Sex differences in the expression of lipid oxidation and glucose uptake genes in muscles of fasted mice

Fasting has become increasingly popular for treatment and prevention of obesity. Sex differences in the mechanisms of adaptation to fasting may contribute to choosing a therapeutic strategy for correction of metabolic disorders. Hepatokine fibroblast growth factor 21 (FGF21) is involved in the adaptation to fasting. Muscles are assumed to be the main energy-consuming tissue in the body, as muscle metabolism plays an important role in the adaptation to nutritional deficit. However, there is still little information on sex differences in muscle and FGF21 physiological response to fasting. Our aim was to find out whether there were sex differences in hormonal regulation and the expression of genes controlling glucose and lipid metabolism in skeletal muscles in response to fasting. We estimated the effect of 24-hour fasting on the expression of genes involved in lipid (Ucp3, Cpt1) and carbohydrate (Slc2a4) metabolism in muscles and evaluated changes in body weight and blood plasma levels of glucose, insulin, free fatty acids (FFA), adiponectin, and FGF21 in male and female C57BL/6J mice. None of the genes studied (Ucp3, Cpt1 and Slc2a4) showed sex-related changes at mRNA levels in control groups, but females exposed to fasting demonstrated a significant increase in the expression of all genes as compared to control. Fasting significantly decreased body weight and glucose blood plasma levels in animals of both sexes but exerted no effect on the levels of insulin or FFA. The adiponectin and FGF21 levels were increased in response to fasting, the increase in females being significant. We were first to show sex dimorphism in muscle gene expression and FGF21 blood level in response to fasting. In females, the greater increase in FGF21 and adiponectin blood levels was positively associated with the greater upregulation of lipid oxidation and glucose uptake gene expression

Genome-Wide association Study of Serum Metabolites in the african american Study of Kidney Disease and Hypertension

The genome-wide association study (GWAS) is a powerful means to study genetic determinants of disease traits and generate insights into disease pathophysiology. to date, few GWAS of circulating metabolite levels have been performed in African Americans with chronic kidney disease. Hypothesizing that novel genetic-metabolite associations may be identified in a unique population of African Americans with a lower glomerular filtration rate (GFR), we conducted a GWAS of 652 serum metabolites in 619 participants (mean measured glomerular filtration rate 45 mL/min/1.73

Production of reactive oxygen species by neutrophils and macrophages of F1 hybrid mice (C57Bl6xCBA) in response to stimulation with cucurbit(n)urils (n = 6, 7, 8)

Background. Due to their very small size, nanomaterials, in particular cucurbiturils, have unique physical and chemical properties that find their application in medicine. However, the toxicity of cucurbiturils is not fully understood; in particular, we are interested in the immunological safety of their use. One of the mechanisms of nanotoxicity is the formation of reactive oxygen species (ROS) by macrophages and neutrophils. Hyperproduction of ROS can lead to oxidative stress and further damage to cell DNA with loss of physiological function and development of pathology.   The aim. Evaluation of the effect of cucurbit[n]urils (n = 6, 7, 8) on the production of reactive oxygen species by mice macrophages and neutrophils.   Materials and methods. F1 hybrid mice (CBAxC57Bl/6) aged 2 months (n = 11) were used in the work. Evaluation of superoxide radical production by peritoneal mouse neutrophils and macrophages was carried out by spectrophotometric method for determining the reduction of p-nitroblue tetrazolium (NBT) to formazan.   Results. It was shown that CB[6] and CB[7] at concentrations of 0.5 and 0.3 mM do not have an inhibitory effect on ROS synthesis, but, on the contrary, significantly increase ROS production by macrophages. In addition, CB[6] 0.3 mM increases the level of ROS in neutrophils.   Conclusion. Cucurbiturils can lead to an increase in the production of ROS in immunocompetent cells, depending on the concentration used (0.3 mM and higher)

A Genome-Wide association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos

Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%-54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value \u3c 1.2 × 1

