Inflammatory bowel disease (IBD), which includes Crohn's and ulcerative colitis, is an inflammatory autoimmune characterized by T-cell infiltration to the colon. Mesenchymal stem cells (MSCs) have potential rescue IBD owing their immunosuppressive capabilities clinical studies shown positive influence on intestinal graft versus host disease. We demonstrate here a new method coat MSCs with antibodies against addressins enhance delivery colon thereby increase therapeutic effectiveness....

It has been reported that retinoic acid (RA) enhances regulatory T (T reg) cell conversion by inhibiting the secretion of cytokines interfere with conversion. This report shows these conclusions provide a partial explanation at best. First, RA not only interfered cytokine but also ability to inhibit reg naive cells. Furthermore, enhanced even in absence inhibitory cytokines. The latter effect depended on receptor α (RARα) did require Smad3, despite fact Smad3 expression. RARα1 isoform was...

Aminoacyl-tRNA Synthetases (ARSs) acylate tRNAs with amino acids. Charging the right acids is first step in translation; therefore, accurate and error-free functioning of ARSs an essential prerequisite for translational fidelity. A recent study found that methionine (Met) can be incorporated into non-Met residues proteins through methionylation to non-cognate under oxidative stress. However, it was not understood how this mis-methionylation achieved. Here, we report methionyl-tRNA synthetase...

Runx2 is a key transcription factor in osteoblast differentiation, and its activity regulated by fibroblast growth factors (FGFs). Craniosynostosis, characterized premature suture closure, results from mutations that generate constitutively active FGF receptors (FGFRs). We previously showed FGF/FGFR-activated protein kinase C (PKC) involved the expression of Runx2. Activated PKCdelta physically interacts with FGF2-stimulated MC3T3-E1 preosteoblastic cells. Immunopurified reacted kinase,...

Colitis-associated colon cancer (CAC) develops as a result of inflammation-induced epithelial transformation, which occurs in response to inflammatory cytokine-dependent downregulation 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and subsequent suppression prostaglandin metabolism. Agents that both enhance 15-PGDH expression suppress cyclooxygenase-2 (COX-2) production may more effectively prevent CAC. Synthetic triterpenoids are class small molecules COX-2 well cytokine signaling. Here,...

In fasting or diabetes, gluconeogenic genes are transcriptionally activated by glucagon stimulation of the cAMP-protein kinase A (PKA)–CREB signaling pathway. Previous work showed pyruvate dehydrogenase (PDK) inhibition in skeletal muscle increases oxidation, which limits availability substrates liver. However, this study found upregulation hepatic PDK4 promoted glucagon-mediated expression genes, whereas knockdown caused opposite effect on gene and decreased glucose production....

Abstract Hepatic stellate cells (HSCs) inhibit T cells, a process that could help the liver to maintain its immunoprivileged status. HSCs secrete latent TGF-β1, but detailed mechanisms by which TGF-β1 is activated and whether it plays any role in HSC-mediated cell suppression remain unclear. Glycoprotein A repetitions predominant (GARP) surface marker of regulatory cells. GARP binds for activation, critical suppress effector cells; however, still unclear present on has impact HSC function....

The interleukin 2 receptor α chain (IL-2Rα) is a component of high affinity IL-2 receptors and thus critically regulates T cell growth other lymphoid functions. Five positive regulatory regions together control lineage-restricted activation-dependent IL-2Rα induction in response to antigen IL-2. We now show that TGF-β cooperates with (TCR) signaling increase gene expression. Moreover, we identify sixth region expression cells treated anti-CD3 + anti-CD28 as well this contains binding sites...

Celastrol is an anti-inflammatory natural triterpenoid, isolated from the herb Tripterygium wilfordii or thunder god vine. Here, we define mechanisms mediating activity of celastrol and demonstrate efficacy a dietary supplement for chemoprevention inflammation-driven carcinogenesis in mice. Dietary (31.25 ppm rodent diet 8 weeks to 25 age) well tolerated protects against LPS-induced acute inflammation C57BL/6 mice, potently suppressing LPS-induction inducible nitric oxide synthase (iNOS),...

