By day 7, MΦ became the predominant myeloid cell type in tendon and there were further delayed increases in other COX metabolites including prostaglandins D2 , F2α , and I2 . Specialized pro-resolving mediators including protectin D1, resolvin D2 and D6, as well as related pathway markers of D-resolvins (17-hydroxy-docosahexaenoic acid), E-resolvins (18-hydroxy-eicosapentaenoic acid), and lipoxins (15-hydroxy-eicosatetraenoic acid) were also increased locally in response to tendon overuse, as were anti-inflammatory fatty acid epoxides of the CYP pathway (eg, epoxy-eicosatrienoic acids). Nevertheless, intratendinous prostaglandins remained markedly increased even following 28 days of tendon overuse together with a lingering MΦ presence. These data reveal a delayed and prolonged local inflammatory response to tendon overuse characterized by an overwhelming predominance of pro-inflammatory eicosanoids and a relative lack of specialized pro-resolving lipid mediators.cAMP responsive element-binding protein H (CREBH) is a hepatic transcription factor to be activated during fasting. We generated CREBH knock-in flox mice, and then generated liver-specific CREBH transgenic (CREBH L-Tg) mice in an active form. CREBH L-Tg mice showed a delay in growth in the postnatal stage. Plasma growth hormone (GH) levels were significantly increased in CREBH L-Tg mice, but plasma insulin-like growth factor 1 (IGF1) levels were significantly decreased, indicating GH resistance. In addition, CREBH overexpression significantly increased hepatic mRNA and plasma levels of FGF21, which is thought to be as one of the causes of growth delay. However, the additional ablation of FGF21 in CREBH L-Tg mice could not correct GH resistance at all. CREBH L-Tg mice sustained GH receptor (GHR) reduction and the increase of IGF binding protein 1 (IGFBP1) in the liver regardless of FGF21. As GHR is a first step in GH signaling, the reduction of GHR leads to impairment of GH signaling. These data suggest that CREBH negatively regulates growth in the postnatal growth stage via various pathways as an abundant energy response by antagonizing GH signaling.Evidence suggests that immunosuppressant therapies protect against harmful effects of endotoxaemia. In this study, we tested whether calcineurin-dependent (cyclosporine/tacrolimus) and -independent (sirolimus) immunosuppressants variably influence nephrotoxicity induced by endotoxaemia and whether this interaction is modulated by testosterone. We investigated the effects of immunosuppressants on renal histopathological, biochemical and inflammatory profiles in endotoxic male rats and the role of androgenic state in the interaction. Six-hour treatment of rats with lipopolysaccharide (LPS, 3 mg/kg) increased (i) serum urea/creatinine, (ii) width of proximal/distal tubules, (iii) tubular degeneration and vacuolation, (iv) Western protein expressions of renal toll-like receptor 4, monocyte chemoattractant protein-1, and NADPH oxidase-2, and (v) serum tumour necrosis factor-α and myeloperoxidase. These endotoxic manifestations were intensified and eliminated upon concurrent exposure to cyclosporine and sirolimus, respectively. The cyclosporine actions appear to be a class rather than a drug effect because similar exacerbation of LPS nephrotoxicity was observed in rats treated with tacrolimus, another calcineurin inhibitor (CNI). Moreover, the deteriorated renal outcomes in LPS/tacrolimus-treated rats were reduced after castration or androgen receptor blockade by flutamide. The data suggest opposite effects for calcineurin-dependent (exaggeration) and -independent immunosuppressants (amelioration) on renal defects of endotoxaemia and implicate androgenic pathways in the worsened endotoxic renal profile induced by CNIs.The pluripotency gene regulatory network of porcine induced pluripotent stem cells(piPSCs), especially in epigenetics, remains elusive. To determine the biological function of epigenetics, we cultured piPSCs in different culture conditions. We found that activation of pluripotent gene- and pluripotency-related pathways requires the erasure of H3K9 methylation modification which was further influenced by mouse embryonic fibroblast (MEF) served feeder. By dissecting the dynamic change of H3K9 methylation during loss of pluripotency, we demonstrated that the H3K9 demethylases KDM3A and KDM3B regulated global H3K9me2/me3 level and that their co-depletion led to the collapse of the pluripotency gene regulatory network. Immunoprecipitation-mass spectrometry (IP-MS) provided evidence that KDM3A and KDM3B formed a complex to perform H3K9 demethylation. The genome-wide regulation analysis revealed that OCT4 (O) and SOX2 (S), the core pluripotency transcriptional activators, maintained the pluripotent state of piPSCs depending on the H3K9 hypomethylation. Further investigation revealed that O/S cooperating with histone demethylase complex containing KDM3A and KDM3B promoted pluripotency genes expression to maintain the pluripotent state of piPSCs. Together, these data offer a unique insight into the epigenetic pluripotency network of piPSCs.

Gestational diabetes mellitus (GDM) has many adverse outcomes that seriously threaten the short-term and long-term health of mothers and infants. This study comprehensively analyzed the clinical diagnostic value of GDM-related clinical indexes and urine polypeptide research results, and established comprehensive index diagnostic models.

