Treatment outcomes of applying external fixator on distal radius fractures: a randomized clinical trial to compare between two directions of force exertion in parallel to radius shaft and perpendicular to the distal radius articular surface.

BACKGROUND: External fixation has been one of the conventional managements of unstable distal radius fracture. The main aim of this paper is to compare two methods of applying distractive force along the radius shaft versus perpendicular to the distal radius articular surface. DESIGN: Sixty patients with unstable distal radius fracture were included in present clinical trial and randomized in two groups, using block randomization method. In group A (first arm), distraction force was exerted parallel to the radius shaft. In group B (second arm), the external fixator was adjusted based on radial and palmar tilt of the mean population healthy wrist so that distraction was exerted perpendicular to the wrist articular surface. METHODS: Radiological and clinical parameters were evaluated in both groups of patients pre-operatively, immediately after surgery, and 6 weeks post-operatively. We also followed up patients clinically at 12 weeks after surgery. Patient-Rated Wrist Evaluation (PRWE), Mayo wrist score, and Quick Disabilities of the Arm, Shoulder and Hand (DASH) questionnaires were used in order to assess patients' clinical and functional states. RESULTS: The method used in group B resulted in better improvement of palmar tilt both immediately (P = 0.007) and at 6 weeks follow up (P = 0.013) post-operatively in comparison with patients in group A. Radius height and radial inclination were also better restored when using the proposed modified method (P = 0.001 and < 0.001, respectively). There was no difference in any of clinical results (range of motion, grip strength, PRWE, Mayo, and DASH scores) between two groups of study, 12 weeks after surgery. CONCLUSION: Applying distractive force perpendicular to the distal radius articular surface seems to improve some radiological outcomes, probably due to better reduction maintenance, when compared with the technique of applying distraction force along distal radius shaft axis. LEVEL OF EVIDENCE: Level I (clinical trial study). TRIAL REGISTRATION: This study is registered at Iranian Registry of Clinical Trials (IRCT) with approval code of IRCT20200313046759N1.

Genetically engineered mesenchymal stromal cells as a new trend for treatment of severe acute graft-versus-host disease.

Mesenchymal stem cells (MSCs) are a population of non-hematopoietic and self-renewing cells characterized by the potential to differentiate into different cell subtypes. MSCs have interesting features which have attracted a lot of attention in various clinical investigations. Some basic features of MSCs are including the weak immunogenicity (absence of MHC-II and costimulatory ligands accompanied by the low expression of MHC-I) and the potential of plasticity and multi-organ homing via expressing related surface molecules. MSCs by immunomodulatory effects could also ameliorate several immune-pathological conditions like graft-versus-host diseases (GVHD). The efficacy and potency of MSCs are the main objections of MSCs therapeutic applications. It suggested that improving the MSC immunosuppressive characteristic via genetic engineering to produce therapeutic molecules consider as one of the best options for this purpose. In this review, we explain the functions, immunologic properties, and clinical applications of MSCs to discuss the beneficial application of genetically modified MSCs in GVHD.

A Proposed TUSC7/miR-211/Nurr1 ceRNET Might Potentially be Disturbed by a cer-SNP rs2615499 in Breast Cancer.

Evidence and in silico analyses showed that TUSC7, miR-211, and Nurr1 may be involved in BC pathogenesis by ceRNET signaling axis. This study aimed to investigate the potential role of TUSC7/miR-211/Nurr1 ceRNET and rs2615499 variant as a novel cer-SNP in BC subjects. The expression assays were conducted by qPCR on tumor tissues (n = 50), tumor-adjacent normal tissues (TANTs) (n = 50), and clinically healthy control tissues (n = 50). The expression of TUSC7 and Nurr1 significantly decreased, but the level of miR-211 significantly increased in tumor tissues compared to TANTs and healthy normal tissues. Altered expression of TUSC7 and miR-211 was associated with poor prognosis of patients. The Nurr1 exhibited a double-edged sword-like activity in BC. In addition, TUSC7, Nurr1, and miR-211 expressions were significantly related to a novel BC-associated rs2615499 (A > C) located in the miR-211 binding site on Nurr1 3'-UTR. In the second part of the study, a case-control study was performed on BC patients (n = 100) and matched healthy controls (n = 100). The genomic DNA was isolated and genotyping was performed using Tetra-Primer ARMS PCR. The CC and AC genotypes were associated with higher expression levels of Nurr1 and worse outcomes of the disease. Our findings revealed that TUSC7 functions as a tumor suppressor in BC potentially via miR-211/Nurr1, which might be disturbed by the cer-SNP rs2615499. However, functional studies are needed to validate these results.

