Metabolic dysfunction-associated steatotic liver disease: Navigating terminological evolution, diagnostic frontiers and therapeutic horizon-an editorial exploration.

Metabolic dysfunction-associated steatotic liver disease (MASLD), once known as non-alcoholic fatty liver disease (NAFLD), represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes. The redefinition of NAFLD in 2023 marked a significant reposition in terminology, emphasizing a broader understanding of liver steatosis and its associated risks. MASLD is now recognized as a major risk factor for liver cirrhosis, hepatocellular carcinoma, and systemic complications such as cardiovascular diseases or systemic inflammation. Diagnostic challenges arise, particularly in identifying MASLD in lean individuals, necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools. Therapeutically, there is an urgent need for effective treatments targeting MASLD, with emerging pharmacological options focusing on, among others, carbohydrate and lipid metabolism. Additionally, understanding the roles of bile acid metabolism, the microbiome, and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches. There is a strong need to emphasize the importance of collaborative efforts in understanding, diagnosing, and managing MASLD to improve physicians' approaches and patient outcomes.

Potential Therapeutic Strategies in the Treatment of Metabolic-Associated Fatty Liver Disease.

Metabolic-associated Fatty Liver Disease is one of the outstanding challenges in gastroenterology. The increasing incidence of the disease is undoubtedly connected with the ongoing obesity pandemic. The lack of specific symptoms in the early phases and the grave complications of the disease require an active approach to prompt diagnosis and treatment. Therapeutic lifestyle changes should be introduced in a great majority of patients; but, in many cases, the adherence is not satisfactory. There is a great need for an effective pharmacological therapy for Metabolic-Associated Fatty Liver Disease, especially before the onset of steatohepatitis. Currently, there are no specific recommendations on the selection of drugs to treat liver steatosis and prevent patients from progression toward more advanced stages (steatohepatitis, cirrhosis, and cancer). Therefore, in this Review, we provide data on the clinical efficacy of therapeutic interventions that might improve the course of Metabolic-Associated Fatty Liver Disease. These include the drugs used in the treatment of obesity and hyperlipidemias, as well as affecting the gut microbiota and endocrine system, and other experimental approaches, including functional foods. Finally, we provide advice on the selection of drugs for patients with concomitant Metabolic-Associated Fatty Liver Disease.

Exenatide prevents statin-related LDL receptor increase and improves insulin secretion in pancreatic beta cells (1.1E7) in a protein kinase A-dependent manner.

Statins are primary drugs in the treatment of hyperlipidemias. This group of drugs is known for its beneficial pleiotropic effects (e.g., reduction of inflammatory state). However, a growing body of evidence suggests its diabetogenic properties. The culpable mechanism is not completely understood and might be related to the damage to pancreatic beta cells. Therefore, we conceived an in vitro study to explore the impact of atorvastatin on pancreatic islet beta cells line (1.1.E7). We evaluated the influence on viability, insulin, low-density lipoprotein (LDL) receptor, and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. A significant drop in mRNA for proinsulin and insulin expression was noted. Concurrently, a rise in LDL receptor at the protein level in cells exposed to atorvastatin was noted. Further experiments have shown that exenatide - belonging to glucagon-like peptide 1 (GLP-1) analogs that are used in a treatment of diabetes and known for its weight reducing properties - can alleviate the observed alterations. In this case, the mechanism of action of exenatide was dependent on a protein kinase A pathway. In conclusion, our results support the hypothesis that statin may have diabetogenic properties, which according to our study is related to reduced insulin expression. The concomitant use of GLP-1 receptor agonist seemed to successfully revert insulin expression.

Monitoring the Transcriptional Activity of Human Endogenous Retroviral HERV-W Family Using PNA Strand Invasion into Double-Stranded DNA.

