Vitamin D and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Novel Mechanistic Insights.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition characterized by abnormal fat accumulation in the liver, often associated with metabolic disorders. Emerging evidence suggests a potential link between vitamin D deficiency and the development and progression of MASLD. The current review provides a concise overview of recent studies uncovering novel mechanistic insights into the interplay between vitamin D and MASLD. Several epidemiological studies have highlighted a significant association between low vitamin D levels and an increased risk of MASLD. Vitamin D, traditionally known for its role in bone health, has now been recognized as a key player in various physiological processes, including immune regulation and inflammation. Experimental studies using animal models have demonstrated that vitamin D deficiency exacerbates liver steatosis and inflammation, suggesting a potential protective role against MASLD. Mechanistically, vitamin D appears to modulate MASLD through multiple pathways. Firstly, the vitamin D receptor (VDR) is abundantly expressed in liver cells, indicating a direct regulatory role in hepatic function. Activation of the VDR has been shown to suppress hepatic lipid accumulation and inflammation, providing a mechanistic basis for the observed protective effects. Additionally, vitamin D influences insulin sensitivity, a critical factor in MASLD pathogenesis. Improved insulin sensitivity may mitigate the excessive accumulation of fat in the liver, thus attenuating MASLD progression. In parallel, vitamin D exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokines implicated in MASLD pathophysiology. Experimental evidence suggests that the immunomodulatory effects of vitamin D extend to the liver, reducing inflammation and oxidative stress, key drivers of MASLD, and the likelihood of hepatocyte injury and fibrosis. Understanding the complex interplay between vitamin D and MASLD provides a basis for exploring targeted therapeutic strategies and preventive interventions. As vitamin D deficiency is a modifiable risk factor, addressing this nutritional concern may prove beneficial in mitigating the burden of MASLD and associated metabolic disorders.

The role of gut barrier dysfunction in postoperative complications in liver transplantation: pathophysiological and therapeutic considerations.

PURPOSE: Gut barrier dysfunction is a pivotal pathophysiological alteration in cirrhosis and end-stage liver disease, which is further aggravated during and after the operational procedures for liver transplantation (LT). In this review, we analyze the multifactorial disruption of all major levels of defense of the gut barrier (biological, mechanical, and immunological) and correlate with clinical implications. METHODS: A narrative review of the literature was performed using PubMed, PubMed Central and Google from inception until November 29th, 2023. RESULTS: Systemic translocation of indigenous bacteria through this dysfunctional barrier contributes to the early post-LT infectious complications, while endotoxin translocation, through activation of the systemic inflammatory response, is implicated in non-infectious complications including renal dysfunction and graft rejection. Bacterial infections are the main cause of early in-hospital mortality of LT patients and unraveling the pathophysiology of gut barrier failure is of outmost importance. CONCLUSION: A pathophysiology-based approach to prophylactic or therapeutic interventions may lead to enhancement of gut barrier function eliminating its detrimental consequences and leading to better outcomes for LT patients.

Exploring the role of IL-1ß in inflammatory bowel disease pathogenesis.

Interleukin 1ß (IL-1ß) is a significant mediator of inflammation and tissue damage in IBD. The balance between IL-1ß and its endogenous inhibitor-IL-1Ra-, plays a critical role in both initiation and regulation of inflammation. However, the precise role of IL-1ß as a causative factor in IBD or simply a consequence of inflammation remains unclear. This review summarizes current knowledge on the molecular and cellular characteristics of IL-1ß, describes the existing evidence on the role of this cytokine as a modulator of intestinal homeostasis and an activator of inflammatory responses, and also discusses the role of microRNAs in the regulation of IL-1ß-related inflammatory responses in IBD. Current evidence indicates that IL-1ß is involved in several aspects during IBD as it greatly contributes to the induction of pro-inflammatory responses through the recruitment and activation of immune cells to the gut mucosa. In parallel, IL-1ß is involved in the intestinal barrier disruption and modulates the differentiation and function of T helper (Th) cells by activating the Th17 cell differentiation, known to be involved in the pathogenesis of IBD. Dysbiosis in the gut can also stimulate immune cells to release IL-1ß, which, in turn, promotes inflammation. Lastly, increasing evidence pinpoints the central role of miRNAs involvement in IL-1ß-related signaling during IBD, particularly in the maintenance of homeostasis within the intestinal epithelium. In conclusion, given the crucial role of IL-1ß in the promotion of inflammation and immune responses in IBD, the targeting of this cytokine or its receptors represents a promising therapeutic approach. Further research into the IL-1ß-associated post-transcriptional modifications may elucidate the intricate role of this cytokine in immunomodulation.

