РОЛЬ ОСТЕОКАЛЬЦИНУ В РЕГУЛЯЦІЇ СЕКРЕЦІЇ ІНСУЛІНУ ТА ОСТЕОТРОПНИХ ЕФЕКТІВ РІЗНИХ КЛАСІВ ПРОТИДІАБЕТИЧНИХ ПРЕПАРАТІВ (огляд літератури і власні дослідження)

Background. Current data suggest that bone tissue produces hormonally active factors - modulators of metabolic processes throughout the body. The most significant osteoproteins is osteocalcin, the non-collagen structural protein of the bone matrix, which is synthesized by osteoblasts and enters the bloodstream during the resorption of bone tissue. Osteocalcin is involved in the regulation of energy balance, insulin secretion, peripheric insulin sensitivity, and adipocyte’s function, while being an important marker of bone remodeling. The aim of this study was to investigate the relationship between osteocalcin levels and metabolic parameters in 97 patients with type 2 diabetes over 50 years of age, in the course of pharmacotherapy using different classes of antidiabetic drugs, namely human insulin, glucagon-like peptide-1 agonists (aGLP), and sodium-glucose co-transporter 2 (SGLT2) inhibitors, depending on presence of obesity. Results. There was found the highest serum osteocalcin level in patients without obese who received a metabolically active therapy with insulin or aGLP-1, comparing to nonobese subjects of SGLT2 inhibitors therapy group. The lowest level of HbA1c and triglycerides observed in non-obese patients on the background of taking aGLP-1. Conclusion. It can be assumed that the factor determining the hypoglycemic efficacy of investigated drugs may be the pathogenesis of type 2 diabetes which depends on the degree of obesity, while the type of antidiabetic therapy has a corrective effect, probably mediated by changes in body weight and fat distribution.Background. Current data suggest that bone tissue produces hormonally active factors - modulators of metabolic processes throughout the body. The most significant osteoproteins is osteocalcin, the non-collagen structural protein of the bone matrix, which is synthesized by osteoblasts and enters the bloodstream during the resorption of bone tissue. Osteocalcin is involved in the regulation of energy balance, insulin secretion, peripheric insulin sensitivity, and adipocyte’s function, while being an important marker of bone remodeling. The aim of this study was to investigate the relationship between osteocalcin levels and metabolic parameters in 97 patients with type 2 diabetes over 50 years of age, in the course of pharmacotherapy using different classes of antidiabetic drugs, namely human insulin, glucagon-like peptide-1 agonists (aGLP), and sodium-glucose co-transporter 2 (SGLT2) inhibitors, depending on presence of obesity. Results. There was found the highest serum osteocalcin level in patients without obese who received a metabolically active therapy with insulin or aGLP-1, comparing to nonobese subjects of SGLT2 inhibitors therapy group. The lowest level of HbA1c and triglycerides observed in non-obese patients on the background of taking aGLP-1. Conclusion. It can be assumed that the factor determining the hypoglycemic efficacy of investigated drugs may be the pathogenesis of type 2 diabetes which depends on the degree of obesity, while the type of antidiabetic therapy has a corrective effect, probably mediated by changes in body weight and fat distribution

ВЗАЄМОЗВ’ЯЗКИ ОСТЕОКАЛЬЦИНУ З ГОРМОНАЛЬНО-МЕТАБОЛІЧНИМИ ПОРУШЕННЯМИ ЧОЛОВІКІВ З ЦУКРОВИМ ДІАБЕТОМ 2 ТИПУ З РІЗНИМ СТУПЕНЕМ ОЖИРІННЯ (огляд літератури і власні дослідження)

