35 research outputs found
Systems Biology Approach Predicts Antibody Signature Associated with Brucella melitensis Infection in Humans
A complete understanding of the factors that determine selection of antigens recognized by the humoral immune response following infectious agent challenge is lacking. Here we illustrate a systems biology approach to identify the antibody signature associated with Brucella melitensis (Bm) infection in humans and predict proteomic features of serodiagnostic antigens. By taking advantage of a full proteome microarray expressing previously cloned 1406 and newly cloned 1640 Bm genes, we were able to identify 122 immunodominant antigens and 33 serodiagnostic antigens. The reactive antigens were then classified according to annotated functional features (COGs), computationally predicted features (e.g., subcellular localization, physical properties), and protein expression estimated by mass spectrometry (MS). Enrichment analyses indicated that membrane association and secretion were significant enriching features of the reactive antigens, as were proteins predicted to have a signal peptide, a single transmembrane domain, and outer membrane or periplasmic location. These features accounted for 67% of the serodiagnostic antigens. An overlay of the seroreactive antigen set with proteomic data sets generated by MS identified an additional 24%, suggesting that protein expression in bacteria is an additional determinant in the induction of Brucella-specific antibodies. This analysis indicates that one-third of the proteome contains enriching features that account for 91% of the antigens recognized, and after B. melitensis infection the immune system develops significant antibody titers against 10% of the proteins with these enriching features. This systems biology approach provides an empirical basis for understanding the breadth and specificity of the immune response to B. melitensis and a new framework for comparing the humoral responses against other microorganisms
Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention
The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in
malignant transformation, prevention of apoptosis, drug resistance and
metastasis. The expression of this pathway is frequently altered in
breast cancer due to mutations at or aberrant expression of: HER2,
ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other
oncogenes and tumor suppressor genes. In some breast cancer cases,
mutations at certain components of this pathway (e.g., PIK3CA) are
associated with a better prognosis than breast cancers lacking these
mutations. The expression of this pathway and upstream HER2 has been
associated with breast cancer initiating cells (CICs) and in some cases
resistance to treatment. The anti-diabetes drug metformin can suppress
the growth of breast CICs and herceptin-resistant HER2+ cells. This
review will discuss the importance of the
EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway primarily in breast cancer but
will also include relevant examples from other cancer types. The
targeting of this pathway will be discussed as well as clinical trials
with novel small molecule inhibitors. The targeting of the hormone
receptor, HER2 and EGFR1 in breast cancer will be reviewed in
association with suppression of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3
pathway.USAMRMC {[}BC022276]; Intramural RECDA Award; Italian Association for
Cancer Research (AIRC); MIUR-PRIN; Italian MIUR-FIRB Accordi di
Programma; Italian ``Ministero dell'Istruzione, dell'Universita e della
Ricerca (Ministry for Education, Universities and Research) - FIRB-MERIT
{[}RBNE08YYBM]; Italian Ministry of Economy and Finance; Italian
Ministry of Health, Ricerca Finalizzata Stemness; MIUR FIRB
{[}RBAP11ZJFA\_001]; CRO; Italian Association for Cancer Research,
(AIRC) (RM PI); Italian Association for Cancer Research, (AIRC)
{[}MCO10016]; Italian Ministry of Health; Regione Friuli Venezia-Giuli
Betulinic acid suppresses constitutive and TNFĪ±āinduced NFāĪŗB activation and induces apoptosis in human prostate carcinoma PCā3 cells
Oroxylin a reverses multi-drug resistance of human hepatoma BEL7402/5-FU cells via downregulation of P-glycoprotein expression by inhibiting NF-ĪŗB signaling pathway
FURIN Inhibition Reduces Vascular Remodeling and Atherosclerotic Lesion Progression in Mice
OBJECTIVE:
Atherosclerotic coronary artery disease is the leading cause of death worldwide, and current treatment options are insufficient. Using systems-level network cluster analyses on a large coronary artery disease case-control cohort, we previously identified PCSK3 (proprotein convertase subtilisin/kexin family member 3; FURIN) as a member of several coronary artery diseaseāassociated pathways. The objective is to determine the role of FURIN in atherosclerosis.
APPROACH AND RESULTS:
In vitro, FURIN inhibitor treatment resulted in reduced monocyte migration and reduced macrophage and vascular endothelial cell inflammatory and cytokine gene expression. In vivo, administration of an irreversible inhibitor of FURIN, Ī±-1-PDX, to hyperlipidemic Ldlrā/ā mice resulted in lower atherosclerotic lesion area and a specific reduction in severe lesions. Significantly lower lesional macrophage and collagen area, as well as systemic inflammatory markers, were observed. MMP2 (matrix metallopeptidase 2), an effector of endothelial function and atherosclerotic lesion progression, and a FURIN substrate was significantly reduced in the aorta of inhibitor-treated mice. To determine FURINās role in vascular endothelial function, we administered Ī±-1-PDX to Apoeā/ā mice harboring a wire injury in the common carotid artery. We observed significantly decreased carotid intimal thickness and lower plaque cellularity, smooth muscle cell, macrophage, and inflammatory marker content, suggesting protection against vascular remodeling. Overexpression of FURIN in this model resulted in a significant 67% increase in intimal plaque thickness, confirming that FURIN levels directly correlate with atherosclerosis.
CONCLUSIONS:
We show that systemic inhibition of FURIN in mice decreases vascular remodeling and atherosclerosis. FURIN-mediated modulation of MMP2 activity may contribute to the atheroprotection observed in these mice