Immune-Based Therapy for COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel zoonotic virus identified as the cause of coronavirus disease 2019 (COVID-19) that has crossed species and infected humans. In order to develop new insights on the immune-based treatments against this disease, it is vital to understand the immunopathology of the COVID-19, implications of the immune response to SARS-CoV-2, and immune dysfunction in response to SARS-CoV-2. There is no approved drug for the treatment of COVID-19. It is, thus, promising to design immune-based treatments that inhibit the infectious mechanism of the virus, improve the inadequate immune response, or regulate the hyperactivated immune response in severely ill patients. According to the antiviral immune response against the virus, antibody-based immunotherapies of COVID-19 include injection of convalescent plasma from recovered patients, high-dose intravenous immunoglobulins (IVIG), monoclonal antibodies, and polyclonal antibodies. Also, cell-based treatment, vaccine-based approaches, cytokine-based immunotherapy, immune checkpoint inhibitors, JAK inhibitors, decoy receptors, and immunosuppressive drugs are discussed in this chapter.

The effects of guluronic acid (G2013), a new emerging treatment, on inflammatory factors in nonalcoholic steatohepatitis patients under in vitro conditions.

BACKGROUND: Nonalcoholic Steatohepatitis (NASH) results from the accumulation of fatty acids in the liver. The elevated production of pro-inflammatory factors is the reason for the hyper inflammation in NASH. The α-L-Guluronic acid (G2013), a new member of NSAID family, is a plant-originated agent with immunomodulatory properties. The current study investigated the effects of G2013 on inflammatory factors in PBMCs of NASH patients. METHODS: PBMCs of 14 NASH patients and 14 healthy controls were isolated and cultured. The patient's cells were treated with low (5 µg/mL) and moderate (25 µg/mL) doses of G2013 alongside the diclofenac optimum dose (3 µg/mL). The expression and secretion levels of variables were assessed by real-time PCR and ELISA, respectively. RESULTS: Findings indicated that the expression levels of TLR4 and NF-κB, as well as the secretion levels of TNF-α and IL-6 cytokines, were significantly elevated in NASH patients compared to healthy individuals. The expression levels of TLR4 and NF-κB were strikingly downregulated in treated cells of patients in both low and moderate doses of G2013. A considerable reduction was obtained in the secretion level of IL-6 using both low and moderate doses of G2013 and in the secretion level of TNF-α using the moderate dose of G2013. CONCLUSION: The results indicated that G2013 could meaningfully decrease the expression and secretion levels of evaluated factors (TLR4, NF-κB, TNF-α, and IL-6) in PMBCs of NASH cases. Since there is no effective treatment for NASH patients, we hope that G2013 would be a promising immunomodulatory agent in reducing inflammation and improvement of patients.

Expression level of long noncoding RNA NKILAmiR103-miR107 inflammatory axis and its clinical significance as potential biomarker in patients with colorectal cancer.

