Steelegregersen1446

Asthma and atopy are considered condition associated with obesity, being affected by genetic and environmental factors. The LEP and ADIPOQ genes, responsible for the expression and secretion of leptin and adiponectin, respectively, and polymorphisms in such genes have been linked to both diseases, independently, and also with the obesity-associated asthma phenotype in populations with high European ancestry and high-income countries. However, in mixed populations, there are few studies evaluating the impact of these variants in genes associated with the phenotype of asthma and obesity. Thus, the aim of this study was to investigate variants in LEP and ADIPOQ associated with asthma and atopy, and whether overweight modifies that effect.

The study involved 203 asthmatics children and 813 control subjects (between 5 and 11years old), with or without overweight, from the SCAALA (Asthma and Allergy Social Changes in Latin America) program. Among them, 831 had data for allergy markers, being 258 atopic and 573 Age Z-Score, the protection observed for asthma between the variants rs11760956, rs11763517 and rs2167270 was lost overweight individuals; The protection observed for atopy was lost in all variants (rs16861205, rs2167270 and rs17151919) in the overweight group.

These results suggest that SNPs on the LEP and ADIPOQ genes may have an impact on atopy and asthma. click here Furthermore, we also show that the asthma and atopy protection attributed to variants on LEP and ADIPOQ genes is lost in individuals exposed to overweight.

