Hypoxia, hypoxia-inducible factors and inflammatory bowel diseases.

Adequate oxygen supply is essential for maintaining the body's normal physiological function. In chronic inflammatory conditions such as inflammatory bowel disease (IBD), insufficient oxygen reaching the intestine triggers the regulatory system in response to environmental changes. However, the pathogenesis of IBD is still under investigation. Recent research has highlighted the significant role of hypoxia in IBD, particularly the involvement of hypoxia-inducible factors (HIF) and their regulatory mechanisms, making them promising therapeutic targets for IBD. This review will delve into the role of hypoxia, HIF, and the associated hypoxia-inflammatory microenvironment in the context of IBD. Potential interventions for addressing these challenging gastrointestinal inflammatory diseases will also be discussed within this framework.

Blockade of Syk modulates neutrophil immune-responses via the mTOR/RUBCNL-dependent autophagy pathway to alleviate intestinal inflammation in ulcerative colitis.

Background: Ulcerative colitis (UC) is a progressive chronic inflammatory disorder. Neutrophils play a critical role in regulating intestinal mucosal homeostasis in UC. Spleen tyrosine kinase (Syk) is involved in several inflammatory diseases. Here, we evaluated the effects and underlying mechanisms of Syk on neutrophil immune-responses in UC. Methods: Syk expression in the colonic tissues of patients with UC was determined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. Colonic biopsies from patients with UC were obtained for single-cell RNA-sequencing. Neutrophils isolated from peripheral blood were pre-treated with R788 (a Syk inhibitor) and gene differences were determined using RNA sequencing. Neutrophil functions were analyzed using qRT-PCR, flow cytometry, and Transwell assay. R788 was administered daily to mice with dextran sulfate sodium (DSS)-induced colitis to verify the effects of Syk on intestinal inflammation. Results: Syk expression was increased in inflamed mucosa and neutrophils of patients with UC and positively correlated with disease activity. Pharmacological inhibition of Syk in neutrophils decreased the production of pro-inflammatory cytokines, chemokines, neutrophil extracellular traps, reactive oxygen species, and myeloperoxidase. Apoptosis and migration of neutrophils were suppressed by Syk blockade. Syk blockade ameliorated mucosal inflammation in DSS-induced murine colitis by inhibiting neutrophil-associated immune responses. Mechanistically, Syk regulated neutrophil immune-responses via the mammalian target of rapamycin kinase/rubicon-like autophagy enhancer-dependent autophagy pathway. Conclusions: Our findings indicate that Syk facilitates specific neutrophil functional responses to mucosal inflammation in UC, and its inhibition ameliorates mucosal inflammation in DSS-induced murine colitis, suggesting its potential as a novel therapeutic target for UC treatment.

Ulcerative Colitis Concomitant with Cytomegalovirus Infection, Bullous Sweet's Syndrome, and Acute Myeloid Leukemia: A Case Report and Literature Review.

Background: Ulcerative colitis (UC) is a chronic, relapsing progressive inflammatory immune disease. There is still no cure for it. Even worse, UC may predispose patients to opportunistic infections, and several extra-intestinal manifestations (EIMs) and comorbidities may antedate, occur with, or postdate the onset of UC, which may increase the mortality risk. But case reports of UC patients simultaneously concomitant with opportunistic infection, EIM, and comorbidity are extremely rare. Case Presentation: We report a case of 51-year-old male patient with incipient UC accompanied by cytomegalovirus (CMV) infection and bullous Sweet's syndrome (bSS, a cutaneous EIM of UC) after treatment with oral mesalazine and prednisolone for 3 weeks. After clearance of the CMV infection by using ganciclovir, the patient was administered two cycles of infliximab to cure UC and bSS; however, he developed acute myeloid leukemia (AML) a month later and died after two cycles of chemotherapy. Conclusion: Based on this rare case of UC concomitant with CMV infection, bSS and AML, we recommend that it is important to distinguish between an acute UC flare and opportunistic infections, especially in patients receiving immunosuppressive therapy, and monitor EIMs and comorbidities timely. Particular attention should be paid to cancer surveillance. Clinicians should be mindful of these facts to adopt optimal therapeutic options to address all aspects of UC. Early initiation of biological therapy may be of benefit to patients with newly diagnosed severe UC.

Ulcerative colitis and thrombocytosis: Case report and literature review.

RATIONALE: Ulcerative colitis (UC) is an autoimmune disease of unknown etiology, sometimes associated with anemia and thrombocytosis. Platelets (PLTs) play a role in amplifying inflammatory and immune responses in chronic inflammation. This study discusses the diagnosis and treatment of a case of UC combined with secondary thrombocytosis and reviews the relevant literature. We report an interaction between thrombocytosis and UC to raise clinicians' awareness of this condition. PATIENT CONCERNS: In the current report, we discuss the case of a 30-year-old female patient who presented with frequent diarrhea and thrombocytosis. DIAGNOSIS: Severe UC combined with intestinal infection was diagnosed based on colonoscopy and intestinal biopsy. The patient had a PLT count >450 × 109/L and was diagnosed with reactive thrombocytosis. INTERVENTIONS AND OUTCOMES: The patient was discharged from the hospital in remission after receiving vedolizumab and anticoagulant treatment. LESSONS: In patients with severe UC with thrombocytosis, clinicians should pay attention to PLTs promoting inflammatory progression, as well as screening for venous thromboembolism risk and prophylactic anti-venous thromboembolism therapy at the time of dosing to avoid adverse effects.