In this study, diagnostic values from the clinical indexes of serum triglyceride (TRIG), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c), and 7 GDM-related urinary polypeptides were analyzed retrospectively. The multiple logistic regression equation, multilayer perceptron neural network model, radial basis function, and discriminant analysis function models of GDM-related indexes were established using machine language.

The results showed that HbA1c had the highest diagnostic value for GDM, with an area under the curve (AUC) of 0.769. When the cut-off value was 4.95, the diagnostic sensitivity and specificity were 70.5% and 70.0%, respectively. Among the seven GDM-related urinary polypeptides, human hemopexin (HEMO) had the highest diagnostic value, with an AUC of 0.690. When the cut-off value was 368.5, the sensitivity and specificity were 79.5% and 43.3%, respectively. The AUC of the multilayer perceptron neural network model was 0.942, followed by binary logistic regression (0.938), radial basis function model (0.909), and the discriminant analysis function model (0.908).

The establishment of a GDM diagnostic model combining blood glucose, blood lipid, and urine polypeptide indexes can lay a foundation for exploring machine language and artificial intelligence in diagnostic systems.

The establishment of a GDM diagnostic model combining blood glucose, blood lipid, and urine polypeptide indexes can lay a foundation for exploring machine language and artificial intelligence in diagnostic systems.Lysophosphatidylinositol (LPI) is a glycero-lysophospholipid and a natural agonist against GPR55. The roles of the LPI/GPR55 axis in the pathogenesis of inflammation have been controversial. In the present study, we attempted to elucidate the roles of the LPI/GPR55 axis in inflammation, especially the secretion of inflammatory cytokines, IL-6 and TNF-α from macrophages. We treated RAW264.7 cells and mouse peritoneal macrophages (MPMs) with LPI and observed that LPI induced the secretion of IL-6 and TNF-α from these cells, as well as the phosphorylation of p38. These responses were inhibited by treatment with CID16020046 (CID), an antagonist against GPR55, or SB202190, an inhibitor of p38 cascade or knockdown of GPR55 with siRNA. Treatment with CID or ML-193, another antagonist against GPR55, attenuated the elevation of inflammatory cytokines in the plasma or tissue of db/db mice and in a septic mouse model induced using lipopolysaccharide, suggesting contributions to the improvement of insulin resistance and protection against organ injuries by treatment with CID or ML-193, respectively. In human subjects, although the serum LPI levels were not different, the levels of LPI in the lipoprotein fractions were lower and the levels in the lipoprotein-depleted fractions were higher in subjects with diabetes. LPI bound to albumin induced the secretion of IL-6 and TNF-α from RAW264.7 cells to a greater degree than LPI bound to LDL or HDL. These results suggest that LPI, especially the albumin-bound form, induced inflammatory cytokines depending on the GPR55/p38 pathway, which might contribute to the pathogenesis of obesity-induced inflammation and acute inflammation.Chronic inflammation-related diseases are characterized by persistent leukocyte infiltration into the underlying tissue. The vascular endothelium plays a major role in this pathophysiological condition. Only few therapeutic strategies focus on the vascular endothelium as a major target for an anti-inflammatory approach. In this study, we present the natural compound-derived carbazole derivative C81 as chemical modulator interfering with leukocyte-endothelial cell interactions. An in vivo assay employing intravital microscopy to monitor leukocyte trafficking after C81 treatment in postcapillary venules of a murine cremaster muscle was performed. Moreover, in vitro assays using HUVECs and monocytes were implemented. The impact of C81 on cell adhesion molecules and the NFκB signaling cascade was analyzed in vitro in endothelial cells. Effects of C81 on protein translation were determined by incorporation of a puromycin analog-based approach and polysome profiling. We found that C81 significantly reduced TNF-activated leukocyte trafficking in postcapillary venules. Similar results were obtained in vitro when C81 reduced leukocyte-endothelial cell interactions by down-regulating cell adhesion molecules. Focusing on the NFκB signaling cascade, we found that C81 reduced the activation on multiple levels of the cascade through promoted IκBα recovery by attenuation of IκBα ubiquitination and through reduced protein levels of TNFR1 caused by protein translation inhibition. We suggest that C81 might represent a promising lead compound for interfering with inflammation-related processes in endothelial cells by down-regulation of IκBα ubiquitination on the one hand and inhibition of translation on the other hand without exerting cytotoxic effects.Over the last decade, multiple studies have highlighted the essential role of gut microbiota in normal infant development. However, the sensitive periods during which gut bacteria are established and become associated with physical growth and maturation of the brain are still poorly defined. This study tracked the assembly of the intestinal microbiota during the initial nursing period, and changes in community structure after transitioning to solid food in infant rhesus monkeys (Macaca mulatta). Anthropometric measures and rectal swabs were obtained at 2-month intervals across the first year of life and bacterial taxa identified by 16S rRNA gene sequencing. At 12 months of age, total brain and cortical regions volumes were quantified through structural magnetic resonance imaging. The bacterial community structure was dynamic and characterized by discrete maturational phases, reflecting an early influence of breast milk and the later transition to solid foods. Commensal microbial taxa varied with diet similar to findings in other animals and human infants; however, monkeys differ in the relative abundances of Lactobacilli and Bifidobacteria, two taxa predominant in breastfed human infants.