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The coronavirus disease 2019 (CVOID-19) has varied clinical manifestations including mild to severe acute respiratory symptoms. Inflammasome complex and mitochondria play an important role in initiating inflammatory responses and could potentially be affected by this infection. To study the inflammasome and mitochondrial fission and fusion gene expression levels in COVID-19 patients, we designed this experiment. The inflammasome and mitochondrial gene expression profiles were determined by real-time polymerase chain reaction in the peripheral blood of 70 hospitalized CVOID-19 patients with mild to moderate symptoms (HOSP) and 30 ICU patients with severe symptoms (ICU) compared to 20 healthy controls (HC). The results indicated that the expression of the dynamin-related protein-1 was extremely suppressed in HOSP while it came back to the normal range in the ICU group. However, the expression of fission 1 protein had a non-significant increase in HOSP and a decrease in the ICU group. The mitofusin-1 and dominant optic atrophy genes showed high expression levels (10-fold) and (70-fold), respectively, in the HOSP group. However, mitofusin-2 significantly decreased in both groups. Although leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) and apoptosis-associated speck-like protein containing a caspase activating and recruitment domain genes dramatically increased in both groups (10 and 4-fold), other inflammasome genes declined in both groups. Finally, Nuclear factor kappa-light-chain-enhancer of activate d B cells (NF-κB) extremely decreased, and Intreleukine-1 showed high expression in ICU patients (3-fold). CVOID-19 infection suppresses the fission genes and elevates the fusion gene expression in mitochondria, and it can cause activation of the inflammasome via the NLRP3 pathway.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar remodeling. Although the abnormalities are primarily prompted by chronic exposure to inhaled irritants, maladjusted and self-reinforcing immune responses are significant contributors to the development and progression of the disease. The p38 isoforms are regarded as pivotal hub proteins that regulate immune and inflammatory responses in both healthy and disease states. As a result, their inhibition has been the subject of numerous recent studies exploring their therapeutic potential in COPD., Main Body: We performed a systematic search based on the PRISMA guidelines to find relevant studies about P38 signaling in COPD patients. We searched the PubMed and Google Scholar databases and used "P38" AND "COPD" Mesh Terms. We applied the following inclusion criteria: (1) human, animal, ex vivo and in vitro studies; (2) original research articles; (3) published in English; and (4) focused on P38 signaling in COPD pathogenesis, progression, or treatment. We screened the titles and abstracts of the retrieved studies and assessed the full texts of the eligible studies for quality and relevance. We extracted the following data from each study: authors, year, country, sample size, study design, cell type, intervention, outcome, and main findings. We classified the studies according to the role of different cells and treatments in P38 signaling in COPD., Conclusion: While targeting p38 MAPK has demonstrated some therapeutic potential in COPD, its efficacy is limited. Nevertheless, combining p38 MAPK inhibitors with other anti-inflammatory steroids appears to be a promising treatment choice. Clinical trials testing various p38 MAPK inhibitors have produced mixed results, with some showing improvement in lung function and reduction in exacerbations in COPD patients. Despite these mixed results, research on p38 MAPK inhibitors is still a major area of study to develop new and more effective therapies for COPD. As our understanding of COPD evolves, we may gain a better understanding of how to utilize p38 MAPK inhibitors to treat this disease. Video Abstract., (© 2023. The Author(s).)

Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease with high morbidity and mortality rates worldwide. Cytokines, which are the main regulators of immune responses, play crucial roles in inflammatory diseases such as COPD. Moreover, certain genetic variations can alter cytokine expression, and changes in cytokine level or function can affect disease susceptibility. Therefore, investigating the association between genetic variations and disease progression can be useful for prevention and treatment. Several studies have explored the association between common genetic variations in cytokine genes and COPD susceptibility. In this study, we summarized the reported studies and, where possible, conducted a systematic review and meta-analysis to evaluate the genetic association between various cytokines and COPD pathogenesis. We extracted relevant articles from PubMed and Google Scholar databases using a standard systematic search strategy. We included a total of 183 studies from 78 separate articles that evaluated 50 polymorphisms in 12 cytokine genes in this study. Our analysis showed that among all reported cytokine polymorphisms (including TNF-α, TGF-β, IL1, IL1RN, IL4, IL4R, IL6, IL10, IL12, IL13, IL17, IL18, IL27, and IL33), only four variants, including TNF-α-rs1800629, TGF-β1-rs6957, IL13-rs1800925, and IL6-rs1800796, were associated with the risk of COPD development. This updated meta-analysis strongly supports the association of TNF-α-rs1800629, TGF-β1-rs6957, IL13-rs1800925, and IL6-rs1800796 variants with a high risk of COPD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: It has been demonstrated in the literature that a dysbiotic microbiome could have a negative impact on the host immune system and promote disease onset or exacerbation. Co-occurrence networks have been widely adopted to identify biomarkers and keystone taxa in the pathogenesis of microbiome-related diseases. Despite the promising results that network-driven approaches have led to in various human diseases, there is a dearth of research pertaining to key taxa that contribute to the pathogenesis of lung cancer. Therefore, our primary goal in this study is to explore co-existing relationships among members of the lung microbial community and any potential gained or lost interactions in lung cancer., Results: Using integrative and network-based approaches, we integrated four studies assessing the microbiome of lung biopsies of cancer patients. Differential abundance analyses showed that several bacterial taxa are different between tumor and tumor-adjacent normal tissues (FDR adjusted p-value < 0.05). Four, fifteen, and twelve significantly different associations were found at phylum, family, and genus levels. Diversity analyses suggested reduced alpha diversity in the tumor microbiome. However, beta diversity analysis did not show any discernible pattern between groups. In addition, four distinct modules of bacterial families were detected by the DBSCAN clustering method. Finally, in the co-occurrence network context, Actinobacteria, Firmicutes, Bacteroidetes, and Chloroflexi at the phylum level and Bifidobacterium, Massilia, Sphingobacterium, and Ochrobactrum at the genus level showed the highest degree of rewiring., Conclusions: Despite the absence of statistically significant differences in the relative abundance of certain taxa between groups, it is imperative not to overlook them for further exploration. This is because they may hold pivotal central roles in the broader network of bacterial taxa (e.g., Bifidobacterium and Massilia). These findings emphasize the importance of a network analysis approach for studying the lung microbiome since it could facilitate identifying key microbial taxa in lung cancer pathogenesis. Relying exclusively on differentially abundant taxa may not be enough to fully grasp the complex interplay between lung cancer and the microbiome. Therefore, a network-based approach can offer deeper insights and a more comprehensive understanding of the underlying mechanisms., (© 2023. The Author(s).)

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death among non-contagious diseases in the world. PDE inhibitors are among current medicines prescribed for COPD treatment of which, PDE-4 family is the predominant PDE isoform involved in hydrolyzing cyclic adenosine monophosphate (cAMP) that regulates the inflammatory responses in neutrophils, lymphocytes, macrophages and epithelial cells The aim of this study is to investigate the cellular and molecular mechanisms of cAMP-PDE signaling, as an important pathway in the treatment management of patients with COPD. In this review, a comprehensive literature review was performed about the effect of PDEs in COPD. Generally, PDEs are overexpressed in COPD patients, resulting in cAMP inactivation and decreased cAMP hydrolysis from AMP. At normal amounts, cAMP is one of the essential agents in regulating metabolism and suppressing inflammatory responses. Low amount of cAMP lead to activation of downstream inflammatory signaling pathways. PDE4 and PDE7 mRNA transcript levels were not altered in polymorphonuclear leukocytes and CD8 lymphocytes originating from the peripheral venous blood of stable COPD subjects compared to healthy controls. Therefore, cAMP-PDE signaling pathway is one of the most important signaling pathways involved in COPD. By examining the effects of different drugs in this signaling pathway critical steps can be taken in the treatment of this disease., Competing Interests: Authors have no conflict of interest to declare., (© 2023 The Authors.)

