Kirkegaardshepard8106

Aberrant redox signaling underlies the pathophysiology of many chronic metabolic diseases, including type 2 diabetes (T2D). Methodologies aimed at rebalancing systemic redox homeostasis have had limited success. A noninvasive, sustained approach would enable the long-term control of redox signaling for the treatment of T2D. We report that static magnetic and electric fields (sBE) noninvasively modulate the systemic GSH-to-GSSG redox couple to promote a healthier systemic redox environment that is reducing. Strikingly, when applied to mouse models of T2D, sBE rapidly ameliorates insulin resistance and glucose intolerance in as few as 3 days with no observed adverse effects. Scavenging paramagnetic byproducts of oxygen metabolism with SOD2 in hepatic mitochondria fully abolishes these insulin sensitizing effects, demonstrating that mitochondrial superoxide mediates induction of these therapeutic changes. Our findings introduce a remarkable redox-modulating phenomenon that exploits endogenous electromagneto-receptive mechanisms for the noninvasive treatment of T2D, and potentially other redox-related diseases.The gut microbiome has been linked to fear extinction learning in animal models. Here, we aimed to explore the gut microbiome and memory domains according to obesity status. A specific microbiome profile associated with short-term memory, working memory, and the volume of the hippocampus and frontal regions of the brain differentially in human subjects with and without obesity. Plasma and fecal levels of aromatic amino acids, their catabolites, and vegetable-derived compounds were longitudinally associated with short-term and working memory. Functionally, microbiota transplantation from human subjects with obesity led to decreased memory scores in mice, aligning this trait from humans with that of recipient mice. RNA sequencing of the medial prefrontal cortex of mice revealed that short-term memory associated with aromatic amino acid pathways, inflammatory genes, and clusters of bacterial species. These results highlight the potential therapeutic value of targeting the gut microbiota for memory impairment, specifically in subjects with obesity.Mitochondrial dysfunction is a hallmark of heart disease. Nicolás-Ávila et al. Celastrol solubility dmso (2020) now find that cardiomyocytes eject dysfunctional mitochondria in exopher vesicles, which require elimination by specialized heart-resident macrophages, altogether supporting proper heart function.The exact principles guiding host-microbe homeostasis in the intestinal tract remain obscure. In a recent issue of Nature, Wu et al. (2020) describe that bacterial-derived inositols are an important principle that shapes regenerative properties of the colonic epithelium. The metabolites activate HDAC3, which represents an important part of the epigenetic machinery.Although a crucial role for mitochondrial metabolism in controlling T regulatory (Treg) cell function has been recognized, its contribution during autoimmunity has not yet been fully elucidated. In this issue of Cell Metabolism, Alissafi and colleagues demonstrate that during autoimmunity, Treg cell functional alterations associate with mitochondrial oxidative stress, dysfunctional mitophagy, and enhanced DNA damage response, culminating with their cell death.In this issue of the Cell Metabolism, Chevalier et al. show that a warm environment produces changes in the composition of intestinal microbiota and that these changes can prevent bone loss due to hypogonadism. Dovetailing with prior studies on the ability of probiotics to reverse hypogonadism-induced osteopenia, the findings reaffirm a central role for the microbiome in regulating bone mass in response to both environmental and hormonal cues.Epidemiological studies suggest that physical exercise or cognitive stimulation might contribute to lower the risk of developing dementia disorders such as Alzheimer's disease (AD). link2 Here, we used the well-established enrichment environment (EE) paradigm to study the impact of prolonged physical activity and cognitive stimulation in a mouse model of AD overexpressing only Aβ4-42 peptides. These mice display age-dependent memory and motor deficits, in the absence of human amyloid precursor protein (APP) overexpression. We demonstrate that housing under EE conditions leads to an entire preservation of recognition and spatial memory, as well as a rescue of motor deficits in this mouse model. Moreover, we find that Tg4-42hom mice present a typical floating phenotype in the Morris water maze task that could be completely ameliorated upon long-term EE housing. Our findings are in line with epidemiological studies suggesting that physical activity and cognitive stimulation might represent efficient strategies to prevent age-related neurodegenerative disorders such as AD.Synthetic lethality triggered by PARP inhibitor (PARPi) yields promising therapeutic results. Unfortunately, tumor cells acquire PARPi resistance, which is usually associated with the restoration of homologous recombination, loss of PARP1 expression, and/or loss of DNA double-strand break (DSB) end resection regulation. Here, we identify a constitutive mechanism of resistance to PARPi. We report that the bone marrow microenvironment (BMM) facilitates DSB repair activity in leukemia cells to protect them against PARPi-mediated synthetic lethality. This effect depends on the hypoxia-induced overexpression of transforming growth factor beta receptor (TGFβR) kinase on malignant cells, which is activated by bone marrow stromal cells-derived transforming growth factor beta 1 (TGF-β1). Genetic and/or