BACKGROUND: Inflammatory cytokines have been observed in colorectal cancer (CRC) tissues and can promote the susceptibility to metastasis of CRC cells. Diverse regulatory mechanisms of long ncRNAs (lncRNAs) and microRNAs (miRNAs) involved in the inflammatory responses are associated with tumor progression. The aim of this research was to investigate the expression level of the nuclear factor-kappa B interacting lncRNA (NKILA)-miR103-miR107 regulatory axis and its clinical significance as a potential biomarker in patients with CRC. MATERIALS AND METHODS: In the present study, we investigated the expression levels of miR103, miR107, and NKILA in 21 paired CRC tissues and corresponding adjacent tissues, using real-time polymerase chain reaction technique. Receiver operating characteristic (ROC) curve was used to analyze the prognostic value of biomarkers and to compare their predictive value. RESULTS: It was found that the expression level of miR103 was significantly increased with the development of CRC (cancerous vs. corresponding normal tissues; 2.29 ± 1.65 vs. 1.16 ± 0.64, P = 0.003). Moreover, miR107 was upregulated in CRC tissues compared with paired normal tissues (2.1 ± 1.4 vs. 1.25 ± 0.83, P = 0.005), while NKILA displayed an opposite expression pattern versus miR103/107, but it was not statistically significant (3.69 ± 5.2 vs. 4.35 ± 5.99, P > 0.05). The ROC analysis demonstrated that miR103 had the best diagnostic ability performance with area under curve of 0.723 (0.545-0.901). CONCLUSION: We identified miR103/107 as tumor-promoting miRNAs with diagnostic value in cancer patients and presumptive negative regulators of NKILA, a potential cancer metastatic suppressor. Strategies that disrupt this regulatory axis might block CRC progression.

Restoring the IL-1ß/NF-κB-induced impaired chondrogenesis by diallyl disulfide in human adipose-derived mesenchymal stem cells via attenuation of reactive oxygen species and elevation of antioxidant enzymes.

Strategies based on mesenchymal stem cell (MSC) therapy for restoring injured articular cartilage are not effective enough in osteoarthritis (OA). Due to the enhanced inflammation and oxidative stress in OA microenvironment, differentiation of MSCs into chondrocytes would be impaired. This study aims to explore the effects of diallyl disulfide (DADS) on IL-1ß-mediated inflammation and oxidative stress in human adipose derived mesenchymal stem cells (hADSCs) during chondrogenesis. MTT assay was employed to examine the effects of various concentrations of DADS on the viability of hADSCs at different time scales to obtain non-cytotoxic concentration range of DADS. The effects of DADS on IL-1ß-induced intracellular ROS generation and lipid peroxidation were evaluated in hADSCs. Western blotting was used to analyze the protein expression levels of IκBα (np), IκBα (p), NF-κB (np) and NF-κB (p). Furthermore, the gene expression levels of antioxidant enzymes in hADSCs and chondrogenic markers at days 7, 14 and 21 of differentiation were measured using qRT-PCR. The results showed that addition of DADS significantly enhanced the mRNA expression levels of antioxidant enzymes as well as reduced ROS elevation, lipid peroxidation, IκBα activation and NF-κB nuclear translocation in hADSCs treated with IL-1ß. In addition, DADS could significantly increase the expression levels of IL-1ß-induced impaired chondrogenic marker genes in differentiated hADSCs. Treatment with DADS may provide an effective approach to prevent the pro-inflammatory cytokines and oxidative stress as catabolic causes of chondrocyte cell death and enhance the protective anabolic effects by promoting chondrogenesis associated gene expressions in hADSCs exposed to OA condition.

Leishmania tropica: suggestive evidences for the effect of infectious dose on pathogenicity and immunogenicity in an experimental model.

