A prediction of the CRNDE role by modulating NF-κB pathway in inflammatory bowel disease (IBD).

Long non-coding RNAs (lncRNAs) regulate multiple pathways and cellular mechanisms. Recent research has emphasized their involvement in the pathogenesis of complex diseases, such as Inflammatory Bowel Disease (IBD) which is characterized by chronic inflammation of the intestines. The two most common types of IBD are ulcerative colitis and Crohn's disease. CRNDE lncRNA was initially detected in colorectal cancer (CRC) and found to be involved in the tumorigenesis pathways. Further studies revealed the role of CRNDE in activating inflammation and promoting the release of inflammatory cytokines. This study utilizes the RNA-seq data analysis and bioinformatics tools to clarify the role of CRNDE in the IBD pathogenesis and confirms its expression in inflamed HT-29 and Caco-2 cell lines and also colonic and blood samples of UC patients and controls ex vivo. Based on our results, CRNDE was significantly upregulated in IBD samples compared to controls in RNA-seq data analysis and Real-time PCR of inflamed HT-29 cell line and colonic biopsies from UC patients. Additionally, predicted that its expression is positively correlated with the pro-inflammatory cytokines production. CRNDE interactions was investigated with several inflammation-related miRNAs and regulatory proteins computationally. Thus, CRNDE upregulation in the colon of IBD patients could be involved in IBD pathogenesis by promoting inflammatory pathways and targeting anti-inflammatory miRNAs.

Oral Formulation of 5-Aminosalicylic Acid-Hemoglobin Bio-Adhesive Nanoparticles Enhance Therapeutic Efficiency in Ulcerative Colitis Mice: A Preclinical Evaluation.

The oral formulation design for colon-specific drug delivery brings some therapeutic benefits in the ulcerative colitis treatment. We recently reported the specific delivery of hemoglobin nanoparticles-conjugating 5-aminosalicylic acid (5-ASA-HbNPs) to the inflamed site. In the current study, the therapeutic effect of the 5-ASA-HbNPs formulation was confirmed in vivo. This evaluation of 5-ASA-HbNPs not only shows longer colonic retention time due to adhesive properties, also provides full support for it as compared with free 5-ASA. It was considered as a suitable bio-adhesive nanoparticle with mucoadhesive property to pass through the mucus layer and accumulate into the mucosa. In UC model mice, a two-fold decrease in the disease activity indexes and colon weight/length ratios was significantly observed in the group treated with 5-ASA-HbNPs. This group received one percent of the standard dosage of 5-ASA (50 µg/kg), while, a similar result was observed for a significant amount of free 5-ASA (5 mg/kg). Furthermore, microscopic images of histological sections of the extracted colons demonstrated that the 5-ASA-HbNPs and 5-ASA groups displayed instances of inflammatory damage within the colon. However, in comparison to the colitis group, the extent of this damage was relatively moderate, suggesting 5-ASA-HbNPs improved therapeutic efficacy with the lower dosage form.

Toll-Like Receptor 7 a Novel Non-Invasive Inflammatory Genetic Sensor for Ulcerative Colitis Remission Monitoring.

Background: Ulcerative colitis (UC) and Crohn's disease (CD) are two major types of inflammatory bowel diseases (IBDs). Toll-like receptors (TLRs) are expressed in the innate immune system compartments, in charge of identifying a wide range of microorganisms. The aim of the present study was to evaluate the expression of TLR-2, -7, and -8 in peripheral blood mononuclear cells (PBMC) of UC patients as a novel non-invasive primary inflammation sensor for monitoring the clinical course of UC candidates. Materials and Methods: In this cross-sectional study, total RNA was extracted from the PBMC of 42 UC patients along with 20 healthy donors. The mRNA levels of TLR-2, -7, and -8 were assessed using the quantitative real-time polymerase chain (qRT-PCR) reaction. Results: The present research study demonstrated no significant changes in TLR-2 mRNA expression in UC patients in comparison with the control group (P = 0.1264), whereas significant elevation (P = 0.0008) was distinguished in the TLR-7 expression of UC participants specifically during the remission course compared with healthy donors and flareup patients (P = 0.0004 and P = 0.0063, respectively). The last selected TLR, TLR-8 was not shown remarkable changes either between UC patients and the control group or between clinical courses of the disease. Conclusion: Here, among three nominated TLRs for predicting UC patients, TLR-7 was potentially selected according to the significant difference in mRNA expression in flareup UC patients and control donors. TLR-7 could be used as a novel non-invasive biomarker for monitoring UC patients in the active course of the disease.