The development of a safe and effective vaccine is essential to protect populations against coronavirus disease 2019 (COVID-19). There are several vaccine candidates under investigation with different mechanisms of action. In the present study, we have evaluated the safety and immunogenicity of a recombinant receptor-binding domain (RBD)-based protein subunit vaccine (Noora vaccine) against COVID-19 in adults. This Phase 1 trial is a randomized, double-blind, placebo-controlled study to evaluate the safety and immunogenicity of the recombinant RBD-based protein subunit vaccine (Noora vaccine) against COVID-19 in healthy adults volunteers. Eligible participants were included in this study after evaluating their health status and considering the exclusion criteria. They were then randomized into three groups and received three doses of vaccine (80 µg, 120 µg, and placebo) on Days 0, 21, and 35. Primary outcomes including solicited, unsolicited, and medically attended adverse events were recorded during this study. Secondary outcomes including the humoral and cellular immunity (including anti-RBD IgG antibody and neutralizing antibody) were measured on Days 0, 21, 28, 35, 42, and 49 by using the ELISA kit and the Virus Neutralization Test (VNT) was performed on day 49. Totally 70 cases were included in this Phase 1 trial and 60 of them completed the study. Safety assessments showed no severe adverse events. Local pain at the vaccine injection site occurred in 80% of the vaccinated volunteers. Induration and redness at the injection site were the other adverse reactions of this vaccine. There was no significant difference between the studied groups regarding adverse reactions. Anti-RBD IgG antibody and neutralizing antibody assessment showed significant seroconversion in comparison to the placebo group (80%, and 100% respectively, p < 0.001). The cellular immunity panel also showed mild to moderate induction of TH1 responses and the VNT showed 78% of seroprotection. The results of this Phase 1 trial showed acceptable safety without serious adverse events and significant seroconversions in the humoral and cellular immunity panel. The dose of 80 µg is an appropriate dose for injection in the next phases of the trial., (© 2022 Wiley Periodicals LLC.)

Immunotoxins are regarded as a type of targeted therapy for killing cells by highly potent bacterial, fungal or plant toxins. Shiga like toxins (SLTs) are a group of bacterial AB5 protein toxins that inhibit host cell protein synthesis through the removal of a single adenine residue from the 28S rRNA and lead to apoptosis. Here, we described the design and usage of a Stx-based immunotoxin that can induce the selective cytotoxicity and apoptosis in Fn-14-positive cells related to the colon and lung cancer. In the present study, the Stx2a-PE15-P4A8 fusion protein was expressed efficiently in E. coli (DE3) system when driven from inclusion bodies by 8 M urea. The Stx2a-PE15-P4A8 fusion protein was expressed efficiently in E. coli (DE3) system and then purified. The purified fusion protein could specifically target Fn-14 receptor existed on colon and lung cancer cell lines and suppress these cells in a dose-dependent manner. In addition, the protein was able to nearly 50 % of apoptotic cell death and maintains about 54 % of its stability after 24 h of incubation in mouse serum at 37 °C. Compared to PE38-P4A8 construct in our previous study, these results showed that the Stx2a-PE15-P4A8 construct can be an efficient therapeutic candidate for cancer immunotherapy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: In this pre-clinical study, we designed a candidate vaccine based on severe acute respiratory syndrome-related -coronavirus 2 (SARS-CoV-2) antigens and evaluated its safety and immunogenicity., Methods: SARS-CoV-2 recombinant protein antigens, including truncated spike protein (SS1, lacking the N-terminal domain of S1), receptor-binding domain (RBD), and nucleoprotein (N) were used. Immunization program was performed via injection of RBD, SS1 +RBD, and SS1 +N along with different adjuvants, Alum, AS03, and Montanide at doses of 0, 40, 80, and 120 μg at three-time points in mice, rabbits, and primates. The humoral and cellular immunity were analyzed by ELISA, VNT, splenocyte cytokine assay, and flow cytometry., Results: The candidate vaccine produced strong IgG antibody titers at doses of 80 and 120 μg on days 35 and 42. Even though AS03 and Montanide produced high-titer antibodies compared to Alum adjuvant, these sera did not neutralize the virus. Strong virus neutralization was recorded during immunization with SS1 +RBD and RBD with Alum. AS03 and Montanide showed a strong humoral and cellular immunity; however, Alum showed mild to moderate cellular responses. Ultimately, no cytotoxicity and pathologic change were observed., Conclusion: These findings strongly suggest that RBD with Alum adjuvant is highly immunogenic as a potential vaccine., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Atopic dermatitis (AD) is a complicated, inflammatory skin disease, which numerous genetic and environmental factors play roles in its development. AD is categorized into different phenotypes and stages, although they are mostly similar in their pathophysiological aspects. Immune response alterations and structural distortions of the skin-barrier layer are evident in AD patients. Genetic makeup, lifestyle, and environment are also significantly involved in contextual factors. Genes involved in AD-susceptibility, including filaggrin and natural moisturizing, cause considerable structural modifications in the skin's lipid bilayer and cornified envelope. Additionally, the skin's decreased integrity and altered structure are accompanied by biochemical changes in the normal skin microflora's dysbiosis. The dynamic immunological responses, genetic susceptibilities, and structural modifications associated with AD's pathophysiology will be extensively discussed in this review, each according to the latest achievements and findings., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease with pulmonary and extra-pulmonary complications. Due to the disease's systemic nature, many investigations investigated the genetic alterations in various biological samples. We aimed to infer causal genes in COPD's pathogenesis in different biological samples using elastic-net logistic regression and the Structural Equation Model. Samples of small airway epithelial cells, bronchoalveolar lavage macrophages, lung tissue biopsy, sputum, and blood samples were selected (135, 70, 235, 143, and 226 samples, respectively). Elastic-net Logistic Regression analysis was implemented to identify the most important genes involved in COPD progression. Thirty-three candidate genes were identified as essential factors in the pathogenesis of COPD and regulation of lung function. Recognized candidate genes in small airway epithelial (SAE) cells have the highest area under the ROC curve (AUC = 97%, SD = 3.9%). Our analysis indicates that macrophages and epithelial cells are more influential in COPD progression at the transcriptome level.

The association of gut microbiota with occurrence and development of colorectal cancer (CRC) has been reported in recent studies. Probiotics have been shown to mediate anti-cancer effects through immune system. The aim of this study was to evaluate the efficacy of Lactobacillus plantarum and Candida albicans in the suppression of azoxymethane-induced CRC in male Fischer 344 rats. 30 adult male Fischer 344 rats were divided into 6 distinct groups (n = 5 per group): non-treated animals, fat-food intake group, fat-food and carcinogen intake group, CRC cancer-induced rats treated with the chemotherapy drug, CRC-induced rats treated with Lactobacillus plantarum, and CRC-induced rats treated with Candida albicans. Identification of Candida albicans isolated from human feces was performed by microbiological, biochemical, and PCR methods. The serum levels of IFN-γ, IL-4, TGF-β, and TNF-α were measured by ELISA. Pathological studies were performed through hematoxylin and eosin (H&E) staining method. The data were analyzed using one-way ANOVA and Tukey's post-hoc analysis. Shrinking cancer cells with very dark nuclei were observed in CRC-induced rats treated with the chemotherapy drug, Lactobacillus plantarum, and Candida albicans indicating the occurrence of apoptosis. Serum levels of IFN-γ, IL-4, and TGF-β significantly decreased compared to the control group (p < 0.05). Lactobacillus plantarum and Candida albicans isolated from the gastrointestinal tract of the elderly and healthy individuals can efficiently improve CRC., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

