Pregnancy induced hypertension and umbilical cord blood DNA methylation in newborns: an epigenome-wide DNA methylation study.

OBJECTIVIES: Pregnancy induced hypertension (PIH) syndrome is a disease that unique to pregnant women and is associated with elevated risk of offspring cardiovascular diseases (CVDs) and neurodevelopmental disorders in their kids. Previous research on cord blood utilizing the Human Methylation BeadChip or EPIC array revealed that PIH is associated with specific DNA methylation site. Here, we investigate the whole genome DNA methylation landscape of cord blood from newborns of PIH mother. METHODS: Whole-genome bisulfite sequencing (WGBS) was used to examine the changes in whole genome DNA methylation in the umbilical cord blood of three healthy (NC) and four PIH individuals. Using methylKit, we discovered Hypo- and hyper- differentially methylated probes (DMPs) or methylated regions (DMRs) in the PIH patients' cord blood DNA. Pathway enrichments were assessed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment assays. DMPs or DMRs relevant to the immunological, neurological, and circulatory systems were also employed for enrichment assay, Metascape analysis and PPI network analysis. RESULTS: 520 hyper- and 224 hypo-DMPs, and 374 hyper- and 186 hypo-DMRs between NC and PIH group, respectively. Both DMPs and DMRs have enhanced pathways for cardiovascular, neurological system, and immune system development. Further investigation of DMPs or DMRs related to immunological, neurological, and circulatory system development revealed that TBK1 served as a hub gene for all three developmental pathways. CONCLUSION: PIH-associated DMPs or DMRs in umbilical cord blood DNA may play a role in immunological, neurological, and circulatory system development. Abnormal DNA methylation in the immune system may also contribute to the development of CVDs and neurodevelopment disorders.

Synthetic Principles of Spiky Au Nanoparticles.

In this work, the synthetic principles of spiky Au nanoparticles (spiky Au NPs) with an average number of spikes of less than or equal to six and controlled core sizes by using Au nanorods as seeds (Au-NR seeds) are summarized on the basis of the results of a series of control experiments. In addition, one empirical equation that can roughly estimate the number of spiky Au NPs is proposed, demonstrated by the results of the products prepared from different aspect ratios of Au-NRs as seeds and non-Au-NR seeds. Moreover, the synthetic principles of spiky Au NPs are further demonstrated by taking the successful synthesis of a serials of spiky Au21×7 NPs. Furthermore, the as-prepared spiky Au@Au11.8Pd88.2 NPs with ultrathin AuPd shells, which are derived from spiky Au21×7 NPs with the smallest cores, can bear excellent catalytic activity (say, E1/2 = 0.947 V) and durability toward the oxygen reduction reaction (ORR) in alkaline conditions, compared with commercial Pt/C catalysts (E1/2 = 0.883 V).

Discovery of once-weekly, peptide-based selective GLP-1 and cholecystokinin 2 receptors co-agonizts.

A group of long-acting, peptide-based, and selective GLP-1R/CCK-2R dual agonizts were identified by rational design. Guided by sequence analysis, structural elements of the CCK-2R agonist moiety were engineered into the GLP-1R agonist Xenopus GLP-1, resulting in hybrid peptides with potent GLP-1R/CCK-2R dual activity. Further modifications with fatty acids resulted in novel metabolically stable peptides, among which 3d and 3 h showed potent GLP-1R and CCK-2R activation potencies and comparable stability to semaglutide. In food intake tests, 3d and 3 h also showed a potent reduction in food intake, superior to that of semaglutide. Moreover, the acute hypoglycemic and insulinotropic activities of 3d and 3 h were better than that of semaglutide and ZP3022. Importantly, the limited pica response following 3d and 3 h administration in SD rats preliminarily indicated that the food intake reduction effects of 3d and 3 h are independent of nausea/vomiting. In a 35-day study in db/db mice, every two days administration of 3d and 3 h increased islet areas and numbers, insulin contents, ß-cell area, ß-cell proliferation, as well as improved glucose tolerance, and decreased HbA1c, to a greater extent than ZP3022 and semaglutide. In a 21-day study in DIO mice, once-weekly administration of 3d and 3 h significantly induced body weight loss, improved glucose tolerance, and normalized lipid metabolism, to a greater extent than semaglutide. The current study showed the antidiabetic and antiobesity potentials of GLP-1R/CCK-2R dual agonizts that warrant further investigation.

A GLP-1/glucagon (GCG)/CCK2 receptors tri-agonist provides new therapy for obesity and diabetes.

BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor dual agonist have promising therapeutic effects in the treatment of obesity and diabetes. Moreover, GLP-1 and cholecystokinin 2 (CCK2 ) dual agonists have been shown to restore pancreas function and improve glycaemic control in preclinical studies. We describe, for the first time, the beneficial effects of GLP-1/glucagon receptor and GLP-1/CCK2 dual agonists, which can be integrated into one peptide, resulting in significant anti-diabetes and anti-obesity effectiveness. EXPERIMENTAL APPROACH: The in vitro potency of this novel peptide Xenopus (x) GLP-1/GCG/CCK2 tri-agonist (xGLP/GCG/gastrin) against GLP-1, GCG, CCK1 and CCK2 receptors was determined on cells expressing the corresponding receptors by cAMP accumulation or ERK1/2 phosphorylation assays. The in vivo anti-diabetes and anti-obesity effects of this tri-agonist xGLP/GCG/gastrin were studied in both db/db and diet induced obesity (DIO) mice. KEY RESULTS: xGLP/GCG/gastrin was a potent and selective GLP-1, GCG and CCK2 tri-agonist. In DIO mice, the metabolic benefits of xGLP-1/GCG/gastrin, such as reduction of body weight and hepatic lipid contents were significantly better than those of the peptide ZP3022 (GLP-1/CCK-2 dual agonist) and liraglutide. In a short-term study in db/db mice, xGLP/GCG/gastrin treatment had considerable effects, increasing islet numbers, islet areas and insulin content. In a long-term treatment study using db/db mice, xGLP-1/GCG/gastrin showed a significantly and sustained improvement in glucose tolerance and glucose control compared with that of liraglutide, ZP3022, cotadutide (GLP-1/GCG dual agonist) and xGLP/GCG-15. CONCLUSIONS AND IMPLICATIONS: These results demonstrate the therapeutic potential of xGLP-1/GCG/gastrin for the treatment of obesity and diabetes.

Telocytes Enhances M1 Differentiation and Phagocytosis While Inhibits Mitochondria-Mediated Apoptosis Via Activation of NF-κB in Macrophages.

Telocytes (TCs), which are a recently discovered interstitial cell type present in various organs and tissues, perform multiple biological functions and participate in extensive crosstalk with neighboring cells. Endometriosis (EMs) is a gynecological disease characterized by the presence of viable endometrial debris and impaired macrophage phagocytosis in the peritoneal environment. Here, CD34/vimentin-positive TCs were co-cultured with RAW264.7 cells in vitro. M1/M2 differentiation-related markers were detected; phagocytosis, energy metabolism, proliferation, apoptosis, and pathway mechanisms were studied; and the mitochondrial membrane potential (ΔΨm) was measured. Furthermore, in an EMs mouse model, the differentiation of macrophages in response to treatment with TC-conditioned medium (TCM) in vivo was studied. The results showed that upon in vitro co-culture with TCM, RAW264.7 cells differentiated more toward the M1 phenotype with enhancement of phagocytosis, increase in energy metabolism and proliferation owing to reduced the loss of ΔΨm, and suppression of dexamethasone-induced apoptosis. Further, along with the activation of NF-κB, Bcl-2 and Bcl-xl, the expression of Bax, cleaved-caspase9, and cleaved-caspase3 reduced in RAW264.7 cells. In addition, the M1 subtype was found to be the dominant phenotype among tissue and peritoneal macrophages in the EMs model subjected to in vivo TCM treatment. In conclusion, TCs enhanced M1 differentiation and phagocytosis while inhibiting apoptosis via the activation of NF-κB in macrophages, which potentially inhibited the onset of EMs. Our findings provide a potential research target and the scope for developing a promising therapeutic strategy for EMs.

Telocytes enhanced in vitro decidualization and mesenchymal-epithelial transition in endometrial stromal cells via Wnt/ß-catenin signaling pathway.

Decidualization of endometrial stromal cells (ESCs) is essential for preparing endometrium for embryo implantation. Telocytes (TCs), a novel type of interstitial cell, exist in the female reproductive tract and participate in the pathophysiology of diseases. This study further investigates the hypothesis that TCs, a source of Wnt, modulates decidualization and MET in ESCs. We had observed differential expression of Wnt ligands in primary mice ESCs and TCs by qPCR. TCM-induced decidualization and MET was assessed in ESCs. Changes in markers for decidualization (cyclin-D3, desmin, d/tPRP), stromal cells (N-cadherin), epithelial cells (E-cadherin), and the Wnt/ß-catenin pathway (ß-catenin, FOXO1) were quantified by western blot and RT-PCR. ß-catenin knockdown in ESCs decreased the degree of TCM-induced decidualization and MET, with significantly reversed expression profiles (P < 0.05). This is the first study to show that TCs can enhance decidualization and MET in ESCs through the Wnt/ß-catenin signaling-pathway. Therefore, we describe a promising cell therapy for gynecological conditions and related reproductive problems associated with defective decidualization.

Accessory ovary may be a treatment for infertility: Case report and review of current literatures.