Selective serotonin reuptake inhibitors and inflammatory bowel disease; Beneficial or malpractice.

IBD, a chronic inflammatory disease, has been manifested as a growing health problem. No Crohn's and Colitis councils have officially ratified anti-depressants as a routine regimen for IBD patients. However, some physicians empirically prescribe them to rectify functional bowel consequences such as pain and alleviate psychiatric comorbidities. On the other side, SSRIs' prescription is accompanied by adverse effects such as sleep disturbances. Prolonged intermittent hypoxia throughout sleep disturbance such as sleep apnea provokes periodic reductions in the partial oxygen pressure gradient in the gut lumen. It promotes gut microbiota to dysbiosis, which induces intestinal inflammation. This phenomenon and evidence representing the higher amount of serotonin associated with Crohn's disease challenged our previous knowledge. Can SSRIs worsen the IBD course? Evidence answered the question with the claim on anti-inflammatory properties (central and peripheral) of SSRIs and illuminated the other substantial elements (compared to serotonin elevation) responsible for IBD pathogenesis. However, later clinical evidence was not all in favor of the benefits of SSRIs. Hence, in this review, the molecular mechanisms and clinical evidence are scrutinized and integrated to clarify the interfering molecular mechanism justifying both supporting and disproving clinical evidence. Biphasic dose-dependent serotonin behavior accompanying SSRI shifting function when used up for the long-term can be assumed as the parameters leading to IBD patients' adverse outcomes. Despite more research being needed to elucidate the effect of SSRI consumption in IBD patients, periodic prescriptions of SSRIs at monthly intervals can be recommended.

Probiotics and probiotic-based vaccines: A novel approach for improving vaccine efficacy.

Vaccination is defined as the stimulation and development of the adaptive immune system by administering specific antigens. Vaccines' efficacy, in inducing immunity, varies in different societies due to economic, social, and biological conditions. One of the influential biological factors is gut microbiota. Cross-talks between gut bacteria and the host immune system are initiated at birth during microbial colonization and directly control the immune responses and protection against pathogen colonization. Imbalances in the gut microbiota composition, termed dysbiosis, can trigger several immune disorders through the activity of the adaptive immune system and impair the adequate response to the vaccination. The bacteria used in probiotics are often members of the gut microbiota, which have health benefits for the host. Probiotics are generally consumed as a component of fermented foods, affect both innate and acquired immune systems, and decrease infections. This review aimed to discuss the gut microbiota's role in regulating immune responses to vaccination and how probiotics can help induce immune responses against pathogens. Finally, probiotic-based oral vaccines and their efficacy have been discussed.

Detection of SARS-CoV-2 Genome in Stool and Plasma Samples of Laboratory Confirmed Iranian COVID-19 Patients.

Coronavirus disease 2019 (COVID19), caused by the severe acute respiratory syndrome coronavirus 2 (SARSCoV2), was first discovered in China in late 2019 and quickly spread worldwide. Although nasopharyngeal swab sampling is still the most popular approach identify SARS-CoV-2 carriers, other body samples may reveal the virus genome, indicating the potential for virus transmission via non-respiratory samples. In this study, researchers looked at the presence and degree of SARS-CoV-2 genome in stool and plasma samples from 191 Iranian COVID-19 patients, and looked for a link between these results and the severity of their disease. SARS-CoV-2 RNA shedding in feces and plasma of COVID-19 patients was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Medical data were collected and evaluated, including Clinical features, demographics, radiological, and laboratory findings of the patients. Plasma samples from 117 confirmed laboratory patients were evaluated and 24 out of 117 patients (20.51%) tested positive for SARS-COV-2 RNA. Besides, 20 out of 74 patients (27.03%) tested positive for SARS-COV-2 RNA in stool samples. There seems to be no relationship between the presence of SARS-CoV-2 genome in fecal and plasma samples of Covid-19 patients and the severity of illness. We provide evidence of the SARS-CoV-2 genome presence in stool and plasma samples of Iranian COVID-19 patients.

