Circular RNAs in tuberculosis: From mechanism of action to potential diagnostic biomarker.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tuberculosis), continues to be a major global health concern. Understanding the molecular intricacies of TB pathogenesis is crucial for developing effective diagnostic and therapeutic approaches. Circular RNAs (circRNAs), a class of single-stranded RNA molecules characterized by covalently closed loops, have recently emerged as potential diagnostic biomarkers in various diseases. CircRNAs have been demonstrated to modulate the host's immunological responses against TB, specifically by reducing monocyte apoptosis, augmenting autophagy, and facilitating macrophage polarization. This review comprehensively explores the roles and mechanisms of circRNAs in TB pathogenesis. We also discuss the growing body of evidence supporting their utility as promising diagnostic biomarkers for TB. By bridging the gap between fundamental circRNA biology and TB diagnostics, this review offers insights into the exciting potential of circRNAs in combatting this infectious disease.

Adsorption behavior of rhamnolipid modified magnetic Co/Al layered double hydroxide for the removal of cationic and anionic dyes.

In the present research, magnetic rhamnolipid-Co/Al layered double hydroxide (MR-LDH) was synthesized to uptake methylene blue (MB) and reactive orange 16 (RO16) from aqueous solution. The main parameters, including pH, adsorbent dosage, contact time, and initial analyte concentration, were optimized to achieve the best adsorption efficiency. Accordingly, the elimination of MB on MR-LDH is improved in the basic medium due to the electrostatic interactions between the negative charge of MR-LDH and the positive charge of MB dye. In contrast, the acidic medium (pH = 3) was favored for RO16 adsorption because of hydrogen bonding between the protonated form of azo dye and protonated hydroxyl groups at the surface of MR-LDH. The calculated maximum adsorption capacities for MB and RO16 were 54.01 and 53.04 mg/g at 313 K, respectively. The Langmuir model, which assumes monolayer adsorption on the adsorbent surface, provides the best explanation for the adsorption of both dyes (R2 = 0.9991 for MB and R2 = 0.9969 for RO16). Moreover, the pseudo-second-order kinetic model best described the adsorption process for MB (R2 = 0.9970) and RO16 (R2 = 0.9941). The proposed adsorbent maintains stable adsorption performance for four consecutive cycles. After each adsorption process, MR-LDH is easily separated by an external magnet. The findings show that MR-LDH was found to be an excellent adsorbent for the removal of both cationic and anionic organic dyes from aqueous solutions.

Assessment of Association between miR-146a Polymorphisms and Expression of miR-146a, TRAF-6, and IRAK-1 Genes in Patients with Brucellosis.

BACKGROUND: Brucellosis is a major zoonosis all over the world. MicroRNAs are significant gene expression regulators and could be involved during the infections and also genetic alterations in the miRNAs sequence can affect primary miRNAs and precursor miRNAs processing and thus alter miRNAs expression. Current research studied the impact of the miR-146a polymorphism on miR-146a, TRAF-6, and IRAK-1 genes expression in patients with brucellosis illness. METHODS AND RESULTS: In this research, 25 patients with brucellosis and 25 healthy participants with determined genotypes for miR-SNP rs2910164 and miR-SNP rs57095329 were recruited. IRAK-1, TRAF-6, and miR-146a expressions in peripheral blood mononuclear cells (PBMCs) were specified by quantitative real- time PCR (qRT-PCR). Moreover, interleukin-1ß (IL-1ß) and tumor necrosis factor- alpha (TNF-α) serum levels were assessed by a sandwich enzyme-linked immunosorbent assay (ELISA) technique. There was no significant difference in the expression level of miR-146a, IRAK-1, and TRAF-6, among the patients with brucellosis and control group. TRAF-6 PBMCs expression levels in the distinctive genotypes of rs2910164 were significantly observed in patients (P = 0.048). No significant distinctions were found in miR-146a, IRAK-1, and TRAF-6 expression levels and among the rs57095329 different genotypes in brucellosis patients and controls. Meanwhile, no significant relationship was found between the rs2910164 and rs57095329 genotypes and the serum level of cytokines mentioned between the two groups. We did not find any association between expression of TRAF-6, miR-146a, and IRAK-1 in PBMCs, and cytokines serum levels with two single nucleotide polymorphisms (SNPs) in miR-146a. CONCLUSIONS: To the best of writers' knowledge, this research is the first one evaluating the probable link between the miR-146a rs2910164 and rs57095329 variant with miRNAs, relevant cytokine levels, and target genes in brucellosis.

