Yang Liu
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Pubmed
Journal: Journal of biochemistry
April/5/2010
Abstract

PERIOD1 (PER1) is a clock gene. We examined the effect of knockdown of PER1 on apoptosis in pancreatic cancer (MIA PaCa-2 and PANC-1) and hepatocellular carcinoma (HepG2) cells. Transfection of siRNA against PER1 into these cells increased the cleaved forms of caspases and poly-ADP-ribose-polymerase and induced apoptosis in all three cell lines. In the two pancreatic cancer cell lines, PER1 knockdown resulted in upregulation of Bax and downregulation of Bcl-2. Expression of p53 was not altered in the two pancreatic cancer cell lines containing mutated p53, but was upregulated in the HepG2 cells containing wild-type p53. Cell proliferation of MIA PaCa-2 and HepG2 was inhibited by PER1 knockdown. We also examined, by immunohistochemical staining, the expression of PER1 in pancreatic cancer tissue and found that PER1 was strongly expressed in pancreatic cancer cells. These results indicate that PER1 acts as an anti-apoptotic factor in pancreatic cancer cells.

Pubmed
Journal: The Biochemical journal
November/12/2012
Abstract

PKB (protein kinase B), also known as Akt, is a key component of insulin signalling. Defects in PKB activation lead to insulin resistance and metabolic disorders, whereas PKB overactivation has been linked to tumour growth. Small-molecule PKB inhibitors have thus been developed for cancer treatment, but also represent useful tools to probe the roles of PKB in insulin action. In the present study, we examined the acute effects of two allosteric PKB inhibitors, MK-2206 and Akti 1/2 (Akti) on PKB signalling in incubated rat soleus muscles. We also assessed the effects of the compounds on insulin-stimulated glucose uptake, glycogen and protein synthesis. MK-2206 dose-dependently inhibited insulin-stimulated PKB phosphorylation, PKBβ activity and phosphorylation of PKB downstream targets (including glycogen synthase kinase-3α/β, proline-rich Akt substrate of 40 kDa and Akt substrate of 160 kDa). Insulin-stimulated glucose uptake, glycogen synthesis and glycogen synthase activity were also decreased by MK-2206 in a dose-dependent manner. Incubation with high doses of MK-2206 (10 μM) inhibited insulin-induced p70 ribosomal protein S6 kinase and 4E-BP1 (eukaryotic initiation factor 4E-binding protein-1) phosphorylation associated with increased eEF2 (eukaryotic elongation factor 2) phosphorylation. In contrast, Akti only modestly inhibited insulin-induced PKB and mTOR (mammalian target of rapamycin) signalling, with little or no effect on glucose uptake and protein synthesis. MK-2206, rather than Akti, would thus be the tool of choice for studying the role of PKB in insulin action in skeletal muscle. The results point to a key role for PKB in mediating insulin-stimulated glucose uptake, glycogen synthesis and protein synthesis in skeletal muscle.

Pubmed
Journal: The Journal of clinical investigation
April/23/2009
Abstract

Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody-induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that maybe responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody-induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family,which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody-induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms,some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody-induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody-induced nephritis and lupus.

Pubmed
Journal: Journal of immunology (Baltimore, Md. : 1950)
August/8/2006
Abstract

We identified a series of immunodominant and subdominant epitopes from alpha fetoprotein (AFP), restricted by HLA-A*0201, which are recognized by the human T cell repertoire. The four immunodominant epitopes have been tested for immunogenicity in vivo, in HLA-A*0201+AFP+ advanced stage hepatocellular cancer (HCC) patients, and have activated and expanded AFP-specific IFN-gamma-producing T cells in these patients, despite high serum levels of this self Ag. Here, we have examined the frequency, function, and avidity of the T cells specific for subdominant epitopes from AFP. We find that T cells specific for several of these epitopes are of similar or higher avidity than those specific for immunodominant epitopes. We then tested the peripheral blood of subjects ex vivo with different levels of serum AFP for the hierarchy of response to epitopes from this Ag and find that HCC patients have detectable frequencies of circulating IFN-gamma-producing AFP-specific CD8+ T cells to both immunodominant and subdominant epitopes. We find the immunodominant and subdominant peptide-specific T cells to be differentially expanded with different modes of Ag presentation. Whereas spontaneous and AFP protein-stimulated responses show evidence for immunodominance, AdVhAFP-transduced dendritic cell-stimulated responses were broader and not skewed. Importantly, these data identify subdominant epitopes from AFP that can activate high-avidity T cells, and that can be detected and expanded in HCC subjects. These subdominant epitope-specific T cells can also recognize tumor cells and may be important therapeutically.

