Hartvigsenmccarty2288

Subsequent experiments using small molecule screening revealed that DMSO enhances direct cardiac reprogramming through inhibition of the CBP/p300 bromodomain, and not its acetyltransferase property.

In conclusion, our work points to a direct molecular target of DMSO, which can be used for augmenting GHMT-induced direct cardiac reprogramming and possibly other cell fate conversion processes.

In conclusion, our work points to a direct molecular target of DMSO, which can be used for augmenting GHMT-induced direct cardiac reprogramming and possibly other cell fate conversion processes.PB1-F2 is a virulence factor of influenza A virus known to increase viral pathogenicity in mammalian hosts. PB1-F2 is an intrinsically disordered protein displaying a propensity to form amyloid-like fibers. However, the correlation between PB1-F2 structures and the resulting inflammatory response is unknown. Here, we used synchrotron-coupled Fourier transform-IR and deep UV microscopies to determine the presence of PB1-F2 fibers in influenza A virus-infected mice. Phorbol 12-myristate 13-acetate concentration In order to study the correlation between PB1-F2 structure and the inflammatory response, transgenic mice expressing luciferase under the control of an NF-κB promotor, allowing in vivo monitoring of inflammation, were intranasally instilled with monomeric, fibrillated, or truncated forms of recombinant PB1-F2. Our intravital NF-κB imaging, supported by cytokine quantification, clearly shows the proinflammatory effect of PB1-F2 fibers compared with N-terminal region of PB1-F2 unable to fibrillate. It is noteworthy that instillation of monomeric PB1-F2 of H5N1 virus induced a stronger inflammatory response when compared with prefibrillated PB1-F2 of H1N1 virus, suggesting mechanisms of virulence depending on PB1-F2 sequence. Finally, using whole-body plethysmography to measure volume changes in the lungs, we quantified the effects of the different forms of PB1-F2 on respiratory parameters. Thus, we conclude that PB1-F2-induced inflammation and respiratory distress are tightly correlated with sequence polymorphism and oligomerization status of the protein.The mechanistic target of rapamycin (mTOR) is often referred to as a master regulator of the cellular metabolism that can integrate the growth factor and nutrient signaling. Fasting suppresses hepatic mTORC1 activity via the activity of the tuberous sclerosis complex (TSC), a negative regulator of mTORC1, to suppress anabolic metabolism. The loss of TSC1 in the liver locks the liver in a constitutively anabolic state even during fasting, which was suggested to regulate peroxisome proliferator-activated receptor alpha (PPARα) signaling and ketogenesis, but the molecular determinants of this regulation are unknown. Here, we examined if the activation of the mTORC1 complex in mice by the liver-specific deletion of TSC1 (TSC1L-/-) is sufficient to suppress PPARα signaling and therefore ketogenesis in the fasted state. We found that the activation of mTORC1 in the fasted state is not sufficient to repress PPARα-responsive genes or ketogenesis. Furthermore, we examined whether the activation of the anabolic program mediated by mTORC1 complex activation in the fasted state could suppress the robust catabolic programming and enhanced PPARα transcriptional response of mice with a liver-specific defect in mitochondrial long-chain fatty acid oxidation using carnitine palmitoyltransferase 2 (Cpt2L-/-) mice. We generated Cpt2L-/-; Tsc1L-/- double-KO mice and showed that the activation of mTORC1 by deletion of TSC1 could not suppress the catabolic PPARα-mediated phenotype of Cpt2L-/- mice. These data demonstrate that the activation of mTORC1 by the deletion of TSC1 is not sufficient to suppress a PPARα transcriptional program or ketogenesis after fasting.The aryl hydrocarbon receptor (AHR) is a transcription factor activated by exogenous halogenated polycyclic aromatic hydrocarbon compounds, including the environmental toxin TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and naturally occurring dietary and endogenous compounds. The activated AHR enhances transcription of specific genes including phase I and phase II metabolism enzymes and other targets genes such as the TCDD-inducible poly(ADP-ribose) polymerase (TiPARP). The regulation of AHR activation is a dynamic process immediately after transcriptional activation of the AHR by TCDD, the AHR is exported from the nucleus to the cytoplasm where it is subjected to proteasomal degradation. However, the mechanisms regulating AHR degradation are not well understood. Here, we studied the role of two enzymes reported to enhance AHR breakdown the cullin 4B (CUL4B)AHR complex, an E3 ubiquitin ligase that targets the AHR and other proteins for ubiquitination, and TiPARP, which targets proteins for ADP-ribosylation, a posttranslational modification that can increase susceptibility to degradation. Using a WT mouse embryonic fibroblast (MEF) cell line and an MEF cell line in which CUL4B has been deleted (MEFCul4b-null), we discovered that loss of CUL4B partially prevented AHR degradation after TCDD exposure, while knocking down TiPARP in MEFCul4b-null cells completely abolished AHR degradation upon TCDD treatment. Increased TCDD-activated AHR protein levels in MEFCul4b-null and MEFCul4b-null cells in which TiPARP was knocked down led to enhanced AHR transcriptional activity, indicating that CUL4B and TiPARP restrain AHR action. This study reveals a novel function of TiPARP in controlling TCDD-activated AHR nuclear export and subsequent proteasomal degradation.Liver fibrosis is a common characteristic of chronic liver diseases. The activation of hepatic stellate cells (HSCs) plays a key role in fibrogenesis in response to liver injury, yet the mechanism by which damaged hepatocytes modulate the activation of HSCs is poorly understood. Our previous studies have established that liver-specific deletion of O-GlcNAc transferase (OGT)leads to hepatocyte necroptosis