Efficient chimeric mouse production using a novel embryonic stem cell line

Embryonic stem cells are commonly used for generation of transgenic mice. Embryonic stem cells could participate in the development of chimeric animals after injection into a blastocyst. Injection of genetically modified embryonic stem cells could lead to germ line transmission of a transgene or genomic modification in chimeric mice. Such founders are used to produce transgenic lines of mice. There are several projects dedicated to production of knock-out mouse lines (KOMP Repository, EUCOMM, Lexicon Genetics). Never-theless, there is a need for complex genome modifications, such as large deletions, reporter genes insertion into the 3’ gene regulatory sequence, or site-specific modifications of the genome. To do that, researchers need an embryonic stem cell line that is able to participate in chimeric animal formation even after prolonged culture in vitro. Several lines of mouse embryonic stem cells were produced in the Laboratory of Developmental Genetics of the Institute of Cytology and Genetics SB RAS. We tested DGES1 cell line (2n = 40, XY) (129S2/SvPasCrl genetic background) for chimeric mice production at the Center for Genetic Resources of Laboratory Animals at ICG SB RAS. Embryonic stem cells were injected into 136 blastocysts (B6D2F1 genetic background), which were transplanted into CD-1 mice. Among 66 progeny, 15 were chimeric, 4 of which were more than 80 % chimeric judged by coat color. All chimeras were males without developmental abnormalities. 10 of 15 males were fertile. Microsatellite analysis of the progeny of chimeric mice revealed embryonic stem cell line DGES1 contribution to the gamete formation. Thus, a novel DGES1 embryonic stem cell line could be efficiently used for transgenic mouse production using B6D2F1 blastocysts and CD-1 recipients

Whole-Genome Sequencing analysis of Human Metabolome in Multi-Ethnic Populations

Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease

A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos

Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%–54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10−10, minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEVrange = 1%–22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology

Experimental opisthorchiasis: a study of blood cells, hematopoiesis and startle reflex in laboratory animals

One of the species of the family Opisthorchiidae, Opisthorchis felineus (O. felineus), causes severe disturbances in humans and animals, and so it is the subject of important research studies. Two weeks after infection we compared the impact of O. felineus invasion on the changes in blood cells composition, bone marrow hematopoiesis and behavioral startlereflex in inbred C57BL/6 male mice and Syrian hamsters (Mesocricetus auratus). Considerable interspecies differences were revealed for many parameters estimated. It was found that the relative weight of the main organ of the peripheral immune system – spleen, is significantly larger in mice than in hamsters. Moreover, the infection with O. felineus caused a significant enlargement of the spleen only in mice. More pronounced changes in the blood cells composition, which was accompanied by activation of hematopoietic stem cells of myeloid and erythroid set, were determined in hamsters. Blood changes in the response to infection in mice were less severe and were not accompanied by the changes in colony formation. Mouse acoustic startle reaction differed from hamster one too. The expression of the startle reaction and the value of pre-pulse inhibition were discriminated in animals of two species. Infected hamsters had no reaction of habituation  to the sound stimulus. In addition, the maturation of O. felineus worms was faster in hamsters than in mice. Data obtained suggest a greater resistance of mice to O. felineus infection, but do not exclude the availability of mice as a model in the study of processes taking place in the host during the development of experimental opisthorchiasis

СИНДРОМ «ЗАПЕРТОГО ЧЕЛОВЕКА» ВСЛЕДСТВИЕ МНОЖЕСТВЕННЫХ ИНФАРКТОВ СТВОЛА ГОЛОВНОГО МОЗГА И ОЧАГОВ ДЕМИЕЛИНИЗАЦИИ ПОСЛЕ ЛУЧЕВОЙ ТЕРАПИИ АДЕНОМЫ ГИПОФИЗА С АКРОМЕГАЛИЕЙ