Pubmed
Journal: Molecular bioSystems
May/9/2016
Abstract

Genome-wide RNA interference screens have greatly facilitated the identification of essential host factors (EHFs) for viral infections, whose knockdown effects significantly influence virus replication but not host cell viability. However, little has been done to link EHFs with another important host factor type, i.e., virus targeting proteins (VTPs) that viruses directly interact with for intracellular survival, hampering the integrative understanding of virus-host interactions. Using EHFs and VTPs for human immunodeficiency virus type 1 (HIV-1) and influenza A virus (IAV) infections, we found in general that despite limited overlap, EHFs and VTPs are both among the most differentially dysregulated genes in host transcriptional response to HIV and IAV infections, and notably they show consistency in regulation orientation. In the human protein-protein interaction network, both EHFs and VTPs hold topologically important positions at the global center, and importantly their direct interactions are statistically significant. We also identified BRCA1 and TP53 (or SMAD3 and PIK3R1) being the most extensive VTP-interacting EHFs (or EHF-interacting VTPs) for HIV-1 and IAV, which hold great potential in deciphering specific infection features and discovery of host directed antivirals. Further, most EHFs are the upstream regulators of VTPs when mapped in the same signaling pathways, some of which present intensive cross links. Collectively, these results provide insights into functional associations of the identified host gene factors for viral infections and highlight the regulatory significance of EHFs, and the necessity of their selective exploitation in confrontation to viral infections.

Pubmed
Journal: The Journal of biological chemistry
January/10/2011
Abstract

DACH1 (Dachshund homolog 1) is a key component of the retinal determination gene network and regulates gene expression either indirectly as a co-integrator or through direct DNA binding. The current studies were conducted to understand, at a higher level of resolution, the mechanisms governing DACH1-mediated transcriptional repression via DNA sequence-specific binding. DACH1 repressed gene transcription driven by the DACH1-responsive element (DRE). Recent genome-wide ChIP-Seq analysis demonstrated DACH1 binding sites co-localized with Forkhead protein (FOX) binding sites. Herein, DACH1 repressed, whereas FOX proteins enhanced, both DRE and FOXA-responsive element-driven gene expression. Reduced DACH1 expression using a shRNA approach enhanced FOX protein activity. As DACH1 antagonized FOX target gene expression and attenuated FOX signaling, we sought to identify limiting co-integrator proteins governing DACH1 signaling. Proteomic analysis identified transcription elongation regulator 1 (TCERG1) as the transcriptional co-regulator of DACH1 activity. The FF2 domain of TCERG1 was required for DACH1 binding, and the deletion of FF2 abolished DACH1 trans-repression function. The carboxyl terminus of DACH1 was necessary and sufficient for TCERG1 binding. Thus, DACH1 represses gene transcription through direct DNA binding to the promoter region of target genes by recruiting the transcriptional co-regulator, TCERG1.