The mitochondrion has a substantial role in innate immunity and inflammasome signaling pathways. Sulfur mustard (SM) induces toxicity in cytoplasmic organelles. We aimed to evaluate the potential therapeutic effect of curcumin on the toxicity of SM analog through measuring gene expression levels of mitochondrial dynamics followed by induction of the inflammasome signaling pathway. After the treatment of pulmonary epithelial cell line (A549) by 2-chloroethyl ethyl sulfide (CEES) (2500 mM) for 48h, the transcriptional activity of mitochondrial fission and fusion genes such as dynamin-related protein 1 (Drp1), mitochondrial fission 1 protein (Fis1), mitofusin-1 (Mfn1), mitofusin-2 (Mfn2), and Dominant optic atrophy (Opa1) and inflammasome pathway genes including absent in melanoma 2 (AIM2), NLR family containing protein 3 (NLRP3), and Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) was measured. Furthermore, the inhibitory effect of curcumin (160 mM) concurrent with SM analog on the expression level of mitochondria and inflammasome genes was investigated. CEES was able to over-express the fission, fusion (Drp1 ~ 8, Fis1 4.5, Mfn2 15, and Opa1 16-fold) and inflammasome genes (AIM2, NLRP3,  8 and 6-fold, respectively), whereas Mfn1 was significantly decreased (0.5-fold) and a not statistically significant decrease was observed in the ASC gene. Curcumin could modulate the effect of CEES, mitigate the expression of fission, fusion, and inflammasome genes exceedingly. However, a major increase in the repairer fusion gene (Mfn1, 6-fold) and complete suppression of the ASC gene were the outcomes of using the curcumin. In conclusion, we suggest curcumin alleviates the disturbance of mitochondrial dynamics and downregulates the inflammasome genes exposed to the CEES.

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterised by airway inflammation and progressive obstruction of the lung airflow. Current pharmacological treatments include bronchodilators, alone or in combination with steroids, or other anti-inflammatory agents, which have only partially contributed to the inhibition of disease progression and mortality. Therefore, further research unravelling the underlying mechanisms is necessary to develop new anti-COPD drugs with both lower toxicity and higher efficacy. Extrinsic signalling pathways play crucial roles in COPD development and exacerbations. In particular, phosphoinositide 3-kinase (PI3K) signalling has recently been shown to be a major driver of the COPD phenotype. Therefore, several small-molecule inhibitors have been identified to block the hyperactivation of this signalling pathway in COPD patients, many of them showing promising outcomes in both preclinical animal models of COPD and human clinical trials. In this review, we discuss the critically important roles played by hyperactivated PI3K signalling in the pathogenesis of COPD. We also critically review current therapeutics based on PI3K inhibition, and provide suggestions focusing on PI3K signalling for the further improvement of the COPD phenotype. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Interaction between a healthy microbiome and the immune system leads to body homeostasis, as dysbiosis in microbiome content and loss of diversity may result in disease development. Due to the ability of probiotics to help and modify microbiome constitution, probiotics are now widely used for the prevention and treatment of different gastrointestinal, inflammatory, and, more recently, respiratory diseases. In this regard, chronic respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma and allergic rhinitis are among the most common and complicated respiratory diseases with no specific treatment until now. Accordingly, many studies have evaluated the therapeutic efficacy of probiotic administration (mostly via the oral route and much lesser nasal route) on chronic respiratory diseases. We tried to summarise and evaluate these studies to give a perspective of probiotic therapy via both the oral and nasal routes for respiratory infections (in general) and chronic respiratory diseases (specifically). We finally concluded that probiotics might be useful for allergic diseases. For asthmatic patients, probiotics can modulate serum cytokines and IgE and decrease eosinophilia, but with no significant reduction in clinical symptoms. For COPD, only limited studies were found with uncertain clinical efficacy. For intranasal administration, although some studies propose more efficiency than the oral route, more clinical evaluations are warranted.

Sulfur Mustard (SM) induces cell injury via exerting oxidative stress, protease-anti protease imbalance, and inflammation. Inflammasome as one part of innate immunity has a critical role in the recognition of cell injuries and the initiation of the inflammation process by releasing IL-1β. Hence, the present study investigated the effects of the sub-lethal doses of 2-chloroethyl ethyl sulfide (CEES) as SM analog on the gene expression level of inflammasome-related genes as well as the potential protective effects of curcumin on this process. The effects of sub-lethal doses (500, 1000, and 2500 mM) of CEES on pulmonary epithelial cell line (A549) were determined at various time points (12, 24, and 48 h). Following the treatment of cells with CEES, the kinetic alterations of the expression levels of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB1), NLR family pyrin domain containing 1 (NLRP1), Caspase-1 (Casp1), and Interleukin-1β (IL-1β)  genes were analyzed; using real-time PCR. In addition, the concurrent protective effects of different doses of curcumin (20, 40, 80, and 160 mM) on modulating the effects of CEES were studied. Although it was found that the lowest sub-lethal dose of CEES (500 mM) was able to up-regulate the inflammasome-related genes, the maximum alterations occurred 48 h after the treatment with the higher sub-lethal dose (2500 mM) of CEES. The maximum alteration occurred in Casp1 (38 fold), IL-1β (19 fold), and NLRP1 (~4 fold) genes (p<0.0001). However, the NF-ĸB gene expression level did not alter following CEES exposure. Even though low doses of curcumin (20, 40, and 80 mM) were able to down-regulate the studied genes, it was found that the treatment of cells with 160 mM of curcumin for 48 h was able to normalize the expression level of all genes. The present study concludes that curcumin as an anti-inflammatory agent may have beneficial immunomodulatory effects following CEES exposure.

Today, the targeted therapies like the use of immunotoxins are increased which targeted specific antigens or receptors on the surface of tumor cells. Fibroblast growth factor-inducible 14 (Fn14) is a cytokine receptor which involves several intercellular signaling pathways and can be highly expressed in the surface of cancer cells. Since the cleavage of enzymatic domain of Pseudomonas exotoxin A (PE) occurs in one step by furin protease, we fused enzymatic subunit of Shiga-like toxin type 2a (Stx2a) with domain II and a portion of Ib of PE to increase the toxicity of Stx. Then, we genetically fused the Fv fragment of an anti-Fn14 monoclonal antibody (P4A8) to STX2a-PE15 and evaluated the STX2a-PE15-P4A8 chimeric protein as a new immunotoxin candidate. In silico analysis showed that the STX2a-PE15-P4A8 is a stable chimeric protein with high affinity to the Fn14 receptor. Despite, the STX2a-PE15-P4A8 can be bind to the B cell receptor, but it has been weakly presented by major histocompatibility complex molecules II (MHC-II). So, it may have a little immunogenicity. On the basis of our in-silico studies we predict that STX2a-PE15-P4A8 can be a good candidate for cancer immunotherapy., Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-021-00079-w., Competing Interests: Conflict of interestThe authors declare that they have no competing interests., (© The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature 2021.)

Acinetobacter baumannii is a serious health threat with a high mortality rate. We have already reported prophylactic effects of IgYs raised against OmpA and Omp34 as well as against inactivated whole-cell (IWC) of A. baumannii in a murine pneumonia model. However, the infection was exacerbated in the mice group that received IgYs raised against the combination of OmpA and Omp34. The current study was conducted to propose reasons for the observed antibody-dependent enhancement (ADE) in addition to the therapeutic effect of specific IgYs in the murine pneumonia model. This phenomenon was hypothetically attributed to topologically inaccessible similar epitopes of OmpA and Omp34 sharing similarity with peptides of mice proteins. In silico analyses revealed that some inaccessible peptides of OmpA shared similarity with peptides of Omp34 and Mus musculus. Specific anti-OmpA and anti-Omp34 IgYs cross-reacted with Omp34 and OmpA respectively. Specific IgYs showed different protectivity against A. baumannii AbI101 in the murine pneumonia model. IgYs triggered against OmpA or IWC of A. baumannii were the most protective antibodies. IgY triggered against Omp34 is ranked next after those against OmpA. The lowest protection was observed in mice received IgYs raised against the combination of rOmpA and rOmp34. In conclusion, specific IgYs against OmpA, Omp34, and IWC of A. baumannii could serve as novel biotherapeutics against A. baumannii pneumonia.