"When," "Where," and "How" of SARS-CoV-2 Infection Affects the Human Cardiovascular System: A Narrative Review.

Coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory coronavirus-2 (SARS-CoV-2). Several explanations for the development of cardiovascular complications during and after acute COVID-19 infection have been hypothesized. The COVID-19 pandemic, caused by SARS-CoV-2, has emerged as one of the deadliest pandemics in modern history. The myocardial injury in COVID-19 patients has been associated with coronary spasm, microthrombi formation, plaque rupture, hypoxic injury, or cytokine storm, which have the same pathophysiology as the three clinical variants of Kounis syndrome. The angiotensin-converting enzyme 2 (ACE2), reninaldosterone system (RAAS), and kinin-kallikrein system are the main proposed mechanisms contributing to cardiovascular complications with the COVID-19 infection. ACE receptors can be found in the heart, blood vessels, endothelium, lungs, intestines, testes, neurons, and other human body parts. SARS-CoV-2 directly invades the endothelial cells with ACE2 receptors and constitutes the main pathway through which the virus enters the endothelial cells. This causes angiotensin II accumulation downregulation of the ACE2 receptors, resulting in prothrombotic effects, such as hemostatic imbalance via activation of the coagulation cascade, impaired fibrinolysis, thrombin generation, vasoconstriction, endothelial and platelet activation, and pro-inflammatory cytokine release. The KKS system typically causes vasodilation and regulates tissue repair, inflammation, cell proliferation, and platelet aggregation, but SARS-CoV-2 infection impairs such counterbalancing effects. This cascade results in cardiac arrhythmias, cardiac arrest, cardiomyopathy, cytokine storm, heart failure, ischemic myocardial injuries, microvascular disease, Kounis syndrome, prolonged COVID, myocardial fibrosis, myocarditis, new-onset hypertension, pericarditis, postural orthostatic tachycardia syndrome, pulmonary hypertension, stroke, Takotsubo syndrome, venous thromboembolism, and thrombocytopenia. In this narrative review, we describe and elucidate when, where, and how COVID-19 affects the human cardiovascular system in various parts of the human body that are vulnerable in every patient category, including children and athletes.

Low Urinary Free Cortisol as a Risk Factor for Patients with Variceal Bleeding.

Background and Objectives: Specificity and reliability issues of the current cortisol assessment methods lead to limitations on the accurate assessment of relative adrenal insufficiency. Although free cortisol provides a more accurate evaluation of adrenal cortisol production, the expense and time-consuming nature of these assays make them impractical for routine use. Research has, thus, focused on alternative methods, such as indirectly measuring free cortisol using Coolens' equation or directly assessing salivary cortisol concentration, which is considered a more favorable approach despite associated challenges like sampling issues and infection risks. The aim of this study was to explore correlations between 24 h urinary free cortisol (UFC), free plasma cortisol, serum total cortisol, and salivary cortisol as potential reliable indices of free cortisol in the setting of variceal bleeding. Additionally, we assessed the predictive value of UFC for 6-week mortality and 5-day treatment failure in patients with liver cirrhosis and variceal bleeding. Materials and Methods: A total of 40 outpatients with liver cirrhosis and variceal bleeding were enrolled. Free cortisol levels in serum, saliva, and urine were assessed using the electrochemiluminescence immunoassay method. For the measurement of plasma-free cortisol, a single quadrupole mass spectrometer was employed. The quantification of free cortisol was fulfilled by analyzing the signal response in the negative ESI-MS mode. Results: UFC was significantly correlated to free plasma cortisol. Negative correlations were demonstrated between UFC, the Child-Pugh (CP) score, and C reactive protein (CRP) levels. In the multivariate analysis, CP stage C was associated with 6-week mortality risk and portal vein thrombosis with 5-day treatment failure using Cox regression and binary logistic regression analyses, respectively. Patients who experienced rebleeding, infection, or death (or any combination of these events) presented with lower levels of UFC. Conclusions: This study suggests that low levels of UFC may impose a risk factor for patients with liver cirrhosis and variceal bleeding. The use of UFC as an index of adrenal cortisol production in variceal bleeding warrants further investigation.