Accessory ovary is a type of ovarian dysplasia, which is often defined as an ovarian tissue placed near and directly connected to the normal ovary or one of ovarian ligaments. It is often asymptomatic, mostly is found or diagnosed at laparotomy, laparoscopy or autopsy. Accessory ovary is often excised during surgery due to its potential malignant behavior. We report a case of endometriosis cyst occurred simultaneously in right side of orthotopic and accessory ovaries, together with torsion 180° of accessory ovarian cyst. Considering that the patient had not given birth and the large size of cysts, exploratory laparotomy was performed. During laparotomy, both site of ovarian cyst have been removed with orthotopic and accessory ovarian tissues preserved. After surgery, a large number of antral follicles were found both in right side of orthotopic and accessory ovaries by ultrasonography. Accessory ovary is considered to have physiological function, and can be preserved as a fertility protection measure for women who have fertility requirements. At present, the definition of ectopic ovary, accessory ovary and supernumerary ovary are very vague and rarely discussed separately. So, we proposed a new way to clarify the concepts of ectopic ovary, accessory ovary and supernumerary ovary. Moreover, we advocated that they should be discussed separately in terms of definition and management measures.

Telocytes enhanced the proliferation, adhesion and motility of endometrial stromal cells as mediated by the ERK pathway in vitro.

Telocytes (TCs) is special interstitial cell that have recently been identified in the female reproductive system. Endometriosis (EMs) is a benign gynecological disease whose etiology is still not fully clear. Implantation and proliferation of endometrial stromal cells (ESCs) out of the uterus are essential processes in the development of EMs. Herein, we investigate the in vitro changes of ESCs when cocultured with TCs, and the potential mechanisms involved. The current results demonstrated that, vimentin-positive/pan cytokeratin-negative ESCs, and TCs with a characteristic structure and immunophenotype (CD34/vimentin double-positive) were successfully isolated and harvested. Morphologically, direct cell-to-cell contacts were observed between TCs and ESCs. Quantitatively, TCs treatment clearly promotes the viability of ESCs, enhances cell cycle progression at G2/M phase and upregulates p-ERK1/2 and cyclin-D3 (all P < 0.05). Functionally, ESCs educated by TCs displayed significantly enhanced adhesion ability and accelerated invasion and migration capacity (all P < 0.05). However, no significant changes were found in the rate of apoptosis and in the expression of AKT signaling pathway proteins in TCs-educated ESCs (both P > 0.05). Therefore, TCs treatment obviously enhanced the in vitro motile and invasive capacity of ESCs, which were mediated by the ERK-cyclin-D3 signaling pathway, likely through direct intercellular contacts and/or juxta-paracrine effects; signaling through this axis therefore increased the likelihood of EMs. The enhanced functions of TCs-educated ESCs not only contribute to a deeper understanding of TCs, but also highlight a new concept regarding the physiopathology and therapy of EMs and associated impaired reproductive function.

An aldo-keto reductase is responsible for Fusarium toxin-degrading activity in a soil Sphingomonas strain.

Degradation of toxins by microorganisms is a promising approach for detoxification of agricultural products. Here, a bacterial strain, Sphingomonas S3-4, that has the ability to degrade the mycotoxin deoxynivalenol (DON) was isolated from wheat fields. Incubation of Fusarium-infected wheat grains with S3-4 completely eliminated DON. In S3-4 DON is catabolized into compounds with no detectable phytotoxicity, 3-oxo-DON and 3-epi-DON, via two sequential reactions. Comparative analysis of genome sequences from two DON-degrading strains, S3-4 and Devosia D17, and one non-DON-degrading strain, Sphingobium S26, combined with functional screening of a S3-4 genomic BAC library led to the discovery that a novel aldo/keto reductase superfamily member, AKR18A1, is responsible for oxidation of DON into 3-oxo-DON. DON-degrading activity is completely abolished in a mutant S3-4 strain where the AKR18A1 gene is disrupted. Recombinant AKR18A1 protein expressed in Escherichia coli catalyzed the reversible oxidation/reduction of DON at a wide range of pH values (7.5 to 11) and temperatures (10 to 50 °C). The S3-4 strain and recombinant AKR18A1 also catabolized zearalenone and the aldehydes glyoxal and methyglyoxal. The S3-4 strain and the AKR18A1 gene are promising agents for the control of Fusarium pathogens and detoxification of mycotoxins in plants and in food/feed products.

9-[4,5-Bis(benzyl-sulfan-yl)-1,3-dithiol-2-yl-idene]-4,5-diaza-fluorene.

In rhe title compound, C(28)H(20)N(2)S(4), the 1,3-dithiol-2-yl-idene and 4,5-diaza-fluoren-9-one (dafone) groups are almost coplanar, making a dihedral angle of only 5.65 (4)°. The two benzyl groups are on different sides of the 1,3-dithiol-2-yl-idene ring, forming a dihedral angle of 35.54 (2)°.