New SNP variants of MARVELD2 (DFNB49) associated with non-syndromic hearing loss in Chinese population.

Non-syndromic hearing loss (NSHL) is a common defect in humans. Variants of MARVELD2 at the DFNB49 locus have been shown to cause bilateral, moderate to profound NSHL. However, the role of MARVELD2 in NSHL susceptibility in the Chinese population has not been studied. Here we conducted a case-control study in an eastern Chinese population to profile the spectrum and frequency of MARVELD2 variants, as well as the association of MARVELD2 gene variants with NSHL. Our results showed that variants identified in the Chinese population are significantly different from those reported in Slovak, Hungarian, and Czech Roma, as well as Pakistani families. We identified 11 variants in a cohort of 283 NSHL cases. Through Sanger sequencing and bioinformatics analysis, we found that c.730G>A variant has detrimental effects in the eastern Chinese population, and may have relatively high correlation with NSHL pathogenicity.

CXCR4-mediated signaling regulates autophagy and influences acute myeloid leukemia cell survival and drug resistance.

CXCR4 surface expression is considered an independent prognostic factor for disease relapse and survival in acute myeloid leukemia (AML) patients. Herein, we investigated targetable autophagy-related mechanisms of CXCR4 for AML therapy. Our experiments show that activation of CXCR4 signaling in AML cells increases autophagic activity and decreases cytarabine-induced apoptosis. Accordingly, combined use of autophagy inhibitors significantly increased the sensitivity of AML cells to cytarabine in vitro and in vivo. Moreover, expression of autophagy-related protein SIRT1 was correlated with SDF-1α-CXCR4 signaling, which interacts with autophagy proteins, such as ATG5 and LC3. Furthermore, in primary human AML samples, high CXCR4 expression was associated with elevated expression levels of SIRT1 and other autophagy-related proteins. Collectively, our data suggest new roles of SDF-1α-CXCR4 signaling on autophagy induction in AML cells, which further promoted their survival under stress. Targeting the SDF-1α-CXCR4-autophagy signaling may contribute to an enhanced efficacy of active treatments.

The role of CXCL12 in tumor microenvironment.

The chemokine ligand C-X-C motif chemokine ligand 12 (CXCL12) is a kind of small molecules of cytokines that widely expressed in diversified tissues. Recent evidence suggests that CXCL12 plays an important role in the communication of tumor cells with their surrounding microenvironment. The interaction of CXCL12 and its receptors subsequently excite the downstream signaling pathways to affect tumor angiogenesis, tumor cell proliferation and chemoresistance, and thus represents a potential target for cancer therapy. Outpouring molecules targeting CXCL12/CXCR4 axis in tumor microenvironment combined with traditional chemotherapy have drawn more and more attentions, which will be a promising method in anti-cancer therapies. Our review focuses on these roles of CXCL12 and summarizes strategies for treating cancer by disrupting this interaction with special emphasis on the CXCR4/CXCL12 axis.

A novel role of the sympatho-adrenergic system in regulating valve calcification.

BACKGROUND: Aortic valve calcification is a progressive process resembling ossification. Recent evidence indicates that the sympathetic nervous system plays an important role in regulating bone deposition and resorption through the beta2-adrenergic receptors (beta2-ARs). The aim of this study is to determine the level and pattern of expression of beta2-ARs in human valve interstitial cells (ICs) and assess their influence on differentiation of the cells into an osteoblast-like phenotype. METHODS AND RESULTS: Immunohistochemical analysis demonstrated a high expression of beta2-ARs, beta1-ARs, beta3-AR,s and receptor activator of nuclear factor-kappaB (RANK) in calcified aortic valves. The expression of beta2-ARs and beta1-ARs mRNA was assessed by real-time TaqMan PCR in cultures of human aortic valve ICs. Human valve ICs treated with the selective beta2-AR agonist, salmeterol, in the presence of osteogenic medium showed a significant 5-fold decrease in the alkaline phosphatase (ALP) activity in comparison to cells treated with osteogenic medium only (P<0.05). Immunocytochemical staining of the valve ICs showed a concomitant reduction in osteocalcin expression. In addition, other beta2-AR agonists caused a reduction in the protein expression of bone markers including ALP, Cbfa-1, and periostin. Human valve ICs treated with norepinephrine, in the presence of osteogenic medium, did not show a significant reduction in the ALP activity. CONCLUSIONS: These findings suggest an important role of the beta2-ARs in regulating valve calcification and may identify potential therapeutic targets.

PEG and DBBF modified porcine hemoglobin and their oxygen-carrying capacity.

Modifications of proteins with polyethylene glycol (PEG) have been proven to enlarge molecule size of proteins, to prolong their retention time in the circulation as well as blunt immune or allergic reactions. Hemoglobin cross-linked with small molecular modifiers turns out to be more stable and to have better oxygen carrying capacity. In the present study, four derivatives of PEG with different activation groups, and several PEGs with different molecular weights were covalently bound to porcine hemoglobin (pHb). PEG-pHbs exhibited a variety of differences in their properties depending on the molecular weights of the used PEGs, the amounts of bound PEGs and the presence or absence of allosteric cofactors. The optimal modification conditions for bis (3, 5-dibromosalicyl) fumarate (DBBF) as well as the physical features and oxygen carrying capacity of DBBF-modified pHb were evaluated. Furthermore, both PEG and DBBF were used simultaneously to modify pHb. The results indicate that the pHbs modified with PEG and DBBF have more stable tetrameric conformations with a molecular weight of 107 kD. Their oxygen half-saturation pressure (P(50)) is around 3.33 kPa which approximates the physiological P(50) of human red blood cells.