IP 4 times a week, for three weeks). Immunohistochemistry, TUNEL assay, and Western blots were used on lung samples. RESULTS: Nanomicellar-curcumin inhibited the in vitro growth of B16 F10 melanoma cells at 20 µM over 72 h. In vivo, 20 mg/kg nanomicellar-curcumin injected IP, delayed tumor cell growth and significantly extended mouse survival rate. Tumor infiltration of regulatory T cells and angiogenesis were reduced, while IFN-γ and CXCL10 were increased. CONCLUSION: Nanomicellar-curcumin can inhibit lung metastasis and growing melanoma via activation of apoptosis, activated T cells and inhibition of angiogenesis, tumor growth and regulatory T cells.

Combination Therapy with Nanomicellar-Curcumin and Temozolomide for In Vitro Therapy of Glioblastoma Multiforme via Wnt Signaling Pathways.

Glioblastoma (GBM) is the most serious brain tumor and shows a high rate of drug resistance. Wnt signaling is a very important pathway in GBM that can activate/inhibit other pathways, such as apoptosis and autophagy. In this study, we evaluated the efficacy of a combination of temozolomide (TMZ) plus curcumin or nanomicellar-curcumin on the inhibition of GBM growth in vitro, via effects on autophagy, apoptosis, and the Wnt signaling pathway. Two concentrations of curcumin and nanomicellar-curcumin (i.e., 20 µM and 50 µM) alone, and in combination with TMZ (50 µM) were used to induce cytotoxicity in the U87 GBM cell line. Wnt signaling-, autophagy-, and apoptosis-related genes were assessed by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blots. All treatments (except 20 µM curcumin alone) significantly decreased the viability of U87 cells compared to controls. Curcumin (50 µM), nanomicellar-curcumin alone and in combination with TMZ significantly decreased the invasion and migration of U87 cells. Autophagy-related proteins (Beclin 1, LC3-I, LC3-II) were significantly increased. Apoptosis-related proteins (Bcl-2 and caspase 8) were also significantly increased, while Bax protein was significantly decreased. The expression levels of Wnt pathway-associated genes (ß-catenin, cyclin D1, Twist, and ZEB1) were significantly reduced.

A novel variant in C5ORF42 gene is associated with Joubert syndrome.

Joubert syndrome (JS) disease is a clinically and genetically heterogeneous disorder with mutations in more than 35 genes involved in its pathogenicity. Molecular genetic methods including next generation sequencing (NGS) and Sanger sequencing are effective techniques used for identifying rare genetic variants that have a strong effect on disease pathogenesis. In this study, we tested a large pedigree with a history of several affected members with JS. At first the proband was sequenced by NGS technique then, confirmed by sanger sequencing method. After this, all available members of the pedigree were subjected to molecular analysis by sanger sequencing technique. The results of this study showed a novel variant in the C5ORF42 gene c.3080A > T: p. D1027V leading to a substitution of a valine for aspartic acid (D1027V) and may be associated with JS. This variant was present in proband compatible with autosomal recessive pattern. Also this variant was present in all parents (both father and mother) of affected individuals in a heterozygous state. It seems that mutations in C5ORF42 gene are associated with JS. However, the substantial mechanism requires further investigation.

Laboratory Parameters in Detection of COVID-19 Patients with Positive RT-PCR; a Diagnostic Accuracy Study.

INTRODUCTION: The role of laboratory parameters in screening of COVID-19 cases has not been definitely established. This study aimed to evaluate the accuracy of laboratory parameters in predicting cases with positive RT-PCR for COVID-19. METHODS: This diagnostic accuracy study was conducted on suspected COVID-19 patients, who presented to Behpooyan Clinic Medical center in Tehran (Iran) from 22 February to 14 March, 2020. Patients were divided into two groups based on the results of real time reverse transcriptase-polymerase chain reaction (RT-PCR) for COVID-19, and the accuracy of different laboratory parameters in predicting cases with positive RT-PCR was evaluated using area under the ROC curve (AUC). RESULTS: Two hundred cases with the mean age of 41.3± 14.6 (range: 19-78) years were studied (0.53% male). The result of RT-PCR for COVID-19 was positive in 70 (35%) cases. Patients with positive RT-PCR had significantly higher neutrophil (NEU) count (p = 0.0001), and C-reactive protein (CRP) (p = 0.04), lactate dehydrogenase (LDH) (p = 0.0001), aspartate aminotransferase (AST) (p = 0.001), alanine aminotransferase (ALT) (p = 0.0001), and Urea (p = 0.001) levels in serum. In addition, patients with positive RT-PCR had lower white blood cell (WBC) count (p = 0.0001) and serum albumin level (p = 0.0001) compared to others. ALT (AUC = 0.879), CRP (AUC = 0.870), NEU (AUC = 0.858), LDH (AUC = 0.835), and Urea (AUC = 0.835) had very good accuracy in predicting cases with positive RT-PCR for COVID-19, respectively. CONCLUSION: Our findings suggest that level of LDH, CRP, ALT and NEU can be used to predict the result of COVID-19 test. They can help in detection of COVID-19 patients.

