Altered Expression of Intestinal Tight Junctions in Patients with Chronic Kidney Disease: A Pathogenetic Mechanism of Intestinal Hyperpermeability.

BACKGROUND: Systemic inflammation in chronic kidney disease (CKD) is associated (as a cause or effect) with intestinal barrier dysfunction and increased gut permeability, with mechanisms not yet fully understood. This study investigated different parameters of the intestinal barrier in CKD patients, especially tight junction (TJ) proteins and their possible association with systemic endotoxemia and inflammation. METHODS: Thirty-three patients with stage I-IV CKD (n = 17) or end-stage kidney disease (ESKD) (n = 16) and 11 healthy controls underwent duodenal biopsy. Samples were examined histologically, the presence of CD3+ T-lymphocytes and the expression of occludin and claudin-1 in the intestinal epithelium was evaluated by means of immunohistochemistry, circulating endotoxin concentrations were determined by means of ELISA and the concentrations of the cytokines IL-1ß, IL-6, IL-8, IL-10 and TNF-α in serum were measured using flow cytometry. RESULTS: Patients with stage I-IV CKD or ESKD had significantly higher serum endotoxin, IL-6, IL-8 and IL-10 levels compared to controls. Intestinal occludin and claudin-1 were significantly decreased, and their expression was inversely correlated with systemic endotoxemia. Regarding occludin, a specific expression pattern was observed, with a gradually increasing loss of its expression from the crypt to the tip of the villi. CONCLUSION: The expression of occludin and claudin-1 in enterocytes is significantly reduced in patients with CKD, contributing to systemic endotoxemia and inflammatory responses in these patients.

Altered Expression of Intestinal Tight Junction Proteins in Heart Failure Patients with Reduced or Preserved Ejection Fraction: A Pathogenetic Mechanism of Intestinal Hyperpermeability.

Although intestinal microbiota alterations (dysbiosis) have been described in heart failure (HF) patients, the possible mechanisms of intestinal barrier dysfunction leading to endotoxemia and systemic inflammation are not fully understood. In this study, we investigated the expression of the intestinal tight junction (TJ) proteins occludin and claudin-1 in patients with HF with reduced (HFrEF) or preserved ejection fraction (HFpEF) and their possible association with systemic endotoxemia and inflammation. Ten healthy controls and twenty-eight patients with HF (HFrEF (n = 14), HFpEF (n = 14)) underwent duodenal biopsy. Histological parameters were recorded, intraepithelial CD3+ T-cells and the expression of occludin and claudin-1 in enterocytes were examined using immunohistochemistry, circulating endotoxin concentrations were determined using ELISA, and concentrations of cytokines were determined using flow cytometry. Patients with HFrEF or HFpEF had significantly higher serum endotoxin concentrations (p < 0.001), a significantly decreased intestinal occludin and claudin-1 expression (in HfrEF p < 0.01 for occludin, p < 0.05 for claudin-1, in HfpEF p < 0.01 occludin and claudin-1), and significantly increased serum concentrations of IL-6, IL-8, and IL-10 (for IL-6 and IL-10, p < 0.05 for HFrEF and p < 0.001 for HFpEF; and for IL-8, p < 0.05 for both groups) compared to controls. Occludin and claudin-1 expression inversely correlated with systemic endotoxemia (p < 0.05 and p < 0.01, respectively). Heart failure, regardless of the type of ejection fraction, results in a significant decrease in enterocytic occludin and claudin-1 expression, which may represent an important cellular mechanism for the intestinal barrier dysfunction causing systemic endotoxemia and inflammatory response.

