Both alcoholic liver disease (ALD) and nonalcoholic fatty liver disease are characterized by massive lipid accumulation in the liver accompanied by inflammation, fibrosis, cirrhosis, and ...hepatocellular carcinoma in a substantial subgroup of patients. At several stages in these diseases, mediators of the immune system, such as cytokines or inflammasomes, are crucially involved. In ALD, chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharides through Toll‐like receptors, e.g., Toll‐like receptor 4. This sensitization enhances the production of various proinflammatory cytokines such as interleukin‐1 (IL‐1) and tumor necrosis factor‐alpha, thereby contributing to hepatocyte dysfunction, necrosis, and apoptosis and the generation of extracellular matrix proteins leading to fibrosis/cirrhosis. Indeed, neutralization of IL‐1 by IL‐1 receptor antagonist has recently been shown to potently prevent liver injury in murine models of ALD. As IL‐1 is clearly linked to key clinical symptoms of acute alcoholic hepatitis such as fever, neutrophilia, and wasting, interfering with the IL‐1 pathway might be an attractive treatment strategy in the future. An important role for IL‐1‐type cytokines and certain inflammasomes has also been demonstrated in murine models of nonalcoholic fatty liver disease. IL‐1‐type cytokines can regulate hepatic steatosis; the NLR family pyrin domain containing 3 inflammasome is critically involved in metabolic dysregulation. Conclusion: IL‐1 cytokine family members and various inflammasomes mediate different aspects of both ALD and nonalcoholic fatty liver disease. (Hepatology 2016;64:955‐965)
Highlights • NAFLD is characterized by dysbiosis. • The intestinal microbiota contributes to NAFLD development. • Innate immunity plays a major role in NAFLD. • Proinflammatory cytokines are the ...driving forces for NASH.
Experimental evidence from the past years highlights a key role for the intestinal microbiota in inflammatory and malignant gastrointestinal diseases. Diet exhibits a strong impact on microbial ...composition and provides risk for developing colorectal carcinoma (CRC). Large metagenomic studies in human CRC associated microbiome signatures with the colorectal adenoma-carcinoma sequence, suggesting a fundamental role of the intestinal microbiota in the evolution of gastrointestinal malignancy. Basic science established a critical function for the intestinal microbiota in promoting tumorigenesis. Further studies are needed to decipher the mechanisms of tumor promotion and microbial co-evolution in CRC, which may be exploited therapeutically in the future.
Experimental evidence from the past years highlights a key role for the intestinal microbiota in inflammatory and malignant gastrointestinal diseases. Diet exhibits a strong impact on microbial composition and provides risk for developing colorectal carcinoma (CRC). Large metagenomic studies in human CRC associated microbiome signatures with the colorectal adenoma-carcinoma sequence, suggesting a fundamental role of the intestinal microbiota in the evolution of gastrointestinal malignancy. Basic science established a critical function for the intestinal microbiota in promoting tumorigenesis. Further studies are needed to decipher the mechanisms of tumor promotion and microbial co-evolution in CRC, which may be exploited therapeutically in the future.
When fixed partial dentures are provided for edentulous areas of the alveolar ridge, the previously impaired masticatory and phonetic functions as well as esthetics are restored immediately; in the ...long run, the restoration helps to stabilize the occlusion, thus maintaining the integrity of the temporomandibular joints and the neuromuscular system. The reabsorption of connective tissues following the loss of teeth as well as the changes in the dimensions of edentulous areas that occur over time will have to be taken into account in that the basic shape of the tooth or teeth to be replaced needs to be modified. Pontics usually present a larger surface than natural teeth; on this surface, plaque may accumulate. The self-cleaning mechanisms are ineffective on the surfaces facing the adjacent teeth or the tissues of the alveolar ridge. For this reason, the pontics and their flexible or rigid connectors to the abutments must be considered the weakest parts of the restoration. The long-term success of the restoration, once periodontal treatment and optimum prosthodontic care have been provided, depends on whether considerations of periodontal prevention played a role in the design of the restoration and on postinsertion periodontal care.
Food, Immunity, and the Microbiome Tilg, Herbert; Moschen, Alexander R
Gastroenterology,
05/2015, Letnik:
148, Številka:
6
Journal Article
Recenzirano
Odprti dostop
There is increasing evidence that ingested diet-borne components are involved in the pathogenesis of disorders such as inflammatory bowel diseases, atherosclerosis, and type 2 diabetes. Nutrients can ...have short- and long-term effects in shaping the composition of the microbiota. Western diets (enriched in fat, phosphatidylcholine, and L-carnitine) promote inflammation and atherosclerosis through specific fatty acids and degradation products such as trimethylamine N-oxide. Other dietary factors such as carbazoles or tryptophan-enriched proteins have anti-inflammatory properties—partly via activation of aryl hydrocarbon receptors. The microbiota and its metabolic machinery produce a myriad of metabolites that serve as important messengers between the diet, microbiota, and host. Short-chain fatty acids affect immune responses and epithelial integrity via G-protein–coupled receptors and epigenetic mechanisms. By increasing our understanding of interactions between diet, immunity, and the microbiota, we might develop food-based approaches to prevent or treat many diseases. There now is scientific evidence to support the adage “we are what we eat,” and this process begins in early life.
Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is released by various cell types and is an attractive biomarker of inflammation, ischemia, infection, and kidney ...damage. Both intestinal and metabolic inflammation, as observed in obesity and related disorders, are associated with increased LCN2 synthesis. While LCN2 in the intestinal tract regulates the composition of the gut microbiota and shows anti-inflammatory activities, it also exhibits proinflammatory activities in other experimental settings. In animal models of metabolic inflammation, type 2 diabetes mellitus (T2DM), or nonalcoholic steatohepatitis (NASH), increased LCN2 expression favors inflammation via the recruitment of inflammatory cells, such as neutrophils, and the induction of proinflammatory cytokines. A better understanding of this crucial marker of innate immunity might pave the way for targeting this pathway in future therapies.
Non-alcoholic fatty liver disease (NAFLD), the major cause of abnormal liver function in the western world, is often associated with obesity and diabetes. In obese individuals, fat accumulation in ...the abdominal region affects both lipid and glucose metabolism, and a liver loaded with fat is insulin resistant. Insulin resistance (IR) is often associated with chronic low-grade inflammation, and numerous mediators released from immune cells and adipocytes contribute to development of IR. Recent results showing an important role for these mediators in NAFLD are providing us with a better understanding of this highly prevalent disease with implications for novel therapy development. This review highlights new aspects in development of liver steatosis and the relevance of various cytokines and adipocytokines in NAFLD.
Insulin resistance (IR) plays a key role in the pathophysiology of obesity-related diseases such as type 2 diabetes and nonalcoholic fatty liver disease. It has been demonstrated that IR is ...associated with a state of chronic low-grade inflammation, and several mediators released from various cell types, including immune cells and adipocytes, have been identified as being involved in the development of IR. Among those are several pro-inflammatory cytokines such as tumor necrosis factor-alpha(TNF-alpha), interleukin (IL)-1, IL-6, and various adipocytokines. Furthermore, several transcription factors and kinases such as c-Jun N-terminal kinase (JNK) and inhibitor of kappa B kinase-beta (IKKbeta), a kinase located proximal of nuclear factor-kappaB (NF-kappaB), participate in this process. Hepatocyte-specific overexpression of NF-kappaB is associated with IR and can mimic all features of fatty liver disease. Whereas the evidence for an important role of many pro-inflammatory pathways in IR in in vitro and animal studies is overwhelming, data from interventional studies in humans to prove this concept are still minor. As a complex network of inflammatory cytokines, adipocytokines, transcription factors, receptor molecules, and acute-phase reactants are involved in the development of IR, new therapeutic approaches in IR-related diseases will be based on a better understanding of their complex interactions.
Obesity and obesity-related disorders play an important role in clinical medicine. Adipose tissue, with its soluble mediators called adipocytokines, has emerged as a major endocrine organ. These ...adipocytokines comprise many mediators such as adiponectin, PBEF (pre-B-cell-enhancing factor)/visfatin, leptin, resistin, retinol-binding protein-4 and others. They play major roles in key aspects of metabolism, such as insulin resistance, fatty acid oxidation, inflammation and immunity. Adiponectin, a prototypic adipocytokine, is of importance in the regulation of insulin resistance, as circulating levels are decreased in obesity and diseases associated with insulin resistance. Besides its major role in regulation of insulin sensitivity, recent evidence suggests potent anti-inflammatory functions for adiponectin. These effects are paralleled by other immune-regulatory properties, such as regulation of endothelial cell function. The in vitro effects of adiponectin have been corroborated by several studies demonstrating potent in vivo anti-inflammatory effects. Many other adipocytokines, such as PBEF/visfatin, leptin, resistin or retinol binding protein-4, are involved in the physiology and pathophysiology of adipocytes, adipose tissue and related diseases. PBEF/visfatin, another recently characterized adipocytokine, has been linked to several inflammatory disease states beyond insulin resistance, such as acute lung injury or inflammatory bowel diseases. It has been recognized for many decades that obesity is accompanied by an increase in cancer and potentially some immune-mediated diseases. Understanding this new exciting world of adipocytokines will be of importance in the development of novel therapies for obesity-associated diseases.
There has been much effort recently to define the role of adipocytokines, which are soluble mediators derived mainly from adipocytes (fat cells), in the interaction between adipose tissue, ...inflammation and immunity. The adipocytokines adiponectin and leptin have emerged as the most abundant adipocyte products, thereby redefining adipose tissue as a key component not only of the endocrine system, but also of the immune system. Indeed, as we discuss here, several adipocytokines have a central role in the regulation of insulin resistance, as well as many aspects of inflammation and immunity. Other adipocytokines, such as visfatin, have only recently been identified. Understanding this rapidly growing family of mainly adipocyte-derived mediators might be of importance in the development of new therapies for obesity-associated diseases.
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