Temporal multiscale modeling of biochemical regulatory networks: Calcium-regulated hepatocyte lipid and glucose metabolism.

Hepatocyte lipid and glucose metabolism is regulated not only by major hormones like insulin and glucagon but also by many other factors, including calcium ions. Recently, mitochondria-associated membrane (MAM) dysfunction combined with incorrect IP3-receptor regulation has been shown to result in abnormal calcium signaling in hepatocytes. This dysfunction could further lead to hepatic metabolism pathology. However, the exact contribution of MAM dysfunction, incorrect IP3-receptor regulation and insulin resistance to the calcium-insulin-glucagon interplay is not understood yet. In this work, we analyze the role of abnormal calcium signaling and insulin dysfunction in hepatocytes by proposing a model of hepatocyte metabolic regulatory network with a detailed focus on the model construction details besides the biological aspect. In this work, we analyze the role of abnormal calcium signaling and insulin dysfunction in hepatocytes by proposing a model of hepatocyte metabolic regulatory network. We focus on the model construction details, model validation, and predictions. We describe the dynamic regulation of signaling processes by sigmoid Hill function. In particular, we study the effect of both the Hill function slope and the distance between Hill function extremes on metabolic processes in hepatocytes as a model of nonspecific insulin dysfunction. We also address the significant time difference between characteristic time of glucose hepatic processing and a typical calcium oscillation period in hepatocytes. Our modeling results show that calcium signaling dysfunction results in an abnormal increase in postprandial glucose levels, an abnormal glucose decrease in fasting, and a decreased amount of stored glycogen. An insulin dysfunction of glucose phosphorylation, glucose dephosphorylation, and glycogen breakdown also cause a noticeable effect. We also get some insight into the so-called hepatic insulin resistance paradox, confirming the hypothesis regarding indirect insulin action on hepatocytes via dysfunctional adipocyte lipolysis.

Prebiotic Syntheses Under Shock in the Water - Formamide - Potassium Bicarbonate - Sodium Hydroxide System.

Syntheses under shock in nitrogen bubbled samples of the water - formamide - bicarbonate - sodium hydroxide system at pH 8.63, 9.46 and 10.44 were performed in the stainless steel preservation capsules. The maximum temperature and pressure in the capsules reached 545 K and 12.5 GPa respectively. Using the LC-MS-MS analysis, the 21 synthesis products have been identified, including amines and polyamines, carboxamide, acetamide and urea derivatives, compounds containing aniline, pyrrolidine, pyrrole, imidazole, as well as alcohol groups. It was found that the Fischer-Tropsch-type syntheses with catalysis on the surface of the stainless steel of the conservation capsule associated with the adsorbed hydrogen cyanide reactions and transamidation processes play the main role in the shock syntheses. Formation reactions of all the above-mentioned compounds have been suggested. It was proposed that hydrogen cyanide, ammonia, isocyanic acid, aminonitrile, aminoacetonitrile, as well as adsorbed species H(a), CH(a), CH2(a), CHOH(a), NH2(a) and H2CNH(a) are especially important for the formation of the products. A reduction reaction of adsorbed bicarbonate with hydrogen to formaldehyde has been first postulated. In the studied system also classical reactions take place - Wöhler's synthesis of urea and Butlerov's synthesis of methenamine. It was suggest that material of meteorites may be an effective catalyst in the Fischer-Tropsch-type syntheses at falling of the iron-nickel meteorites in the water - formamide regions on the early Earth. It was concluded that life could have originated due to the impact of meteorites on alkaline water-formamide lakes located near volcanoes on the early Earth.