Current knowledge on multiple sclerosis pathophysiology, disability progression assessment and treatment options, and the role of autologous hematopoietic stem cell transplantation.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that affects nearly 2.8 million people each year. MS distinguishes three main types: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). RRMS is the most common type, with the majority of patients eventually progressing to SPMS, in which neurological development is constant, whereas PPMS is characterized by a progressive course from disease onset. New or additional insights into the role of effector and regulatory cells of the immune and CNS systems, Epstein-Barr virus (EBV) infection, and the microbiome in the pathophysiology of MS have emerged, which may lead to the development of more targeted therapies that can halt or reverse neurodegeneration. Depending on the type and severity of the disease, various disease-modifying therapies (DMTs) are currently used for RRMS/SPMS and PPMS. As a last resort, and especially in highly active RRMS that does not respond to DMTs, autologous hematopoietic stem cell transplantation (AHSCT) is performed and has shown good results in reducing neuroinflammation. Nevertheless, the question of its potential role in preventing disability progression remains open. The aim of this review is to provide a comprehensive update on MS pathophysiology, assessment of MS disability progression and current treatments, and to examine the potential role of AHSCT in preventing disability progression.

Intraluminal assessment of inflammatory factors in patients with intracranial aneurysms.

BACKGROUND: The formation, growth, and rupture of intracranial aneurysms (IA) are due to several pathophysiological mechanisms, including focal hemodynamic injury and inflammation of the arterial wall. We investigated the differences between venous, parent artery, and intra-aneurysmal blood by measuring inflammatory factors and antibodies in patients with ruptured (rIA) or unruptured intracranial aneurysms (uIA). METHOD: A prospective study was performed in patients who presented with IA and required endovascular treatment. Blood was drawn from the lumen of the aneurysm sac, the parent artery, and the peripheral veins, to determine the serum concentrations of complement factors C3, C4, IgG, IgM, IgA antibodies, and C-reactive protein (CRP). RESULTS: Thirty-six patients (15 with uIA and 21 with rIA) were enrolled in the study. In both groups, C3, C4, IgM, IgG, and IgA showed a gradual decrease from venous to intra-aneurysmal samples, but only IgG in the parent artery and intra-aneurysmal samples reached a significant decrease in uIA compared with venous samples. Accordingly, C3 and IgG concentrations in the intra-aneurysmal samples showed a significant decrease in rIA compared with venous samples. A significant increase in CRP concentrations was observed in parent artery and intra-aneurysmal samples from patients with rIA compared with patients with uIA; a significant increase in C3 concentrations was observed in parent artery samples from patients with rIA compared with patients with uIA, and a significant decrease in IgM concentrations was observed in venous, parent artery, and intra-aneurysmal samples from patients with rIA compared with patients with uIA. CONCLUSIONS: A decrease in C3 and IgG in the aneurysm sac indicates activation of the complement system in the arterial wall. CRP in the aneurysm sac and lumen of the parent artery was significantly increased in ruptured compared with unruptured aneurysms, whereas venous, parent artery, and intra-aneurysmal IgM were decreased in ruptured compared with unruptured aneurysms. These results argue for the role of an ongoing inflammatory process in aneurysms leading to their growth and rupture.

Patterns, Cost, and Immunological Response of MDR vs. Non MDR-Bacteremia: A Prospective Cohort Study.

BACKGROUND: Antimicrobial resistance (AMR) is a significant global health concern, posing a critical challenge for the effective management of infectious diseases. This study aimed to compare the immunological response, clinical outcomes, and associated costs in patients with bacteremia due to antibiotic-resistant vs. susceptible bacterial microorganisms. METHODS: This study was a single-center, prospective cohort study conducted from May 2017 to November 2019. The study population consisted of patients admitted with a confirmed diagnosis of bacteremia. RESULTS: A total of 116 patients were included, with 53 (45.7%) harboring non-multidrug-resistant (non-MDR) bacterial isolates and 63 (54.3%) harboring multidrug-resistant (MDR) bacterial isolates. Patients with MDR bacteremia had more severe clinical presentations, as indicated by higher SOFA and APACHE II scores. Results revealed higher all-cause mortality rates (39.7% vs. 17%) and median healthcare costs (€4791 vs. €2843.5) in the MDR bacteremia group. Moreover, MDR bacteremia was linked to higher levels of TNF-a, indicating a differential immune response. Furthermore, MDR bacteremia was found to be an independent predictor of mortality (OR = 3.216, 95% CI: 1.338-7.730, p = 0.009) and increased healthcare costs (effect size of approximately 27.4%). CONCLUSION: These findings underscore the significant impact of antimicrobial resistance in healthcare settings, highlighting the urgency of addressing the challenges posed by MDR microorganisms.