Overview of Three Proliferation Pathways (Wnt, Notch, and Hippo) in Intestine and Immune System and Their Role in Inflammatory Bowel Diseases (IBDs).

Inflammatory bowel disease (IBD) is a disorder, which involves the gastrointestinal (GI) tract consisting Crohn's disease (CD) and ulcerative colitis (UC). The etiology of this disease is not yet clear and, hence, there are numerous medications and treatments for patients with IBD, although a definite and permanent treatment is still missing. Therefore, finding novel therapeutic approaches are vital for curing patients with IBD. In the GI tract, there are various lineages of cells with different roles that their existence is necessary for the barrier function of intestinal epithelial cells (IECs). Therefore, signaling pathways, which manage the hemostasis of cell lineages in intestine, such as Wnt, Notch, and Hippo, could have crucial roles in regulation of barrier function in the intestine. Additionally, these signaling pathways function as a governor of cell growth, tissue homeostasis, and organ size. In patients with IBD, recent studies have revealed that these signaling pathways are dysregulated that it could result in depletion or excess of a cell lineage in the intestine. Moreover, dysregulation of these signaling pathways in different cell lineages of the immune system could lead to dysregulation of the immune system's responses in IBD. In this article, we summarized the components and signaling of Wnt, Notch, and Hippo pathways and their role in the intestine and immune system. Furthermore, we reviewed latest scientific literature on the crosstalk among these three signaling pathways in IBD. An overview of these three signaling pathways and their interactions in IBD could provide a novel insight for prospective study directions into finding efficient medications or treatments.

High prevalence of SARS-Coronavirus-2 in patients with inflammatory bowel disease and the role of soluble angiotensin converting Enzyme2.

Context: Patients with inflammatory bowel disease (IBD) were found to have the higher intestinal expression of Angiotensin-Converting Enzyme2 (ACE2) that could consequently increase susceptibility to COVID-19 infection.Objective: This study reports the outcomes of COVID-19 infection in a large cohort of IBD patients. We compare levels of serum ACE and IFN-α between COVID19 patients with and without IBD. We performed a cross-sectional retrospective multicenter study.Methods: We enrolled patients with IBD screened for SARS-COV-2 in six medical centres in Iran from June to November 2020. The blood samples were drawn to measure COVID-19 IgM and IgG, and serum levels of sACE2, sACE1, and interferon-α, regardless of suspicious symptoms have done the molecular test.Results: A total of 534 IBD patients were included in the study. Of these, 109 (20.0%) cases had detectable IgG and IgM against SARS-CoV-2. sACE2 levels were higher in IBD patients than controls, whereas ACE1and IFN-α levels were similar among groups.

Evaluation of adalimumab effects on left ventricle performance by echocardiography indexes among patients with immunosuppressant refractory ulcerative colitis.

Background and aims: Inflammatory bases lead to a simultaneous flourishing of cardiovascular complications with inflammatory bowel disease (IBD). As a released cytokine, tumor necrosis factor-α (TNF-α) can either disrupt or preserve cardiovascular performance. Due to this controversy, this study aimed to appraise the short-term anti-TNF (adalimumab [ADA]) relics on cardiac function by gauging the echocardiography indexes in patients with immunosuppressant refractory ulcerative colitis (UC). Methods: All cases with a definite diagnosis of UC were included based on providing written informed consent and owning the severe form of active disease (Mayo score ≥7), which did not dampen with immunosuppressant. Patients were excluded in the case of previous cardiac ailments/risk factors and prior related surgical or pharmaceutical intervention. Transthoracic echocardiography (TTE) was carried out before and 3 months after biological regimen allocation and changes in indexes [ejection fraction (EF), left ventricular end-diastolic volume (LVEDV)/left ventricular end-systolic volume (LVESV), and global longitudinal strain (GLS) in standard parasternal short axis from mid-ventricular level, two-, three-, and four-chamber apical long axes] were compared via statistical analyses. Results: The study consisted of 13 (65%) men and 7 (35%) women, with a mean age of 36.54 ± 11.3 years. Participants mainly possessed Montreal class I (45%) and an average of 3.25 years of disease duration. The intervention significantly controlled inflammation [endoscopic Mayo score (P = 0.001), partial Mayo score (P = 0.001), and C-reactive protein (P = 0.001)]. Endoscopic and clinical remission was obtained in 7 (35%) and 9 (45%) patients, respectively; however, no significant discrepancy related to the LVEDV (P = 0.86), LVESV (P-value = 0.25), EF (P-value = 0.06), and GLS in standard parasternal short axis (P = 0.73), long axis [apical 2-chamber (P-value = 0.61), apical 3-chamber (P-value = 0.15), and apical 4-chamber (P-value = 0.19) views] was observed before and after the intervention. Furthermore, no statistically significant correlation between disease activity and cardiac function was found, neither before nor after ADA administration. Conclusion: The present perusal found no deterioration in left ventricular function indexes with ADA intervention among patients with IBD without cardiac ailment. Thus, prescribing the anti-TNF to alleviate the inflammation can be carried out with less concern about cardiac consequences and considering other adverse traces in the target group.