Pubmed
Journal: Blood
August/16/2007
Abstract

Natural-killer (NK)-cell dysfunction and IFN-gamma deficiencies have been associated with increased incidence of both malignancy and infection. The immunologic basis of NK-cell defects in cancer-bearing hosts has not been extensively studied. Here, we demonstrate that multiple lineages of tumors, including thymoma, breast cancer, colon cancer, and melanoma cell lines, interrupt functional maturation during NK-cell development in the bone marrow. The immature NK cells in the periphery of tumor-bearing mice had impaired IFN-gamma production but seemingly normal cytotoxicity. T cells are not involved in this NK maturation arrest, because T-cell depletion did not restore NK-cell development. Moreover, the extent of tumor-cell infiltration into the bone marrow does not correlate with defective NK maturation. Interestingly, the defect was associated with a significant reduction in the IL-15Ralpha+ cells in the non-T, non-NK compartment of bone marrow cells and restored by overexpression of IL-15. Our data demonstrate that tumor growth can impede functional maturation of NK cells, most likely by interrupting the requisite IL-15 signaling pathway.

Pubmed
Journal: Journal of virology
November/20/2012
Abstract

The distal portion of rotavirus (RV) VP4 spike protein (VP8*) is implicated in binding to cellular receptors, thereby facilitating viral attachment and entry. While VP8* of some animal RVs engage sialic acid, human RVs often attach to and enter cells in a sialic acid-independent manner. A recent study demonstrated that the major human RVs (P[4], P[6], and P[8]) recognize human histo-blood group antigens (HBGAs). In this study, we performed a phylogenetic analysis of RVs and showed further variations of RV interaction with HBGAs. On the basis of the VP8* sequences, RVs are grouped into five P genogroups (P[I] to P[V]), of which P[I], P[IV], and P[V] mainly infect animals, P[II] infects humans, and P[III] infects both animals and humans. The sialic acid-dependent RVs (P[1], P[2], P[3], and P[7]) form a subcluster within P[I], while all three major P genotypes of human RVs (P[4], P[6], and P[8]) are clustered in P[II]. We then characterized three human RVs (P[9], P[14], and P[25]) in P[III] and observed a new pattern of binding to the type A antigen which is distinct from that of the P[II] RVs. The binding was demonstrated by hemagglutination and saliva binding assay using recombinant VP8* and native RVs. Homology modeling and mutagenesis study showed that the locations of the carbohydrate binding interfaces are shared with the sialic acid-dependent RVs, although different amino acids are involved. The P[III] VP8* proteins also bind the A antigens of the porcine and bovine mucins, suggesting the A antigen as a possible factor for cross-species transmission of RVs. Our study suggests that HBGAs play an important role in RV infection and evolution.

Pubmed
Journal: PloS one
March/29/2015
Abstract

To better understand the olfactory mechanisms in the two lepidopteran pest model species, the Helicoverpa armigera and H. assulta, we conducted transcriptome analysis of the adult antennae using Illumina sequencing technology and compared the chemosensory genes between these two related species. Combined with the chemosensory genes we had identified previously in H. armigera by 454 sequencing, we identified 133 putative chemosensory unigenes in H. armigera including 60 odorant receptors (ORs), 19 ionotropic receptors (IRs), 34 odorant binding proteins (OBPs), 18 chemosensory proteins (CSPs), and 2 sensory neuron membrane proteins (SNMPs). Consistent with these results, 131 putative chemosensory genes including 64 ORs, 19 IRs, 29 OBPs, 17 CSPs, and 2 SNMPs were identified through male and female antennal transcriptome analysis in H. assulta. Reverse Transcription-PCR (RT-PCR) was conducted in H. assulta to examine the accuracy of the assembly and annotation of the transcriptome and the expression profile of these unigenes in different tissues. Most of the ORs, IRs and OBPs were enriched in adult antennae, while almost all the CSPs were expressed in antennae as well as legs. We compared the differences of the chemosensory genes between these two species in detail. Our work will surely provide valuable information for further functional studies of pheromones and host volatile recognition genes in these two related species.