Epigenetic Regulation in Lean Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD), the most prominent cause of chronic liver disease worldwide, is a rapidly growing epidemic. It consists of a wide range of liver diseases, from steatosis to nonalcoholic steatohepatitis, and predisposes patients to liver fibrosis, cirrhosis, and even hepatocellular carcinoma. NAFLD is strongly correlated with obesity; however, it has been extensively reported among lean/nonobese individuals in recent years. Although lean patients demonstrate a lower prevalence of diabetes mellitus, central obesity, dyslipidemia, hypertension, and metabolic syndrome, a percentage of these patients may develop steatohepatitis, advanced liver fibrosis, and cardiovascular disease, and have increased all-cause mortality. The pathophysiological mechanisms of lean NAFLD remain vague. Studies have reported that lean NAFLD demonstrates a close association with environmental factors, genetic predisposition, and epigenetic modifications. In this review, we aim to discuss and summarize the epigenetic mechanisms involved in lean NAFLD and to introduce the interaction between epigenetic patterns and genetic or non genetic factors. Several epigenetic mechanisms have been implicated in the regulation of lean NAFLD. These include DNA methylation, histone modifications, and noncoding-RNA-mediated gene regulation. Epigenetics is an area of special interest in the setting of lean NAFLD as it could provide new insights into the therapeutic options and noninvasive biomarkers that target this under-recognized and challenging disorder.

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.

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.

Intestinal barrier dysfunction as a key driver of severe COVID-19.

The intestinal lumen harbors a diverse consortium of microorganisms that participate in reciprocal crosstalk with intestinal immune cells and with epithelial and endothelial cells, forming a multi-layered barrier that enables the efficient absorption of nutrients without an excessive influx of pathogens. Despite being a lung-centered disease, severe coronavirus disease 2019 (COVID-19) affects multiple systems, including the gastrointestinal tract and the pertinent gut barrier function. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can inflict either direct cytopathic injury to intestinal epithelial and endothelial cells or indirect immune-mediated damage. Alternatively, SARS-CoV-2 undermines the structural integrity of the barrier by modifying the expression of tight junction proteins. In addition, SARS-CoV-2 induces profound alterations to the intestinal microflora at phylogenetic and metabolomic levels (dysbiosis) that are accompanied by disruption of local immune responses. The ensuing dysregulation of the gut-lung axis impairs the ability of the respiratory immune system to elicit robust and timely responses to restrict viral infection. The intestinal vasculature is vulnerable to SARS-CoV-2-induced endothelial injury, which simultaneously triggers the activation of the innate immune and coagulation systems, a condition referred to as "immunothrombosis" that drives severe thrombotic complications. Finally, increased intestinal permeability allows an aberrant dissemination of bacteria, fungi, and endotoxin into the systemic circulation and contributes, to a certain degree, to the over-exuberant immune responses and hyper-inflammation that dictate the severe form of COVID-19. In this review, we aim to elucidate SARS-CoV-2-mediated effects on gut barrier homeostasis and their implications on the progression of the disease.

Urinary free cortisol is a reliable index of adrenal cortisol production in patients with liver cirrhosis.

BACKGROUND: The measurement of total and free cortisol has been studied as a clinical index of adrenal cortisol production in patients with liver cirrhosis. Correlations between free plasma and salivary cortisol have previously been reported in stable cirrhotic patients. Urinary free cortisol constitutes an index of adrenal cortisol production; however, it has never been used in assessing adrenal function in patients with liver cirrhosis. AIMS: The aim of this observational study was to determine associations between urinary free cortisol, serum total, salivary, measured and calculated plasma free cortisol levels in cirrhotics, determining which of them can be used as an indirect index of free cortisol levels. Moreover, we investigated the potential use of 24 h urinary free cortisol as a prognostic factor for mortality. METHODS: Seventy-eight outpatients with liver cirrhosis were included. Serum, salivary and urinary free cortisol were measured using the electrochemiluminenscence immunoassay. Plasma free cortisol determination was conducted using a single quadrupole mass spectrometer. The quantification of free cortisol was achieved by determining the signal response on negative ESI-MS mode. RESULTS: Twenty-four hour urinary free cortisol levels correlated with free cortisol determined by mass spectrometer, total cortisol and calculated free cortisol levels. Patients with low levels of urinary free cortisol presented a significantly higher mortality rate compared to those with high levels. The factors associated with death risk were determined by Cox regression. In the multivariate analysis, two models were applied; in the first model, CP score, PVT and urinary free cortisol were found to be significantly related to patients' survival, whereas in the second, MELD score, ascites and urinary free cortisol were independently related to survival. CONCLUSIONS: This study suggests that 24 h urinary free cortisol could be considered as a potential index of adrenal cortisol production in patients with liver cirrhosis and it potentially detects patients with a high mortality risk.

