Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with a very poor prognosis and constantly growing incidence. Among other primary risks of HCC, metabolic disorders and obesity have been extensively investigated over recent decades. The latter can promote nonalcoholic fatty liver disease (NAFLD) leading to the inflammatory form of nonalcoholic steatohepatitis (NASH), that, in turn, promotes HCC. Molecular determinants of this pathogenic progression, however, remain largely undefined. In this study, we have focussed on the investigation of α-dicarbonyl compounds (α-dC), highly reactive and tightly associated with overweight-induced metabolic disorders, and studied their potential role in NAFLD and progression toward HCC using murine models. NAFLD was induced using high-fat diet (HFD). Autochthonous HCC was induced using transposon-based stable intrahepatic overexpression of oncogenic NRAS G12V in mice lacking p19 Arf tumor suppressor. Our study demonstrates that the HFD regimen and HCC resulted in strong upregulation of α-dC in the liver, heart, and muscles. In addition, an increase in α-dC was confirmed in sera of NAFLD and NASH patients. Furthermore, higher expression of the receptor for advanced glycation products (RAGE) was detected exclusively on immune cells and not on stroma cells in livers of mice with liver cancer progression. Our work confirms astable interplay of liver inflammation, carbonyl stress mediated by α-dC, and upregulated RAGE expression on CD8 + Tand natural killer (NK) cells in situ in NAFLD and HCC, as key factors/determinants in liver disease progression. The obtained findings underline the role of α-dC and RAGE + CD8 + Tand RAGE + NK cells as biomarkers and candidates for a local therapeutic intervention in NAFLD and malignant liver disease.
Overweight and obesity are health conditions tightly related to a number of metabolic complications collectively called “metabolic syndrome” (MetS). Clinical diagnosis of MetS includes the presence of the increased waist circumference or so-called abdominal obesity, reduced high density lipoprotein level, elevated blood pressure, and increased blood glucose and triacylglyceride levels. Different approaches, including diet-induced and genetically induced animal models, have been developed to study MetS pathogenesis and underlying mechanisms. Studies of metabolic disturbances in the fruit fly Drosophila and mammalian models along with humans have demonstrated that fruit flies and small mammalian models like rats and mice have many similarities with humans in basic metabolic functions and share many molecular mechanisms which regulate these metabolic processes. In this paper, we describe diet-induced, chemically and genetically induced animal models of the MetS. The advantages and limitations of rodent and Drosophila models of MetS and obesity are also analyzed.
Параоксонази - це група ферментів ссавців з арилдиалкілфосфатазною активністю, і найбільш вивченою з праоксоназ є параоксоназа 1 (PON 1). Параоксоназа 1 вперше була описана у 1940-х роках як фермент, виявлений у тканинах ссавців, здатний гідролізувати фосфорорганічні пестициди. Однак останні дослідження показали, що PON 1 також відіграє захисну роль при захворюваннях, пов’язаних із запаленням і оксидативним стресом та виявляє протизапальні, антиоксидантні, антиатерогенні, антидіабетичні, антимікробні та детоксикаційні властивості. Зокрема, PON 1 важлива для захисту від судинних захворювань, оскільки метаболізує окислені ліпіди у складі ліпопротеїдних комплексів крові. Деякі дослідження показують, що знижена активність PON 1 пов’язана з ризиком розвитку серцево-судинних захворювань, а також ожиріння, метаболічного синдрому та раку. Тому визначення активності параоксонази можна вважати важливим біомаркером у діагностиці вищевказаних захворювань. У цій роботі ми оптимізували умови спектрофотометричного визначення активності параоксанази в крові та печінці мишей. Адаптовано протокол для визначення арилестеразної активності PON1 з використанням нітрофенілацетату як субстрату. Концентрація нітрофенілацетату 3,2 ммоль/л була обрана для визначення параоксонази в тканинах мишей. Питома активність PON 1 у цих тканинах була різною - 210±17 мОд/мг у плазмі крові та 66,5±8,5 мОд/мг у супернатанті печінки. Рекомендований об'єм надосадової рідини для визначення PON 1 становить 5 мкл для плазми та 10 мкл для печінки в реакційній суміші загальним об'ємом 1,25 мл.
Metabolic syndrome (MetS) is a pathologic multifaceted condition characterized by elevated triacylglycerides, decreased high density lipoproteins, insulin resistance, increased blood pressure and fasting glucose. Together these abnormalities increase a risk of cardiovascular diseases and type 2 diabetes mellitus. Overnutrition and sedentary lifestyle followed by overweight and obesity are the main contributing factors to MetS development. The pathogenesis of MetS is very complex and not fully elucidated. The studies support the concept of oxidant/antioxidant imbalance and low-grade inflammation playing main roles in its manifestations. Diagnosis with MetS and the development of MetS complications can be detected and monitored via specific serum biomarkers. In this paper, we describe classical metabolic, hormonal and pro-/anti-inflammatory markers which are the most frequently used for MetS diagnostic and research. They include serum lipid profile (triacylglycerides, total cholesterol, low and high density lipoproteins), blood pressure, fasting glucose and HOMA-IR index, levels of anti-inflammatory adiponectin, pro-inflammatory C-reactive protein and cytokines (TNF-α, IL-1β, IL-6, etc.). We also analyze advantages of additional criteria such as levels of oxidative damages, appetite hormones (leptin, ghrelin), apolipoproteins and oxylipins, the composition of gut microbiota and levels of microbiome-derived metabolites, the ratios between different parameters as helpful biomarkers of MetS and concomitant cardiovascular diseases.
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