Purpose: Chitosan is a natural polymer that has excellent properties include biocompatibility, biodegradability, no cytotoxicity, high charge density, low cost, mucoadhesive, permeation enhancing (ability to cross tight junction), and immunomodulating ability that makes the spectrum of its applicability much broader. This study was conducted to investigate the stabilizing, preservative and immunogenicity properties of N-trimethyl chitosan nanospheres (N-TMCNS)., Materials and Methods: The tetanus toxoid (TT) was encapsulated into N-TMCNS and then characterized by scanning electron microscope, atomic force microscope, and dynamic light scattering. For stabilizer assay of N-TMCNS after storage of TT-N-TMCNS at different temperatures for 3 weeks, they were used for immunization of mice and different temperatures groups' anti-TT-N-TMCNS production compared with other groups. Finally, the immunized mice were challenged with tetanus toxin. The preservation activity of TT-N-TMCNS against Escherichia coli was compared with thimerosal formulated TT., Results: Our results revealed that heat-treated TT-N-TMCNS could induce higher titer of neutralizing immunoglobulin G in compared to TT vaccine and was able to protect the mice better than TT vaccine in challenge test. Furthermore, N-TMCNS as a preservative inhibited the growth of E. coli more effective than thimerosal., Conclusion: Overall, the obtained results indicated that the N-TMCNS is one of the best stabilizer and preservative agent that can be used in the formulation of TT vaccine., Competing Interests: No potential conflict of interest relevant to this article was reported., (© Korean Vaccine Society.)

Background: Streptococcus pneumonia (pneumococcus) is a human bacterial pathogen causing a range of mild to severe infections. The complicated transcriptome patterns of pneumococci during the colonization to infection process in the human body are usually determined by measuring the expression of essential virulence genes and the comparison of pathogenic with non-pathogenic bacteria through microarray analyses. As systems biology studies have demonstrated, critical co-expressing modules and genes may serve as key players in biological processes. Generally, Sample Progression Discovery (SPD) is a computational approach traditionally used to decipher biological progression trends and their corresponding gene modules (clusters) in different clinical samples underlying a microarray dataset. The present study aimed to investigate the bacterial gene expression pattern from colonization to severe infection periods (specimens isolated from the nasopharynx, lung, blood, and brain) to find new genes/gene modules associated with the infection progression. This strategy may lead to finding novel gene candidates for vaccines or drug design., Results: The results included essential genes whose expression patterns varied in different bacterial conditions and have not been investigated in similar studies., Conclusions: In conclusion, the SPD algorithm, along with differentially expressed genes detection, can offer new ways of discovering new therapeutic or vaccine targeted gene products.

Objectives: Cisplatin is one of the common chemotherapy drugs for bladder cancer, and resistance to this drug is one of the major obstacles to effective chemotherapy. MicroRNAs (miRNAs) are a category of small noncoding RNAs that can regulate the expression of numerous genes. Recent studies showed that miRNAs can act as a powerful regulator of chemo-sensitivity in cancer cells. Hence, this study aimed to investigate the effects of miRNA-486-5p on cisplatin-sensitivity of different bladder cancer cells., Material and Methods: The 5637 and EJ138 cancer cells were treated with miRNA-486-5p and cisplatin, individually or in combination., Results: Afterward, the cytotoxicity effects of these treatments were determined by MTT assay and the increased cisplatin-sensitivity observed in both cell lines, especially, 5637 cells. Moreover, subG1 phase cell cycle arrest, changes in the expression of caspase-9, caspase-3, P53, SIRT1, OLFM4, SMAD2, and Bcl-2 genes and nuclear fragmentation also revealed the induction of apoptosis in all treatments, which increased in combination groups. Also, the combination of miRNA-486-5p with cisplatin significantly down-regulated the expression of migration associated genes including ROCK, CD44, and MMP-9 as compared with cisplatin alone., Conclusion: Altogether, these results indicated that the miRNA-486-5p could induce apoptosis and inhibit cell migration ability of the cells. It seems that pre-electroporation of cells with miRNA-486-5p has useful results in the enhancement of cisplatin sensitivity of 5637 and EJ138 cancer cells and this combination may be a promising treatment strategy for bladder cancer therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

CTLA4-Ig (Abatacept) has been produced to suppress immune response by inhibition of T cells functions in autoimmune disease. A new drug, which is called belatacept, has recently been recently developed that is more efficient. The development has been occurred by two substitutions (A29Y, L104E) in the extracellular domain of CTLA4. In the present study, the bioinformatics analysis was used in order to make a new structure that has a better function in comparison with belatacept. Firstly, eight different structures were designed. Thereafter, the secondary and 3D structures, mRNA structure, docking of chimeric proteins with CD80/CD86, antigenicity and affinity of designed chimeric molecules were predicted. Based on the criteria, a new candidate molecule was selected and its gene synthesized. The gene was cloned and expressed in E. coli BL21 (DE3) successfully. The purified rCTLA4-Ig was analyzed by SDS-PAGE, western blotting, and ELISA. Circular dichroism analysis (CD analysis) was used for characterization of the rCTLA4-Ig. Affinity of rCTLA4-Ig was also evaluated by the flow cytometry method. Finally, its biological activity was determined by T cell inhibition test. The results showed rCTLA4-Ig and the belatacept protein have some similarities in structure and function. In addition, rCTLA4-Ig was able to bind CD80/CD86 and inhibit T cell function. Although flow cytomery results showed that the standard protein (CTLA4-Ig), represented better affinity than rCTLA4-Ig, the recombinant protein was able to inhibit T cell proliferation as well as CTLA4-Ig.

Objective: Due to the importance of Chronic obstructive pulmonary disease (COPD) as the fourth cause of mortality worldwide and the lack of studies evaluating the prevalence of bacterial infections in disease exacerbation, this systematic review and meta-analysis was performed to determine the prevalence rate of bacterial infections in COPD patients., Methods: PubMed, ISI Web of Science, and Scopus databases were systematically searched for population-based prevalence studies (1980-2018). MeSH terms for "Bacterial infections" and "AECOPD" were used as search keywords. The selected studies were filtered according to the inclusion and exclusion criteria. Fixed and random-effects models were used for estimation of summary effect sizes. Between-study heterogeneity, as well as publication bias, were calculated., Results: Finally, 118 out of 31,440 studies were selected. The overall estimation of the prevalence of bacterial infection was 49.59% [95% confidence interval (CI) 0.4418-0.55]. The heterogeneity in estimating the pooled prevalence of bacterial infections was shown in the studies (Cochran Q test: 6615, P < 0.0001, I 2  = 98.23%). In addition, S. pneumoniae, H. influenzae, M. catarrhalis, A. baumannii, P. aeruginosa, and S. aureus were the most prevalent reported bacteria., Conclusions: Our results as the first meta-analysis for the issue demonstrated that bacterial infections are an important risk factor for AECOPD. Further studies must be performed for understanding the exact role of bacterial agents in AECOPD and help physicians for more applicable preventive and therapeutic measurements.

Asthma is the most common respiratory disease accompanied by lung inflammatory disorders. The main symptoms are airway obstruction, chronic inflammation due to mast cell and eosinophil activity, and the disturbance of immune responses mostly mediated by the Th2 response. Genetic background and environmental factors also contribute to the pathogenesis of asthma. Today, microRNAs (miRNAs) are known as remarkable regulators of gene expression. As a small group of noncoding single-strand RNAs, mature miRNAs (~21 nucleotides) modulate the gene expression by targeting complement RNAs at both transcriptional and posttranscriptional levels. The role of miRNAs in the pathogenesis of many diseases such as allergies, asthma, and autoimmunity has been vastly studied. This review provides a thorough research update on the role of miRNAs in the pathogenesis of asthma and their probable role as diagnostic and/or therapeutic biomarkers., (© 2019 Wiley Periodicals, Inc.)

