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.

Inclisiran-A Revolutionary Addition to a Cholesterol-Lowering Therapy.

Hypercholesterolemia plays a crucial role in the development of atherosclerosis, but it remains an undertreated and underdiagnosed disease. Taking into consideration the high prevalence of lipid disorders, long duration of the asymptomatic course of the disease, life-threatening complications resulting from inaccurate therapy, and stringent treatment goals concerning LDL cholesterol level in the prevention of cardiovascular events, novel lipid-lowering therapies have been introduced in the last few years. In this article, a drug belonging to the group of small interfering RNA (siRNA) called inclisiran is described. It is a novel molecule that increases the number of LDL receptors (LDLRs) on the surface of hepatic cells by preventing the formation of proprotein convertase subtilisin/kexin type 9 (PCSK9) responsible for the degradation of LDLRs. With great potential for lowering plasma LDL cholesterol level, high liver specificity, comfortable dosing regimen, and good tolerance without significant adverse effects, it could play an important part in future hypolipemic therapies.

Insight into the Evolving Role of PCSK9.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, which leads to an increase in the level of cholesterol in the blood. This mechanism and the fact that gain of function (GOF) mutations in PCSK9 are responsible for causing familial hypercholesterolemia whereas loss-of-function (LOF) mutations are associated with hypocholesterolemia, prompted the invention of drugs that block PCSK9 action. The high efficiency of PCSK9 inhibitors (e.g., alirocumab, evolocumab) in decreasing cardiovascular risk, pleiotropic effects of other lipid-lowering drugs (e.g., statins) and the multifunctional character of other proprotein convertases, were the cause for proceeding studies on functions of PCSK9 beyond cholesterol metabolism. In this article, we summarize the current knowledge on the roles that PCSK9 plays in different tissues and perspectives for its clinical use.

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.

The impact of exenatide (a GLP-1 agonist) on markers of inflammation and oxidative stress in normal human astrocytes subjected to various glycemic conditions.

GLP-1 agonists such as exenatide and liraglutide are novel drugs for the treatment of diabetes and obesity. While improvements in glycemic control can rely on an incretin effect, the mechanisms behind the loss of weight following therapy have yet to be completely elucidated, and seem to be associated with alterations in eating habits, resulting from changes in cytokines e.g. interleukin 1ß (IL-1ß) and oxidative signaling in the central nervous system (CNS). Increased levels of IL-1ß and reactive oxygen species have been demonstrated to exert anorexigenic properties, and astrocytes appear to actively participate in maintaining the integrity of the CNS, which includes the paracrine secretion of inflammatory cytokines and involvement in the redox status. Therefore, the present study decided to explore the influence of exenatide [a glucagon-like peptide 1 (GLP-1 agonist)] on inflammatory and oxidative stress markers in cultured human astrocytes as a potential target for weight reduction therapies. In an experimental setting, normal human astrocytes were subjected to various glycemic conditions, including 40 mg/dl-hypoglycemic, 100 mg/dl-normoglycemic and 400 mg/dl-hyperglycemic, and exenatide, which is a GLP-1 agonist. The involvement of intracellular signaling by a protein kinase A (PKA) in the action of exenatide was estimated using a specific PKA inhibitor-PKI (14-22). The expression levels of IL-1ß, nuclear factor kappa κB (NFκB), glial-fibrillary acidic protein (GFAP), p22 NADPH oxidase, glutathione peroxidase, catalase, superoxide dismutase 1, and reactive oxidative species were measured. The present study demonstrated that varying glucose concentrations in the culture media did not affect the protein expression or the level of reactive oxygen species. Conversely, exenatide led to an increase in IL-1ß in normoglycemic culture conditions, which was accompanied by the increased expression of p22, glutathione peroxidase and the reduced expression of GFAP. Changes in the expression of IL-1ß and p22 were dependent on the activation of PKA. The present study concluded that exenatide predominantly affected astrocytes in normoglycemic conditions, and hypothesize that this impact demonstrated one of novel mechanisms associated with astrocyte signaling that may contribute to weight loss.