The bone hormone osteocalcin is formed by osteoblasts and is partially released into the bloodstream during bone resorption, being a biomarker of bone remodeling. Osteocalcin also plays an important role in the endocrine regulation of metabolic and energy processes in the body and in their coordination. Osteocalcin uses a feedback mechanism to regulate insulin secretion, insulin sensitivity of peripheral tissues, and adipokine levels. In general, the secretion of osteocalcin and insulin are important factors in the formation of hormonal-metabolic phenotype, body composition, determination of regional distribution and metabolic activity of both bone and adipose tissue.The aim of this study was to establish the relationship between osteocalcin concentration and hormonal changes in men with type 2 diabetes with and without obesity on the background of involutive changes. Results. 64 men with type 2 diabetes, older than 50 years, were divided into 2 groups by BMI: 1) non-obese, BMI <30 kg / m2 (n = 31); 2) -obese, BMI ≥ 30 kg / m2 (n = 33). Lower levels of insulin secretion (lower serum C-peptide and insulin levels) were observed in non-obese patients in the absence of a compensatory increase in proinsulin levels. It can be assumed that the increase in the concentration of osteocalcin in group 1 is compensatory, although it does not have a significant effect on blood glucose levels. However, it may have a protective effect on the severity of insulin resistance syndrome and related metabolic disorders. Lower levels of osteocalcin in the obese group were associated with a higher degree of insulin resistance and insulin secretion. There was no significant difference between the two groups in serum proinsulin levels, as well as in androgen supply, which was assessed by the levels of total testosterone, testosteronestradiol-binding globulin, and free testosterone index. Conclusion. Lower levels of osteocalcin may be a marker of an increased risk of adverse metabolic changes in obese patients with type 2 diabetes, followed by complications compared to non-overweight patientsThe bone hormone osteocalcin is formed by osteoblasts and is partially released into the bloodstream during bone resorption, being a biomarker of bone remodeling. Osteocalcin also plays an important role in the endocrine regulation of metabolic and energy processes in the body and in their coordination. Osteocalcin uses a feedback mechanism to regulate insulin secretion, insulin sensitivity of peripheral tissues, and adipokine levels. In general, the secretion of osteocalcin and insulin are important factors in the formation of hormonal-metabolic phenotype, body composition, determination of regional distribution and metabolic activity of both bone and adipose tissue.The aim of this study was to establish the relationship between osteocalcin concentration and hormonal changes in men with type 2 diabetes with and without obesity on the background of involutive changes. Results. 64 men with type 2 diabetes, older than 50 years, were divided into 2 groups by BMI: 1) non-obese, BMI <30 kg / m2 (n = 31); 2) -obese, BMI ≥ 30 kg / m2 (n = 33). Lower levels of insulin secretion (lower serum C-peptide and insulin levels) were observed in non-obese patients in the absence of a compensatory increase in proinsulin levels. It can be assumed that the increase in the concentration of osteocalcin in group 1 is compensatory, although it does not have a significant effect on blood glucose levels. However, it may have a protective effect on the severity of insulin resistance syndrome and related metabolic disorders. Lower levels of osteocalcin in the obese group were associated with a higher degree of insulin resistance and insulin secretion. There was no significant difference between the two groups in serum proinsulin levels, as well as in androgen supply, which was assessed by the levels of total testosterone, testosteronestradiol-binding globulin, and free testosterone index. Conclusion. Lower levels of osteocalcin may be a marker of an increased risk of adverse metabolic changes in obese patients with type 2 diabetes, followed by complications compared to non-overweight patient

Alkaloids of narrow-leaved lupine as a factor determining alternative ways of the crop’s utilization and breeding