A brief review on DNA vaccines in the era of COVID-19.

This article provides a brief overview of DNA vaccines. First, the basic DNA vaccine design strategies are described, then specific issues related to the industrial production of DNA vaccines are discussed, including the production and purification of DNA products such as plasmid DNA, minicircle DNA, minimalistic, immunologically defined gene expression (MIDGE) and Doggybone™. The use of adjuvants to enhance the immunogenicity of DNA vaccines is then discussed. In addition, different delivery routes and several physical and chemical methods to increase the efficacy of DNA delivery into cells are explained. Recent preclinical and clinical trials of DNA vaccines for COVID-19 are then summarized. Lastly, the advantages and obstacles of DNA vaccines are discussed.

Association between risk of brucellosis and genetic variations in MicroRNA-146a.

BACKGROUND: Single nucleotide polymorphisms (SNPs) are the most common types of DNA changes in the human genome that leading to phenotypic differences in humans. MicroRNAs (miRNAs) are usually affected by various bacterial infections, and they are involved in controlling the immune responses. MicroRNA-146a (miR-146a) plays an essential role in the development of infectious and inflammatory diseases. The aim of the present study was to investigate the association between risk of brucellosis and genetic variations in miR-146a. METHODS: This case-control study was conducted on 108 Brucellosis patients and 108 healthy controls. We genotyped two SNPs (rs2910164 and rs57095329) of the miR-146a using tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) and restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) methods. RESULTS: The rs2910164 SNP was significantly associated with brucellosis in co-dominant [OR = 4.27, 95% CI = (2.35-7.79, P = 0.001] and dominant [OR = 3.52, 95% CI = (1.97-6.30, P = 0.001] models. Co-dominant (P = 0.047) and recessive (P = 0.018) models were significant at position rs57095329 between the two groups of patient and healthy. The A C haplotype (rs2910164 and rs57095329) was associated with brucellosis in the assessed population [OR (95% CI) = 1.98 (1.22-3.20), P = 0.0059]. CONCLUSIONS: Consequently, our study demonstrated significant differences in genotype and haplotype frequencies of miR-146a variants between brucellosis patients and controls. Further studies on the larger sample sizes are required to verify the observed associations.

microRNAs in human brucellosis: A promising therapeutic approach and biomarker for diagnosis and treatment.

INTRODUCTION: Human brucellosis is a zoonotic bacterial disease with up to 500,000 new cases each year. The major evasion mechanisms from the host immune system by Brucella are restraint of complement pathway and Toll-like receptors signaling pathways, interference with efficient antigen presentation to CD4-positive T lymphocytes, selective subversion of autophagy pathways, inhibition of dendritic cell stimulation, inhibition of autophagolysosomal fusion, and macrophage apoptosis. Many molecular and cellular pathways contribute to brucellosis that microRNAs have a vital function in the immunopathogenesis of this disease. In this regard, these molecules apply for their roles by modulating various events like inflammatory reactions and immune defense. Recently, in the case of immunity to human brucellosis, it has been shown that microRNAs play an important role in immunity against these bacteria. METHODS AND RESULTS: In this study, we tried to review the immune defense and immunopathogenesis of Brucella infection and highlight the current knowledge of the microRNAs in infected cells by Brucella pathogens. The recent findings suggest that the regulation of microRNAs expression is impaired during brucellosis infection, which may contribute to disease progression or inhibition by modulating immune responses against this pathogen. CONCLUSIONS: The interplay between miRNAs and Brucella pathogens and the underlying process required comprehensive examination to unravel the novel therapeutic or diagnostic approaches.

Immunometabolism in human brucellosis: An emerging field of investigation.

In recent years, extreme attention has been focused on the role of immunometabolism in the regulation of immune cell responses in healthy individuals during infection, autoimmunity, and cancer. In the infection biology area, it has been shown that there is a close relationship between the immune system and the host metabolic changes. Brucella species is an intracellular coccobacillus that infects humans and mammals, which led to brucellosis. Brucella species with host-specific evolutionary mechanisms allow it to hide from or manipulate cellular immunity and achieve intracellular persistence. Intracellular bacterial pathogens such as Brucella species also employ host cell resources to replicate and persist inside the host. Targeting these host systems is one promising strategy for developing novel antimicrobials to tackle intracellular infections. This study will summarize the role of metabolic reprogramming in immune cells and their relationship to brucellosis.