Pubmed
Journal: Annals of neurology
June/14/2011
Abstract

Currently, stroke laboratory examinations are usually performed in the centralized hospital laboratory, but often planned thrombolysis is given before all results are available, to minimize delay. In this study, we examined the feasibility of gaining valuable time by transferring the complete stroke laboratory workup required by stroke guidelines to a point-of-care laboratory system, that is, placed at a stroke treatment room contiguous to the computed tomography, where the patients are admitted and where they obtain neurological, laboratory, and imaging examinations and treatment by the same dedicated team. Our results showed that reconfiguration of the entire stroke laboratory analysis to a point-of-care system was feasible for 200 consecutively admitted patients. This strategy reduced the door-to-therapy-decision times from 84 ± 26 to 40 ± 24 min (p < 0.001). Results of most laboratory tests (except activated partial thromboplastin time and international normalized ratio) revealed close agreement with results from a standard centralized hospital laboratory. These findings may offer a new solution for the integration of laboratory workup into routine hyperacute stroke management.

Pubmed
Journal: Journal of the Air & Waste Management Association (1995)
January/16/2008
Abstract

We develop a method that uses both the total column aerosol optical depth (AOD) and the fractional AOD values for different aerosol types, derived from Multiangle Imaging SpectroRadiometer (MISR) aerosol data, to estimate ground-level concentrations of fine particulate matter (PM2.5) mass and its major constituents in eastern and western United States. Compared with previous research on linking column AOD with ground-level PM2.5, this method treats various MISR aerosol components as individual predictor variables. Therefore, the contributions of different particle types to PM2.5 concentrations can be estimated. When AOD is greater than 0.15, MISR is able to distinguish dust from non-dust particles with an uncertainty level of approximately 4%, and light-absorbing from non-light-absorbing particles with an uncertainty level of approximately 20%. Further analysis shows that MISR Version 17 aerosol microphysical properties have good sensitivity and internal consistency among different mixture classes. The retrieval uncertainty of individual fractional AODs ranges between 5 and 11% in the eastern United States, and between 11 and 31% in the west for non-dust aerosol components. These results provide confidence that the fractional AOD models with their inherent flexibility can make more accurate predictions of the concentrations of PM2.5 and its constituents.

Pubmed
Journal: PloS one
December/12/2012
Abstract

Mycoplasma bovis is the causative agent of Mycoplasma bovis-associated disease (MbAD). Although the mechanisms underlying M. bovis adherence to host cells is not clear, recent studies have shown that the cell surface protein α-enolase facilitates bacterial invasion and dissemination in the infected host. In this study, we cloned, expressed and purified recombinant M. bovis α-enolase and induced polyclonal anti-α-enolase antibodies in rabbits. M. bovis α-enolase was detected in the cytoplasmic and membrane protein fractions by these antibodies. Triple immunofluorescence labeling combined with confocal laser scanning microscopy (CLSM) revealed that the plasminogen (Plg) enhanced the adherence of M. bovis to embryonic bovine lung (EBL) cells; the values obtained for adherence and inhibition are consistent with this finding. Interestingly, we found that trace amounts of trypsin acted as a more effective enhancer of cell adherence than Plg. Hence, our data indicate that surface-associated M. bovis α-enolase is an adhesion-related factor of M. bovis that contributes to adherence by binding Plg.

Pubmed
Journal: Journal of the American Society of Nephrology : JASN
May/23/2017
Abstract

AKI confers increased risk of progression to CKD. αKlotho is a cytoprotective protein, the expression of which is reduced in AKI, but the relationship of αKlotho expression level to AKI progression to CKD has not been studied. We altered systemic αKlotho levels by genetic manipulation, phosphate loading, or aging and examined the effect on long-term outcome after AKI in two models: bilateral ischemia-reperfusion injury and unilateral nephrectomy plus contralateral ischemia-reperfusion injury. Despite apparent initial complete recovery of renal function, both types of AKI eventually progressed to CKD, with decreased creatinine clearance, hyperphosphatemia, and renal fibrosis. Compared with wild-type mice, heterozygous αKlotho-hypomorphic mice (αKlotho haploinsufficiency) progressed to CKD much faster, whereas αKlotho-overexpressing mice had better preserved renal function after AKI. High phosphate diet exacerbated αKlotho deficiency after AKI, dramatically increased renal fibrosis, and accelerated CKD progression. Recombinant αKlotho administration after AKI accelerated renal recovery and reduced renal fibrosis. Compared with wild-type conditions, αKlotho deficiency and overexpression are associated with lower and higher autophagic flux in the kidney, respectively. Upregulation of autophagy protected kidney cells in culture from oxidative stress and reduced collagen 1 accumulation. We propose that αKlotho upregulates autophagy, attenuates ischemic injury, mitigates renal fibrosis, and retards AKI progression to CKD.