Leishmania (L.) tropica is a causative agent of cutaneous and occasionally visceral or viscerotropic leishmaniasis in humans. The dose of parasites influences the course and outcome of disease in some Leishmania species. The effect of parasite dose on L. tropica infection in an experimental model was studied in the current paper. High and low doses of L. tropica were used for ear infection of BALB/c mice and lesion development, parasite load, and cytokine responses were assessed. L. major infection was used for comparison. Pre-infected mice were challenged in the footpad by a fixed high dose of L. tropica, and immune response and protection level were evaluated. High dose L. tropica infection in comparison to low dose results in higher lesion diameters, higher load of parasite in draining lymph node, higher levels of interferon-γ and interleukin-10, dissemination of parasite to spleen, and induction of protection against further L. tropica challenge. Comparison of L. tropica with L. major showed that L. tropica results in lower lesion diameters, more potential for growth in lymph nodes at early phases of infection, parasite dissemination to spleen, lower levels of IL-10, and a permanent lower cytokine response against low parasite dose in comparison to high dose. Our findings suggest that for L. tropica infection, only the high dose results in visceralization of the parasite and protection against further challenge of L. tropica. Therefore, the parasite dose may be an important factor in pathogenesis and immunity in L. tropica infection.

The impact of donor and recipient KIR genes and KIR ligands on the occurrence of acute graft-versus-host disease and graft survival after HLA-identical sibling hematopoietic stem cell transplantation

Background/aim: After allogeneic hematopoietic stem cell transplantation (allo-HSCT), donor natural killer (NK) cells trigger alloreactions against potential recipient cells by their killer immunoglobulin-like receptors (KIRs). This study investigated whether KIR/HLA genotypes and KIR haplotypes of donors and recipients exhibit a critical function in the prevalence of acute graft-versus-host disease (aGVHD) and persistence of the graft after HLA-identical sibling allo-HSCT for patients with hematological malignancies. Materials and methods: We studied KIR and HLA genotypes in 115 related donors and recipients (56 patients with AML and 59 patients with ALL) who had received allo-HSCT from HLA-matched sibling donors. We evaluated 17 KIR genes and some alleles, including their ligands, using the PCR-SSP assay. Results: KIR gene frequency results between donors and recipients showed that donors had more activating KIR than their recipients. Chi-square comparison of KIR genotype frequencies in donors versus recipients revealed a significant difference (P < 0.001). We found a survival association between the donor lacking and the recipient having group B KIR haplotypes, although this was not statistically significant. Conclusion: This study suggests that we could exploit NK cell alloreactivity as a part of the optimization of donor selection and potential immunotherapeutic regimens to help facilitate good engraftment and reduce the risk of aGVHD incidence after allo-HSCT.

Evaluating the Protective Effects and Mechanisms of Diallyl Disulfide on Interlukin-1ß-Induced Oxidative Stress and Mitochondrial Apoptotic Signaling Pathways in Cultured Chondrocytes.

The protective effects and mechanisms of DADS on IL-1ß-mediated oxidative stress and mitochondrial apoptosis were investigated in C28I2 human chondrocytes. The effect of various concentrations of DADS (1, 5 10, 25, 50, and 100 µM) on C28I2 cell viability was evaluated in different times (2, 4, 8, 16, and 24 h) to obtain the non-cytotoxic concentrations of drug by MTT-assay. The protective effect of non-toxic concentrations of DADS on experimentally induced oxidative stress and apoptosis by IL-1ß in C28I2 was evaluated. The effects of DADS on IL-1ß-induced intracellular ROS production and lipid peroxidation were detected and the proteins expression of Nrf2, Bax, Bcl-2, caspase-3, total and phosphorylated JNK, and P38 MAPKs were analyzed by Western blotting. The mRNA expression of detoxifying phase II/antioxidant enzymes including heme oxygenase-1, NAD(P)H quinine oxidoreductase, glutathione S-transferase-P1, catalase, superoxide dismutase-1, glutathione peroxidase-1, -3, -4 were evaluated by reverse transcription-polymerase chain reaction. DADS in 1, 5, 10, and 25 µM concentrations had no cytotoxic effect after 24 h. Pretreatment with DADS remarkably increased Nrf2 nuclear translocation as well as the genes expression of detoxifying phase II/antioxidant enzymes and reduced IL-1ß-induced elevation of ROS, lipid peroxidation, Bax/Bcl-2 ratio, caspase-3 activation, and JNK and P38 phosphorylation. DADS could considerably reduce IL-1ß-induced oxidative stress and consequent mitochondrial apoptosis, as the major mechanisms of chondrocyte cell death in an experimental model of osteoarthritis. It may be considered as natural product in protecting OA-induced cartilage damage in clinical setting. J. Cell. Biochem. 118: 1879-1888, 2017. © 2017 Wiley Periodicals, Inc.