Resolvins: Emerging Players in Autoimmune and Inflammatory Diseases.

Resolvins, belonging to the group of specialized proresolving mediators (SPMs), are metabolic products of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and are synthesized during the initial phases of acute inflammatory responses to promote the resolution of inflammation. Resolvins are produced for termination of neutrophil infiltration, stimulation of the clearance of apoptotic cells by macrophages, and promotion of tissue remodeling and homeostasis. Metabolic dysregulation due to either uncontrolled activity of pro-inflammatory responses or to inefficient resolution of inflammation results in chronic inflammation and may also lead to atherosclerosis or other chronic autoimmune diseases such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus, vasculitis, inflammatory bowel diseases, and type 1 diabetes mellitus. The pathogenesis of such diseases involves a complex interplay between the immune system and, environmental factors (non-infectious or infectious), and critically depends on individual susceptibility to such factors. In the present review, resolvins and their roles in the resolution of inflammation, as well as the role of these mediators as potential therapeutic agents to counteract specific chronic autoimmune and inflammatory diseases are discussed.

Prevalence of astrovirus, adenovirus, and sapovirus infections among Iranian children with acute gastroenteritis.

AIM: This study aimed to determine the prevalence of Human Astroviruses (HAstVs), enteric Adenoviruses (HAdVs), and Sapoviruses (SaVs) in acute diarrhea patients, as well as their relation to age, sex, and season. BACKGROUND: Acute gastroenteritis is one of the most common diseases affecting children <5 years old and viral agents with approximately >75% are the major causative agent of acute infectious diarrhea. After Rotavirus and Norovirus, the greater viral agents of acute gastroenteritis include HAstVs, HAdVs, and SaVs. To the best of our knowledge, there are sparse studies in Iran detecting at least three enteric viruses as causative agents of diarrhea simultaneously. METHODS: The sample was collected from children referring to pediatric medical centers in Tehran, Iran; they were tested for Astrovirus, enteric Adenovirus, and Sapovirus by conventional PCR method. The association of incidence of viral enteric agents was evaluated with age, sex and seasonal pattern in children <5 years old. RESULTS: The positive case number among acute gastroenteritis patients was 17/120 (14.1%). Patients ranged in age within 1-60 months, but 52.9% were aged ≤ 12 months. Males comprised the majority (70.6), and the male: female ratio was 2.4. HAstV was the most frequently detected virus (6.7%), while SaVs were detected only in 2.5% of cases. Mixed infections were not detected in these samples. The highest rate of HAstV was identified in winter (66.7%), HAdV in fall (66.7%), and SaV in winter (33.3%). CONCLUSION: These findings underscore the importance of monitoring the epidemiology of HAstV, HAdV, and SaV as causative agents of viral diarrhea infections.

Pancreatic ß-cell regeneration: From molecular mechanisms to therapy.

Pancreatic ß cells are a type of cells that are present in the islets of Langerhans. These cells are highly specialized for the secretion of insulin in response to low increasing of blood glucose levels. Hence, pancreatic ß cells could contribute to maintaining systemic glucose homeostasis. Increasing evidence has revealed that a variety of internal (ie, genetic and epigenetic factors) and external factors (ie, radical-oxidative stress) are involved in the protection and/or regeneration of pancreatic ß cells. The pathways regulating ß-cell replication have been intensely investigated. Glucose has an important role in cell cycle entry of quiescent ß cells, which exerts its effect via glucose metabolism and unfolded proteins. A variety of growth factors, hormones, and signaling pathways (ie, calcium-calcineurin nuclear factor of activated T cells) are others factors that could affect ß-cell replication under different conditions. Therefore, a greater understanding of the underlying pathways involved in the regeneration and protection of pancreatic ß cells could lead to finding and developing new therapeutic approaches. Utilization of stem cells and various phytochemical agents have provided new aspects for preventing ß-cell degeneration and stimulating the endogenous regeneration of islets. Thus, these therapeutic platforms could be used as potential therapies in the treatment of insulin-dependent diabetes mellitus. Here, we summarized the various mechanisms involved in pancreatic ß-cell regeneration. Moreover, we highlighted different therapeutic approaches which could be used for the regeneration of pancreatic ß cells.