Narrow-leaved lupine (Lupinus angustifolius L.), a valuable leguminous crop adapted to a wide range of climatic conditions, has a very short history of domestication. For many centuries it was used mainly as a green manure, since the success and prospects of the multi-purpose use of the species depend on its breeding improvement, in particular, on a particular concentration of alkaloids in seeds and green mass. The first varieties of scientific breeding were created only in the 1930s after the appearance of low-alkaloid mutants. Despite wide prospects for use in various areas of the national economy, unstable productivity and susceptibility to diseases hinder the production of this crop. Obviously, breeders deal only with a small part of the gene pool of the species and limited genetic resources, using mainly low-alkaloid (sweet) genotypes to create new varieties. The genetic potential of the species can be used more efficiently. At the same time, it is rational to create highly alkaloid (bitter) varieties for green manure, while food and feed varieties should not lose their adaptive potential, in particular, resistance to pathogens, due to the elimination of alkaloids. In this regard, it seems to be a productive idea to create ‘bitter/sweet’ varieties combining a high content of alkaloids in the vegetative organs and low in seeds, which can be achieved by regulating the synthesis/transport of alkaloids in the plant. The paper discusses the current state of use of the species as a green manure, fodder, food plant. Information is given on the quantity and qualitative composition of narrow-leaved lupine alkaloids, their applied value, in particular, fungicidal, antibacterial, insecticidal, the use of lupine alkaloids as active principles of drugs. Along with promising breeding considerations, the possibility of using technologies for processing raw high-alkaloid materials with the accompanying extraction of valuable ingredients for pharmaceuticals is discussed. Information is briefly presented about the genomic resources of the species and the prospects for their use in marker-assistant selection and genome editing

Selection of an optimal method for screening the collection of narrow-leaved lupine held by the Vavilov Institute for the qualitative and quantitative composition of seed alkaloids

Narrow-leaved lupine (Lupinus аngustifolius L.) is a widely cultivated leguminous forage and green manure crop with a potential for human nutrition. However, the presence of secondary metabolites – alkaloids – in lupine seeds considerably affects the quality of raw produce, reducing its nutritive value; in addition, high concentrations of alkaloids are toxic to humans and animals. Therefore, plant breeders working with lupine need to gain knowledge about the variability of alkaloid content in seeds of different genotypes and search for the sources of their low concentrations in the crop’s gene pool. The collection of narrow-leaved lupine genetic resources held by the N.I. Vavilov Institute of Plant Genetic Resources (VIR) offers wide opportunities for such search by means of mass screening. For its part, largescale gene pool screening requires the selection of an optimal technique to measure alkaloid content in seeds, so that it would be easily reproducible and as little labor-, time- and fund-consuming as possible. The results of the search for such method are presented. Qualitative and quantitative indices were compared when target compounds had been extracted with multicomponent mixtures and individual reagents (chloroform, methanol, etc.) and the extracts analyzed using gas chromatography-mass spectrometry. High-performance liquid chromatography combined with mass spectrometry was also employed. Five major alkaloids were found to be present in all types of extracts: lupanine, 13-hydroxylupanine (dominant ones), angustifoline, sparteine, and isolupanine. The fullest extraction of alkaloids was observed when the extractant with an added alkaline agent was used (425 mg/100 g). The lowest level of extraction was registered with chloroform (216 mg/100 g). The significance of the differences was confirmed statistically

Факторы риска развития асептического некроза головки бедренной кости у пациентов с системной красной волчанкой