Background and Objective: TNF-α -308 G/A variant is recognized to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Although many studies have investigated the association of TNF-α-308 and COPD risk, a deep understanding of this association is lacking due to small subjects sizes and insufficiently study designs among different investigations. In this study, a systematic review and meta-analysis was performed based on published reports on the association of TNF-α and COPD., Method: The published studies concerned the association between TNF-α and COPD were identified using a systematic research in Scopus, Google Scholar, and PubMed up to April 2018. A total of 46 different papers studying the rs1800629 variant in TNF-α gene were included. Then, human studies were selected to further analysis regardless of papers language., Results: Based on the results, the major outcome of this meta-analysis can be represented as follows: individuals with GG and GA genotypes possess less risk of developing COPD (OR = 0.58, 95%CI: (0.44-0.79), P < 0.00) compared to AA genotype carriers. In contrast, the AA genotype carriers of the TNF-α rs1800629 has a significantly higher risk of developing COPD (OR = 1.83, 95%CI: (1.34-2.51), P < 0.00) compared to GG carrier. Despite the previous meta-analysis results which reported significantly decreasing of heterogeneity with ethnicity, we found that the source of controls has a significant contribution to observed heterogeneity., Conclusions: Thanks to the global burden of COPD studies, proving TNF-α 308 gene variant as an independent factor in its pathogenesis opens new insights to diagnosis and management of COPD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Sulfur mustard (SM) is a destructive and harmful chemical agent for the eyes, skin and lungs that causes short-term and long-term lesions and was widely used in Iraq war against Iran (1980-1988). SM causes DNA damages, oxidative stress, and Inflammation. Considering the similarities between SM and COPD (Chronic Obstructive Pulmonary Disease) pathogens and limited available treatments, a novel therapeutic approach is not developed. Gene therapy is a novel therapeutic approach that uses genetic engineering science in treatment of most diseases including chronic obstructive pulmonary disease. In this review, attempts to presenting a comprehensive study of mustard lung and introducing the genes therapy involved in chronic obstructive pulmonary disease and emphasizing the pathways and genes involved in the pathology and pathogenesis of sulfur Mustard. It seems that, given the high potential of gene therapy and the fact that this experimental technique is a candidate for the treatment of pulmonary diseases, further study of genes, vectors and gene transfer systems can draw a very positive perspective of gene therapy in near future., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Interleukins are cytokines involved in systemic inflammation and immune system regulation. Many studies have investigated the association between common genetic variations in interleukin-coding genes and COPD susceptibility. In this study, a systematic review and meta-analysis was performed to evaluate the association between interleukin gene variations and COPD pathogenesis. Association studies were retrieved from PubMed and Google Scholar databases using the standard systematic search strategy. A total of 26 different studies evaluating eight polymorphisms in four interleukin genes were included in this study. In overall comparisons, IL1β-rs16944, -rs1143627, -rs1143634, IL13-rs20541 polymorphisms were found not to be associated with the increased risk for developing COPD. However, IL1RN-rs2234663 and IL13-rs1800925 showed a strong association with COPD. We showed that the CC genotype carriers of the IL6-rs1800795 are at significantly higher risk of developing COPD (OR = 1.31, 95% CI: 1.04-1.64, P = 0.01) compared to GG carriers. In case of IL6-rs1800796, individuals with CC and CG genotypes showed a lower risk to develop COPD (OR = 0.46, 95%CI: 0.32-0.66, P > 0.00). This updated meta-analysis strongly supports the association of IL1RN-rs2234663, IL6-rs1800795, -rs1800795 and IL13-rs1800925 variants with COPD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The mustard lung is a late consequence of exposure to sulfur mustard (SM) in veterans who had participated in the Iraq-Iran war. Three mechanisms are contributed in the pathogenesis of mustard lung including oxidative stress, protease-antiprotease imbalance, and dysregulated immune response. In the context of the immune response, the role of the inflammasome complex and their inflammatory cytokines are important. This study aims to investigate the inflammasome pathway and their inflammatory cytokine (i.e IL-1 and IL-18) in the peripheral blood of mustard lung patients as well as chronic obstructive pulmonary disease (COPD) patients. This research was conducted as a cross-sectional analytical study on 15 SM patients and was compared with 15 COPD patients and 15 healthy controls. The real-time polymerase chain reaction was used to assess gene expression levels of inflammasome components (NLRP1, NLRP3, NLRC4, and ASC), inflammatory cytokines (IL-1β, IL-18, and IL-1βR), and IL-37 as an anti-inflammatory cytokine. Finally, the data were analyzed by SPSS version 21 software. The gene expression level of molecules involved in inflammasome pathway showed a slight increase in the peripheral blood of SM and COPD patients compared to the control group. However, this difference was not statistically significant. Only IL-37 and NLRP1 had a significant increase in mustard lung and COPD patients; compared to healthy controls (p<0.05). Due to the normal expression of genes involved in the inflammasome pathway, it can be stated that the inflammasome pathway is not active in the blood of mustard lung patients.

Along with robust immunogenicity, an ideal vaccine candidate should be able to produce a long lasting protection. In this regard, the frequency of memory B-cells is possibly an important factor in memory B-cell persistency and duration of immunological memory. On this basis, binding domains of tetanus toxin (HcT), botulinum type A1 toxin (HcA), and heat-labile toxin (LTB) were selected as antigen models that induced long-term, midterm and short-term immune memory, respectively. In the present study, the frequency of total memory B-cells after immunization with HcT, HcA and LTB antigens after 90 and 180 days, and also after one booster, in 190 days, was evaluated. The results showed a significant correlation between frequency of total memory B-cells and duration of humoral immunity. Compared to other antigens, the HcT antibody titers and HcT total memory B-cell populations were greater and persistent even after 6 months. At 6 months after the final immunization, all HcT- and HcA-immunized mice survived against tetanus and botulinum toxins, and also LT toxin binding to GM1 ganglioside was blocked in LTB-immunized mice. We conclude the frequency of memory B-cells and their duration are likely a key factor for vaccine memory duration., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: Acinetobacter baumannii, an increasingly serious health threat, is considered as one of the six most dangerous microbes of high mortality rate. However, treatment of its infections is difficult because of the lack of efficient antibiotic or commercial vaccines. Passive immunization through administration of specific antibodies such as IgY, could be an attractive practical solution., Methods and Results: In the current study, antigenicity of two recombinant outer membrane proteins (OmpA and Omp34) as well as inactivated whole cell of A. baumannii was assessed by ELISA. Moreover, prophylactic effects of specific IgY antibodies (avian antibody) raised against these antigens were evaluated in a murine pneumonia model. The specific IgY antibodies had various prophylactic effects in the pneumonia model. OmpA was the most potent antigen in terms of triggering antibody and conferring protection. While a synergic effect was observed in ELISA for antibodies raised against a combination of OmpA and Omp34 (which are known as Omp33-36 and Omp34 kDa), an antagonistic effect was unexpectedly seen in challenges. The reason for this phenomenon remains to be precisely addressed., Conclusion: All the specific IgY antibodies could protect mice against pneumonia caused by A. baumannii., Significance and Impact of the Study: The specific IgY antibodies could be employed as a pharmaceutical against pneumonia caused by A. baumannii., (© 2018 The Society for Applied Microbiology.)

Chronic obstructive pulmonary disease (COPD) is known as a progressive lung disease and the fourth leading cause of death worldwide. Despite valuable efforts, there is still no accurate diagnostic and prognostic tool for COPD. Hence, it seems that finding new biomarkers could contribute to provide better therapeutic platforms for COPD patients. Among various biomarkers, microRNAs (miRNAs) have emerged as new biomarkers for the prognosis and diagnosis of patients with COPD. It has been shown that deregulation of miRNAs targeting a variety of cellular and molecular pathways such as Notch, Wnt, hypoxia-inducible factor-1α, transforming growth factor, Kras, and Smad could be involved in COPD pathogenesis. Multiple lines of evidence have indicated that extracellular vesicles such as exosomes could carry a variety of cargos (i.e., mRNAs, miRNAs, and proteins) which transfer various cellular and molecular signals to recipient cells. Here, we summarized various miRNAs which could be applied as diagnostic and prognostic biomarkers in the treatment of patients with COPD. Moreover, we highlighted the role of extracellular vesicles containing miRNAs as diagnostic and prognostic biomarkers in COPD patients., Competing Interests: There are no conflicts of interest.