Cross-talk between immune system and microbiota in COVID-19.

INTRODUCTION: Human gut microbiota plays a crucial role in providing protective responses against pathogens, particularly by regulating immune system homeostasis. There is a reciprocal interaction between the gut and lung microbiota, called the gut-lung axis (GLA). Any alteration in the gut microbiota or their metabolites can cause immune dysregulation, which can impair the antiviral activity of the immune system against respiratory viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. AREAS COVERED: This narrative review mainly outlines emerging data on the mechanisms underlying the interactions between the immune system and intestinal microbial dysbiosis, which is caused by an imbalance in the levels of essential metabolites. The authors will also discuss the role of probiotics in restoring the balance of the gut microbiota and modulation of cytokine storm. EXPERT OPINION: Microbiota-derived signals regulate the immune system and protect different tissues during severe viral respiratory infections. The GLA's equilibration could help manage the mortality and morbidity rates associated with SARS-CoV-2 infection.

Probiotic-Induced Tolerogenic Dendritic Cells: A Novel Therapy for Inflammatory Bowel Disease?

Inflammatory bowel diseases (IBDs) are immune-mediated, chronic relapsing diseases with a rising prevalence worldwide in both adult and pediatric populations. Treatment options for immune-mediated diseases, including IBDs, are traditional steroids, immunomodulators, and biologics, none of which are capable of inducing long-lasting remission in all patients. Dendritic cells (DCs) play a fundamental role in inducing tolerance and regulating T cells and their tolerogenic functions. Hence, modulation of intestinal mucosal immunity by DCs could provide a novel, additional tool for the treatment of IBD. Recent evidence indicates that probiotic bacteria might impact immunomodulation both in vitro and in vivo by regulating DCs' maturation and producing tolerogenic DCs (tolDCs) which, in turn, might dampen inflammation. In this review, we will discuss this evidence and the mechanisms of action of probiotics and their metabolites in inducing tolDCs in IBDs and some conditions associated with them.

Mesenchymal Stem Cell Spheroids Embedded in an Injectable Thermosensitive Hydrogel: An In Situ Drug Formation Platform for Accelerated Wound Healing.

The ability of mesenchymal stem cells (MSCs) to enhance cutaneous wound healing has been well established. Extensive expansion of cells to reach sufficient cell numbers for regenerating tissues has always limited cell-based therapies. An ingenious solution to address this challenge is to develop a strategy to increase the immunomodulatory effects of MSCs without expanding them. In this study, we employed a simple characteristic of cells. It was observed that an optimized three-dimensional (3D) MSC culture in spheroid forms significantly improved their paracrine effects. An electrospray (ES) encapsulation apparatus was used to encapsulate individual or 3D spheroid MSCs into microscale alginate beads (microbeads). Furthermore, alginate microbeads were embedded in an injectable thermosensitive hydrogel matrix, which gels at skin temperature. The hydrogel fills and seals the wounds cavities, maintains high humidity at the wound area, absorbs exudate, and fixes microbeads, protecting them from direct contact with the harsh wound environment. In vitro investigations revealed that secretion of interleukin 10 (IL-0) and transforming growth factor ß1 (TGF-ß1) gene was gradually enhanced, providing a delivery platform for prolonged release of bioactive molecules. In vivo study on full-thickness wounds showed granulation and re-epithelialization, only after 7 days. Moreover, increased expression of α-smooth muscle actin (α-SMA) in the first 14 days after treatment ensured wound contraction. Besides, a gradual decrease in α-SMA secretion resulted in reduced scar formation. Well-organized collagen fibrils and high expression of the angiogenesis biomarker CD31 confirmed the promoting effect of the hydrogel on the wound-healing process. The proposed wound-dressing system would potentially be used in scalable and effective cell-based wound therapies.