Objective: to identify risk factors for the development of the femoral head aseptic necrosis (FHAN) and osteoarthritis (OA) of the hip joint (HJ) in patients with systemic lupus erythematosus (SLE) according to a retrospective analysis.Material and methods.The retrospective study included data from the case histories of 103 patients with SLE who underwent total hip arthroplasty (HA) (unilateral in 82 patients, bilateral in 21). The total follow-up period ranged from 2 years to 21 years. Among the patients included in thestudy, the majority were women (86.4%), the ratio of women and men was 7:1. At the time of surgery, the average age of women was 36.3±13.25 years, men – 36.2±9.57 years, duration of the disease – 168.0±132.5 months. SLE activity was assessed using the SLEDAI-2K scale. All patients were taking glucocorticoids (GC). The average duration of GC treatment was 89.0±87.2 months. 71.8% of patients received immunosuppressive therapy: hydroxychloroquine – 55.3%, azathioprine – 10.7%, methotrexate – 5.8%. The functional status of hip joint was determined using the Harris scale; by the time of surgery, the average score was 45.6±13.1 points. Pain intensity was assessed using a visual analogue scale and reached an average of 70.1±16.0 mm.Results and discussion. In 58.5% of patients with SLE, the indication for HA was FHAN (Group 1) and in 41.6% – OA of HJ (Group 2). At the time of HA, the duration of the disease was longer and the age was higher in group 2 than in group 1 (p<0.05). An analysis of individual clinical manifestations of SLE that preceded the development of HJ pathology revealed that arthritis and the presence of an antinuclear factor, ANF, were associated with the development of FHAN (p=0.022 and p=0.04, respectively). At the onset of the disease, patients of the 1st group, compared with patients of the 2nd group, more often had lesions of the skin, kidneys and serositis (22.9 and 20.5%; 14.5 and 11.7%; 68.7 and 64.7 %, respectively), but they were less likely to have mucous membranes and the central nervous system (CNS) involvement (14.5 and 23.5%; 10.4 and 17.6%, respectively). However, these differences did not reach statistical significance. Almost all of these disease manifestations, with the exception of the mucous membranes and the CNS lesions, were more often observed in patients with the development of FHAN, which indicates a higher activity of the disease at the onset of SLE. At the time of HA, we did not find any relationship between SLE activity and FHAN formation and hip OA. Patients of the 1st and 2nd groups in the same number of cases had mild (56.2 and 58.8%, respectively) and moderate (35.4 and 32.4%, respectively) activity according to SLEDAI-2K. No activity (SLEDAI-2K – 0 points) was also observed in patients of both groups with the same frequency (8.3 and 8.8% of cases, respectively). Associations of cumulative and daily doses of GC with the development of FHAN and OA of HJ were not revealed. In the 1st group, the average daily dose of GC was slightly higher, and the cumulative dose was less than in the 2nd group (8.59±4.75 and 7.79±5.39 mg; 20.0±11.9 and 23.8±19.2 g, respectively), but these differences were not significant (p>0.05).Conclusion. In SLE patients, the incidence of FHAN and HJ OA was comparable. At the time of HA, SLE patients with HJ OA were older and had a longer duration of the disease than patients with FHAN. The risk factors for FHAN were arthritis and ANF positivity at the onset of SLE.Цель исследования – выявить факторы риска развития асептического некроза головки бедренной кости (АНГБК) и остеоартрита (ОА) тазобедренного сустава (ТБС) у пациентов с системной красной волчанкой (СКВ) по данным ретроспективного анализа.Материал и методы. В ретроспективное исследование включены данные историй болезни 103 пациентов с СКВ, которым проводилось тотальное эндопротезирование (ТЭ) ТБС (у 82 пациентов – одностороннее, у 21 – двустороннее). Общий период наблюдения колебался от 2 лет до 21 года. Среди больных, включенных в исследование, преобладали женщины (86,4%), соотношение женщин и мужчин – 7:1. На момент операции возраст женщин составлял в среднем 36,3±13,25 года, мужчин – 36,2±9,57 года, длительность заболевания – 168,0±132,5 мес. Активность СКВ оценивали по шкале SLEDAI-2K. Все пациенты принимали глюкокортикоиды (ГК). Средняя продолжительность лечения ГК – 89,0±87,2 мес. Иммуносупрессивную терапию получали 71,8% больных: гидроксихлорохин – 55,3%, азатиоприн –10,7%, метотрексат – 5,8%. Функциональный статус ТБС определяли по шкале Харриса, к моменту операции средний счет составлял 45,6±13,1 балла. Интенсивность боли оценивалась по визуальной аналоговой шкале и достигала в среднем 70,1±16,0 мм.Результаты и обсуждение. У 58,5% больных СКВ показанием для ТЭ служил АНГБК (1-я группа) и у 41,6% – ОА ТБС (2-я группа). На момент ТЭ длительность болезни и возраст во 2-й группе были больше, чем в 1-й (р<0,05). Анализ отдельных клинических проявлений СКВ, предшествовавших развитию патологии ТБС, выявил, что с развитием АНГБК ассоциировались такие признаки, как артрит и наличие антинуклеарного фактора – АНФ (р=0,022 и р=0,04 соответственно). В дебюте заболевания пациенты 1-й группы по сравнению с пациентами 2-й группы чаще имели поражение кожи, почек и серозит (22,9 и 20,5%; 14,5 и 11,7%; 68,7 и 64,7% соответственно), но у них реже встречалось травмирование слизистых оболочек и центральной нервной системы – ЦНС (14,5 и 23,5%; 10,4 и 17,6% соответственно). Однако эти различия не достигали статистической значимости. Практически все указанные проявления болезни, за исключением поражения слизистых оболочек и ЦНС, чаще наблюдались у пациентов с развитием АНГБК, что свидетельствует о более высокой активности болезни в дебюте СКВ. На момент ТЭ ТБС мы не обнаружили взаимосвязи активности СКВ с формированием АНГБК и ОА ТБС. У пациентов 1-й и 2-й групп в одинаковом числе случаев имелась низкая (56,2 и 58,8% соответственно) и умеренная (35,4 и 32,4% соответственно) степень активности по SLEDAI-2K. Отсутствие активности (SLEDAI-2K – 0 баллов) наблюдалось у пациентов обеих групп также с одинаковой частотой (8,3 и 8,8% случаев соответственно). Ассоциации кумулятивной и суточной дозы ГК с развитием АНГБК и ОА ТБС не выявлено. В 1-й группе средняя суточная доза ГК была несколько больше, а кумулятивная доза – меньше, чем во 2-й (8,59±4,75 и 7,79±5,39 мг; 20,0±11,9 и 23,8±19,2 г соответственно), однако эти различия были незначимы (р>0,05).Заключение. У больных СКВ частота развития АНГБК и ОА ТБС была сопоставимой. На момент ТЭ ТБС больные СКВ с ОА ТБС были старше и имели большую длительность заболевания, чем пациенты с АНГБК. Факторами риска возникновения АНГБК являлись артрит и позитивность по АНФ в дебюте СКВ