pharmacological targeting of the TGF-β1-TGFβR kinase axis results in the restoration of the sensitivity of malignant cells to PARPi in BMM and prolongs the survival of leukemia-bearing mice. Our finding may lead to the therapeutic application of the TGFβR inhibitor in patients receiving PARPis.Despite the important roles of protein kinase Cε (PKCε) and transient receptor potential vanilloind 1 (TRPV1) in inflammatory hypersensitivity, how PKCε is involved in the regulation of thermal hyperalgesia is not fully understood. We report here that PKCε is SUMOylated at a C-terminal lysine residue (K534), which enhances the sensitivity of the TRPV1 channel. We demonstrate that PKCε phosphorylation promotes its SUMOylation, which in turn regulates the phosphorylation level of TRPV1 serine 800 residue via controlling the binding of PKCε and TRPV1 and increased PKCε kinase activity. More importantly, the reduced ability of PKCε knockdown mice to develop inflammatory thermal hyperalgesia was rescued by viral infection of lumbar 4/5 dorsal root ganglia neurons of wild-type PKCε, but not the SUMOylation-deficient PKCε mutant. Therefore, the SUMOylation of PKCε potentiates inflammatory thermal hyperalgesia through stabilizing the interaction with TRPV1 to enhance its function by phosphorylation.mTOR is a serine/threonine kinase and a master regulator of cell growth and proliferation. Raptor, a scaffolding protein that recruits substrates to mTOR complex 1 (mTORC1), is known to be phosphorylated during mitosis, but the significance of this phosphorylation remains largely unknown. Here we show that raptor expression and mTORC1 activity are dramatically reduced in cells arrested in mitosis. Expression of a non-phosphorylatable raptor mutant reactivates mTORC1 and significantly reduces cytotoxicity of the mitotic poison Taxol. This effect is mediated via degradation of PDCD4, a tumor suppressor protein that inhibits eIF4A activity and is negatively regulated by the mTORC1/S6K pathway. Moreover, pharmacological inhibition of eIF4A is able to enhance the effects of Taxol and restore sensitivity in Taxol-resistant cancer cells. These findings indicate that the mTORC1/S6K/PDCD4/eIF4A axis has a pivotal role in the death versus slippage decision during mitotic arrest and may be exploited clinically to treat tumors resistant to anti-mitotic agents.Early developmental specification can be modeled by differentiating embryonic stem cells (ESCs) to embryoid bodies (EBs), a heterogeneous mixture of three germ layers. Here, we combine single-cell transcriptomics and genetic recording to characterize EB differentiation. We map transcriptional states along a time course and model cell fate trajectories and branchpoints as cells progress to distinct germ layers. link3 To validate this inferential model, we propose an innovative inducible genetic recording technique that leverages recombination to generate cell-specific, timestamp barcodes in a narrow temporal window. We validate trajectory architecture and key branchpoints, including early specification of a primordial germ cell (PGC)-like lineage from preimplantation epiblast-like cells. We further identify a temporally defined role of DNA methylation in this PGC-epiblast decision. Our study provides a high-resolution lineage map for an organoid model of embryogenesis, insights into epigenetic determinants of fate specification, and a strategy for lineage mapping of rapid differentiation processes.Immune cells in the mucosal barriers of vertebrates are highly heterogeneous in their origin and function. This heterogeneity is further exemplified by the recent discovery of ectoderm-derived immune cells-metaphocytes in zebrafish epidermis. Yet, whether non-hematopoiesis-derived immune cells generally exist in barrier tissues remains obscured. Here, we report the identification and characterization of an endoderm-derived immune cell population in the gill and intestine of zebrafish. Transcriptome analysis reveals that the endoderm-derived immune cells are myeloid-like cells with high similarities to the ectoderm-derived metaphocytes in epidermis. Like metaphocytes in epidermis, the endoderm-derived immune cells are non-phagocytic but professional in external soluble antigen uptake. Depletion of the endoderm-derived immune cells in gill hinder the local immune response to external soluble stimulants. This study demonstrates a general existence of non-hematopoiesis-derived immune cells in zebrafish mucosal barriers and challenges the prevalent view that resident immune cells in mucosal barriers arise exclusively from hematopoiesis.Endogenous PIEZO1 channels of native endothelium lack the hallmark inactivation often seen when these channels are overexpressed in cell lines. Because prior work showed that the force of shear stress activates sphingomyelinase in endothelium, we considered if sphingomyelinase is relevant to endogenous PIEZO1. Patch clamping was used to quantify PIEZO1-mediated signals in freshly isolated murine endothelium exposed to the mechanical forces caused by shear stress and membrane stretch. Neutral sphingomyelinase inhibitors and genetic disruption of sphingomyelin phosphodiesterase 3 (SMPD3) cause PIEZO1 to switch to profoundly inactivating behavior. Ceramide (a key product of SMPD3) rescues non-inactivating channel behavior. Its co-product, phosphoryl choline, has no effect. In contrast to ceramide, sphingomyelin (the SMPD3 substrate) does not affect inactivation but alters channel force sensitivity. The data suggest that sphingomyelinase activity, ceramide, and sphingomyelin are determinants of native PIEZO gating that enable sustained activity.