The emerging role of probiotics as a mitigation strategy against coronavirus disease 2019 (COVID-19).

COVID-19 is an acute respiratory infection accompanied by pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has affected millions of people globally. To date, there are no highly efficient therapies for this infection. Probiotic bacteria can interact with the gut microbiome to strengthen the immune system, enhance immune responses, and induce appropriate immune signaling pathways. Several probiotics have been confirmed to reduce the duration of bacterial or viral infections. Immune fitness may be one of the approaches by which protection against viral infections can be reinforced. In general, prevention is more efficient than therapy in fighting viral infections. Thus, probiotics have emerged as suitable candidates for controlling these infections. During the COVID-19 pandemic, any approach with the capacity to induce mucosal and systemic reactions could potentially be useful. Here, we summarize findings regarding the effectiveness of various probiotics for preventing virus-induced respiratory infectious diseases, especially those that could be employed for COVID-19 patients. However, the benefits of probiotics are strain-specific, and it is necessary to identify the bacterial strains that are scientifically established to be beneficial.

Bacterial co-infections with SARS-CoV-2.

The pandemic coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has affected millions of people worldwide. To date, there are no proven effective therapies for this virus. Efforts made to develop antiviral strategies for the treatment of COVID-19 are underway. Respiratory viral infections, such as influenza, predispose patients to co-infections and these lead to increased disease severity and mortality. Numerous types of antibiotics such as azithromycin have been employed for the prevention and treatment of bacterial co-infection and secondary bacterial infections in patients with a viral respiratory infection (e.g., SARS-CoV-2). Although antibiotics do not directly affect SARS-CoV-2, viral respiratory infections often result in bacterial pneumonia. It is possible that some patients die from bacterial co-infection rather than virus itself. To date, a considerable number of bacterial strains have been resistant to various antibiotics such as azithromycin, and the overuse could render those or other antibiotics even less effective. Therefore, bacterial co-infection and secondary bacterial infection are considered critical risk factors for the severity and mortality rates of COVID-19. Also, the antibiotic-resistant as a result of overusing must be considered. In this review, we will summarize the bacterial co-infection and secondary bacterial infection in some featured respiratory viral infections, especially COVID-19.

Overview of the current promising approaches for the development of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine.

Coronavirus disease 2019 (COVID-19) is a pandemic infectious disease caused by the novel coronavirus called SARS-CoV-2. There is a gap in our understanding regarding the immunopathogenesis of COVID-19. However, many clinical trials are underway across the world for screening effective drugs against COVID-19. Nevertheless, currently, no proven effective therapies for this virus exists. The vaccines are deemed as a significant part of disease prevention for emerging viral diseases, since, in several cases, other therapeutic choices are limited or non-existent, or that diseases result in such an accelerated clinical worsening that the efficacy of treatments is restricted. Therefore, effective vaccines against COVID-19 are urgently required to overcome the tremendous burden of mortality and morbidity correlated with SARS-CoV-2. In this review, we will describe the latest evidence regarding outstanding vaccine approaches and the challenges for vaccine production.

The importance of intracellular bacterial biofilm in infectious diseases.

Various bacterial species, previously known as extracellular pathogens, can reside inside different host cells by adapting to intracellular modes by forming microbial aggregates with similar characteristics to bacterial biofilms. Additionally, bacterial invasion of human cells leads to failure in antibiotic therapy, as most conventional anti-bacterial agents cannot reach intracellular biofilm in normal concentrations. Various studies have shown that bacteria such as uropathogenic Escherichia coli, Pseudomonas aeruginosa, Borrelia burgdorferi,Moraxella catarrhalis, non-typeable Haemophilus influenzae, Streptococcus pneumonia, and group A Streptococci produce biofilm-like structures within the host cells. For the first time in this review, we will describe and discuss the new information about intracellular bacterial biofilm formation and its importance in bacterial infectious diseases.

Role of microRNAs in Staphylococcus aureus infection: Potential biomarkers and mechanism.