Pubmed
Journal: Journal of immunology (Baltimore, Md. : 1950)
June/30/2008
Abstract

Dogma that the regulatory T cell (Treg) prevents catastrophic autoimmunity throughout the lifespan relies on the assumption that the FoxP3 locus is transcribed exclusively in Treg. To test the assumption, we used the Rag2(-/-) and the Rag2(-/-) mice with the Scurfy (sf) mutation (FoxP3(sf/Y) or FoxP3(sf/sf)) to evaluate FoxP3 expression outside of the lymphoid system. Immunohistochemistry and real-time PCR revealed FoxP3 expression in breast epithelial cells, lung respiratory epithelial cells, and prostate epithelial cells, although not in liver, heart, and intestine. The specificity of the assays was confirmed, as the signals were ablated by the Scurfy mutation of the FoxP3 gene. Using mice with a green fluorescence protein open reading frame knocked into the 3' untranslated region of the FoxP3 locus, we showed that the locus is transcribed broadly in epithelial cells of multiple organs. These results refute an essential underlying assumption of the dogma and question the specificity of FoxP3-based Treg depletion.

Pubmed
Journal: Journal of materials science. Materials in medicine
January/9/2013
Abstract

Acellular biological tissues, including bovine pericardia (BP), have been proposed as natural biomaterials for tissue engineering. However, small pore size, low porosity and lack of extra cellular matrix (ECM) after native cell extraction directly restrict the seed cell adhesion, migration and proliferation and which is a vital problem for ABP's application in the tissue engineered heart valve (TEHV). In the present study, we treated acellular BP with acetic acid, which increased the scaffold pore size and porosity and conjugated RGD polypeptides to ABP scaffolds. After 10 days of culture in vitro, the human mesenchymal stem cells (hMSCs) attached the best and proliferated the fastest on RGD-modified acellular scaffolds, and the cell has grown deep into the scaffold. In contrast, a low density of cells attached to the unmodified scaffolds, with few infiltrating into the acellular tissues. These findings support the potential use of modified acellular BP as a scaffold for tissue engineered heart valves.

Pubmed
Journal: Gastroenterology
January/19/2012
Abstract

OBJECTIVE

Intestinal microbes induce homeostatic mucosal immune responses, but can also cause inappropriate immune activation in genetically susceptible hosts. Although immune responses to bacterial products have been studied extensively, little is known about how intestinal inflammation affects functions of commensal luminal microbes.

METHODS

Microarrays and real-time polymerase chain reaction were used to profile transcriptional changes in luminal bacteria from wild-type and IL-10(-/-) mice monoassociated with a nonpathogenic, murine isolate of Escherichia coli (NC101, which causes colitis in gnotobiotic IL-10(-/-) mice). Colonic inflammation and innate and adaptive immune responses were measured in wild-type and IL-10(-/-) mice monoassociated with mutant NC101 that lack selected, up-regulated genes, and in IL-10(-/-) mice that were colonized with a combination of mutant and parental NC101. We measured intracellular survival of bacteria within primary macrophages from mice and resulting production of tumor necrosis factor.

RESULTS

Bacteria from IL-10(-/-) mice with colitis had significant up-regulation of the stress-response regulon, including the small heat shock proteins IbpA and IbpB that protect E coli from oxidative stress, compared to healthy, wild-type controls. In IL-10(-/-) mice, expression of ibpAB reduced histologic signs of colon inflammation, secretion of interleukin-12/23p40 in colonic explant cultures, serologic reactivity to NC101 antigens, and secretion of interferon-gamma by stimulated mesenteric lymph node cells. Infection of primary macrophages by bacteria that express ibpAB was associated with decreased intracellular survival and reduced secretion of tumor necrosis factor.