Аваскулярный некроз при системной красной волчанке: тотальное эндопротезирование тазобедренного сустава при мутации в гене V (Leiden) фактора свертывания крови (клиническое наблюдение)

The article provides a description of the systemic lupus erythematosus patient with multiple avascular bone necrosis (ABN), homozygous mutation in clotting factor V (Leiden) gene, who successfully underwent the total hip replacement. The role of high doses of glucocorticoids and coagulation disorders, in particular the homozygous mutation in factor V (Leiden) gene, in the development of ABN is discussed.В статье приводится описание пациентки с системной красной волчанкой, множественными аваскулярными некрозами костей (АВН), гомозиготной мутацией в гене V фактора свертывания крови, успешно перенесшей тотальное эндопротезирование тазобедренного сустава. Обсуждается роль в развитии АВН высоких доз глюкокортикоидов и нарушений свертывания крови, в частности гомозиготной мутации Leiden

Reduction of Hydrophilic Ubiquinones by the Flavin in Mitochondrial NADH:Ubiquinone Oxidoreductase (Complex I) and Production of Reactive Oxygen Species†

ABSTRACT: NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria is a complicated, energy-transducing, membrane-bound enzyme that contains 45 different subunits, a non-covalently bound flavin mononucleotide, and eight iron-sulfur clusters. The mechanisms of NADH oxidation and intramolecular electron transfer by complex I are gradually being defined, but the mechanism linking ubiquinone reduction to proton translocation remains unknown. Studies of ubiquinone reduction by isolated complex I are problematic because the extremely hydrophobic natural substrate, ubiquinone-10, must be substituted with a relatively hydrophilic analogue (such as ubiquinone-1). Hydrophilic ubiquinones are reduced by an additional, non-energy-transducing pathway (which is insensitive to inhibitors such as rotenone and piericidin A). Here, we show that inhibitor-insensitive ubiquinone reduction occurs by a ping-pong type mechanism, catalyzed by the flavin mononucleotide cofactor in the active site for NADH oxidation. Moreover, semiquinones produced at the flavin site initiate redox cycling reactions with molecular oxygen, producing superoxide radicals and hydrogen peroxide. The ubiquinone reactant is regenerated, so the NADH:Q reaction becomes superstoichiometric. Idebenone, an artificial ubiquinone showing promise in the treatment of Friedreich’s Ataxia, reacts at the flavin site. The factors which determine the balance of reactivity between the two sites of ubiquinone reduction (the energy-transducing site and the flavi