Locked-in syndrome (LIS) is a rare neurological disorder, usually appears as a result of the pons cerebellar damage, mostly after the brain stroke. Locked-in syndrome is characterized by the paralysis of skeletal muscles (respiratory, facial, pharyngeal, lingual and muscles of the extremities). Patient is unable to speak and breath, facial expressions and voluntary movements are also impossible. Acromegaly is a disease that can be described by the increase of the growth hormone (GH) and Insulin-like growth factor (IGF-1) and develops in most cases due to the pituitary adenomas. Pituitary adenoma (PA) can be treated by neurosurgical techniques, pharmaceutical and radiation therapy (RT). We present a clinical case of 33-year-old woman with PA-caused acromegaly, that developed muscle weakness, nausea, vomit and respiratory disturbance in a 2 months after the radiation therapy. Subacute comatose state was developed in the patient. MRI of the brain revealed a multi-focal lesion of the media-basal regions on both sides, frontal corpus callosum and brain stem. Differential diagnosis included an acute demyelination (SD, PML), viral encephalitis and vasculitis. Treatment included methylprednisolone pulse therapy and plasmapheresis. The consciousness cleared up, but there was no spontaneous breathing, tetraplegia persisted. Autoimmune and infectious diseases was excluded. The homozygous mutation PAI-1-675 4G/4G was found. In this case, acromegaly induced endothelial dysfunction was the pathogenesis factor of multiple cerebral infarctions and demyelinating lesions, as well as RT and its proven pathological influence on the vascular wall and the fibrinolytic system. The revealed thrombophilia was also a factor of multiple cerebral infarctions. A Potential combination of pathogenic factors in the development of cerebral should be taken into account in predicting complications of RT. Cиндром «запертого человека» (СЗЧ) является редким неврологическим расстройством, обычно возникающим в результате поражения моста мозга, чаще всего вследствие инсульта. При СЗЧ возникает паралич скелетных мышц (дыхательные, лицевые, глотки, языка, а также конечностей), т. е. утрачивается способность к речи, мимике, произвольным движениям, дыханию. Акромегалия – заболевание, при котором наблюдается повышение уровня гормона роста (GH), инсулиноподобного фактора роста 1 (IGF-1), и развивается в большинстве случаев при аденомах гипофиза. При лечении аденомы гипофиза применяют нейрохирургические методики, медикаментозную и лучевую терапию (ЛТ). В представленном клиническом наблюдении у 33-летней женщины через 2 месяца после дистанционной ЛТ опухоли гипофиза, проявлявшейся акромегалией, появилась мышечная слабость, тошнота, рвота, нарушения дыхания. Развилось подостро коматозное состояние. При магнитно-резонансной томографии головного мозга выявлено многоочаговое поражение медиобазальных отделов обоих полушарий, передних отделов мозолистого тела и ствола. Дифференциальный диагноз включал острую демиелинизацию (SD, PML), вирусный энцефалит и васкулит. Пациентка получила пульс-терапию Метилпреднизолоном, плазиообмен. Сознание прояснилось, но самостоятельное дыхание не восстановилось, оставалась тетраплегия. Аутоиммунные заболевания и инфекционные болезни были исключены. Обнаружена мутантная гомозигота PAI-1-675 4G\4G. В данном случае, вероятно, патогенетическими факторами развития множественных инфарктов и очагов демиелинизации выступили как сама акромегалия, приводящая к эндотелиальной дисфункции, так и ЛТ с ее доказанным патологическим воздействием на сосудистую стенку и фибринолитическую систему. Множественным инфарктам способствовала и выявленная тромбофилия. Возможное сочетание патогенетических факторов развития инфарктов головного мозга следует учитывать при прогнозировании осложнений ЛТ

Publisher Correction:Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals (Nature Genetics, (2020), 52, 12, (1314-1332), 10.1038/s41588-020-00713-x)

In the version of this article originally published, the e-mail address of corresponding author Patricia B. Munroe was incorrect. The error has been corrected in the HTML and PDF versions of the article