Inflammasomes are multiprotein intracellular complexes which are responsible for the activation of inflammatory responses. Among various subtypes of inflammasomes, NLRP3 has been a subject of intensive investigation. NLRP3 is considered to be a sensor of microbial and other danger signals and plays a crucial role in mucosal immune responses, promoting the maturation of proinflammatory cytokines interleukin 1β (IL-1β) and IL-18. NLRP3 inflammasome has been associated with a variety of inflammatory and autoimmune conditions, including inflammatory bowel diseases (IBD). The role of NLRP3 in IBD is not yet fully elucidated as it seems to demonstrate both pathogenic and protective effects. Studies have shown a relationship between genetic variants and mutations in NLRP3 gene with IBD pathogenesis. A complex interaction between the NLRP3 inflammasome and the mucosal immune response has been reported. Activation of the inflammasome is a key function mediated by the innate immune response and in parallel the signaling through IL-1β and IL-18 is implicated in adaptive immunity. Further research is needed to delineate the precise mechanisms of NLRP3 function in regulating immune responses. Targeting NLRP3 inflammasome and its downstream signaling will provide new insights into the development of future therapeutic strategies.
Through food intake, humans obtain a variety of nutrients that are essential for growth, cellular function, tissue development, energy, and immune defense. A special interaction between nutrients and gut-associated lymphoid tissue occurs in the intestinal tract. Enterocytes of the intestinal barrier act as sensors for antigens from nutrients and the intestinal microbiota, which they deliver to the underlying immune system of the lamina propria, triggering an immune response. Studies investigating the mechanism of influence of nutrition on immunological outcomes have highlighted an important role of macronutrients (proteins, carbohydrates, fatty acids) and micronutrients (vitamins, minerals, phytochemicals, antioxidants, probiotics) in modulating immune homeostasis. Nutrients exert their role in innate immunity and inflammation by regulating the expression of TLRs, pro- and anti-inflammatory cytokines, thus interfering with immune cell crosstalk and signaling. Chemical substrates derived from nutrient metabolism may act as cofactors or blockers of enzymatic activity, influencing molecular pathways and chemical reactions associated with microbial killing, inflammation, and oxidative stress. Immune cell function appears to be influenced by certain nutrients that form parts of the cell membrane structure and are involved in energy production and prevention of cytotoxicity. Nutrients also contribute to the initiation and regulation of adaptive immune responses by modulating B and T lymphocyte differentiation, proliferation and activation, and antibody production. The purpose of this review is to present the available data from the field of nutritional immunology to elucidate the complex and dynamic relationship between nutrients and the immune system, the delineation of which will lead to optimized nutritional regimens for disease prevention and patient care.
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.
Non-alcoholic fatty liver disease is a highly prevalent medical condition, characterized by intrahepatic fat accumulation which may eventually lead to hepatic inflammation, cell death and reactive fibrosis. Obesity and metabolic disturbances constitute significant contributors to liver steatosis pathogenesis, however, there is a growing awareness that fatty liver may emerge even in normal weight or metabolically healthy individuals. In recent years, advanced imaging techniques have revealed that liver steatosis is quite common in inflammatory bowel disease patients, suggesting that intestinal inflammation and disturbances of the liver-gut axis may also play a key role in non-alcoholic fatty liver disease pathophysiology. The current review focuses on the co-occurrence of the two disorders, integrating research findings on epidemiology, clinical characteristics and common pathophysiological processes. The study of liver steatosis in inflammatory bowel disease patients may provide useful insights on the complex links between dietary fat intake, metabolic dysregulation, gut physiology and intrahepatic cellular mechanisms underlying liver inflammation and damage.
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.
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