The role of vitamin D receptor polymorphisms in the course of chronic hepatitis C infection.

Background: Vitamin D and its receptor (VDR) exert important immunoregulatory functions that contribute to liver homeostasis. The aim of this study was to investigate the influence of FokI, ApaI, BsmI and TaqI VDR polymorphisms on cirrhosis development and laboratory variables in patients with chronic hepatitis C (CHC). Methods: A total of 48 patients were enrolled in this retrospective, observational study and underwent genotype analysis; their medical records were examined to obtain relevant data. Results: The cumulative rate of progression to cirrhosis during the course of CHC was 31.3% after a median period of 11 years from diagnosis. Importantly, in multivariate analysis, FokI ff (adjusted hazard ratio [aHR] 13.6, 95% confidence interval [CI] 2.51-73.73; P=0.002) and ApaI aa (aHR 4.69, 95%CI 1.13-19.43; P=0.033) genotypes were independently associated with progression to cirrhosis. The presence of the aa genotype was also associated with higher liver stiffness measurements measured by transient elastography compared to the AA/Aa genotype (12.3kPa interquartile range [IQR] 9.6-17.3 vs. 7.1kPa IQR 5.6-11.1; P=0.012). In addition, higher HCV RNA and lower serum albumin levels were observed in patients with the tt genotype of the TaqI polymorphism compared to TT/Tt carriers, and in patients with the aa genotype compared to AA/Aa carriers. In haplotype analysis, no association was found between any haplotype and disease progression. Conclusions: In patients with CHC, laboratory parameters are influenced by VDR polymorphisms and the development of cirrhosis is related to homozygosity for the dominant trait of ApaI and FokI variants.

The impact of metabolic health on non-alcoholic fatty liver disease (NAFLD). A single center experience.

BACKGROUND: The role of patients' metabolic clinical and biochemical profile in NAFLD has not been extensively explored. AIMS: The aim of the study was to assess the role of metabolic health in NAFLD patients and to examine liver disease progression in these populations. METHODS: The medical charts of 569 patients diagnosed with fatty liver were thoroughly reviewed; 344 patients were excluded because of other chronic liver diseases. Metabolically healthy people were defined as those who met none of the following criteria: blood pressure ≥ 130/85 mmHg or under hypertension treatment, fasting glucose ≥ 100 mg/dl or under diabetes treatment, serum triglycerides > 150 mg/dl, high density lipoprotein-cholesterol <40/50 mg/dl for men/women. Study participants were followed-up over a median period of 22 months. RESULTS: The present observational case-control study included 225 NAFLD patients; 14 (6.2%) were metabolically healthy. Metabolically healthy participants were younger (p = 0.006), had lower age at diagnosis (p = 0.002), lower levels of γ-GT (p = 0.013), fasting glucose (p <0.001) and triglycerides (p <0.001) and higher HDL-cholesterol (p = 0.005) compared to metabolically non-healthy. By the last follow up assessment, 8 metabolically healthy patients had developed dyslipidemia; 1 patient (14.4%) had presented liver disease progression compared to 8 patients (10.5%) from the unhealthy group (p = 0.567). In multivariate analysis, diabetes mellitus (p = 0.017) and hemoglobin levels (p = 0.009) were the sole independent predictors of disease progression. No significant difference was observed in liver disease progression-free survival rates among the two patient groups (p = 0.503). CONCLUSIONS: Metabolically healthy NAFLD patients presented with a favorable biochemical profile; however, they were diagnosed with NAFLD at a younger age and the liver disease progression risk was similar to that of metabolically unhealthy patients. These findings suggest that metabolically healthy NAFLD may not constitute a benign condition and patients could potentially be at increased risk of metabolic syndrome and liver disease progression.

Molecular Mechanisms Underlying IL-33-Mediated Inflammation in Inflammatory Bowel Disease.