In the presented assay, we elaborated a method for distinguishing sequences that are genetically closely related to each other. This is particularly important in a situation where a fine balance of the allele abundance is a point of research interest. We developed a peptide nucleic acid (PNA) strand invasion technique for the differentiation between multiple sclerosis-associated retrovirus (MSRV) and ERVWE1 sequences, both molecularly similar, belonging to the human endogenous retrovirus HERV-W family. We have found that this method may support the PCR technique in screening for minor alleles which, in certain conditions, may be undetected by the standard PCR technique. We performed the analysis of different ERVWE1 and MSRV template mixtures ranging from 0 to 100% of ERVWE1 in the studied samples, finding the linear correlation between template composition and signal intensity of final reaction products. Using the PNA strand invasion assay, we were able to estimate the relative ERVWE1 expression level in human specimens such as U-87 MG, normal human astrocytes cell lines and placental tissue. The results remained in concordance with those obtained by semi-quantitative or quantitative PCR.

Exenatide and metformin express their anti-inflammatory effects on human monocytes/macrophages by the attenuation of MAPKs and NFκB signaling.

Metformin and exenatide are effective antidiabetic drugs, and they seem to have pleiotropic properties improving cardiovascular outcomes. Macrophages' phenotype is essential in the development of atherosclerosis, and it can be modified during antidiabetic therapy, resulting in attenuated atherogenesis. The mechanism orchestrating this phenomenon is not fully clear. We examined the impact of exenatide and metformin on the level of TNF alpha, MCP-1, reactive oxygen species (ROS), and the activation of mitogen-activated protein kinases (MAPK), nuclear factor kappa B (NFκB), and CCAAT/enhancer-binding protein beta (C/EBP beta) in human monocytes/macrophages. We found that both drugs reduced levels of TNF alpha, ROS, and NFκB binding activity to a similar extent. Compared to metformin, exenatide was more effective in reducing MCP-1 levels. We noted that Compound C (AMPK inhibitor) reduced the impact of exenatide on cytokines, ROS, and NFκB in cultures. Both drugs elevated the C/EBP beta phosphorylation level. Experiments on MAPKs showed effective inhibitory potential of exenatide toward p38, JNK, and ERK, whereas metformin inhibited JNK and ERK only. Exenatide was more effective in the inhibition of JNK than metformin. Interestingly, an in vitro setting additive effect of drugs was absent. In conclusion, here, we report that metformin and exenatide inhibit the proinflammatory phenotype of human monocytes/macrophages via influence on MAPK, C/EBP beta, and NFκB. Exenatide was more effective than metformin in reducing MCP-1 expression and JNK activity. We also showed that some effects of exenatide relied on AMPK activation. This shed light on the possible mechanisms responsible for pleiotropic effects of metformin and exenatide.

Exenatide (a GLP-1 agonist) expresses anti-inflammatory properties in cultured human monocytes/macrophages in a protein kinase A and B/Akt manner.

BACKGROUND: Incretin-based therapies in the treatment of type 2 diabetes mellitus are associated with significant improvements in glycemic control, which are accompanied by a beneficial impact on atherosclerosis. Macrophages are essential in the development of atherosclerotic plaques and may develop features that accelerate atherosclerosis (classically activated macrophages) or protect arterial walls against it (alternatively activated macrophages). Therefore, we explored whether beneficial actions of exenatide are connected with the influence on the macrophages' phenotype and synthesis of inflammatory and anti-inflammatory cytokines. METHODS: Monocytes/macrophages were harvested from 10 healthy subjects. Cells were cultured in the presence of exenatide, exendin 9-39 (GLP-1 antagonist), LPS, IL-4, PKI (PKA inhibitor) and triciribine (PKB/Akt inhibitor). We measured the effects of the above-mentioned compounds on markers of macrophages' phenotype (inducible nitrous oxide (iNOS), arginase 1 (arg1) and mannose receptors) and concentration of nitrite, IL-1ß, TNF-α and IL-10. RESULTS: Exenatide significantly increased the level of IL-10 and decreased both TNF-α and IL-1ß in LPS-treated monocytes/macrophages. Furthermore exenatide increased the expression of arg1-a marker of classical activation and reduced the LPS-induced expression of iNOS-a marker of classical activation. According to experiments with protein kinases inhibitors we found that proinflammatory markers were protein kinase A dependent, whereas the activation of alternative activation was similarly reliant on protein kinase A and B/Akt. CONCLUSIONS: We showed that exenatide skewed the macrophages phenotype toward anti-inflammatory phenotype and this effect is predominantly attributable to protein kinase A and to a less extent to B/Akt activation.