Endocrine diseases as causes of secondary hyperlipidemia.

Cardiovascular diseases are among the leading causes of increased morbidity and mortality in developed and developing countries. One of the most important risk factors responsible for atherosclerosis and subsequent cardiovascular diseases is hyperlipidaemia. Currently, hyperlipidaemias are divided into several clinical entities. The greatest risk is associated with hypercholesterolaemia. As a result, modern guidelines for the treatment and prevention of atherosclerosis focus predominantly on the reduction of LDL-cholesterol. Hypertriglyceridaemia and atherogenic dyslipidaemia, which are responsible for a less significant increase in the cardiovascular risk, are nowadays secondary targets of the treatment. During the work-up for hyperlipidaemia one of the essential actions is the exclusion of secondary causes of the lipid abnormalities. Those include, among others, endocrine diseases, diabetes, drugs, nephrotic syndrome, and pregnancy. Data regarding the impact of endocrine disease and diabetes on the lipid profile are scattered. In this review, the authors aimed to perform a thorough analysis of the available publications regarding the topic and the preparation of a comprehensive review dealing with the incidence, clinical features, and the therapy of hyperlipidaemias in patients with endocrine disease.

Benefits and risks of the treatment with fibrates--a comprehensive summary.

INTRODUCTION: The need to reduce residual cardiovascular risk led to the development of novel therapeutic strategies to improve patients' outcomes. The residual risk in people with atherogenic dyslipidemia, despite LDL reduction obtained mainly by statins, remains high. Fibrates in those patients lead to significant clinical improvements. Those include reduction in the progression of atherosclerosis, which translates into decrease in cardiovascular events and improvements in microvascular diabetic complications. Furthermore, there are other clinical and biochemical benefits connected with fibrate therapy (e.g. improved insulin sensitivity). Nevertheless, similar to all effective therapeutic modalities, fibrates are associated with unfavorable effects that may lead to complications or treatment discontinuation. Here, we provide up-to-date review of benefits and potential risks associated with the therapy with fibrates. Area covered: A review of available data from clinical trials, meta-analyses and case-reports on the efficacy of fibrate treatment was performed. A specific attention was given to clinical and biochemical benefits as well as adverse events that were reported. Expert commentary: Fibrates are performing well as drugs that reduce residual risk in patients with atherogenic dyslipidemia and hypertriglyceridemia. The adverse events rate is not negligible, but definitely manageable by selection of proper target population and supervision of treated patients.

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.

Fibrates in the management of atherogenic dyslipidemia.

INTRODUCTION: Significant advancements in the treatment of hypercholesterolemia have recently been achieved. However, a considerable level of residual cardiovascular risk still affects patients' outcomes. Atherogenic dyslipidemia is one of the major constituents of residual risk. Fibrates, PPAR alpha agonists, which modify lipid profile and have numerous pleiotropic effects, seem to be drugs of choice in patients with atherogenic dyslipidemia. These drugs are effective both in monotherapy and combined therapy with statins. Areas covered: A review of clinical trials and experimental studies on fibrates and their use in the treatment of lipid disorders has been performed. Expert commentary: Fibrates are an effective and safe group of drugs to treat patients with atherogenic dyslipidemia. In this particular population of patients, they improve cardiovascular outcomes. Benefits of fibrate treatment extend beyond the impact of lipid profile. Significant improvements in carbohydrate metabolism, adipokines levels, thrombosis and inflammation were also noted.

Metformin reduces the expression of NADPH oxidase and increases the expression of antioxidative enzymes in human monocytes/macrophages cultured in vitro.

[This retracts the article DOI: 10.3892/etm.2016.2977.].

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.

Current and future trends in the lipid lowering therapy.