and spontaneous fibrosis. Here, we report that OGT-deficient hepatocytes secrete trefoil factor 2 (TFF2) that activates HSCs and contributes to the fibrogenic process. The expression and secretion of TFF2 are induced in OGT-deficient hepatocytes but not in WT hepatocytes. TFF2 activates the platelet-derived growth factor receptor beta signaling pathway that promotes the proliferation and migration of primary HSCs. TFF2 protein expression is elevated in mice with carbon tetrachloride-induced liver injury. These findings identify TFF2 as a novel factor that mediates intercellular signaling between hepatocytes and HSCs and suggest a role of the hepatic OGT-TFF2 axis in the process of fibrogenesis.Angiopoietin like 4 (ANGPTL4) has been proved to play an important role in lipid and glucose metabolism disorders and related cardiovascular diseases, but its role in the formation of cirrhosis still needs to be further explored. Therefore, the aim of this study was to investigate the role of ANGPTL4 in the development of liver cirrhosis and its mechanism, as well as its effect on Kupffer cell polarization and hepatic stellate cell activation. The ELISA and RT-qPCR assay were used to detect the content of ANGPTL4 in serum and mRNA expression in cells and tissues respectively. The expression of ANGPTL4, Arg1 and Mrc2 in Kupffer cells was measured by Western blot. The percentage of CD163+ and CD206+ cells was measured by flow cytometry. Mice cirrhosis model was established, and the expression of ANGPTL4 was interfered by injecting sh-ANGPTL4 lentiviral vector into caudal vein. The results revealed that ANGPTL4 was significantly up-regulated in liver cirrhosis patients and HBV induced liver injury cell models. Further studies found that interference with ANGPTL4 regulated CD163 and inhibited the polarization and proinflammatory effects of KCs，as well as inhibited the activation of hepatic stellate cells (HSCs) and fibrosis. More importantly, Interference with ANGPTL4 inhibits the progression of liver cirrhosis in mice. What's more, TLR4/NF-κB pathway was involved in the molecular mechanism of ANGPTL4 on Kupffer cells and hepatic stellate cells. It is suggested that the mechanism of sh-ANGPTL4 suppressing the polarization of KCs and the activation of hepatic stellate cells (HSCs) is to regulate the TLR4/NF-κB signaling pathways.Chronic myeloid leukemia (CML) is a reciprocal translocation disorder driven by a breakpoint cluster region (BCR)-Abelson leukemia virus (ABL) fusion gene that stimulates abnormal tyrosine kinase activity. Tyrosine kinase inhibitors (TKIs) are effective in treating Philadelphia chromosome (Ph) + CML patients. link2 However, the appearance of TKI-resistant CML cells is a hurdle in CML treatment. Therefore, it is necessary to identify novel alternative treatments targeting tyrosine kinases. This study was designed to determine whether C-X-C chemokine receptor 2 (CXCR2) could be a novel target for TKI-resistant CML treatment. Interleukin 8 (IL-8), a CXCR2 ligand, was significantly increased in the bone marrow serum of initially diagnosed CML patients and TKI-resistant CML cell conditioned media. CXCR2 antagonists suppressed the proliferation of CML cells via cell cycle arrest in the G2/M phase. CXCR2 inhibition also attenuated mTOR, c-Myc, and BCR-ABL expression, leading to CML cell apoptosis, irrespective of TKI responsiveness. link3 Moreover, SB225002, a CXCR2 antagonist, caused higher cell death in TKI-resistant CML cells than TKIs. Using a mouse xenograft model, we confirmed that SB225002 suppresses tumor growth, with a prominent effect on TKI-resistant CML cells. Our findings demonstrate that IL-8 is a prognostic factor for the progression of CML. Inhibiting the CXCR2-mTOR-c-Myc cascade is a promising therapeutic strategy to overcome TKI-sensitive and TKI-insensitive CML. Thus, CXCR2 blockade is a novel therapeutic strategy to treat CML, and SB225002, a commercially available CXCR2 antagonist, might be a candidate drug that could be used to treat TKI-resistant CML.Quinone-based small molecules are the promising structures for antiproliferative drug design and can induce apoptosis in cancer cells. Among them, one of the quinolinequinones, named as 6-anilino-5,8-quinolinequinone, LY83583 has the ability to inhibit the growth of cancer cells as an inhibitor of cyclase. The biological potential of all synthesized compounds as the analogs of the identified lead molecule LY83583 that possessed the antiproliferative efficiency was determined. The two series of the LY83583 analogs containing electron-withdrawing or electron-donating group(s) were synthesized and subsequently in vitro evaluated for their cytotoxic activity against K562, Jurkat, MT-2, and HeLa cell lines using MTT assay. All the LY83583 analogs showed antiproliferative activity with good IC50 values (less than positive control imatinib). Four analogs from each series were also selected for the determination of selectivity against human peripheral blood mononuclear cells (PBMCs). The analog AQQ15 showed high potency towards all cancer cell lines with almost similar selectivity of imatinib. In order to get a better insight into cytotoxic effects of the analog AQQ15 in K562 cells, further apoptotic effects due to annexin V/ethidium homodimer III staining, ABL1 kinase inhibition, and DNA cleaving ability were examined. The analog AQQ15 induced apoptotic cell death in K562 cells with 34.6% compared to imatinib (6.5%). This analog showed no considerable ABL1 kinase inhibitory activity but significant DNA cleavage activity indicating DNA fragmentation-induced apoptosis. Besides, molecular docking studies revealed that the analog AQQ15 established proper interactions with the deoxyribose sugar attached with the nucleobases adenine and guanidine respectively, in the minor groove of the double helix of DNA. In silico predicted pharmacokinetic parameters of this analog were found to comply with the standard range making it an efficient anticancer drug candidate for further research.