Murine Dermal Lymphatic Endothelial Cell Isolation.

The lymphatic system participates in the regulation of immune surveillance, lipid absorption, and tissue fluid balance. The isolation of murine lymphatic endothelial cells is an important process for lymphatic research, as it allows the performance of in vitro and biochemical experiments on the isolated cells. Moreover, the development of Cre-lox technology has enabled the tissue-specific deficiency of genes that cannot be globally targeted, leading to the precise determination of their role in the studied tissues. The dissection of the role of certain genes in lymphatic physiology and pathophysiology requires the use of lymphatic-specific promoters, and thus, the experimental verification of the expression levels of the targeted genes. Methods for efficient isolation of lymphatic endothelial cells from wild-type or transgenic mice enable the use of ex vivo and in vitro assays to study the mechanisms regulating the lymphatic functions and the identification of the expression levels of the studied proteins. We have developed, standardized and present a protocol for the efficient isolation of murine dermal lymphatic endothelial cells (DLECs) via magnetic bead purification based on LYVE-1 expression. The protocol outlined aims to equip researchers with a tool to further understand and elucidate important players of lymphatic endothelial cell functions, especially in facilities where fluorescence-activated cell sorting equipment is not available.

Exploring the Role of Vitamin D and the Vitamin D Receptor in the Composition of the Gut Microbiota.

The microbiome has a major impact on human physiology and plays a critical role in enhancing or impairing various physiological functions such as regulation of the immune system, metabolic activities, and biosynthesis of vitamins and hormones. Variations in the gut microbial community play a critical role in both health and disease. Regulation of calcium and bone metabolism, as well as cellular functions such as proliferation, apoptosis, differentiation, and immune modulation, are among the known effects of vitamin D. These biological functions are primarily carried out through the binding of vitamin D to the vitamin D receptor (VDR), a member of the nuclear receptor superfamily. The immunomodulatory properties of vitamin D suggest that this molecule plays an important role in various diseases. Maintenance of immune homeostasis appears to occur in part through the interaction of the gut microbiota with vitamin D. Increasing evidence points to the central role of vitamin D in maintaining mucosal barrier function, as vitamin D deficiency has been associated with disruption of gut barrier integrity, translocation of bacteria into the bloodstream, and systemic inflammation. In parallel, a bidirectional interaction between vitamin D and the gut microbiota has been demonstrated as data show upregulation of intestinal VDR expression and downregulation of inflammatory markers in response to fermentation products. The aim of this review is to provide an overview of the evidence of a link between the gut microbiome and vitamin D, with a focus on data from experimental models and translational data from human studies related to vitamin D-induced changes in gut microbiota composition.

Alexithymic characteristics and interoceptive abilities are associated with disease severity and levels of C-reactive protein and cytokines in patients with inflammatory bowel disease.

Background: Alexithymia and atypical gut-brain signaling have been linked to the pathophysiology of inflammatory bowel disease (IBD). We herein assessed IBD patients' alexithymia levels and interoceptive abilities, and detected potential correlations with psychological distress, symptom severity and disease activity, and inflammation indices. Methods: Adult IBD outpatients and healthy controls were recruited. Alexithymia was assessed using the Toronto Alexithymia Scale, interoceptive accuracy using the Heartbeat Counting Test (cardiac interoception) and the Water Load Test-II (gastric interoception), and interoceptive sensibility using the Multidimensional Assessment of Interoceptive Awareness (MAIA). Results: Forty-one patients with Crohn's disease (CD), 16 with ulcerative colitis (UC), and 50 healthy controls were included. In CD patients, the level of externally oriented thinking and total alexithymia score were correlated with disease activity (P=0.027 and P=0.047, respectively), while in UC patients difficulties in identifying emotions were linked to disease activity (P=0.007). In CD patients, the Noticing, Not-Worrying and Emotional Awareness MAIA subscale score were correlated with C-reactive protein levels (P=0.005, P=0.048 and P=0.005), the Noticing subscale score with interleukin (IL)-1ß levels (r=-0.350, P=0.039), the Not-Distracting subscale score with IL-6 levels (r=-0.402, P=0.017), and the Emotional Awareness subscale score with IL-1ß (r=-0.367, P=0.030) and IL-6 (r=-0.379, P=0.025) levels. Finally, in UC patients, the Not-Worrying subscale score was significantly associated with IL-6 levels (r=-0.532, P=0.049), while difficulties in identifying emotions were linked to IL-8 levels (r=0.604, P=0.022). Conclusion: Emotional and interoceptive processing is associated with IBD disease activity, suggesting a potential implication for IBD pathophysiology.