Atherosclerosis is an inflammatory disease that affects arterial wall. It leads to wall thickening and its instability. As a result a reduction in lumen diameter and blood flow is observed. This manifests predominantly as the affectation of vascular bed of coronary (myocardial infarction), cerebral, carotid (ischemic stroke) or peripheral arteries (limb amputation). One of the most important factors that accelerate atherosclerosis is hyperlipidemia. According to current guidelines the main attention should be focused on the treatment of hyperlipidemia (beside the prevention, which includes proper diet, physical activity and risk factors avoidance). Major attention is given to LDL (low-density lipoprotein) cholesterol (LDL-C) level as primary, and triglyceride level as secondary targets of therapy. As a result of recent clinical findings and continuous research in the field of hypolipidemic drugs it seems practical to review recent data and show potential new pathways that may be useful in the treatment of hyperlipidemia. The review is divided into several parts presenting the widely used and well-known hypolipidemic drugs. In the first part a brief review of contemporary drugs affecting LDL cholesterol is shown. The second part contains information regarding currently available drugs reducing triglycerides level. The third part describes several novel and promising groups of drugs that are still on various steps of clinical development. In the last part drugs affecting HDL (high-density lipoprotein) level were presented.

Metformin reduces the expression of NADPH oxidase and increases the expression of antioxidative enzymes in human monocytes/macrophages cultured in vitro.

The treatment of diabetes and its complications is a key challenge for healthcare professionals. Accelerated atherosclerosis is associated with progressive diabetes, and it has been indicated that macrophages serve a crucial function in this process. Currently, the first-line treatment of diabetes is based on metformin, which is an inducer of AMP-activated protein kinase (AMPK) and belongs to the biguanide class of pharmaceuticals. It has been previously demonstrated that metformin exhibits more than just hypoglycemic effects. Therefore, the aim of the present study was to investigate the in vitro impact of metformin on cell viability and the expression levels of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase (p22phox), a major enzyme in reactive oxygen species generation, and the three antioxidative enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) in monocytes/macrophages derived from 10 healthy volunteers. The effects of metformin were observed in the presence or absence of lipopolysaccharide (LPS), which was administered to induce oxidative stress. Furthermore, certain cells were treated with compound C, an inhibitor of AMPK, in order to determine the mechanistic role played by AMPK in the oxidative changes in the macrophages. Cell viability was evaluated using trypan blue and MTT assays. The mRNA and protein expression levels of p22phox and the various antioxidative enzymes were determined using polymerase chain reaction and western blot analysis, respectively. The results indicated that metformin, predominantly in LPS-pretreated monocytes/macrophages, reduced the expression levels of p22phox and increased those of SOD and GPx, but had only a minor effect on CAT levels. Therefore, metformin appears to alter the oxidative status of macrophages toward increasingly antioxidative activity, which may account for the pleiotropic effects observed during metformin treatment.

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.

[Peripartum cardiomyopathy, acute autoimmune pancreatitis and periadipose tissue inflammation - autoimmune reaction?]. / Kardiomiopatia pologowa a ostre zapalenie trzustki i tkanki tluszczowej - reakcja autoimmunologiczna?

A case of 26 year-old female with peripartum cardiomyopathy, acute pancreatitis, periadipose tissue inflammation due to unknown cause and multiple organ dysfunction syndrome complication is presented.

Short-term antihypertensive therapy lowers the C-reactive protein level.

INTRODUCTION: There is a growing body of data concerning significant interactions between markers of inflammation and cardiovascular diseases such as hypertension accompanied by elevated levels of plasma C-reactive protein (CRP). Therefore CRP is thought to be an independent risk factor of cardiovascular diseases. MATERIAL/METHODS: The aim of this study was to evaluate the effects of antihypertensive therapy (perindopril, bisoprolol and combined therapy) on plasma CRP concentration in 67 subjects with mild or moderate hypertension who have been treatment-naive and otherwise healthy. RESULTS: The results show a correlation between CRP level and blood pressure values. BP reduction was associated with a decrease in CRP concentration. The CRP-lowering effect of perindopril and bisoprolol was comparable and the degree of reduction might reflect their similar influence on blood pressure. Combined treatment influenced the CRP level to a greater extent than both monotherapies. CONCLUSIONS: Plasma CRP level was lowered by antihypertensive therapy independently of the drug applied. The CRP level did not normalize completely in moderate hypertensive patients.