CONCLUSIONS

Chronic intestinal inflammation causes functional alterations in gene expression in commensal gut bacterium (E coli NC101). Further studies of these expression patterns might identify therapeutic targets for patients with inflammatory bowel diseases.

Pubmed
Journal: Journal of the American Chemical Society
September/25/2013
Abstract

Studying chemomechanical coupling at interfaces is important for fields ranging from lubrication and tribology to microfluidics and cell biology. Several polymeric macro- and microscopic systems and cantilevers have been developed to image forces at interfaces, but few materials are amenable for molecular tension sensing. To address this issue, we have developed a gold nanoparticle sensor for molecular tension-based fluorescence microscopy. As a proof of concept, we imaged the tension exerted by integrin receptors at the interface between living cells and a substrate with high spatial (<1 μm) resolution, at 100 ms acquisition times and with molecular specificity. We report integrin tension values ranging from 1 to 15 pN and a mean of ~1 pN within focal adhesions. Through the use of a conventional fluorescence microscope, this method demonstrates a force sensitivity that is 3 orders of magnitude greater than is achievable by traction force microscopy or polydimethylsiloxane micropost arrays, which are the standard in cellular biomechanics.

Pubmed
Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
December/18/2007
Abstract

Microglial activation is a key feature in Alzheimer's disease and is considered to contribute to progressive neuronal injury by release of neurotoxic products. The innate immune receptor Toll-like-receptor 4 (TLR4), localized on the surface of microglia, is a first-line host defense receptor against invading microorganisms. Here, we show that a spontaneous loss-of-function mutation in the Tlr4 gene strongly inhibits microglial and monocytic activation by aggregated Alzheimer amyloid peptide resulting in a significantly lower release of the inflammatory products IL-6, TNFalpha and nitric oxide. Treatment of primary murine neuronal cells with supernatant of amyloid peptide-stimulated microglia demonstrates that Tlr4 contributes to amyloid peptide-induced microglial neurotoxicity. In addition, stimulation experiments in transfected HEK293 cells allowed to define a tri-molecular receptor complex consisting of TLR4, MD-2 and CD14 necessary for full cellular activation by aggregated amyloid peptide. A clinical relevance of these findings is supported by a marked upregulation of Tlr4 mRNA in APP transgenic mice and by an increased expression of TLR4 in Alzheimer's disease brain tissue associated with amyloid plaque deposition. Together, these observations provide the first evidence for a role of the key innate immune receptor, TLR4, in neuroinflammation in Alzheimer's disease.

Pubmed
Journal: Biomaterials
June/3/2013
Abstract

Most of the exogenous biomaterials for tendon repair have limitations including lower capacity for inducing cell proliferation and differentiation, poorer biocompatibility and remodeling potentials. To avoid these shortcomings, we intend to construct an engineered tendon by stem cells and growth factors without exogenous scaffolds. In this study, we produced an engineered scaffold-free tendon tissue (ESFTT) in vitro and investigated its potentials for neo-tendon formation and promoting tendon healing in vivo. The ESFTT, produced via tendon-derived stem cells (TDSCs) by treatment of connective tissue growth factor (CTGF) and ascorbic acid in vitro, was characterized by histology, qRT-PCR and immunohistochemistry methods. After ESFTT implanted into the nude mouse, the in vivo fluorescence imaging, histology and immunohistochemistry examinations showed neo-tendon formation. In a rat patellar tendon window injury model, the histology, immunohistochemistry and biomechanical testing data indicated ESFTT could significantly promote tendon healing. In conclusion, this is a proof-of-concept study demonstrating that ESFTT could be a potentially new approach for tendon repair and regeneration.

