Slc39a7/zip7 Plays a Critical Role in Development and Zinc Homeostasis in Zebrafish

Background: Slc39a7/Zip7, also known as Ke4, is a member of solute carrier family 39 (Slc39a) and plays a critical role in regulating cell growth and death. Because the function of Zip7 in vivo was unclear, the present study investigated the function of zip7 in vertebrate development and zinc metabolism using zebrafish as a model organism. Principal Finding: Using real-time PCR to determine the gene expression pattern of zip7 during zebrafish development, we found that zip7 mRNA is expressed throughout embryonic development and into maturity. Interestingly, whole mount in situ hybridization revealed that while zip7 mRNA is ubiquitously expressed until 12 hours post-fertilization (hpf); at 24 hpf and beyond, zip7 mRNA was specifically detected only in eyes. Morpholino-antisense (MO) gene knockdown assay revealed that downregulation of zip7 expression resulted in several morphological defects in zebrafish including decreased head size, smaller eyes, shorter palates, and shorter and curved spinal cords. Analysis by synchrotron radiation X-ray fluorescence (SR-XRF) showed reduced concentrations of zinc in brain, eyes, and gills of zip7-MO-injected embryos. Furthermore, incubation of the zip7 knockdown embryos in a zinc-supplemented solution was able to rescue the MO-induced morphological defects. Significance: Our data suggest that zip7 is required for eye, brain, and skeleton formation during early embryonic development in zebrafish. Moreover, zinc supplementation can partially rescue defects resulting from zip7 gene knockdown. Taken together, our data provide critical insight into a novel function of zip7 in development and zinc homeostasis in vivo in zebrafish

Adipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL 316,243-stimulated lipolysis

Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism. To our surprise, adipocyte-specific overproduction of HA leads to smaller adipocytes and protects mice from high-fat-high-sucrose-diet-induced obesity and glucose intolerance. Adipocytes also have more free glycerol that can be released upon beta3 adrenergic stimulation. Improvements in glucose tolerance were not linked to increased plasma HA. Instead, an HA-driven systemic substrate redistribution and adipose tissue-liver crosstalk contributes to the systemic glucose improvements. In summary, we demonstrate an unexpected improvement in glucose metabolism as a consequence of HA overproduction in adipose tissue, which argues against the use of systemic HA synthesis inhibitors to treat obesity and T2D

Adipocyte mesenchymal transition contributes to mammary tumor progression

Obesity is associated with increased cancer incidence and progression. However, the relationship between adiposity and cancer remains poorly understood at the mechanistic level. Here, we report that adipocytes from tumor-invasive mammary fat undergo de-differentiation to fibroblast-like precursor cells during tumor progression and integrate into the tumor microenvironment. Single-cell sequencing reveals that these de-differentiated adipocytes lose their original identities and transform into multiple cell types, including myofibroblast- and macrophage-like cells, with their characteristic features involved in immune response, inflammation, and extracellular matrix remodeling. The de-differentiated cells are metabolically distinct from tumor-associated fibroblasts but exhibit comparable effects on tumor cell proliferation. Inducing de-differentiation by Xbp1s overexpression promotes tumor progression despite lower adiposity. In contrast, promoting lipid-storage capacity in adipocytes through MitoNEET overexpression curbs tumor growth despite greater adiposity. Collectively, the metabolic interplay between tumor cells and adipocytes induces adipocyte mesenchymal transition and contributes to reconfigure the stroma into a more tumor-friendly microenvironment

Dichloridobis[1-(2,4,6-trimethylphenyl)-1H-imidazole-κN3]copper(II)

In the title complex, [CuCl2(C12H14N2)2], the Cu2+ cation is situated on an inversion centre and is coordinated by two N atoms from symmetry-related 1-mesityl-1H-imidazole ligands and by two chloride anions in a slightly distorted square-planar geometry. In the organic ligand, the dihedral angle between the benzene ring of the mesityl moiety and the imidazole ring is 76.99 (18)°. Weak intramolecular C—H...Cl hydrogen-bonding interactions consolidate the molecular conformation

Phenotypical Conversions of Dermal Adipocytes as Pathophysiological Steps in Inflammatory Cutaneous Disorders

Adipocytes from the superficial layer of subcutaneous adipose tissue undergo cyclic de- and re-differentiation, which can significantly influence the development of skin inflammation under different cutaneous conditions. This inflammation can be connected with local loading of the reticular dermis with lipids released due to de-differentiation of adipocytes during the catagen phase of the hair follicle cycle. Alternatively, the inflammation parallels a widespread release of cathelicidin, which typically takes place in the anagen phase (especially in the presence of pathogens). Additionally, trans-differentiation of dermal adipocytes into myofibroblasts, which can occur under some pathological conditions, can be responsible for the development of collateral scarring in acne. Here, we provide an overview of such cellular conversions in the skin and discuss their possible involvement in the pathophysiology of inflammatory skin conditions, such as acne and psoriasis

