AIMTo study the effects of linagliptin on the structural signs of non-alcoholic fatty liver disease (NAFLD) in db/db mice.METHODSMale diabetic db/db mice (BKS.Cg-Dock7m+/+Leprdb/J) aged 10 wk received the dipeptidyl peptidase 4 (DPP4) inhibitor linagliptin (10 mg/kg) or saline as a placebo once per day by gavage for 8 wk. Intact db/db mice served as controls. Structural changes in the liver were analyzed from light and electron microscopic images of sections from intact, placebo-treated and linagliptin-treated animals. We estimated the changes in hepatocytes, sinusoidal cells, liver microvasculature and lymphatic roots. Hepatic staining for lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) was assessed by immunohistochemistry.RESULTSIn 18-wk-old diabetic mice, liver steatosis (predominantly microvesicular and mediovesicular steatosis) was accompanied by dilation of the roots of the lymphatic system, interlobular blood vessels and bile canaliculi. Compared to saline-treated mice, linagliptin-treated mice exhibited a reduction in the mean numeral densities of hepatocytes with lipid droplets (92.4% ± 1.7% vs 64.9% ± 5.8% per field of view, P = 0.0002) and a lower proportion of hepatocytes with a high density of lipid droplets (20.7% ± 3.6% vs 50.4% ± 3.1%, P = 0.0007). We observed heterogeneous hepatocytes and relatively preserved cell structures in the linagliptin group. Dilation of blood and lymphatic vessels, as well as ultrastructural changes in the hepatocyte endoplasmic reticulum and mitochondria, were alleviated by linagliptin treatment. In intact and placebo-treated mice, immunohistochemical staining for LYVE-1 was observed in the endothelial cells of interlobular lymphatic vessels and on the membranes of some endothelial sinusoidal cells. We observed an enlarged LYVE-1 reaction area in linagliptin-treated mice compared to intact and placebo-treated mice. The improvement in the structural parameters of the liver in linagliptin-treated mice was independent to changes in the plasma glucose levels.CONCLUSIONThe DPP4 inhibitor linagliptin alleviates liver steatosis and structural changes in the hepatic microvasculature and lymphatic roots in a model of NAFLD in diabetic db/db mice.

Obesity and diabetes mellitus are known to lead to the development of metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). The mechanisms of programmed cell death are actively involved in maintaining cellular homeostasis along development of NAFLD. Proteins of the BCL-2 family are key regulators of physiological and pathological apoptosis. Homozygous males of BKS.Cg-Dock7 m Lepr db /+/+/J mice (db/db mice) are charac terized by progressive obesity and the development of type 2 diabetes mellitus (DM2) with severe hyperglycemia at 4-8 weeks and organ lesions at 8-10 weeks of age. The aim of this research was to study the expression of mo lecular cell regulators of apoptosis in liver cells of db/db mice males at different stages of obesity and diabetes development (at the age of 10 and 18 weeks). Immunohistochemical analysis (using the indirect avidin-biotin peroxidase method) and morphometric evaluation of the expression of the antiapoptotic protein Bcl-2 and the proapoptotic protein Bad in liver cells of studied animals at different stages of obesity and DM2 were carried out. An excess of the value of the Bcl-2 protein staining area over the Bad protein staining area was revealed in the liver of 10-week-old animals. The Bcl-2/Bad expression area ratio in 10-week-old animals was twice as high as in 18-week-old animals, which indicates the presence of conditions for blocking apoptosis in the liver of younger db/ db mice. At the 18th week of life, db/db mice displayed an almost threefold increase in the expression area of the Bad protein against the background of an unchanged expression of the Bcl-2 protein. The decrease in the Bcl-2/Bad staining area ratio in 18-week-old animals was due to the increase in the Bad expression area, which indicates the absence of antiapoptotic cell protection and creates conditions for activation of the mitochondrial pathway of apoptosis in the liver of male db/db mice with pronounced signs of obesity and DM2.

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We studied the effects of a melatonin-aluminum oxide-polymethylsiloxane complex (complex M) on the expression of apoptosis regulators Bcl-2 and Bad in the liver of homozygous db/db BKS.Cg-Dock7+/+Lepr/J mice with obesity and type 2 diabetes. Complex M or placebo was administered daily through the gastric tube during weeks 8-16 of life. In mice with type 2 diabetes mellitus receiving placebo, enhanced immunohistochemical reactions for proapoptotic Bad protein and weak response for anti-apoptotic Bcl-2 protein were observed. Administration of complex M shifted the ratio of apoptosis regulators: the area of Bcl-2 expression significantly increased and against the background of reduced Bad expression area. These findings attest to antiapoptotic effect of complex M in the liver on the model of type 2 diabetes mellitus.

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XXI век известен как век ожирения и сахарного диабета 2-го типа -эти заболевания являются основными причинами неалкогольной жировой болезни печени. Тяжёлые формы болезни, такие как неалкогольный стеатогепатит и цирроз печени, связаны с процессом апоптоза. Известны различные пути активации и подавления апоптоза. В печени мышей в модели ожирения и сахарного диабета 2-го типа основными активаторами процессов апоптоза являются интенсивность липопероксидации и окислительного стресса в клетках. Целью настоящего исследования стало изучение особенностей влияния линаглиптина на процессы апоптоза в печени в модели ожирения и сахарного диабета 2-го типа на основании экспрессии антиапоптотического белка Bcl-2. Исследование проводилось на самцах db/db мышей, которые имеют дефект гена рецептора лептина. Линаглиптин или плацебо вводились ежедневно через желудочный зонд с 10-й по 18-ю недели жизни. У мышей, получавших плацебо, была выявлена слабая экспрессия антиапоптотического белка Bcl-2, в то время как у группы, получавшей линаглиптин было зафиксировано значительное усиление его экспрессии. Полученные данные свидетельствуют о «попытке» линаглиптина воздействовать на клетки печени и ограничить развитие апоптоза.

The virulence of the species of the entomopathogenic fungi Lecanicillium psalliotae (strain Vl 78), L. dimorphum (Vl 79) and L. pissodis (ARSEF 8057) against bean aphid Megoura viciae Buckt and greenhouse whitefly Trialeurodes vaporariorum Westwood has been compared with the virulence of well-studied species L. muscarium (Vl 21, Vl 72), L. lecanii (Vl 5), L. longisporum (Vl 13). Species L. longisporum (Vl 13), L. muscarium (Vl 72), L. psalliotae (Vl 78) had a virulence of more than 80% against bean aphid, other strains showed the virulence less than 60%. All strains except L. longisporum (Vl 13) had a high virulence about 75–100% against the greenhouse whitefly. As appeared, the species L. psalliotae (Vl 78) has the perspectives against the both insect species. Its virulence corresponds to the similar level of mortality caused by the well-studied species L. muscarium.