Creeping Fat in Crohn's Disease-Surgical, Histological, and Radiological Approaches.

During the course of Crohn's disease, the response of mesenteric adipose tissue to the production of inflammatory mediators and bacterial invasion through the intestinal mucosa results in the formation of creeping fat. Creeping fat describes the arresting finger-like projections that surround the inflamed bowel. In this review, the microscopic and macroscopic features of creeping fat and histological evidence for the importance of this tissue are discussed. Moreover, the most recent insights into the radiological assessment of creeping fat in patients with Crohn's disease are reported. Advances in imaging techniques have revolutionized the possibility of visualization and quantification of adipose tissue depots with excellent accuracy. Visceral fat has been significantly correlated with various Crohn's-disease-related outcomes. Despite the difficulties in distinguishing physiologic perienteric fat from creeping fat, the growing interest in fat-wrapping in Crohn's disease has rejuvenated radiologic research. With regard to the noninvasive fat-wrapping assessment, a novel CT enterography-based mesenteric creeping fat index has been developed for the mitigation of the confounding effect of normal retroperitoneal and perienteric adipose tissue. Research on machine learning algorithms and computational radiomics in conjunction with mechanistic studies may be the key for the elucidation of the complex role of creeping fat in Crohn's disease.

The Influence of Single Nucleotide Polymorphisms on Vitamin D Receptor Protein Levels and Function in Chronic Liver Disease.

Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene have been associated with chronic liver disease. We investigated the role of VDR SNPs on VDR protein levels and function in patients with chronic liver disease. VDR expression levels were determined in peripheral T lymphocytes (CD3+VDR+), monocytes (CD14+VDR+), and plasma from patients (n = 66) and healthy controls (n = 38). Genotyping of SNPs and the determination of expression of VDR/vitamin D-related genes were performed by using qPCR. The effect of FokI SNP on vitamin D-binding to VDR was investigated by molecular dynamics simulations. CD14+VDR+ cells were correlated with the MELD score. The ApaI SNP was associated with decreased CD3+VDR+ levels in cirrhotic patients and with higher liver stiffness in HCV patients. The BsmI and TaqI SNPs were associated with increased VDR plasma concentrations in cirrhotic patients and decreased CD14+VDR+ levels in HCV patients. The FokI SNP was associated with increased CD3+VDR+ levels in cirrhotic patients and controls. VDR polymorphisms were significantly related to the expression of genes critical for normal hepatocyte function and immune homeostasis. VDR expression levels were related to the clinical severity of liver disease. VDR SNPs may be related to the progression of chronic liver disease by affecting VDR expression levels.

Creeping Fat in the Pathogenesis of Crohn's Disease: An Orchestrator or a Silent Bystander?

Although the phenomenon of hypertrophied adipose tissue surrounding inflamed bowel segments in Crohn's disease has been described since 1932, the mechanisms mediating the creeping fat formation and its role in the pathogenesis of the disease have not been fully unraveled. Recent advances demonstrating the multiple actions of adipose tissue beyond energy storage have brought creeping fat to the forefront of scientific research. In Crohn's disease, dysbiosis and transmural injury compromise the integrity of the intestinal barrier, resulting in an excessive influx of intraluminal microbiota and xenobiotics. The gut and peri-intestinal fat are in close anatomic relationship, implying a direct reciprocal immunologic relationship, whereas adipocytes are equipped with an arsenal of innate immunity sensors that respond to invading stimuli. As a result, adipocytes and their progenitor cells undergo profound immunophenotypic changes, leading to adipose tissue remodeling and eventual formation of creeping fat. Indeed, creeping fat is an immunologically active organ that synthesizes various pro- and anti-inflammatory cytokines, profibrotic mediators, and adipokines that serve as paracrine/autocrine signals and regulate immune responses. Therefore, creeping fat appears to be involved in inflammatory signaling, which explains why it has been associated with a higher severity or complicated phenotype of Crohn's disease. Interestingly, there is growing evidence for an alternative immunomodulatory function of creeping fat as a second barrier that prevents an abnormal systemic inflammatory response at the expense of an increasingly proliferating profibrotic environment. Further studies are needed to clarify how this modified adipose tissue exerts its antithetic effect during the course of Crohn's disease.