Exenatide (a GLP-1 agonist) improves the antioxidative potential of in vitro cultured human monocytes/macrophages.

Macrophages are dominant cells in the pathogenesis of atherosclerosis. They are also a major source of reactive oxygen species (ROS). Oxidative stress, which is particularly high in subjects with diabetes, is responsible for accelerated atherosclerosis. Novel antidiabetic drugs (e.g., glucagon-like peptide-1 (GLP-1) agonists) were shown to reduce ROS level. Therefore, we conceived a study to evaluate the influence of exenatide, a GLP-1 agonist, on redox status in human monocytes/macrophages cultured in vitro, which may explain the beneficial effects of incretin-based antidiabetic treatment. Human macrophages obtained from 10 healthy volunteers were in vitro subjected to the treatment with GLP-1 agonist (exenatide) in the presence of lipopolysaccharide (LPS), antagonist of GLP-1 receptors (exendin 9-39), or protein kinase A inhibitor (H89). Afterwards, reactive oxygen species, malondialdehyde level, NADPH oxidase, and antioxidative enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase] expression was evaluated. Finally, we estimated the activity of the abovementioned enzymes in the presence of H89. According to our findings, exenatide reduced ROS and malondialdyhyde (MDA) level by decreasing the expression of ROS-generating NADPH oxidase and by increasing the expression and activities of SOD and GSH-Px. We also showed that this effect was significantly inhibited by exendin 9-39 (a GLP-1 antagonist) and blocked by H89. Exenatide improved the antioxidative potential and reduced oxidative stress in cultured human monocytes/macrophages, and this finding may be responsible for the pleiotropic effects of incretin-based therapies. This effect relied on the stimulation of GLP-1 receptor.

Autoimmune polyglandular syndrome type 2 induced by treatment with interferon alpha.

Interferon α therapy has been reported to result in a variety of autoimmune side effects and to increase the risk of thyroid dysfunction. Autoimmune polyglandular syndromes are rarely described conditions characterized by the combination of at least 2 autoimmune endocrinopathies and nonendocrine autoimmunopathies, differing in the immunologic features of their pathogenesis. In light of research carried out in recent years, it seems that autoimmune polyendocrine syndromes occur much more frequently than previously estimated. In this article, the authors describe autoimmune polyglandular syndrome type 2 composed of autoimmune thyroid disease, Addison's disease and premature ovarian failure in a 37-year old woman after treatment of hairy cell leukemia with interferon α. Because of the underlying disorder, interferon α treatment had to be continued, and therefore the patient was prescribed with levothyroxine, hydrocortisone, fludrocortisone and oral contraceptives. Termination of interferon α therapy was associated with a spontaneous normalization of thyroid and adrenal functions, and therefore levothyroxine, hydrocortisone and fludrocortisone treatment was withdrawn.

Potential benefit of paracetamol administration in adult-onset Still's disease.

Still's disease is a rare, systemic inflammatory disease of unknown etiology, characterized by daily high fever, transient rash, arthritis, and organ involvement including lymphadenopathy, hepatosplenomegaly, pleuritis or pericarditis. The diagnosis of the disease is based on clinical signs and symptoms, and requires exclusion of infectious, neoplastic, and other autoimmune diseases. Treatment options include non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, sometimes in combination with immunosuppressive agents. We report the case of a 21-year-old man with a recent diagnosis of Still's disease. The fever, resistant to NSAIDs, resolved after treatment with paracetamol and the patient's general condition also improved. The present case has been the first to demonstrate that paracetamol may be an effective agent in adult-onset Still's disease.