Association of IL28B (IFNL3) rs12979860 mRNA levels, viral load, and liver function among HCV genotype 1a patients.

AIM: The present study was designed to evaluate the correlation of interleukin 28B (IL28B, IFNL3) rs12979860 mRNA levels, viral load, and liver function among hepatitis C virus (HCV) patients genotype 1a. BACKGROUND: HCV is considered essentially hepatotropic and is a major health problem around the world. METHODS: This study included 100 HCV-infected patients with HCV genotype1a (G1a) and rs12979860 CC genotype. These patients were divided into two groups according to HCV treatment. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and HCV Load were measured and recorded for each patient. IL28B mRNA levels were determined using real-time polymerase chain reaction assay, and their correlation with clinical data were analyzed. STRING was applied to construct a network and identify interactions between IL28B (IFNL3) and its significant neighbor proteins. RESULTS: The results revealed a significant relationship between the ALT as well as ALP levels with IL28B rs12979860 mRNA expression level in men, and also with age >50 years. In the treated group, AST level and HCV load had a significant relationship with IL28B mRNA expression level. The results showed that the level of ALP and AST decreased significantly with increased IL28B mRNA expression level in the treated and untreated group, respectively. STRING database showed that IL28B (IFNL3) interacted with ten important neighbor proteins with some of these proteins being involved in signal transduction pathway activating antiviral response. CONCLUSION: This study indicated that rs12979860CC genotype could predict IL28B mRNA expression level in HCV-infected patients with G1a. Furthermore, IL28B mRNA expression level may serve as a useful marker for the development of G1a HCV-associated outcomes.

Molecular mechanisms, prevalence, and molecular methods for familial combined hyperlipidemia disease: A review.

Familial combined hyperlipidemia (FCHL) is the most common genetic dyslipidemia disorder which is accompanied by increasing of triglyceride and cholesterol. This disorder is a complex genetic disease although it also has monogenic forms. The familial form has several criteria for diagnosis that can be distinguished of nonfamilial position. It has been shown that a variety of internal and external risk factors are involved in the pathogenesis of FCHL. Environmental factors and the genetic background also play an important role in the FCHL pathogenesis. Many mechanisms and pathways are involved in lipid metabolism (ie, dysfunctional adipose tissue, hepatic fat and very low-density lipoprotein overproduction, triglyceride-rich lipoproteins, and clearance of low-density lipoprotein particles) that could lead to FCHL. Individuals with a positive family history like those who have a positive family history of cardiovascular diseases are more predispositions for this disorder. To date several methods have been used to identify the genetic background of the FCHL. In the current review, we summarized the prevalence and the molecular mechanisms involved in the FCHL disease. Moreover, we highlighted the used molecular methods for determining the genes involved in the FCHL.

MicroRNA in leukemia: Tumor suppressors and oncogenes with prognostic potential.

Leukemia is known as a progressive malignant disease, which destroys the blood-forming organs and results in adverse effects on the proliferation and development of leukocytes and their precursors in the blood and bone marrow. There are four main classes of leukemia including acute leukemia, chronic leukemia, myelogenous leukemia, and lymphocytic leukemia. Given that a variety of internal and external factors could be associated with the initiation and progression of different types of leukemia. One of the important factors is epigenetic regulators such as microRNAs (miRNAs) and long noncoding RNAs (ncRNA). MiRNAs are short ncRNAs which act as tumor suppressor (i.e., miR-15, miR-16, let-7, and miR-127) or oncogene (i.e., miR-155, miR-17-92, miR-21, miR-125b, miR-93, miR-143-p3, miR-196b, and miR-223) in leukemia. It has been shown that deregulation of these molecules are associated with the initiation and progression of leukemia. Hence, miRNAs could be used as potential therapeutic candidates in the treatment of patients with leukemia. Moreover, increasing evidence revealed that miRNAs could be used as diagnostic and prognostic biomarkers in monitoring patients in early stages of disease or after received chemotherapy regimen. It seems that identification and development of new miRNAs could pave to the way to the development new therapeutic platforms for patients with leukemia. Here, we summarized various miRNAs as tumor suppressor and oncogene which could be introduced as therapeutic targets in treatment of leukemia.