Creeping fat, a common feature of Crohn's disease, is the wrapping of mesenteric fat around the intestinal wall, resulting in mucosal response aggravation and lesion exacerbation through releasing pro-inflammatory molecules and cells to the gut, leading to worsened disease course.

HIV-1 Transcriptional Activator Tat Inhibits IL2 Expression by Preventing the Presence of Pol II on the IL2 Promoter.

HIV-1 infection leads to a gradual loss of T helper cells, chronic immune activation, and eventual immune system breakdown. HIV-1 causes deregulation of the expression of IL-2, a cytokine important for T helper cell growth and survival, which is downregulated in HIV-1 patients. The present study addresses the regulation of IL2 expression via HIV-1 Tat transcriptional activator. We used J-LAT cells, a T cell line that serves as a latency model for studies of HIV-1 expression in T cells, and as controls a T cell line lacking HIV-1 elements and a T cell line with a stably integrated copy of the HIV-1-LTR promoter. We show that endogenously expressed Tat inhibits IL2 transcription in J-Lat cells via its presence in the ARRE-1/2 elements of the IL2 promoter and that the inhibition of IL2 expression is mediated by Tat inhibiting Pol II activity at the IL2 promoter, which is mediated by preventing the presence of Pol II at the ARRE-1/2 elements. Overall, Tat is present at the IL2 promoter, apart from its cognate HIV-1 LTR target. This supports our current knowledge of how HIV-1 affects the host transcriptional machinery and reflects the potential of Tat to disrupt transcriptional regulation of host genes to manipulate cell responses.

Gene Polymorphisms and Biological Effects of Vitamin D Receptor on Nonalcoholic Fatty Liver Disease Development and Progression.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with increasing prevalence worldwide. The genetic and molecular background of NAFLD pathogenesis is not yet clear. The vitamin D/vitamin D receptor (VDR) axis is significantly associated with the development and progression of NAFLD. Gene polymorphisms may influence the regulation of the VDR gene, although their biological significance remains to be elucidated. VDR gene polymorphisms are associated with the presence and severity of NAFLD, as they may influence the regulation of adipose tissue activity, fibrosis, and hepatocellular carcinoma (HCC) development. Vitamin D binds to the hepatic VDR to exert its biological functions, either by activating VDR transcriptional activity to regulate gene expression associated with inflammation and fibrosis or by inducing intracellular signal transduction through VDR-mediated activation of Ca2+ channels. VDR activity has protective and detrimental effects on hepatic steatosis, a characteristic feature of NAFLD. Vitamin D-VDR signaling may control the progression of NAFLD by regulating immune responses, lipotoxicity, and fibrogenesis. Elucidation of the genetic and molecular background of VDR in the pathophysiology of NAFLD will provide new therapeutic targets for this disease through the development of VDR agonists, which already showed promising results in vivo.

Alterations in gut immunological barrier in SARS-CoV-2 infection and their prognostic potential.