Targeted apoptosis in ovarian cancer cells through mitochondrial dysfunction in response to Sambucus nigra agglutinin

Ovarian carcinoma (OC) patients encounter the severe challenge of clinical management owing to lack of screening measures, chemoresistance and finally dearth of non-toxic therapeutics. Cancer cells deploy various defense strategies to sustain the tumor microenvironment, among which deregulated apoptosis remains a versatile promoter of cancer progression. Although recent research has focused on identifying agents capable of inducing apoptosis in cancer cells, yet molecules efficiently breaching their survival advantage are yet to be classified. Here we identify lectin, Sambucus nigra agglutinin (SNA) to exhibit selectivity towards identifying OC by virtue of its specific recognition of α-2, 6-linked sialic acids. Superficial binding of SNA to the OC cells confirm the hyper-sialylated status of the disease. Further, SNA activates the signaling pathways of AKT and ERK1/2, which eventually promotes de-phosphorylation of dynamin-related protein-1 (Drp-1). Upon its translocation to the mitochondrial fission loci Drp-1 mediates the central role of switch in the mitochondrial phenotype to attain fragmented morphology. We confirmed mitochondrial outer membrane permeabilization resulting in ROS generation and cytochrome-c release into the cytosol. SNA response resulted in an allied shift of the bioenergetics profile from Warburg phenotype to elevated mitochondrial oxidative phosphorylation, altogether highlighting the involvement of mitochondrial dysfunction in restraining cancer progression. Inability to replenish the SNA-induced energy crunch of the proliferating cancer cells on the event of perturbed respiratory outcome resulted in cell cycle arrest before G2/M phase. Our findings position SNA at a crucial juncture where it proves to be a promising candidate for impeding progression of OC. Altogether we unveil the novel aspect of identifying natural molecules harboring the inherent capability of targeting mitochondrial structural dynamics, to hold the future for developing non-toxic therapeutics for treating OC

Pastoralism and Emergent Complex Settlement in the Middle Bronze Age, Azerbaijan: Isotopic analyses of mobility strategies in transformation

Objectives. This article explores the scale and seasonal patterns of mobility at the complex settlement site of Qızqala during the Middle Bronze Age (2400–1,500 BCE). By integrating human bone, teeth, and environmental samples this research tests the hypothesis of the persistent importance of community-wide seasonal pastoral transhumance during the early formation of complex settlement systems of the South Caucasus. Methods. This research applies stable oxygen and radiogenic strontium isotope analyses on incremental samples of human tooth enamel, bulk tooth enamel, and bone to resolve mobility patterns. Sequential and bulk sampling techniques elucidate seasonal and residential mobility behaviors. Extensive environmental isotope samples of plant and water were collected through regional survey and establish local and regional isotopic baselines, which are compared to human isotope analysis results. Results. Qızqala individuals exhibit low isotopic variability compared to regional contemporaries. 87Sr/86Sr ratios from human remains indicate seasonal and residential isotopic variability within the baseline ranges of local landscapes. δ18O values display erratic patterns, but correspond to seasonal variability with fluctuations between highland and lowland altitudinal zone baseline values. Conclusions. Results suggest that isotopic analysis of multiple elements and sequential enamel samples offers finer resolution on the complexities of human mobility strategies and elucidate the daily lives of often overlooked mobile populations. Higher resolution of individual mobility reveals shared routine behaviors that underscore the importance of diverse social collaborations in forming complex polities in the South Caucasus