Staphylococcus aureus is known as a common pathogen that colonizes 30% of healthy humans. Additionally, this bacterium can cause a number of serious infections, that is, endocarditis, bacteremia, pneumonia, wound, skin infections, and tissue abscesses. A variety of cellular and molecular pathways and targets are involved in response against S. aureus. Among them, microRNAs (miRNAs) have crucial roles in response against S. aureus. In this regard, it has been shown that these molecules exert their regulatory roles via modulating a wide range of events, such as inflammatory reactions, host innate, and adaptive immunity. Current works have provided insight into the crucial involvement of miRNAs in immune defense toward Staphylococcal infections. Herein, we highlighted the current findings on the deregulation of different miRNAs in S. aureus-infected cells. Moreover, we summarized the mechanisms and targets of miRNAs in S. aureus infections.

The biofilm-associated bacterial infections unrelated to indwelling devices.

Biofilms are microbial communities established in the self-produced extracellular substances that include up to 80% of associated microbial infections. During biofilm formation, bacterial cells shift from the planktonic forms to aggregated forms surrounded by an extracellular polymeric substance. The bacterial biofilm shows resistance against immune reactions as well as antibiotics and is potentially able to cause disorders by both device-related and nondevice-related infections. The nondevice-related bacterial biofilm infections include dental plaque, urinary tract infections, cystic fibrosis, otitis media, infective endocarditis, tonsillitis, periodontitis, necrotizing fasciitis, osteomyelitis, infectious kidney stones, and chronic inflammatory diseases. In this review, we will summarize and examine the literature about bacterial biofilm infections unrelated to indwelling devices.

Evaluation of the relationship between IL-12, IL-13 and TNF-α gene polymorphisms with the susceptibility to brucellosis: a case control study.

BACKGROUND: The cytokine gene polymorphism is important for the genetic susceptibility of infectious diseases. The aim of the present study was to investigate the relationship between TNF-α, IL-12, and IL-13 gene polymorphisms and predisposition to brucellosis. METHODS: In this study, 107 patients with brucellosis and 107 healthy individuals were evaluated. The SNPs of TNF-α)- 238 G/A) and IL-12 (+ 1188 A/C) were done by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and IL-13 genotyping at positions - 1512 (A/C) and - 1112 (C/T) were analysis by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) methods. IL-12, IL-13 and TNF-α serum levels were measured by a sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: IL-13 (-1512A/C) was associated with Brucellosis risk in dominant model (OR (95% CI) = 2.17 (1.02-4.62)), P-value = 0.041. However, there was no difference in allele and genotype frequencies of TNF-α)- 238 G/A), IL-12 (+ 1188 A/C) and IL-13 [- 1512 (A/C) and - 1112 (C/T)] between patients and controls. Serum levels of IL-12 and TNF-α were significantly more frequent in the patients than in the control groups. CONCLUSIONS: The IL-13 gene polymorphism can be used as a biomarker for detecting susceptibility to Brucella disease.

Association of interleukin-17 gene polymorphisms and susceptibility to brucellosis in Hamadan, western Iran.

IL-17is one of the most important inflammatory cytokines that stimulate immunity responses in humans infected with Brucella species, acting as a regulator that reduces release of γ-IFN, thus increasing resistance to brucellosis. Gene polymorphisms in the regulatory regions of cytokine-encoding genes affect the amountsof cytokines produced and play a fundamental role in infectious diseases. The aim of this study was to determine the association between IL-17 gene polymorphisms and susceptibility to brucellosis. In this case-control study, 86 patients with brucellosis and 86 healthy persons in Hamadan, western Iran, from September 2014 to September 2016, were included. IL-17 genetic variants at positions rs4711998 A/G, rs8193036 C/T, rs3819024 A/G, rs2275913 A/G, rs3819025 A/G, rs8193038 A/G, rs3804513 A/T, rs1974226 A/G and rs3748067 A/G were analyzed by restriction fragment length polymorphism-PCR. Serum IL-17 titers were measured by sandwich ELISA. GG genotypes at positions rs4711998 and rs3748067 were present significantly more frequently in patients with brucellosis than in controls (P < 0.05). The AA genotype at positions rs4711998, rs2275913 and rs3748067 and GG genotype at position rs19744226 were present significantly more frequently in controls than in the patient group. These results suggest that the AA genotype at positions rs3748067, rs3819025 and rs4711998 and GG genotype at position rs3819024 are likely protective factors against brucellosis, whereas the GG genotype at positions rs3748067, rs3819025 and rs4711998 and AA genotype at position rs3819024 may be risk factors against the disease. No significant relationships were found between serum IL-17 titers and genotypes of the single-nucleotide polymorphisms.