Clinical significance of NDRG3 in patients with breast cancer.

AIM: The expression level of NDRG3 gene is investigated among breast cancer (BC) patients. METHODS: Real-time quantitative PCR was performed. RESULTS:  NDRG3 was downregulated in BC patients particularly in advanced stage of the disease. HER2 status was significantly correlated with the expression of NDRG3. Also, triple-negative BC patients showed low levels of NDRG3 expression in comparison to other subtypes. Lastly, the expression of NDRG3 had significant impact on survival, with NDRG3 downregulated patients having the worst event-free survival rate among others. CONCLUSION: We have presented that NDRG3 might be a tumor suppressor candidate. NDRG3 downregulation might be involved in the tumorigenesis and development of invasive BC in an advanced phase of the disease.

Experiences of selected countries in the use of public-private partnership in hospital services provision.

OBJECTIVE: To review the experiences of selected countries in the use of public-private partnership in the provision of hospital services. METHODS: This comparative study was conducted in 2015 in Iran. To collect data, valid databases as well as articles, theses, reports and related books in the field of private-sector partnership in hospital services were employed. Using purposive sampling, countries such as the United Kingdom, Spain, Canada, Turkey, Australia and Lesotho, which had successful experiences in the field of application of the public-private partnership in hospital services, were included. Likewise, the only experience in Iran in this field was also reviewed. Studies done between 1980 and 2015 were examined. The results obtained from each country were compared. RESULTS: Implementing public-private partnership had great and valuable outcomes and achievements for governmental hospitals. Moreover, clinical and nonclinical service delivery, hospital utilisation and management along with building, repairing and supportive operations through public-private partnership contracts can be differently divided among the partners. Furthermore, duration of the projects ranged from 12 to 40 years in different countries, depending on the type of the model used. CONCLUSIONS: A successful experience in the use of the public-private partnership in the provision of hospital services was observed.

Does PTEN gene mutation play any role in Li-Fraumeni syndrome.

BACKGROUND: Li-Fraumeni syndrome (LFS) is one of the most serious hereditary cancer syndromes with a high risk of malignancy in childhood. This syndrome is an autosomal dominant cancer predisposing syndrome due to a germline mutation in the TP53 tumor suppressor gene. METHODS: In this study, a representative family case of Li-Fraumeni syndrome is described. The proband of this family was a 43-year-old male who had osteosarcoma of the mandible and a positive family history of cancer. His mother died at the age of 29 of brain cancer; his sister died at the age of 18 of breast cancer; his brother died at the age of 36 of liver cancer; and another sister of his died at the age of 16 of leukemia. Complete sequence analysis of the TP53 and PTEN genes was performed in this family. We used standard diagnostic tools such as sequencing and multiplex ligation-dependent probe amplification (MLPA) to analyze these two genes in this family. The exons and flanking exon-intron junctions of the TP53 and PTEN genes were sequenced. RESULTS: We detected a germline mutation in the TP53 gene in this family that was previously reported as somatic mutation in LFS in the catalogue of somatic mutations in cancer (COSMIC). In addition, according to the International Agency for Research of Cancer (IARC) database, a 19-year-old male patient with sarcoma was recently reported to have this germline mutation. We also found two new IVS variations in the PTEN gene, one of which can be a suggestive evidence of an effect on the splicing of PTEN. CONCLUSION: Genomic modifications for tumor risk and genotype-phenotype correlations in LFS are still to be identified. We believe every new finding in this area can provide new insights into the pathogenesis and progression of Li-Fraumeni syndrome.

A case study to investigate the effects of Chlorhexidine mouthwash on serum cytokines levels in children with Asthma.