Pubmed
Journal: Nature medicine
May/27/2002
Abstract

Amplification of the gene encoding the ErbB2 (Her2/neu) receptor tyrosine kinase is critical for the progression of several forms of breast cancer. In a large-scale clinical trial, treatment with Herceptin (trastuzumab), a humanized blocking antibody against ErbB2, led to marked improvement in survival. However, cardiomyopathy was uncovered as a mitigating side effect, thereby suggesting an important role for ErbB2 signaling as a modifier of human heart failure. To investigate the physiological role of ErbB2 signaling in the adult heart, we generated mice with a ventricular-restricted deletion of Erbb2. These ErbB2-deficient conditional mutant mice were viable and displayed no overt phenotype. However, physiological analysis revealed the onset of multiple independent parameters of dilated cardiomyopathy, including chamber dilation, wall thinning and decreased contractility. Additionally, cardiomyocytes isolated from these conditional mutants were more susceptible to anthracycline toxicity. ErbB2 signaling in cardiomyocytes is therefore essential for the prevention of dilated cardiomyopathy.

Pubmed
Journal: Neurobiology of aging
June/21/2009
Abstract

In Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB) and amyotrophic lateral sclerosis (ALS), neuroinflammatory responses are considered to contribute to neuronal injury. Recently, the innate immune receptors, toll-like receptors (TLRs) and the LPS receptor (CD14) have been related to neurodegeneration. In this study, we systematically assessed the expression of most TLRs and CD14 in AD, PD/DLB and ALS using murine models of these diseases and human post-mortem brain tissues. A common upregulation of TLR2 and CD14 was found in all three animal models. While these two receptors could also be detected in AD patient tissues, they were absent from DLB and ALS tissues. This uniform pattern of innate immune response in animal models of neurodegenerative diseases clearly indicates that this response is part of a non-specific neuroinflammatory effector phase rather than a disease-specific event. The less dynamic disease progression in humans and the location (extracellular versus intracellular) of the aggregated proteins deposits might explain the divergent results seen between animal models and human tissues.

Pubmed
Journal: Fish & shellfish immunology
December/15/2016
Abstract

This study investigated the effects of dietary vitamin C on the growth, and head kidney, spleen and skin immunity, structural integrity and related signaling molecules mRNA expression levels of young grass carp (Ctenopharyngodon idella). A total of 540 grass carp (264.37 ± 0.66 g) were fed six diets with graded levels of vitamin C (2.9, 44.2, 89.1, 133.8, 179.4 and 224.5 mg/kg diet) for 10 weeks. Subsequently, a challenge test was conducted by injection of Aeromonas hydrophila and the survival rate recorded for 14 days. The results indicated that compared with optimal vitamin C supplementation, vitamin C deficiency (2.9 mg/kg diet) decreased lysozyme (LA) and acid phosphatase (ACP) activities, and complement 3 and complement 4 (C4) contents (P < 0.05), down-regulated the mRNA levels of antimicrobial peptides [liver expressed antimicrobial peptide (LEAP) 2A, LEAP-2B, hepcidin, β-defensin] and anti-inflammatory cytokines-related factors, interleukin (IL) 4/13A, IL-4/13B (only in head kidney), IL-10, IL-11, transforming growth factor (TGF) β1, TGF-β2, inhibitor of κBα and eIF4E-binding protein 1 (P < 0.05), and up-regulated pro-inflammatory cytokines-related factors, tumor necrosis factor α, interferon γ2, IL-1β, IL-6, IL-8, IL-12 P35 (only in spleen), IL-12 P40, IL-15, IL-17D, nuclear factor κB p65, IκB kinases (IKKα, IKKβ, IKKγ), target of rapamycin and ribosomal protein S6 kinase 1 mRNA levels (P < 0.05) in the head kidney and spleen under injection fish of A. hydrophila, suggesting that vitamin C deficiency could decrease fish head kidney and spleen immunity and cause inflammation. Meanwhile, compared with optimal vitamin C supplementation, vitamin C deficiency decreased the activities and mRNA levels of copper/zinc superoxide dismutase, manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase, glutathione S-transferases and glutathione reductase (P < 0.05), and down-regulated zonula occludens (ZO) 1, ZO-2, Claudin-b, -c, -3c, -7a, -7b, B-cell lymphoma-2, inhibitor of apoptosis protein, NF-E2-related factor 2 mRNA levels (P < 0.05), increased reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl contents (P < 0.05), and up-regulated Claudin-12, 15a, -15b, Fas ligand, mitogen-activated protein kinase kinase 6, p38 mitogen-activated protein kinase, B-cell lymphoma protein 2 associated X protein, apoptotic protease activating factor-1, caspase-3, -7, -8, -9, Kelch-like ECH-associating protein (Keap) 1a and Keap 1b mRNA levels (P < 0.05) in the head kidney and spleen under injection fish of A. hydrophila, suggesting that vitamin C deficiency could decrease fish head kidney and spleen structural integrity through depression of antioxidative ability, induction of apoptosis and disruption of tight junctional complexes. In addition, except the activities of ACP and MnSOD, and mRNA expression levels of TGF-β1, Occludin and MnSOD, the effect of vitamin C on fish head kidney, spleen and skin immunity and structural integrity other indicators model are similar under infection of A. hydrophila. Finally, the vitamin C requirement for the growth performance (PWG) of young grass carp was estimated to be 92.8 mg/kg diet. Meanwhile, the vitamin C requirement for against skin lesion morbidity of young grass carp was estimated to be 122.9 mg/kg diet. In addition, based on the biochemical indices [immune indices (LA activity in the head kidney and C4 content in the spleen) and antioxidant indices (MDA content in the head kidney and ROS content in the spleen)] the vitamin C requirements for young grass carp were estimated to be 131.2, 137.5, 135.8 and 129.8 mg/kg diet, respectively.