Brucellosis Causes Alteration in Trace Elements and Oxidative Stress Factors.

Brucellosis is regarded as one of the most common diseases among humans and livestock. In the present study, we aimed to assess the effect of this disease on the level of various cations including copper (Cu), manganese (Mn), zinc (Zn), and magnesium (Mg) as well as oxidative stress status in the serum of people suffering from brucellosis. The present case-study was carried out on 40 patients with brucellosis (case) and 20 healthy people (control). Blood specimens were taken from all the people and the level of essential trace elements and oxidative stress status were measured. The serum level of copper in the case group (165.39 ± 43.19 µg/dl) was significantly higher compared with that in the control group (122.12 ± 28.88 µg/dl). Whereas the serum level of zinc was significantly lower in the case group compared with that in the control group (76.47 ± 28.88 vs. 92.85 ± 23.16 µg/dl). The manganese and magnesium serum levels did not differ significantly between the two groups. Furthermore, total antioxidant capacity level was significantly lower in the case group (122.12 ± 28.22 µmol/ml) than that in the control group (3.08 ± 0.12 µmol/ml) and the level of serum malondialdehyde was significantly higher in the case group (7.20 ± 0.23 mmol/ml) than that in the control group (4.0 ± 0.19 mmol/ml). Brucellosis can cause alteration in the serum level of essential trace elements. Moreover, the present study indicated that brucellosis produces oxidative stress in patients.

Analysis of IL-10 and IL-6 Gene Polymorphisms and Their Serum Levels in Patients with Brucellosis: A Case Control Study.

BACKGROUND: It seems that polymorphism in the regulatory areas of cytokine genes affects the cytokine production capacity and may play a role in the development of infectious diseases. Interleukin-10 (IL-10) and Interleukin-6 (IL-6), which are cytokines of Th2, cause the macrophage become inactive and patient conditions get worse. METHODS: In this case-control study, 60 patients with brucellosis and 60 healthy participants were recruited. IL-10 genotyping at positions -1082 (G/A), -819 (C/T), and -592 (C/A) and IL-6 genotyping at position -174 (G/C) were analyzed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) methods. The levels of IL-10 and IL-6 were determined by a sandwich enzyme-linked immunosorbent assay in sera of study population. RESULTS: The AA and CC genotypes of the IL-10 gene at positions -1082 G/A and -819 C/T were significantly more frequent in patients in comparison to controls, respectively. The AG genotype of the IL-10 gene at positions -1082 G/A was significantly more frequent in control groups than the patients. Serum levels of IL-10 and IL-6 were significantly more frequent in the patients than in the control groups. CONCLUSIONS: Our study showed that the AA and CC genotypes at positions -1082 and -819 are very important, respectively. These results suggest that IL-10 (-1082 G/A) GG genotype may be considered as a risk factor for brucellosis, while the AG genotype might be a protective factor against the disease.

Conventional, molecular methods and biomarkers molecules in detection of septicemia.

Sepsis is a leading cause of morbidity and mortality in hospitalized patients worldwide and based on studies, 30-40% of all cases of severe sepsis and septic shock results from the blood stream infections (BSIs). Identifying of the disease, performing laboratory tests, and consequently treatment are factors that required for optimum management of BSIs. In addition, applying precise and immediate identification of the etiologic agent is a prerequisite for specific antibiotic therapy of pathogen and thereby decreasing mortality rates. The diagnosis of sepsis is difficult because clinical signs of sepsis often overlap with other noninfectious cases of systemic inflammation. BSIs are usually diagnosed by performing a series of techniques such as blood cultures, polymerase chain reaction-based methods, and biomarkers of sepsis. Extremely time-consuming even to take up to several days is a major limitation of conventional methods. In addition, yielding false-negative results due to fastidious and slow-growing microorganisms and also in case of antibiotic pretreated samples are other limitations. In comparison, molecular methods are capable of examining a blood sample obtained from suspicious patient with BSI and gave the all required information to prescribing antimicrobial therapy for detected bacterial or fungal infections immediately. Because of an emergency of sepsis, new methods are being developed. In this review, we discussed about the most important sepsis diagnostic methods and numbered the advantage and disadvantage of the methods in detail.