Asthma is an airways inflammatory disease and the most common chronic disease of childhood, which causes most hospital visits and placing a heavy financial burden on families and communities. Interleukins 4, 5 and 13, play a central role in the pathogenesis of asthma. Given the importance of oral hygiene in asthmatic patients and IL-4 and 5 are involved in the inflammatory process of periodontitis, the effect of chlorhexidine as mouthwash on asthma attacks in children on serum cytokines is necessary. In this study, 375 children with asthma were divided into two groups using or non-using chlorhexidine. Blood samples were taken and cytokines were measured by ELISA. From 375 patients, 17 patients were excluded. In this study, 171 males and 187 females participated and there were 180 patients in asthma group and 178 patients in asthma/Chlorhexidine group. The levels of IL-4, IL-5 and IL-13 had no significant difference (p > 0.05) between Asthma and Asthma/Chlorhexidine groups. Using chlorhexidine as mouthwash in children with asthma had no effect on the type 2 cytokines and may not trigger an asthma attack via allergo-inflammatory mechanism.

Displacement of the hip center of rotation after arthroplasty of Crowe III and IV dysplasia: a radiological and biomechanical study.

To study the direction and biomechanical consequences of hip center of rotation (HCOR) migration in Crowe type III and VI hips after total hip arthroplasty, post-operative radiographs and CT scans of several unilaterally affected hips were evaluated. Using a three-dimensional model of the human hip, the HCOR was moved in all directions, and joint reaction force (JRF) and abductor muscle force (AMF) were calculated for single-leg stance configuration. Comparing to the normal side, HCOR had displaced medially and inferiorly by an average of 23.4% and 20.8%, respectively, of the normal femoral head diameter. Significant decreases in JRF (13%) and AMF (46.13%) were observed in a presumptive case with that amount of displacement. Isolated inferior displacement had a small, increasing effect on these forces. In Crowe type III and IV hips, the HCOR migrates inferiorly and medially after THA, resulting in a decrease in JRF, AMF, and abductor muscle contraction force.

Osteoid osteoma of the hand and wrist: a report of 25 cases.

BACKGROUND: The hand and wrist bones are infrequent sites for osteoid osteoma, and its diagnosis can be difficult. This paper reports 25 cases of osteoid osteoma in the hand and wrist. METHODS: Records of the 25 patients who had pathological conditions of osteoid osteoma of the hand and wrist were reviewed and analyzed. RESULTS: Twenty-five cases of osteoid osteoma of the hand and wrist were treated in 20 years period. The average age was 25.2±7.6 years (range, 16 to 46 years) with men to women and right to left side ratio of 5.25 and 4 respectively. The most common site was in the proximal phalanx (ten cases). The diagnosis was made using x-rays, three- phase Technetium bone scans, CT, and MRI and all the diagnoses were confirmed by histological examination. The average time from the onset of symptom to successful treatment was 16.3±11.1 months, and at a mean follow-up of 36.6±46.9 mouths. Five recurrences of disease took place in which three of them were operated elsewhere. All five patients subsequently were treated and cured by reoperation. CONCLUSION: Osteoid osteoma is relatively rare lesions in the hand and wrist that can be a persistent source of hand and wrist pain. Patients under age of 40 who have otherwise unexplained pain should be evaluated.

An unusual case of preaxial polydactyly of the hand (triplication of the thumbs).

Preaxial polydactyly is the most common duplication pattern in white and Asian populations (1). It is a congenital anomaly with a wide range of manifestations. Current classification do not have the capacity to classify all different types of radial polydactyly. We describe here a very rare and unusual case of bilateral preaxial polydactyly (triplication) in a woman and report the operations results. We have not found similar case in the literature. Our case is unique and did not fit into the classification systems described for thumb polydactyly.

Radiographic indices in one hundred fifty normal Iranian wrists.