Role of Serum/Glucocorticoid-Regulated Kinase 1 (SGK1) in Immune and Inflammatory Diseases.

Serum/glucocorticoid-regulated kinase 1 (SGK1), a member of the serine/threonine protein kinase gene family, is primarily regulated by serum and glucocorticoids. SGK1 is involved in the development of tumors and fibrotic diseases. However, relatively little research has been conducted on their role in immune and inflammatory diseases. SGK1 may act as a pivotal immune regulatory gene by modulating immune cells (e.g., T cells, macrophages, dendritic cells, and neutrophils) and functions and is involved in the pathogenesis of some immune and inflammatory diseases, such as inflammatory bowel disease, multiple sclerosis, allergic diseases, sepsis, and major depressive disorder. This review aims to provide an overview of the latest research focusing on the immune and inflammatory regulatory roles of SGK1 and provide new insights into diagnostic and therapeutic approaches for immune and inflammatory diseases.

The role of long noncoding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) in immune diseases.

The long noncoding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) has been shown to be involved in the pathogenesis of several diseases. Herein, we discuss recent developments and insights into NEAT1 and its contribution to a variety of immune disorders. Our evaluations revealed that NEAT1's function in immune diseases seems to be focused on the modulation of paraspeckle expression and it is primarily associated with the nuclear retention of its mRNA. NEAT1 is also involved in the sequestration of paraspeckle proteins and in affecting the transcriptional expression of specific immune regulators. The expression of NEAT1 may be aberrantly upregulated in several immune pathologies, indicating that it could serve as a potential prognostic biomarker in these conditions. We summarized describing the expression changes and the role of NEAT1 in several immune diseases. We also described the mechanism of its regulation of the immune cell differentiation and function of NEAT1 in different disease.

Signal transduction mechanism of exosomes in diabetic complications (Review).

Exosomes are vesicles with a particle size of 30-120 nm that are secreted by cells through exocytosis. The composition of an exosome includes a lipid bilayer and its internal package of biological molecules, such as proteins, ribonucleotides and deoxyribonucleotides. Diabetes is a chronic and refractory disease. The complications induced by high blood glucose have become a major problem in global public health and the pathogenesis of diabetic complications remains to be fully elucidated. In recent years, it has been gradually recognized that exosomes from different cell sources and their related molecules, particularly exosomal proteins and microRNAs, have an important role in the pathogenesis of diabetic complications, allowing for the exploration of the pathogenesis of diabetic complications from a molecular perspective. The present review summarizes the latest studies on exosomes from different cell sources in the pathogenesis of diabetic complications, which may provide novel targets for the prevention and treatment of diabetic complications.

IRF5 Acts as a Potential Therapeutic Marker in Inflammatory Bowel Diseases.

BACKGROUND: Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory disorders. As is well known, interferon regulatory factor (IRF) 5 is closely associated with the pathogenesis of various inflammatory diseases. But the exact role of IRF5 in IBD remains unclear. METHODS: In this study, we detected IRF5 expression in peripheral blood mononuclear cells (PBMCs) and inflamed mucosa from IBD patients by immunohistochemistry, western blot, and quantitative real-time polymerase chain reaction. Peripheral blood CD4+ T cells were stimulated with inflammatory cytokines and transfected by lentivirus. RESULTS: In active IBD patients, the expression of IRF5 in PBMCs and inflamed colonic tissues was obviously increased and significantly associated with disease activity. Ectopic overexpression of IRF5 could promote the differentiation of IBD CD4+ T cells into Th1 and Th17 cells by regulating T-bet and RAR related orphan receptor C, whereas knockdown of IRF5 had the opposite effects. Tumor necrosis factor (TNF)-α upregulated expression of IRF5 in CD4+ T cells, but anti-TNF treatment with infliximab could markedly reduce IRF5 expression in CD4+ T cells and intestinal mucosa of CD patients. CONCLUSION: Our study reveals a novel mechanism that IRF5 levels are correlated with disease activity in IBD and might function as a possible marker for the management of IBD via regulating Th1 and Th17 immune responses and cytokine production.

Novel adeno­associated virus­based genetic vaccines encoding hepatitis C virus E2 glycoprotein elicit humoral immune responses in mice.

Hepatitis C virus (HCV) infection remains a major public health issue despite the introduction of several direct­acting antiviral agents (DAAs), with some 185 million individuals infected with HCV worldwide. There is an urgent need for an effective prophylactic HCV vaccine. In the present study, we constructed genetic vaccines based on novel recombinant adeno­associated viral (rAAV) vectors (AAV2/8 or AAV2/rh32.33) that express the envelope glycoprotein E2 from the HCV genotype 1b. Expression of HCV E2 protein in 293 cells was confirmed by western blot analysis. rAAV2/8.HCV E2 vaccine or rAAV2/rh32.33.HCV E2 vaccine was intramuscularly injected into C57BL/6 mice. HCV E2­specific antigen was produced, and long­lasting specific antibody responses remained detectable XVI weeks following immunization. In addition, the rAAV2/rh32.33 vaccine induced higher antigen­specific antibody levels than the rAAV2/8 vaccine or AAV plasmid. Moreover, both AAV vaccines induced neutralizing antibodies against HCV genotypes 1a and 1b. Finally, it is worth mentioning that neutralizing antibody levels directed against AAV2/rh32.33 were lower than those against AAV2/8 in both mouse and human serum. These results demonstrate that AAV vectors, especially the AAVrh32.33, have particularly favorable immunogenicity for development into an effective HCV vaccine.