Abstract Chromatin remodelers regulate the nucleosome barrier during transcription, DNA replication, and repair. The chromatin remodeler RSF1 is enriched at mitotic centromeres, but functional consequences of this enrichment are not completely understood. Shugoshin (Sgo1) protects centromeric cohesion mitosis requires BuB1-dependent histone H2A phosphorylation (H2A-pT120) for localization. Loss Sgo1 centromeres causes chromosome missegregation. Here, we show that regulates localization to...

Functional effector T cells in the tumor microenvironment (TME) are critical for successful anti-tumor responses. cell function is dependent on their ability to differentiate from a naïve state, infiltrate into site, and exert cytotoxic functions. The factors dictating whether particular can successfully undergo these processes during challenge not yet completely understood. Piezo1 mechanosensitive cation channel with high expression both CD4+ CD8+ cells. Previous studies have demonstrated...

Proteasomes degrade intracellular proteins to generate antigenic peptides that are recognized by the adaptive immune system and promote anticancer immunity. However, tumors subvert antigen presentation machinery escape immunosurveillance. We hypothesized proteasome activation could concomitantly increase abundance diversity in multiple myeloma cells. High-throughput screens revealed histone deacetylase 6 (HDAC6) inhibitors activated proteasomes unmask neoantigens amplify tumor-specific...

The synthetic triterpenoid, CDDO-Me, has potent antiproliferative and antioxidant properties. However, its immunomodulatory effects in the context of LPS challenge are incompletely defined. Pretreatment with oral CDDO-Me significantly improved survival following lethal-dose mice. To define this protection further, we measured pretreatment on splenocyte populations cytokine production challenge, using low-level as an vivo control for reducing production. Despite similar decreases levels...

Lenalidomide (LEN) is commonly used as part of induction therapy in transplant-eligible patients with multiple myeloma. However, LEN use associated increased chance peripheral blood stem cell (PBSC) collection failure. This has led to early receiving LEN-containing regimens, and the mobilization agents such plerixafor. Despite potential significant clinical implications, impact on autograft composition unclear. We examined effect exposure hematopoietic progenitors collected grafts 94 who...

The cyclin-dependent kinase inhibitor p27Kip1 is a tumor suppressor whose intrinsic activity in cancer cells correlates with aggressiveness, invasiveness, and impaired cell differentiation. Here we explore whether indirectly influences progression by restricting expansion survival of effector memory T (TEM) populations preclinical model spontaneous colitis-associated colorectal (CAC). We show mRNA protein expression to be significantly decreased the colons mice cell-restricted deletion TGF-β...

Synthetic oleanane triterpenoids (SOTs) are small molecules with broad anticancer properties. A recently developed SOT, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-2-yl)-1H-imidazole (CDDO-2P-Im or '2P-Im'), exhibits enhanced activity and improved pharmacokinetics over CDDO-Im, a previous generation SOT. However, the mechanisms leading to these properties not defined. Here, we show synergy of 2P-Im proteasome inhibitor ixazomib in human multiple myeloma (MM) cells murine...

To develop a new radiosensitizer, we screened chemical library and selected one reagent, N'-(phenyl-pyridin-2-yl-methylene)-hydrazine carbodithioic acid methyl ester (PHCM), which was already known to have antifungal antimicrobial properties. PHCM enhanced radiation-induced cell death its mean calculated dose enhancement ratio 1.17. found induce the phosphorylation of p38 mitogen-activated protein kinase, combined treatment with radiation down-regulated Bcl-2. In xenograft assay, group...

Immune cells and the cytokines they produce are important mediators of transition from colitis to colon cancer, but mechanisms mediating this disease progression poorly understood. Interferon gamma (IFN-γ) is known contribute pathogenesis through immune modulatory mechanisms, direct effects on endothelial epithelial homeostasis. Here we explore whether IFN-γ influences tumor by expanding effector memory T (TEM) population restricting expression suppressors in a preclinical model spontaneous...

Continuous treatment with parathyroid hormone (PTH) or excess endogenous PTH due to primary hyperparathyroidism causes increased bone resorption and, subsequently, decreased volume. Our previous studies showed that myeloid Elf-1-like factor (MEF) not only suppresses osteoblast differentiation through inhibition of Runx2 activity and other osteogenesis-related genes but also specifically increases the expression Mab21, a potential transcriptional repressor differentiation. Here we show JNK1...