Although coronavirus disease 2019 (COVID-19) is primarily associated with mild respiratory symptoms, a subset of patients may develop more complicated disease with systemic complications and multiple organ injury. The gastrointestinal tract may be directly infected by SARS-CoV-2 or secondarily affected by viremia and the release of inflammatory mediators that cause viral entry from the respiratory epithelium. Impaired intestinal barrier function in SARS-CoV-2 infection is a key factor leading to excessive microbial and endotoxin translocation, which triggers a strong systemic immune response and leads to the development of viral sepsis syndrome with severe sequelae. Multiple components of the gut immune system are affected, resulting in a diminished or dysfunctional gut immunological barrier. Antiviral peptides, inflammatory mediators, immune cell chemotaxis, and secretory immunoglobulins are important parameters that are negatively affected in SARS-CoV-2 infection. Mucosal CD4+ and CD8+ T cells, Th17 cells, neutrophils, dendritic cells, and macrophages are activated, and the number of regulatory T cells decreases, promoting an overactivated immune response with increased expression of type I and III interferons and other proinflammatory cytokines. The changes in the immunologic barrier could be promoted in part by a dysbiotic gut microbiota, through commensal-derived signals and metabolites. On the other hand, the proinflammatory intestinal environment could further compromise the integrity of the intestinal epithelium by promoting enterocyte apoptosis and disruption of tight junctions. This review summarizes the changes in the gut immunological barrier during SARS-CoV-2 infection and their prognostic potential.

Association of Antiretroviral Therapy with Platelet Function and Systemic Inflammatory Response in People Living with HIV: A Cross-Sectional Study.

People living with HIV (PLWHIV) present an increased risk of adverse cardiovascular events. We aimed to assess whether antiretroviral therapy (ART) pharmacologically enhances platelet reactivity and platelet activation intensity, and explore the potential association with underlying inflammatory status. This was a cross-sectional cohort study carried out among PLWHIV on diverse ART regimens. Platelet reactivity and activation intensity were assessed using the bedside point-of-care VerifyNow assay, in P2Y12 reaction units (PRU), measurements of monocyte-platelet complexes, and P-selectin and GPIIb/IIIa expression increase, following activation with ADP, respectively. Levels of major inflammatory markers and whole blood parameters were also evaluated. In total, 71 PLWHIV, 59 on ART and 22 healthy controls, were included in this study. PRU values were significantly elevated in PLWHIV compared to controls [Mean; 257.85 vs. 196.67, p < 0.0001], but no significant differences were noted between ART-naïve or ART-experienced PLWHIV, or between TAF/TDF and ABC based regimens, similar to systemic inflammatory response. However, within-group analysis showed that PRUs were significantly higher in ABC/PI vs ABC/INSTI or TAF/TDF + PI patients, in line with levels of IL-2. PRU values did not correlate strongly with CD4 counts, viral load, or cytokine values. P-selectin and GPIIb/IIIa expression increased following ADP activation and were significantly more prominent in PLWHIV (p < 0.005). Platelet reactivity and platelet activation intensity were shown to be increased in PLWHIV, but they did not appear to be related to ART initiation, similar to the underlying systemic inflammatory response.

Vitamin D and Microbiome: Molecular Interaction in Inflammatory Bowel Disease Pathogenesis.

Studies of systemic autoimmune diseases point to characteristic microbial patterns in various diseases, including inflammatory bowel disease (IBD). Autoimmune diseases, and IBD in particular, show a predisposition to vitamin D deficiency, leading to alterations in the microbiome and disruption of intestinal epithelial barrier integrity. This review examines the role of the gut microbiome in IBD and discusses how vitamin D-vitamin D receptor (VDR)-associated molecular signaling pathways contribute to the development and progression of IBD through their effects on gut barrier function, the microbial community, and immune system function. The present data demonstrate that vitamin D promotes the proper function of the innate immune system by acting as an immunomodulator, exerting anti-inflammatory effects, and critically contributing to the maintenance of gut barrier integrity and modulation of the gut microbiota, mechanisms that may influence the IBD development and progression. VDR regulates the biological effects of vitamin D and is related to environmental, genetic, immunologic, and microbial aspects of IBD. Vitamin D influences the distribution of the fecal microbiota, with high vitamin D levels associated with increased levels of beneficial bacterial species and lower levels of pathogenic bacteria. Understanding the cellular functions of vitamin D-VDR signaling in intestinal epithelial cells may pave the way for the development of new treatment strategies for the therapeutic armamentarium of IBD in the near future.

miRNA Molecules-Late Breaking Treatment for Inflammatory Bowel Diseases?