Background: Regarding to the importance of cholera in Iran and the potential advantages of egg yolk antibody (IgY) for immunotherapy, the aim of this study was to produce IgY antibody against V. cholerae Lipopolysaccharide (LPS) and determine its potential for V. cholerae treatment., Methods: LPS was prepared, and the Anti-V. cholerae LPS IgY was purified from egg yolk and serially diluted in phosphate-buffered saline (PBS), mixed with V. cholerae and then gavaged into several groups of suckling mice., Results: The yield of Anti-LPS IgY extraction was 40 mg/Egg yolk. The results demonstrated that up to approximately 75 ng of IgY can detect specifically V. cholerae. The lowest protective dose of anti-V. cholerae LPS IgY was 2.5 μg., Conclusions: The produced anti-Vibrio LPS specific IgY showed a good reactivity with its specific antigen and it may use as a complimentary oral immunotherapy for cholera disease., (Copyright © 2018. Published by Elsevier Inc.)

Colorectal cancer (CRC) is known as the third common cancer worldwide and an important public health problem in different populations. Several genetics and environmental risk factors are involved in the development and progression of CRC including chromosomal abnormalities, epigenetic alterations, and unhealthy lifestyle. Identification of risk factors and biomarkers could lead to a better understanding of molecular pathways involved in CRC pathogenesis. MicroRNAs (miRNAs) are important regulatory molecules which could affect a variety of cellular and molecular targets in CRC. A large number of studies have indicated deregulations of some known tissue-specific miRNAs, for example, miR-21, miR-9, miR-155, miR-17, miR-19, let-7, and miR-24 as well as circulating miRNAs, for example, miR-181b, miR-21, miR-183, let-7g, miR-17, and miR-126, in patients with CRC. In the current review, we focus on the findings of preclinical and clinical studies performed on tissue-specific and circulating miRNAs as diagnostic biomarkers and therapeutic targets for the detection of patients at various stages of CRC., (© 2017 Wiley Periodicals, Inc.)

Omp33-36 in A. baumannii, a bacterium causing serious nosocomial infections, is a virulence factor associated with the pathogen metabolic fitness as well as its adherence and invasion to human epithelial cells. This protein is also involved in interaction of the bacteria with host cells by binding to fibronectin. Moreover, Omp33-36 renders cytotoxicity to A. baumannii in addition to inducing apoptosis and modulation of autophagy. In the present study, an integrated strategy is launched to pierce into the 3D structure of Omp33-36 protein. The signal peptide within the sequence was determined, then, topology as well as secondary and tertiary structures of the protein were predicted. The mature protein assigned as a 14-stranded barrel in which residues 1-19 is removed as signal peptide. The obtained 3D models were evaluated in terms of quality; and then, served as queries to find similar protein structures. The hits were analyzed regarding topology among which 14-stranded were considered. The most qualified model was refined and then its sequence aligned to its counterpart similar structure protein (CymA from Klebsiella oxytoca). The determined structure of Omp33-36 could justify its porin function and carbapenem-resistance associated with the loss of this protein., (Copyright © 2018. Published by Elsevier Ltd.)

Omp34, also known as Omp34kDa or Omp33-36 is a virulence factor associated with A. baumannii metabolic fitness or its adherence and invasion to human epithelial cells. This protein is also introduced as a specific antigen which could induce strong antibody responses. In the present in silico study, recent vaccine design strategies such as 'antigen minimization' and 'high epitope density' were invoked to design a soluble immunogen with higher antigenicity. As an advantage, the tools employed in the current study are easily available. Exposed peptides in linear B-cell epitopes were predicted and their conservancy and immunogenicity were evaluated. In this regard, constructs were designed by removal of inappropriate regions. Based on the obtained results the external loops (L1-L7) were exclusively considered of which L3, L6 and L7 were the most appropriate of which the most appropriate were in L3>L6>L7 order while L2 was assigned as an inappropriate peptide. The final construct, named Omp34-4, encompasses three copies of L3, two copies of L6 and L7 and one copy of L1, L4 and L5. The designed construct is predicted to be a soluble antigen with enhanced epitope density and antigenicity. Omp34 is present in >1600 strains of A. baumannii with ≥98% identity. So, it could be applicable in diagnostic kits and an immunotherapy choice against A. baumannii. It could be presumed that co-administration of Omp34-4 and a recently designed OmpA-derived antigen could confer sufficient protection against A. baumannii-associated infections. In vitro and in vivo experiments are needed to confirm all these data. The innovative approach could be generalized to vaccine designs focused on OMPs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: The present study was aimed at comparing tetanus toxoid (TT)‑loaded-chitosan nanoparticles with aluminum hydroxide as a common vaccine adjuvant., Background: Tetanus remains to be a major public health problem. Nanoparticles have been extensively used as immune adjuvants. Tetanus toxoid (TT) encapsulated in chitosan nanoparticles is considered to be a promising tetanus vaccine candidate., Methods: TT‑loaded chitosan nanoparticles were prepared by the ionic gelation method. The nanoparticles were studied by SEM for their size and morphology. In vivo study was conducted to evaluate the immunity response using mice divided into 4 groups and injected with encapsulated toxoid. The immune responses were then measured using indirect ELISA., Results: The purity and integrity of antigen were confirmed by SDS-PAGE electrophoresis. The size of nanoparticles was estimated at 100 nm. As a result, the IgG antibody levels were 1.9, 1.76, and 0.87 in chitosan nanoparticles, aluminum hydroxide, and TT alone groups, respectively. Also, the immune responses were significantly higher in immunized groups compared to control groups vaccinated with free adjuvant vaccines (p < 0.05)., Conclusions: The quality and efficacy of toxoid‑loaded chitosan nanoparticles were reasonable. It enhanced the immune responses as much as aluminum hydroxide adjuvant does and thus may be a good alternative candidate (Tab. 1, Fig. 3, Ref. 16).

Objectives: Breast cancer is one of the most common cancers in the world and is on the increase. MUC1 and HER2 as tumor-associated antigens (TAAs) are abnormally expressed to some extent in 75-80% of breast cancers. In our present research, a novel chimeric MUC1-HER2 (HM) protein was designed and used to study whether an immune response can be generated against these TAAs. In vitro analysis of the HER2-MUC1 construct confirmed the co-expression of MUC1 and HER2., Materials and Methods: BALB/c mice were immunized with this novel chimeric protein. The humoral immune response was assessed by enzyme-linked immunosorbent assay (ELISA). Then, BALB/c mice were injected subcutaneously 2×105 4T1-MUC1-HER2 tumor cells. Subsequently, tumor size and tumor necrosis measurements, MTT, cytokines assay and survival test were performed., Results: The results implied a critical role of HER2 and MUC1 antibodies in vaccination against breast cancer. This engineered protein can be a good vaccine to stop breast cancer., Conclusion: The results implied a critical role of HER2 and MUC1 antibodies in vaccination against breast cancer. This engineered protein can be a good vaccine to stop breast cancer.