Pubmed
Journal: Mutation research
August/18/2008
Abstract

To investigate the effects of pre-exposure of mouse testis to low-dose (12)C(6+) ions on cytogenetics of spermatogonia and spermatocytes induced by subsequent high-dose irradiation, the testes of outbred Kun-Ming strain mice were irradiated with 0.05Gy of (12)C(6+) ions as the pre-exposure dose, and then irradiated with 2Gy as challenging dose at 4h after per-exposure. Poly(ADP-ribose) polymerase (PARPs) activity and PARP-1 protein expression were respectively measured by using the enzymatic and Western blot assays at 4h after irradiation; chromosomal aberrations in spermatogonia and spermatocytes were analyzed by the air-drying method at 8h after irradiation. The results showed that there was a significant increase in the frequency of chromosomal aberrations and significant reductions of PARP activity and PARP-1 expression level in the mouse testes irradiated with 2Gy of (12)C(6+) ions. However, pre-exposure of mouse testes to a low dose of (12)C(6+) ions significantly increased PARPs activity and PARP-1 expression and alleviated the harmful effects induced by a subsequent high-dose irradiation. PARP activity inhibitor 3-aminobenzamide (3-AB) treatment blocked the effects of PARP-1 on cytogenetic adaptive response induced by low-dose (12)C(6+) ion irradiation. The data suggest that pre-exposure of testes to a low dose of heavy ions can induce cytogenetic adaptive response to subsequent high-dose irradiation. The increase of PARP-1 protein induced by the low-dose ionizing irradiation may be involved in the mechanism of these observations.

Pubmed
Journal: Breast cancer research and treatment
May/1/2011
Abstract

BRCA1 is closely related to the pathogenesis of breast cancer, BRCA1 mRNA is reduced in sporadic breast cancer cells despite the lack of mutations. In the present report, we find that MyoD expression and BRCA1 expression is correlated in sporadic breast tumors, overexpression of MyoD and c-myb stimulates BRCA1 expression, knockdown of MyoD and c-myb attenuates BRCA1 expression and attenuates the ability of BRCA1 to protect cells against hydrogen peroxide. MyoD and c-myb interact with p300 and PCAF, forming activating transcriptional complexes which bind to E-box and c-myb sites on the BRCA1 promoter and activate its transcription by inducing histone acetylation. Regulation of BRCA1 expression by MyoD and c-myb complexes may be part of an integral signaling pathway that determines and explains breast cancer susceptibility. Detection expression status of the various proteins in these complexes may predispose to the onset of sporadic breast cancer.

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