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PubMed Journal Database | JCI insight RSS

10:04 EST 21st February 2020 | BioPortfolio

The US National Library of Medicine and National Institutes of Health manage PubMed.gov which comprises of more than 29 million records, papers, reports for biomedical literature, including MEDLINE, life science and medical journals, articles, reviews, reports and  books.

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For example view all recent relevant publications on Epigenetics and associated publications and clincial trials.

Showing PubMed Articles 1–25 of 323 from JCI insight

Transcriptional co-repressor Sin3a regulates hippocampal synaptic plasticity via Homer1/mGluR5.

Long-term memory depends on the control of activity-dependent neuronal gene expression, which is regulated by epigenetic modifications. The epigenetic modification of histones is orchestrated by the opposing activities of two classes of regulatory complexes: permissive co-activators and silencing co-repressors. Much work has focused on co-activator complexes, but little is known about the co-repressor complexes that suppress the expression of plasticity-related genes. Here, we define a critical role for the...

TNFα regulates diabetic macrophage function through the histone acetyl-transferase, MOF.

A critical component of wound healing is the transition from the inflammatory phase to the proliferation phase to initiate healing and remodeling of the wound. Macrophages are critical for the initiation and resolution of the inflammatory phase during wound repair. In diabetes, macrophages display a sustained inflammatory phenotype in late wound healing characterized by elevated production of inflammatory cytokines such as TNFα. Previous studies have shown that an altered epigenetic program directs diabeti...

The UPR preserves mature oligodendrocyte viability and function in adults by regulating autophagy of PLP.

Maintaining cellular proteostasis is essential for oligodendrocyte viability and function; however, its underlying mechanisms remain unexplored. The UPR, comprising three parallel branches IRE1, PERK, and ATF6α, is a major mechanism that maintains cellular proteostasis by facilitating protein folding, attenuating protein translation, and enhancing autophagy and ERAD. Here we reported that impaired UPR in oligodendrocytes via deletion of PERK and ATF6α did not affect developmental myelination, but caused l...

Aim2-Mediated/IFN-β-Independent Regulation of Gastric Metaplastic Lesions via CD8+ T Cells.

Development of gastric cancer is often preceded by chronic inflammation, but the immune cellular mechanisms underlying this process are unclear. Here we demonstrated that an inflammasome molecule, absent in melanoma 2 (Aim2), was upregulated in gastric cancer patients, and in spasmolytic polypeptide-expressing metaplasia (SPEM) of chronically Helicobacter felis (H. felis)-infected stomachs in mice. However, we found that Aim2 was not necessary for inflammasome function during gastritis. In contrast, Aim2 de...

Fibroblast subtypes define a metastatic matrisome in breast cancer.

Small primary breast cancers can show surprisingly high potential for metastasis. Clinical decision making for tumor aggressiveness, including molecular profiling, relies primarily on analysis of the cancer cells. Here we show that this is insufficient; that the stromal microenvironment of the primary tumor plays a key role in tumor-cell dissemination and implantation at distant sites. We previously described two cancer-associated fibroblasts (CAFs) that either express (CD146pos) or lack (CD146neg) CD146 (o...

Mesenchymal stromal cells shape the MDS microenvironment by inducing suppressive monocytes that dampen NK cell function.

Altered bone marrow hematopoiesis and immune suppression is a hallmark of myelodysplastic syndrome (MDS). While the bone marrow microenvironment influences malignant hematopoiesis, the mechanism leading to MDS-associated immune suppression is unknown. We tested whether mesenchymal stromal cells (MSCs) contribute to this process. Here, we developed a model to study cultured MSCs from MDS patients compared to similar aged matched normal controls for regulation of immune function. MSCs from MDS patients (MDS-M...

Differential decay of intact and defective proviral DNA in HIV-1-infected individuals on suppressive antiretroviral therapy.

The relative stabilities of the intact and defective HIV genomes over time during effective antiretroviral therapy (ART) have not been fully characterized.

Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis.

Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently-discovered damage-associated molecular pattern. Understanding the precise mechanism by which it exacerbates inflammation is essential. Here we identified that eCIRP is a new biologically active endogenous ligand of triggering receptor expressed on myeloid cells-1 (TREM-1), fueling inflammation in sepsis. Surface plasmon resonance revealed a strong binding affinity between eCIRP and TREM-1, and FRET assay confirmed eCIRP's interaction wit...

Extracellular CIRP induces macrophage endotoxin tolerance through IL-6R-mediated STAT3 activation.

Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern, whose effect on macrophages is not entirely elucidated. Here we identified that eCIRP promotes macrophage endotoxin tolerance. Septic mice had higher serum levels of eCIRP; this was associated with a reduced ex vivo immune response of their splenocytes to LPS. Pretreatment of macrophages with recombinant murine (rm) CIRP resulted in a tolerance to LPS stimulation as demonstrated by a significant reduction of T...

Monocyte-derived alveolar macrophage Apolipoprotein E participates in pulmonary fibrosis resolution.

Recent studies have presented compelling evidence that it is not tissue-resident, but rather monocyte-derived alveolar macrophages (TR-AMs vs. Mo-AMs) are essential to development of experimental lung fibrosis. However, whether Apolipoprotein E (ApoE), which is produced abundantly by Mo-AMs in the lung, plays a role in the pathogenesis is unclear. In this study, we found that pulmonary ApoE was almost exclusively produced by Mo-AMs in mice with bleomycin induced lung fibrosis. We showed although ApoE was no...

EMRE is essential for mitochondrial calcium uniporter activity in a mouse model.

The mitochondrial calcium uniporter is widely accepted as the primary route of rapid calcium entry into mitochondria, where increases in matrix calcium contribute to bioenergetics but also mitochondrial permeability and cell death. Hence, regulation of uniporter activity is critical to mitochondrial homeostasis. The uniporter subunit EMRE is known to be an essential regulator of the channel-forming protein MCU in cell culture, but EMRE's impact on organismal physiology is less understood. Here we characteri...

Dlx1/2 mice have abnormal enteric nervous system function.

Decades ago, investigators reported that mice lacking DLX1 and DLX2, transcription factors expressed in the enteric nervous system (ENS), die with possible bowel motility problems. These problems were never fully elucidated. We found that mice lacking DLX1 and DLX2 (Dlx1/2-/- mice) had slower small bowel transit and reduced or absent neurally-mediated contraction complexes. In contrast, small bowel motility seemed normal in adult mice lacking DLX1 (Dlx1-/-). Even with detailed anatomic studies, we found no ...

Genetic modification increases the survival and the neuroregenerative properties of transplanted neural stem cells.

Cell therapy raises high hopes for better treatment of brain disorders. However, the majority of transplanted cells often die soon after transplantation and those that survive initially continue to die in the subacute phase, diminishing the impact of transplantations. In this study, we genetically modified transplanted human neural stem cells (hNSCs), from two distant embryonic SCs lines (H9 and RC17) to express one of four prosurvival factors - Hif1a, Akt1, Bcl-2, or Bcl-xl - and studied how these modifica...

Differences in the induced latent HIV reservoir in perinatal and adult infection.

The HIV latent reservoir in resting memory CD4+ T cells prevents cure. Therapeutics to reactivate and eliminate this reservoir are in clinical trials in adults, but not in pediatric populations. We determined, ex vivo, the inducibility and size of the latent reservoir in perinatal compared with adult infections using the Tat/rev Induced Limiting Dilution Assay (TILDA), in which a single-round (12hr) of CD4+ T cell stimulation with PMA/ionomycin maximally activates T cells and leads to proviral expression wi...

TGFβ inhibition via CRISPR promotes the long-term efficacy of CAR-T cells against solid tumors.

In recent years, CAR-T cell therapy has proven to be a promising approach against cancer. Nonetheless, this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME). Here we demonstrated that knocking out the endogenous TGFβ receptor II (TGFBR2) in CAR-T cells with CRISPR/Cas9 technology could reduce the induced regulatory T-cell (iTreg) conversion and prevent the exhaustion of CAR-T cells. Meanwhile, TGFBR2 edited CAR-T cel...

Cellular and molecular architecture of hematopoietic stem cells and progenitors in genetic models of bone marrow failure.

Inherited bone marrow failure syndromes (IBMFSs) such as Fanconi Anemia (FA) and Shwachman-Diamond syndrome (SDS) feature progressive cytopenia and a risk of acute myeloid leukemia (AML). Using deep phenotypic analysis of early progenitors in FA/SDS bone marrow samples we revealed selective survival of progenitors that phenotypically resembled granulocyte-monocyte progenitors (GMP). Whole exome and targeted sequencing of GMP-like cells in leukemia-free patients revealed a higher mutation load than in health...

Chronic liver disease and impaired hepatic glycogen metabolism in argininosuccinate lyase deficiency.

Liver disease in urea cycle disorders (UCDs) ranges from hepatomegaly and chronic hepatocellular injury to cirrhosis and end-stage liver disease. However, the prevalence and underlying mechanisms are unclear.