Background and Objective: Chronic obstructive pulmonary disease (COPD) is a chronic progressive lung disease. On the other hand, viral infections of the airway are associated with the acute exacerbations of COPD. A systematic review and meta-analysis were performed to determine the prevalence rate of viral infections in acute exacerbations of COPD patients., Methods: PubMed database was systematically searched for population-based prevalence studies (1930-2017). Fixed and random effects models were used for estimation of summary effect-sizes. Between-study heterogeneity and publication bias were also calculated. "Viral infections" and "COPD patients with exacerbations" were the two critical inclusion criteria., Results: Twenty-eight studies were selected out of 26078 articles for the present review. The overall estimation of the prevalence of viral infection was 0.374 (95% C.I: 0.359-0.388). Also, the evident heterogeneity of viral infection was observed among the studies (Cochran Q test, p value < 0.001 and I-squared = 97.5%). The highest and lowest prevalence rate was related to rhinovirus and echovirus, respectively. Also, the results of this study showed that the prevalence of viral infection in exacerbated COPD patients has fluctuation during the years with a slight increase and decrease., Conclusions: The results of this systematic review demonstrated that respiratory viral infections have an important role in the acute exacerbation of COPD (AECOPD). In addition, determining the exact geographic epidemiology of these viruses is very important to manage the treatment of these infections., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Sulfur mustard (SM) is an extremely toxic gas used in chemical warfare to cause massive lung injury and death. Victims exposed to SM gas acutely present with inhalational lung injury, but among those who survive, some develop obstructive airway diseases referred to as SM-lung syndrome. Pathophysiologically, SM-lung shares many characteristics with smoking-induced chronic obstructive pulmonary disease (COPD), including airway remodeling, goblet cell metaplasia, and obstructive ventilation defect. Some of the hallmarks of COPD pathogenesis, which include dysregulated lung inflammation, neutrophilia, recruitment of interleukin 17A (IL -17A) expressing CD4 + T cells (Th17), and the paucity of lung regulatory T cells (Tregs), have also been described in SM-lung. Areas covered: A literature search was performed using the MEDLINE, EMBASE, and Web of Science databases inclusive of all literature prior to and including May 2017. Expert commentary: Here we review some of the recent findings that suggest a role for Th17 cell-mediated inflammatory changes associated with pulmonary complications in SM-lung and suggest new therapeutic approaches that could potentially alter disease progression with immune modulating biologics that can restore the lung Th17/Treg balance.

The long lasting inflammation and immune dysregulation is one of the main mechanisms involved in lung complication of veterans exposed to sulfur mustard (SM) gas. Th17/Treg cells have an important role in immunopathogenesis of chronic obstructive pulmonary disease (COPD) and mustard lung disease. In this study, expression of cytokines genes levels related to Th17/Treg cells was determined in peripheral blood mononuclear (PBMC) of mustard lung patients and was compared with COPD patients and healthy controls (HC). Real time-polymerase chain reaction was used to assay genes expression levels of Th17 related cytokines (IL-17, IL-6 and TGF-β) and Treg related cytokines (IL-10, TGF-β). IL-17 gene expression level considerably was higher in SM patients (9.98±0.65, p<0.001), and COPD (4.75±0.71, p<0.001), compare to HC group. Also, gene expression level of IL-6 in the SM group (3.31±0.93, p<0.001) and COPD group (2.93±0.21, p<0.001) were significantly higher than the HC group. The IL-10 gene expression level showed a high increase in SM patients (4.12±0.91, p<0.01), and COPD (2.1±0.45, p<0.01). Finally, the TGF-β gene expression level was increased in SM patients (4.91±0.69, p<0.001) as well as in COPD group (5.41±0.78, p<0.001). In SM patients, IL-17 (R=-0.721, p<0.05), IL-6 (R=-0.621, p<0.05) and TGF-β (R=-0.658, p<0.05) had significant negative association with FEV1 (%). Inversely, Il-10 showed positive correlation (R=0.673) with FEV1 (%). Th17/Treg cells related cytokines genes were highly expressed and imbalanced in peripheral blood mononuclear cells of SM and COPD patients which correlated with pulmonary dysfunction.

In this work, a novel nanocomposite film consisting of the Au nanoparticles/graphene-chitosan has been designed to construct an impedimetric immunosensor for a rapid and sensitive immunoassay of botulinum neurotoxin A (BoNT/A). BoNT/A antibody was immobilized on glassy carbon electrode modified with Au nanoparticles/graphene-chitosan for the signal amplification. The fabrication of immunosensor was extensively characterized by using transmission electron microscopy (TEM), scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray diffraction (XRD), Fourier transform infrared (FTIR), cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS). The impedance changes, due to the specific immuno-interactions at the immunosensor surface that efficiently restricted the electron transfer of redox probe Fe(CN) 6 4-/3- were utilized to detect BoNT/A. The measurements were highly targeted specific and linear with logarithmic BoNT/A concentrations in PBS, milk and human serum across a 0.27-268pgmL -1 range and associated with a detection limit of 0.11pgmL -1 ., (Copyright © 2016. Published by Elsevier B.V.)

In this work, a novel nanocomposite consisting of electrosynthesized gold nanodendrites and chitosan nanoparticles (AuNDs/CSNPs) has been prepared to fabricate an impedimetric immunosensor based on a screen printed carbon electrode (SPCE) for the rapid and sensitive immunoassay of botulinum neurotoxin A (BoNT/A). BoNT/A polyclonal antibody was immobilized on the nanocomposite-modified SPCE for the signal amplification. The structure of the prepared nanocomposite was investigated by transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS). The charge transfer resistance (R CT ) changes were used to detect BoNT/A as the specific immuno-interactions at the immunosensor surface that efficiently limited the electron transfer of Fe(CN)₆ 3-/4- as a redox probe at pH = 7.4. A linear relationship was observed between the %∆ R CT and the concentration logarithm of BoNT/A within the range of 0.2 to 230 pg·mL -1 with a detection limit (S/N = 3) of 0.15 pg·mL -1 . The practical applicability of the proposed sensor was examined by evaluating the detection of BoNT/A in milk and serum samples with satisfactory recoveries. Therefore, the prepared immunosensor holds great promise for the fast, simple and sensitive detection of BoNT/A in various real samples.

Outer membrane protein A (OmpA) is the most promising vaccine candidate against one of the most successful nosocomial pathogens, A. baumannii. Despite advantages of the antigen, its cytotoxicity could be considered as a challenge in clinical trials. In order to improve this effective immunogen, rational vaccine design strategies such as structure-based vaccinology should be assessed. However, native structure of OmpA remains controversial. The present study is conducted to address the native structure of OmpA; then, a novel immunogen with lower toxicity and higher antigenicity was designed based on structural vaccinology. Various bioinformatic and immunoinformatic tools were harnessed to perform analyses such as topology, secondary structure, and tertiary structure predictions as well as B-cell epitope predictions. A novel 12-stranded model is suggested for OmpA. K 320 and K 322 were substituted by Alanine, "NADEEFWN" sequence was replaced by "YKYDFDGVNRGTRGTSEEGTL", Position 1-24 at the N-terminus and the C-terminal sequence "VVQPGQEAAAPAAAQ" were removed. The designed construct has more epitope density and antigenic properties with higher immunogenicity while its cytotoxicity is decreased. Moreover, this single cross-protective antigen could trigger antibodies rendering protection against two important nosocomial pathogens i.e. Pseudomonas aeruginosa and A. baumannii., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: AFn14R can serve as an ideal target for cancer immunotherapy. Here, a combined bioinformatic and experimental approach was applied to characterize an immunotoxin consisting of single-chain variable fragment antibody that targets Fn14 and a toxin fragment (PE38)., Methods & Results: Flow cytometry results showed that the rate of PE38-P4A8 binding to Fn14 was approximately 60 and 40% in HT-29 and A549 cells, respectively. Moreover, 1 ng/µl of immunotoxin was able to lyse approximately 53 and 41% of HT-29 and A549, respectively. PE38-P4A8 showed stability in mouse serum (∼90%) after 3-h incubation. Most importantly, using bioinformatics for determining the structure and function of fusion proteins can be very helpful in designing of experiments., Conclusion: Coupled with bioinformatics, experimental approaches revealed that PE38-P4A8 could be used as a promising therapeutic agent for cancer cells expressing Fn14.