Interleukin-33 (IL-33) is a cytokine defined by its pleiotropic function, acting either as a typical extracellular cytokine or as a nuclear transcription factor. IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), interact with both innate and adaptive immunity and are considered critical regulators of inflammatory disorders. The IL-33/ST2 axis is involved in the maintenance of intestinal homeostasis; on the basis of their role as pro- or anti-inflammatory mediators of first-line innate immunity, their expression is of great importance in regard to mucosal defenses. Mucosal immunity commonly presents an imbalance in inflammatory bowel disease (IBD). This review summarizes the main cellular and molecular aspects of IL-33 and ST2, mainly focusing on the current evidence of the pro- and anti-inflammatory effects of the IL-33/ST2 axis in the course of ulcerative colitis and Crohn's disease, as well as the molecular mechanisms underlying the association of IL-33/ST2 signaling in IBD pathogenesis. Although IL-33 modulates and impacts the development, course, and recurrence of the inflammatory response, the exact role of this molecule is elusive, and it seems to be associated with the subtype of the disease or the disease stage. Unraveling of IL-33/ST2-mediated mechanisms involved in IBD pathology shows great potential for clinical application as therapeutic targets in IBD treatment.

Nucleic acid vaccines: A taboo broken and prospect for a hepatitis B virus cure.

Although a prophylactic vaccine is available, hepatitis B virus (HBV) remains a major cause of liver-related morbidity and mortality. Current treatment options are improving clinical outcomes in chronic hepatitis B; however, true functional cure is currently the exception rather than the rule. Nucleic acid vaccines are among the emerging immunotherapies that aim to restore weakened immune function in chronically infected hosts. DNA vaccines in particular have shown promising results in vivo by reducing viral replication, breaking immune tolerance in a sustained manner, or even decimating the intranuclear covalently closed circular DNA reservoir, the hallmark of HBV treatment. Although DNA vaccines encoding surface antigens administered by conventional injection elicit HBV-specific T cell responses in humans, initial clinical trials failed to demonstrate additional therapeutic benefit when administered with nucleos(t)ide analogs. In an attempt to improve vaccine immunogenicity, several techniques have been used, including codon/promoter optimization, coadministration of cytokine adjuvants, plasmids engineered to express multiple HBV epitopes, or combinations with other immunomodulators. DNA vaccine delivery by electroporation is among the most efficient strategies to enhance the production of plasmid-derived antigens to stimulate a potent cellular and humoral anti-HBV response. Preliminary results suggest that DNA vaccination via electroporation efficiently invigorates both arms of adaptive immunity and suppresses serum HBV DNA. In contrast, the study of mRNA-based vaccines is limited to a few in vitro experiments in this area. Further studies are needed to clarify the prospects of nucleic acid vaccines for HBV cure.

Toward a new era of hepatitis B virus therapeutics: The pursuit of a functional cure.

Hepatitis B virus (HBV) infection, although preventable by vaccination, remains a global health problem and a major cause of chronic liver disease. Although current treatment strategies suppress viral replication very efficiently, the optimal endpoint of hepatitis B surface antigen (HBsAg) clearance is rarely achieved. Moreover, the thorny problems of persistent chromatin-like covalently closed circular DNA and the presence of integrated HBV DNA in the host genome are ignored. Therefore, the scientific community has focused on developing innovative therapeutic approaches to achieve a functional cure of HBV, defined as undetectable HBV DNA and HBsAg loss over a limited treatment period. A deeper understanding of the HBV life cycle has led to the introduction of novel direct-acting antivirals that exert their function through multiple mechanisms, including inhibition of viral entry, transcriptional silencing, epigenetic manipulation, interference with capsid assembly, and disruption of HBsAg release. In parallel, another category of new drugs aims to restore dysregulated immune function in chronic hepatitis B accompanied by lethargic cellular and humoral responses. Stimulation of innate immunity by pattern-recognition receptor agonists leads to upregulation of antiviral cytokine expression and appears to contribute to HBV containment. Immune checkpoint inhibitors and adoptive transfer of genetically engineered T cells are breakthrough technologies currently being explored that may elicit potent HBV-specific T-cell responses. In addition, several clinical trials are attempting to clarify the role of therapeutic vaccination in this setting. Ultimately, it is increasingly recognized that elimination of HBV requires a treatment regimen based on a combination of multiple drugs. This review describes the rationale for progressive therapeutic interventions and discusses the latest findings in the field of HBV therapeutics.