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis.

ADPKD is the most common genetic cause of end stage kidney disease (ESRD). The treatment options for ADPKD are limited. We observed an upregulation in several IGF-1 pathway genes in the kidney of the Pkd1RC/RC mice. Pregnancy-associated plasma protein-A (PAPP-A), a metalloproteinase which cleaves inhibitory insulin-like growth factor binding proteins (IGFBPs), increasing the local bioactivity of IGF-1 was highly induced in the kideny of ADPKD mice. PAPP-A levels were high in cystic fluid and kidneys of huma...

Pneumonia recovery reprograms the alveolar macrophage pool.

Community-acquired pneumonia is a widespread disease with significant morbidity and mortality. Alveolar macrophages are tissue-resident lung cells that play a crucial role in innate immunity against bacteria that cause pneumonia. We hypothesized that alveolar macrophages display adaptive characteristics after resolution of bacterial pneumonia. We studied mice one to six months after self-limiting lung infections with Streptococcus pneumoniae, the most common cause of bacterial pneumonia. Alveolar macrophage...

Rescuing compounds for Lesch-Nyhan disease identified using stem cell-based phenotypic screening.

Lesch-Nyhan disease (LND) is a rare monogenic disease caused by deficiency of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and is characterized by severe neuropsychiatric symptoms that currently cannot be treated. Predictive in vivo models are lacking for screening and evaluating candidate drugs because LND-associated neurological symptoms are not recapitulated in HGPRT-deficient animals. Here, we used human neural stem cells and neurons derived from induced pluripotent ...

Alcohol exposure-induced neurovascular inflammatory priming impacts ischemic stroke and is linked with brain perivascular macrophages.

Alcohol abuse is a major public health problem worldwide causing a wide range of preventable morbidity and mortality. In this translational study, we show that heavy drinking (HD) (≥6 standard drinks/day) is independently associated to a worse outcome of ischemic stroke patients. To study the underlying mechanisms of this deleterious effect of HD, we then performed an extensive analysis of the brain inflammatory responses of mice exposed or not to 10% alcohol before and after ischemic stroke. Inflammatory...

Fetal and amniotic fluid iron homeostasis in healthy and complicated murine, macaque, and human pregnancy.

Adequate iron supply during pregnancy is essential for fetal development. However, how fetal or amniotic fluid iron levels are regulated during healthy pregnancy, or pregnancies complicated by intraamniotic infection or inflammation (IAI) is unknown. We evaluated amniotic fluid and fetal iron homeostasis in normal and complicated murine, macaque, and human pregnancy. In mice, fetal iron endowment was affected by maternal iron status but amniotic fluid iron concentrations changed little during maternal iron ...

Regnase-1 degradation is crucial for interleukin-33- and interleukin-25-mediated ILC2 activation.

Group-2 innate lymphoid cells (ILC2s) are a critical innate source of type-2 cytokines in allergic inflammation. Although ILC2s are recognized as a critical cell population in the allergic inflammation, the regulatory mechanism(s) of ILC2s are less well understood. Here, we show that Regnase-1, an immune-regulatory RNase that degrades inflammatory mRNAs, negatively regulates ILC2 function, and that IkB kinase (IKK) complex-mediated Regnase-1 degradation is essential for IL-33- and IL-25-induced ILC2 activat...

The RNFT2/IL3Rα axis regulates IL3 signaling and innate immunity.

Interleukin-3 (IL3) receptor α (IL3Rα) is the alpha subunit of the ligand-specific IL3 receptor and initiates intracellular signaling in response to IL3. IL3 amplifies pro-inflammatory signaling and cytokine storm in murine sepsis models. Here we found that RNFT2 (RING finger transmembrane-domain containing protein 2, also TMEM118), a previously uncharacterized RING finger ubiquitin E3 ligase, negatively regulated IL3-dependent cellular responses through IL3Rα ubiquitination and degradation in the protea...

Arp2/3 inactivation causes intervertebral disc and cartilage degeneration with dysregulated TonEBP-mediated osmoadaptation.

Extracellular matrix and osmolarity influence the development and homeostasis of skeletal tissues through Rho GTPase-mediated alteration of the actin cytoskeleton. This study investigated whether the actin-branching Arp2/3 complex, a downstream effector of the Rho GTPases Cdc42 and Rac1, plays a critical role in maintaining the health of matrix-rich and osmotically loaded intervertebral discs and cartilage. Mice with constitutive intervertebral disc and cartilage-specific deletion of the critical Arp2/3 sub...


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