Cyclin Y Is Involved in the Regulation of Adipogenesis and Lipid Production

<div><p>A new member of the cyclin family cyclin Y (CCNY) is involved in the regulation of various physiological processes. In this study, the role of CCNY in energy metabolism was characterized. We found that compared with wild-type (WT) mice, <i>Ccny</i> knockout (KO) mice had both lower body weight and lower fat content. The <i>Ccny</i> KO mice also had a higher metabolic rate, resisted the stress of a high-fat diet, and were sensitive to calorie restriction. The expression levels of UCP1 and PGC1α were significantly higher in the brown adipose tissue (BAT) of the <i>Ccny</i> KO mice than that of the WT littermate controls, whereas there was no significant difference in BAT weight between the WT and the <i>Ccny</i> KO mice. In addition, the down-regulation of <i>Ccny</i> resulted in suppression of white adipocyte differentiation both <i>in vivo</i> and <i>in vitro</i>, while the expression of <i>Ccny</i> was up-regulated by C/EBPα. Furthermore, both hepatocytes and HepG2 cells that were depleted of <i>Ccny</i> were insensitive to insulin stimulation, consistent with the significant inhibition of insulin sensitivity in the liver of the <i>Ccny</i> KO mice, but no significant changes in WAT and muscle, indicating that CCNY is involved in regulating the hepatic insulin signaling pathway. The hepatic insulin resistance generated by <i>Ccny</i> depletion resulted in down-regulation of the sterol-regulatory element-binding protein (SREBP1) and fatty acid synthase (FASN). Together, these results provide a new link between CCNY and lipid metabolism in mice, and suggest that inhibition of CCNY may offer a therapeutic approach to obesity and diabetes.</p></div

Nanozyme Sensor Based on Au Nanoparticles/N-Doped Porous Carbon Composites for Biosensing

The rational construction of nanomaterials with boosted peroxidase (POD)-like activity is momentous in artificial enzyme design and biological catalytic fields. Herein, a hybrid nanozyme, gold nanoparticles/N-doped porous carbon (AuNPs/NPC), is fabricated via a supramolecular assembly-assisted pyrolysis strategy and engineered as a peroxidase mimic. In this strategy, a melamine-cyanurate supramolecular aggregate can be employed not only as a self-vanishing template to gain porous morphology but also as a nitrogen source to achieve an exceptional high N doping. The obtained NPC is then subsequently used to immobilize AuNPs via an in situ reduction approach. Benefiting from well-dispersed ultrafine AuNPs, high N content, hierarchical porous architecture, and the synergistic effect of AuNPs and NPC, the fabricated nanozyme exhibits enhanced POD-like activity, making it a potential alternative to peroxidase mimics. Besides, the AuNPs/NPC shows highly electrocatalytic properties, which could serve as a signal amplification platform for ultrasensitively detecting hydrogen peroxide (H2O2). The hybrid nanozyme-based electrochemical sensor shows a linear relationship within 0.2–7000 μM. Significantly, the sensitivity and limit of detection of the fabricated sensor are 285.9 μA mM–1 cm–2 and 67 nM, respectively. Also, this biosensor is applied to detect H2O2 in human serum samples and A549 cells with desirable results. Therefore, the present work offers a facile strategy for the fabrication of a high N-contained hybrid nanozyme to simulate the catalytic activity of natural enzymes and exhibits broad prospects in biosensing, mimicking-enzyme catalytic fields, and clinical diagnosis

Bmp6 expression can be regulated independently of liver iron in mice.

The liver is the primary organ for storing iron and plays a central role in the regulation of body iron levels by secretion of the hormone Hamp1. Although many factors modulate Hamp1 expression, their regulatory mechanisms are poorly understood. Here, we used conditional knockout mice for the iron exporter ferroportin1 (Fpn1) to modulate tissue iron in specific tissues in combination with iron-deficient or iron-rich diets and transferrin (Tf) supplementation to investigate the mechanisms underlying Hamp1 expression. Despite liver iron overload, expression of bone morphogenetic protein 6 (Bmp6), a potent-stimulator of Hamp1 expression that is expressed under iron-loaded conditions, was decreased. We hypothesized that factors other than liver iron must play a role in controlling Bmp6 expression. Our results show that erythropoietin and Tf-bound iron do not underlie the down-regulation of Bmp6 in our mice models. Moreover, Bmp6 was down-regulated under conditions of high iron demand, irrespective of the presence of anemia. We therefore inferred that the signals were driven by high iron demand. Furthermore, we also confirmed previous suggestions that Tf-bound iron regulates Hamp1 expression via Smad1/5/8 phosphorylation without affecting Bmp6 expression, and the effect of Tf-bound iron on Hamp1 regulation appeared before a significant change in Bmp6 expression. Together, these results are consistent with novel mechanisms for regulating Bmp6 and Hamp1 expression