Association between variants of the autophagy related gene ATG16L1 in inflammatory bowel diseases and clinical statues.

AIM: In the present study, two main variants of ATG16L1 gene, rs2241880 T300A and rs2241879 C/T, were evaluated in IBD patients as well as in remission and flareup phase across an Iranian population for the first time. BACKGROUND: Inflammatory bowel disease (IBD) has found increasing global incidence and prevalence in recent years especially among pediatrics. ATG16L1 is the major gene that regulates autophagy pathway. The autophagy pathway also affects dysbiosis. METHODS: Genomic DNA was isolated from peripheral blood samples following salting out extraction method. The genotypes of ATG16L1 polymorphisms rs2241880 T300A and rs2241879 C/T were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: In this case control study, a total of 101 IBD patients (75 ulcerative colitis (UC) and 26 Crohn's disease (CD)) and 99 healthy controls were evaluated. In the present study, a significant association was found between rs2241879 single nucleotide polymorphism on ATG16L1 gene and increased risk of IBD among an Iranian population (P=0.01). There was no statistically significant relationship between rs2241880 and IBD risk (P= 0.42). The effect on these two variants was investigated in relapse and flareup phase which was not significant either, but in CD, rs2241879 and rs2241880 were difference in the relapse phase. CONCLUSION: The results showed that ATG16L1 gene rs2241879 has a significant relationship with increased risk of IBD among an Iranian population. Individuals with C allele showed a significant relationship with 1.68-fold increased risk of IBD (P=0.01; adjusted OR=1.68; 95% CI=1.13-2.50).

Variants in two gene members of the TNF ligand superfamily and hepatitis C virus chronic disease.

AIM: To assess the possible correlation between single nucleotide polymorphisms (SNPs) of two members of TNF ligand superfamily genes, tumor necrosis factor-α (TNF-α) and lymphotoxin-α (LTA), and HCV chronic disease. BACKGROUND: The causes of disease progression from hepatitis C virus (HCV) infection to chronic liver disease still remains unclear. Abnormal production of the cytokines alleged to be contributed to progression of the disease or viral persistence. Regulatory mechanisms that control the production of cytokines including genetic polymorphisms, especially at coding/regulatory regions of genes, may affect expression and secretion of the cytokines. METHODS: In this case-control investigation, 258 individuals with serologically proven chronic HCV infection and 277 healthy controls were studied. Genotyping of rs1799964 variant of TNF-α and rs909253 intronic variant in LTA gene were performed. To confirm the results of genotyping, 10% of the specimens analyzed again by sequencing approach. RESULTS: In this investigation, a significant association was observed between the TNF-α TC genotype and chronic HCV infection (P = 0.035). Moreover, the frequency of C allele was significantly different between control subjects in comparison with chronic HCV patients (P=0.02). On the other hand, no association was found between LTA gene polymorphism and susceptibility to chronic HCV infection. CONCLUSION: These findings indicate that genetic variants like single nucleotide polymorphism in TNF-α rs1799964, could be a host factor associated with susceptibility to HCV chronic infection. However, further large scale investigations are needed to confirm this finding.

Apoptosis markers of circulating leukocytes are associated with the clinical course of inflammatory bowel disease.