Purpose: Sulfur mustard (SM) lung is a heterogeneous disease associated with abnormal inflammatory immune responses. The Th17/Treg axis imbalance is associated with the pathogenesis of chronic inflammatory pulmonary disease. We aimed to determine the distribution of different Th17 and Treg cells in patients with SM lung and chronic obstructive pulmonary disease (COPD) and evaluate the clinical implications in this homeostasis., Methods: In this analytical cross-sectional study, CD4 (+) Foxp3(+ )Treg and CD4(+) IL-17(+ )Th17 cells were measured in peripheral blood mononuclear cells (PBMCs) and transbronchial biopsy (TBB) samples of 15 SM-exposed patients, 12 COPD and 13 healthy controls (HCs). The potential correlation between the ratio of Th17/Tregs and lung function was evaluated with multivariate logistic regression (MLR) analysis., Results: The frequency of CD4 (+) FoxP3(+) Tregs and CD4 (+) IL-17(+) Th17 was increased ∼1.7-fold (8.71/4.95) and ∼2.7-fold (1.028/0.371) respectively, in the PBMC of SM patients compared with the health controls (p < 0.001). The results indicated that there were increases in the frequency of Th17 and Tregs cells in the patients with COPD versus the HC, that is, ∼2.6-fold (0.987/0.371) and ∼1.4-fold (7.12/4.95), respectively; but they did not reach to SM level (p ≥ 0.05). Moreover, in the TBB samples, the CD4 (+) IL-17(+ )Th17 and CD4(+) FoxP3(+ )Tregs numbers were significantly higher in SM and COPD patients than HC (p < 0.05). The Th17 and Treg cells were inversely correlated with forced expiratory volume in 1s (FEV1%) (r = -0.351, p   = 0.001; r = -0.344, p = 0.021) and FEV1/FVC (r = -0.44, p = 0.001; r = -0.302, p = 0.011), respectively. Instead, positive correlations were found between Treg/Th17 ratios and forced FEV1%pred (r = 0.156, p = 0.007), as well as FEV1/FVC ratio (r = 0.334, p = 0.006)., Conclusions: The imbalance of Th17/Treg has a key role in immunopathogenesis of chronic phase of mustard lung disease.

Staphylococcus aureus are potent human pathogens possessing arsenal of virulence factors. Staphylococcal food poisoning (SFP) and respiratory infections mediated by staphylococcal enterotoxin B (SEB) are common clinical manifestations. Many diagnostic techniques are based on serological detection and quantification of SEB in different food and clinical samples. Aptamers are known as new therapeutic and detection tools which are available in different ssDNA, dsDNA and protein structures. In this study, we used a new set of ssDNA aptamers against SEB. The methods used included preparation of a dsDNA library using standard SEB protein as the target analyte, affinity chromatography matrix in microfuge tubes, SELEX procedures to isolate specific ssDNA-aptamer as an affinity ligand, aptamer purification using ethanol precipitation method, affinity binding assay using ELISA, aptamer cloning and specificity test. Among 12 readable sequences, three of them were selected as the most appropriate aptamer because of their affinity and specificity to SEB. This study presents a new set of ssDNA aptamer with favorable selectivity to SEB through 12 rounds of SELEX. Selected aptamers were used to detect SEB in infected serum samples. Results showed that SEB c1 aptamer (2 µg SEB/100 nM aptamer) had favorable specificity to SEB (kd  = 2.3 × 10(-11) ). In conclusion, aptamers can be considered as useful tools for detecting and evaluating SEB. The results showed that affinity chromatography was an affordable assay with acceptable accuracy to isolate sensitive and selective novel aptamers. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

In this study, we investigated expression changes of Th17/Treg-related cytokine in transbronchial lung biopsy (TBLBs) of sulfur mustard (SM) exposure, stable chronic obstructive pulmonary disease (COPD) patients and also compared it with a healthy control (HC) group. Here, ROR-γt, FoxP3, and Treg/Th17-related cytokines (IL-10, IL-17A, IL-6, and TGF-β1) were assessed using a combination of RT-QPCR and ELISA in 11 SM-exposed cases, 9 patients with GOLD stage II COPD diagnosed, and 8 HC. Our results showed that the levels of Foxp3 expression were lower and ROR-γt expression was higher in SM and COPD patients when compared with HC (all p values were less than 0.001). The relative Foxp3 expressions and Foxp3/ROR-γt ratio were positively correlated with FEV1 (%) pred (R = 0.682 and R = 0.602, respectively; p ≤ 0.001). However, the relative ROR-γt expressions were inversely correlated with FEV1 (%) pred (R= -0.75, p = 0.003) and relative Foxp3 expression (R= -0.704, p = 0.003). The mRNA and protein expression of IL-10 were significantly decreased in SM and COPD patients compared with HC (p < 0.001). An increase of IL-17A (∼7.2 fold) and TGF-β1 (∼5.6 fold) are involved in the lung exacerbation of SM and COPD patients. The expression of IL-6 was variable between three groups (p ≥ 0.05). In addition, an inverse correlation were observed between FEV1 (%) pred and expressions of IL-17A (R= -0.741), IL-6 (R= -0.673) and TGF-β1 (R= -0.632) (p ≤ 0.001). Instead, positive correlation was found between IL-10 ratios and FEV1 (%) pred (R = 0.777, p = 0.001). These findings suggest that Treg/Th17-mediated distributions are involved in the progression of chronic lung injury of SM and COPD patients.

Infectious diarrhoea remains an emerging problem in the world health program. Among diarrheagenic agents, Vibrio cholerae and enterotoxigenic and enterohemorrhagic Escherichia coli are critical enteropathogens. AB5 toxin produced by these bacteria, heat-labile enterotoxin (LT), cholera enterotoxin (CT), and shiga-like cytotoxin (STX) can target the immune system and are subunit vaccine candidates. A chemically-synthesized chimeric construct composed of the binding subunits of these toxins (LTB, STXB, and CTXB) was developed based on bioinformatics studies. The whole chimeric protein (rLSC) and each of the segments (rLTB, rSTXB, and rCTXB) were expressed in a prokaryotic expression system (E. coli), purified, and analysed for their immunogenic properties. The results indicate that these recombinant proteins were effectively able to present appropriate epitopes to an animal model of the immune system which could result in and increase IgG in serum and immune responses that protect against the binding activity of these toxins. The immunological assays revealed that the sera of immunized mice prevented toxins from binding to their specific receptors and neutralized their toxic effects. The proposed construct should be considered as a potent immunogen to prevent toxicity and diarrhoea., (Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Brucellosis is the most common zoonotic bacterial disease. Prevention of human brucellosis is achieved through pasteurization of dairy products, appropriate sanitation and vaccination of domestic animals against the Brucella species. B. abortus unlipidated 19 kDa outer membrane protein (U-Omp19) is a promising candidate for a subunit vaccine against brucellosis. This study investigates immunogenicity of Omp19 alone and with Freund's adjuvant (Omp19-IFA) and N-trimethyl chitosan (TMC/Omp19) nanoparticles, as well as the effect of Omp19 administration route on immunological responses and protection. The omp19 gene was expressed in E. coli BL21 (DE3). After purification, the recombinant Omp19 was loaded onto TMC nanoparticles by ionic gelation with tripolyphosphate. Particle size and loading efficiency of the nanoparticles were determined. Omp19-IFA was administered intraperitoneally while TMC/Omp19 nanoparticles were administered orally and intraperitoneally. The results indicated that intraperitoneal (i.p.) immunization by Omp19-IFA and TMC/Omp19 nanoparticles induced Th1 and Th2 immune responses, respectively, whereas oral immunization of TMC/Omp19 nanoparticles induced a mixed Th1/Th17 immune response. Moreover, oral immunization increased IgA levels in feces. Immunized mice were challenged with virulent B. melitensis 16 M and B. abortus 544. Oral immunization with TMC/Omp19 nanoparticles induced a remarkably high protection level against B. melitensis and B. abortus. The results showed that immunization route has a pivotal role in immune response polarization and protective efficiency of Omp19 antigen. Also, it was deduced that the higher protection level achieved through oral administration of TMC/Omp19 nanoparticles may be due to the elicited Th17 response.