These results suggest that SNPs on the LEP and ADIPOQ genes may have an impact on atopy and asthma. Furthermore, we also show that the asthma and atopy protection attributed to variants on LEP and ADIPOQ genes is lost in individuals exposed to overweight.Multiple morphological abnormalities of the sperm flagella (MMAF) is defined as deformities that cause sperm motility disorders, further resulting in male infertility. However, the reported genes related to sperm flagellar defects can only explain approximately 60% of human MMAF cases. Here, we report two novel compound heterozygous mutations, c.16246_16247insCCCAAATATCACC (p. T5416fs*7) and c.17323C > T (p.Q5774*), in the fibrous sheath-interacting protein 2 gene (FSIP2; OMIM 615796) in an infertile patient by whole-exome sequencing (WES). Western blotting and immunofluorescence staining confirmed that the compound heterozygous mutations abrogated FSIP2 protein expression. Notably, our staining revealed that FSIP2 is expressed in the cytoplasm of primary germ cell and flagella of spermatids during the spermiogenesis. Moreover, intracytoplasmic sperm injection (ICSI) was carried out using sperm from this patient; however, pregnancy failed after embryo transfer through one cycle. Our findings may be helpful in establishing a genetic diagnosis for MMAF, as well as provide additional beneficial knowledge for genetic counseling and infertility treatment.Gilbert's syndrome (GS) is a mild condition characterized by periods of hyperbilirubinemia, which results in variations in the UDP-glucuronosyltransferase 1 (UGT1A1) gene. Variant genotypes of UGT1A1 vary in different populations in the world. The present study aimed to determine the genotype of the UGT1A1 promoter and exon that are related to the serum total bilirubin (STB) level in the Chinese Han population. A total of 120 individuals diagnosed with GS (GS group) and 120 healthy individuals (non-GS group) were enrolled. Routine blood, liver function tests, and antibodies associated with autoimmune liver diseases were assessed. Blood samples were collected for DNA purification. Sequencing of the UGT1A1 promoter and exons was conducted for post segment amplification by PCR. Compound heterozygous UGT1A1*28 and UGT1A1*6 (25/120, 20.83%), single homozygous UGT1A1*28 (24/120, 20.00%) and single heterozygous UGT1A1*6 (18/120, 15.00%) were the most frequent genotypes in the GS group. However, single heterozygous UGT1A1*6 (30/120, 25.00%) and single heterozygous UGT1A1*28 (19/120, 15.83%) were the most frequent genotypes in the non-GS group. Further, the frequencies of single homozygous UGT1A1*28, compound heterozygous UGT1A1*28 and UGT1A1*6, and compound heterozygous UGT1A1*28, UGT1A1*6 and UGT1A1*27 were significantly higher in the GS group than those in the non-GS group. The STB levels of GS patients with the homozygous UGT1A1*28 genotype were remarkably higher than those of patients with other genotypes. Homozygous UGT1A1*28 and heterozygous UGT1A1*6 variants were associated with the highest and lowest risks of hyperbilirubinemia, respectively. Our study revealed that compound heterozygous UGT1A1*28 and UGT1A1*6, or single homozygous UGT1A1*28 are major genotypes associated with GS in Chinese Han people. These findings might facilitate the precise genomic diagnosis of Gilbert's syndrome.SPINDLIN1-Z (SPIN1Z), a member of the Spin/Ssty(Y-linked spermiogenesis specific transcript) protein family, participates in the early embryonic development process. Our previous RNA-seq analysis indicates that the level of Spin1z was abundantly expressed in male embryonic stem cells (ESCs) and primitive germ cells (PGCs), we speculate that Spin1z may play an important role in chicken male differentiation. Therefore, the loss- and gain-of-function experiments provide solid evidence that Spin1z is both necessary and sufficient to initiate male development in chicken. Furthermore, chromatin immunoprecipitation (ChIP) assay and the dual-luciferase assay was performed to further confirm that Spin1z contributed to chicken male differentiation by inhibiting the Tcf4 transcription. Our findings provide a novel insight into the molecular mechanism for chicken male differentiation.Paraquat dichloride (PQ) is a non-selective herbicide which has been the subject of numerous toxicology studies over more than 50 years. This paper describes the development of a physiologically-based pharmacokinetic (PBPK) model of PQ kinetics for the rat, mouse and dog, firstly to aid the interpretation of studies in which no kinetic measurements were made, and secondly to enable the future extension of the model to humans. Existing pharmacokinetic data were used to develop a model for the rat and mouse. Simulations with this preliminary model were then used to identify key data gaps and to design a new blood binding study to reduce uncertainty in critical aspects of the model. The new data provided evidence to support the model structure, and its predictive performance was then assessed against dog and rat datasets not used in model development. The PQ-specific model parameters are the same for all three species, with only the physiological parameters varying between species. This consistency across species provides a strong basis for extrapolation to other species, as demonstrated here for the dog. The model enables a wide range of PQ data to be linked together to provide a broad understanding of PQ pharmacokinetics in rodents and the dog, showing that the key aspects of PQ kinetics in these species are understood and adequately encapsulated within the model.By extending our Paraquat (PQ) work to include primates we have implemented a modelling and simulation strategy that has enabled PQ pharmacokinetic data to be integrated into a single physiologically based pharmacokinetic (PBPK) model that enables more confident extrapolation to humans. link2 Because available data suggested there might be differences in PQ kinetics between primates and non-primates, a radiolabelled study was conducted to characterize pharmacokinetics and excretion in Cynomolgus monkeys. Following single intravenous doses of 0.01 or 0.1 mg paraquat dichloride/kg bw, plasma PQ concentration-time profiles were dose-proportional. Excretion up to 48 h (predominantly urinary) was 82.9%, with ca. 10% remaining unexcreted. In vitro blood binding was similar across Cynomolgus monkeys, humans and rat. Our PBPK model for the rat, mouse and dog, employing a single set of PQ-specific parameters, was scaled to Cynomolgus monkeys and well represented the measured plasma concentration-time profiles over 14 days. Addition of a cartilage compartment to the model better captured the percent remaining in the monkeys at 48 h, whilst having negligible effect on model predictions for the other species. The PBPK model performed well for all four species, demonstrating there is little difference in PQ kinetics between non-primates and primates enabling a more confident extrapolation to humans. Scaling of the PBPK model to humans, with addition of a human-specific dermal submodel based on in vitro human dermal absorption data, provides a valuable tool that could be employed in defining internal dosimetry to complement human health risk assessments.Owing to the technological advancements, including next generation sequencing, the significance of deregulated epigenetic mechanisms in cancer initiation, progression and treatment has become evident. link3 The accumulating knowledge relating to the epigenetic markers viz. DNA methylation, Histone modifications and non-coding RNAs make them one of the most interesting candidates for developing anti-cancer therapies. The reversibility of deregulated epigenetic mechanisms through environmental and dietary factors opens numerous avenues in the field of chemoprevention and drug development. Recent studies have proven that plant-derived natural products encompass a great potential in targeting epigenetic signatures in cancer and numerous natural products are being explored for their possibility to be considered as "epi-drug". This review intends to highlight the major aberrant epigenetic mechanisms and summarizes the essential functions of natural products like Resveratrol, Quercetin, Genistein, EGCG, Curcumin, Sulforaphane, Apigenin, Parthenolide and Berberine in modulating these aberrations. This knowledge along with the challenges and limitations in this field has potential and wider implications in developing novel and successful therapeutic strategies. The increased focus in the area will possibly provide a better understanding for the development of dietary supplements and/or drugs either alone or in combination. The interaction of epigenetics with different hallmarks of cancer and how natural products can be utilized to target them will also be interesting in the future therapeutic approaches.Diabetic nephropathy (DN) is a chronic inflammatory renal disease induced by hyperglycemia. Recent studies have implicated cyclin-dependent kinase 9 (CDK9) in inflammatory responses and renal fibrosis. In this study, we explored a potential role of CDK9 in DN by using cultured mouse mesangial cell line SV40 MES-13 and streptozotocin-induced type 1 mouse model of diabetes. We inhibited CDK9 in mice and in cultured cells by a highly selective CDK9 inhibitor, LDC000067 (LDC), and evaluated inflammatory and fibrogenic outcome by mRNA and protein analyses. Our studies show that treatment of diabetic mice with LDC significantly inhibits the levels of inflammatory cytokines and fibrogenic genes in kidney specimens. These reductions were associated with improved renal function. We also found that LDC treatment suppressed MAPK-AP1 activation. We then confirmed the involvement of CDK9 in cultured SV40 MES-13 cells and showed that deficiency in CDK9 prevents glucose-induced inflammatory and fibrogenic proteins. This protection was also afforded by suppression of MAPK-AP1.