AIM: Here we aimed at evaluating whether the apoptosis status of circulating leukocytes of inflammatory bowel diseases (IBD) patients is attributed to the diseases clinical status. BACKGROUND: Defects in the programmed cell death of inflammatory cells is known as to play a major role in the pathogenesis of IBD, and has been associated with the clinical efficacy of therapeutic agents. METHODS: A total of 50 IBD patients, 25 with remission and 25 with flare-up phase of the disease, who their disease was confirmed by colonoscopy, were included in this cross-sectional study. Pro-apoptotic Bax and anti-apoptotic Bcl-2 mRNA expression, along with Bax/Bcl-2 ratio, as measures of apoptotic status, were assessed in the Peripheral blood mononuclear cell (PBMC) of the patients using semi-quantitative Real-time PCR method. RESULTS: The mean Bax mRNA expression level was 0.54±0.12 in flare-up group and 0.53±0.13 in remission group (p=0.8). The mean Bcl-2 mRNA expression level was 0.63±0.13 in flare-up group and 0.55±0.12 in remission group (p=0.03). The mean Bax/Bcl-2 ratio was 0.88±0.17 in flare-up group and 1±21 in remission group (p=0.05). The mean Bax/Bcl-2 ratio was not statistically significant between different disease types (p=0.54) or therapeutic agents (p=0.7). CONCLUSION: According to our results, alteration in markers of apoptosis could be traced in the circulating leukocytes of IBD patients, which suggest a potential for clinical application of apoptosis markers in disease monitoring and prediction of relapse.

Association between TNF-α rs1799964 and RAF1 rs1051208 MicroRNA binding site SNP and gastric cancer susceptibility in an Iranian population.

AIM: The aim of this study was to find the relationship between rs1799964 in TNF-α gene as well as rs1051208 of RAF1 gene SNPs on GC in an Iranian population. BACKGROUND: Gastric cancer (GC) is the second leading cause of cancer-related death worldwide after lung cancer. Tumor necrosis factor (TNF) is one of the most important factors in the pathogenesis of this cancer. Single nucleotide polymorphisms have a principle role in gene expression of TNF-α and miRNAs which may lead to gastric cancer. METHODS: In a case-control study, we investigated the risk of GC in 198 Iranians. For this purpose, 5 mL of peripheral blood was collected in EDTA -containing tube and genomic DNA was isolated. Genotyping of SNPs was also performed by PCR-RFLP; to approve the outcome, 10% of genotyping results with RFLP were sequenced. RESULTS: The comparison between case and control groups revealed a significant association between the rs1051208 C allele of RAF1 gene and GC (P = 0.04). We did not observe any remarkable association between TNF-α -1031 in gastric cancer patients and the healthy control group. CONCLUSION: The results indicated that C allele in RAF1 gene plays a role in susceptibility to gastric cancer. Therefore, SNPs are among notable biomarkers for predicting susceptibility to dreadful diseases, especially cancers.

Evaluation of tumor necrosis factor (TNF)-α mRNA expression level and the rs1799964 polymorphism of the TNF-α gene in peripheral mononuclear cells of patients with inflammatory bowel diseases.

Crohn's disease (CD) and ulcerative colitis (UC) are types of chronic inflammatory bowel disease (IBD) of which the actual causes remain unknown. Emerging data indicate that alterations in cytokine synthesis may be involved in IBD pathogenesis. The aim of the present study was to determine whether the tumor necrosis factor (TNF)-α mRNA expression level and rs1799964 polymorphism are the genetic susceptibility component of IBD development. The TNF-α mRNA expression level of peripheral blood mononuclear cells (PBMCs) was measured using comparative reverse-transcription quantitative polymerase chain reaction (PCR). Genomic DNA from 201 individuals (CD: n=15; UC: n=86; control subjects: n=100) was analyzed for the presence of the TNF-α-1031 polymorphism by PCR-restriction fragment length polymorphism. An increased TNF-α mRNA expression level was additionally observed in the CC genotype of the -1031 TNF-α gene polymorphism compared with the TC and TT genotypes (P<0.05). Furthermore, the present results revealed that there was no significant difference in the genotype/allele frequencies of the -1031 TNF-α gene polymorphism in Iranian IBD patients. By comparison, the TNF-α mRNA expression level was evaluated in patients with a history of taking medications and demonstrated a significant association in the group that received the 5-ASA + Pred + AZA,5. 5-ASA + Pred + AZA + IFX when compared with the other groups (P<0.05). Thus, these results support the hypothesis that overexpression of the TNF-α gene, which correlated with the CC genotype, may represent a genetic risk factor for Iranian IBD.