MicroRNAs (miRNAs) are a group of non-coding RNAs that play a critical role in regulating epigenetic mechanisms in inflammation-related diseases. Inflammatory bowel diseases (IBDs), which primarily include ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic recurrent inflammation of intestinal tissues. Due to the multifactorial etiology of these diseases, the development of innovative treatment strategies that can effectively maintain remission and alleviate disease symptoms is a major challenge. In recent years, evidence for the regulatory role of miRNAs in the pathogenetic mechanisms of various diseases, including IBD, has been accumulating. In light of these findings, miRNAs represent potential innovative candidates for therapeutic application in IBD. In this review, we discuss recent findings on the role of miRNAs in regulating inflammatory responses, maintaining intestinal barrier integrity, and developing fibrosis in clinical and experimental IBD. The focus is on the existing literature, indicating potential therapeutic application of miRNAs in both preclinical experimental IBD models and translational data in the context of clinical IBD. To date, a large and diverse data set, which is growing rapidly, supports the potential use of miRNA-based therapies in clinical practice, although many questions remain unanswered.

Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases.

Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide. The increasing disease burden worldwide, lack of response to current biologic therapeutics, and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy. Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics. Sphingosine-1-phosphate (S1P) receptor (S1PR) modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement. S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival, differentiation, migration, proliferation, immune response, and lymphocyte trafficking. T lymphocytes play an important role in regulating inflammatory responses. In inflamed IBD tissue, an imbalance between T helper (Th) and regulatory T lymphocytes and Th cytokine levels was found. The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD. S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking, lymphocyte number, lymphocyte activity, cytokine production, and contributing to gut barrier function.

Vitamin D-VDR Novel Anti-Inflammatory Molecules-New Insights into Their Effects on Liver Diseases.

There is consistent evidence that vitamin D deficiency is strongly associated with liver dysfunction, disease severity, and poor prognosis in patients with liver disease. Vitamin D and its receptor (VDR) contribute to the regulation of innate and adaptive immune responses. The presence of genetic variants of vitamin D- and VDR-associated genes has been associated with liver disease progression. In our recent work, we summarized the progress in understanding the molecular mechanisms involved in vitamin D-VDR signaling and discussed the functional significance of VDR signaling in specific cell populations in liver disease. The current review focuses on the complex interaction between immune and liver cells in the maintenance of liver homeostasis and the development of liver injury, the interplay of vitamin D and VDR in the development and outcome of liver disease, the role of vitamin D- and VDR-associated genetic variants in modulating the occurrence and severity of liver disease, and the therapeutic value of vitamin D supplementation in various liver diseases. The association of the vitamin D-VDR complex with liver dysfunction shows great potential for clinical application and supports its use as a prognostic index and diagnostic tool.

Molecular basis of vitamin D action in inflammatory bowel disease.

There is growing evidence of vitamin D involvement in immune regulation and gut barrier function, suggesting that vitamin D may play a critical role in the development of inflammatory bowel disease (IBD). This review presents advances in the molecular mechanisms of vitamin D and vitamin D receptor (VDR) signaling with respect to barrier integrity and innate/adaptive immunity in the gut, as well as recent findings in uncovering the biological link between vitamin D-associated genetic variants and IBD. Experimental data have revealed a mechanistic basis for the contribution of vitamin D to the pathogenesis of IBD. The vitamin D/VDR complex is involved in the regulation of innate and adaptive immune responses to pathogenic threats by acting as an immunomodulator and alleviating inflammation in experimental IBD models and IBD patients, contributing to intestinal homeostasis. Vitamin D has been associated with the promotion of antimicrobial peptide secretion, down-regulation of dendritic cell activity, induction of tolerogenic rather than pro-inflammatory T-cell differentiation and function, and increased production of anti-inflammatory cytokines, highlighting its potential therapeutic value for IBD. Elucidating the complex interplay between vitamin D/VDR and the pathogenesis of IBD is critical for the development of novel therapeutic interventions and for the potential use of this molecule as a prognostic and diagnostic tool in clinical practice.