BACKGROUND: Radiography is the most widely available imaging modality. Precise evaluations of wrist x-ray can help diagnosis and evaluate the prognosis of many wrist disorders. METHODS: We measured length, angles and indices in 150 posteroanterior and lateral wrist x-rays to determine normal dimensions and variations according to age and sex. All x-rays were made with standard exposure, with the wrist and forearm in a neutral position. RESULTS: The average carpal height ratio was 0.52±0.03 with the Youm method and 1.5±0.09 with the Nattrass method. Mean ulnar variance was +0.99±1.6 mm and mean radial inclination was 25±4 degrees. The average radial tilt was 10±5.1 degrees. Mean scapholunate angle was 50±8.4 degrees (normal range 40-60). CONCLUSION: Carpal height, third metacarpal and capitate length were smaller in women than in men. There was a significant positive relationship between all dimensions. Our data base may be used to follow-up in conditions such as carpal instability, osteoarthritis and osteonecrosis, as well as for clinical research.

Association of Aberrant Promoter Methylation Changes in the Suppressor of Cytokine Signaling 3 (SOCS3) Gene with Susceptibility to Crohn's Disease.

Background: Growing evidence supports that changes in the methylation state of Inflammatory Bowel Disease (IBD)-associated genes could significantly alter levels of gene expression, potentially contributing to disease onset and progression. We supposed that alterations in DNA methylation status at promoter region within the suppressor of cytokine signaling 3 (SOCS3) gene in intestinal tissues may be involved in the susceptibility to Crohn's Disease (CD). Methods: DNA methylation status in the promoter region of the human SOCS3 gene of intestinal tissues from 15 patients with CD and 15 age- and sex-matched healthy controls were profiled using the real-time Quantitative Multiplex Methylation Specific PCR (QM-MSP) assay. Results: Based on methylation assay data profiling, we found that patients with CD showed a higher degree of methylation of the SOCS3 gene promoter region than did the healthy controls (unmethylated DNA in CD vs. healthy controls; 0.00048±0.0011 vs. 0.07±0.142, p<0.000). Conclusion: The data presented here demonstrate that aberrant methylation of the CpG islands within promoter regions of SOCS3 gene in colonic mucosa of CD was associated with mucosal inflammatory status, providing insights into the involvement of methylation could contribute to the initiation of the inflammatory process and development of CD.

Pulmonary Delivery of Levamisole Nanoparticles as an Immunomodulator Affecting Th and a Potential ADAM10 Inhibitor to Ameliorate Severe Allergic Asthma.

Asthma is a common chronic lung disease without absolute treatment, and hypersensitivity reactions and type 2 immune responses are responsible for asthma pathophysiology. ADAM10 as a metalloproteinase transmembrane protein is critical for development of Th2 responses, and levamisole as an anthelmintic drug has immunomodulatory effects, which not only regulates ADAM10 activity but also can suppress the bone marrow and neutrophil production. Therefore, in the present study, nanoparticles were used as a levamisole delivery system to reduce bone marrow suppression, and the immunomodulatory and ADAM10 inhibitory effects of levamisole were studied in allergic asthma. Asthmatic mice were treated with PLGA-levamisole nanoparticles. Then, AHR, BALF, and blood cell counts, levels of the IgG1 subclass, total and OVA-specific IgE, IL2, IL-4, IL-5, IL-10, IL-13, IL-17, IL-25, IL-33, INF-γ, and TNF-α, gene expression of FoxP3, T-bet, RORγt, PU.1, GATA3, FcεRII, CysLT1R, eotaxin, and ADAM10, and lung histopathology were evaluated. PLGA-LMHCl with considered characteristics could control airway hyper-responsiveness, eosinophils in the BALF, levels of immunoglobulins, Th2-, Th9-, and Th17-derived cytokines and pivotal genes, eosinophilic inflammation, hyperplasia of the goblet cell, and hyperproduction of mucus and could increase Th1- and Treg-derived cytokines and also pivotal genes. It could also modulate the ADAM10 activity and had no effect on the number of neutrophils in the bloodstream. The novel safe nanodrug had no side effect on the bone marrow to produce neutrophils and could control the allegro-immuno-inflammatory response of asthma.