Denatonium and Naringenin Promote SCA-9 Tumor Growth and Angiogenesis: Participation of Arginase

Submandibular gland (SMG) is one of the major salivary glands, and is formed by acinar cells that are conveyed to the oral cavity by a duct system. We had previously reported that T2R receptors that were originally identified in gustatory tissues were also present in murine SMG. The addition of bitter compounds to the gland reduced nitric oxide production and downregulated amylase secretion. In this work, we investigated the effect of two different bitter compounds namely denatonium and naringenin on tumor progression as well as the presence of T2R in SCA-9 cells derived from a murine tumor induced in SMG. Both compounds increased tumor cell proliferation in bi- and three-dimensional cultures. These effects were mediated by the activation of arginase and the inhibition of nitric oxide synthase. Denatonium and naringenin also increased vascular endothelial growth factor-A expression via arginase and tumor neovascularization in vivo. T2R6 and T2R4 were identified in SCA-9 cells by immunostaining. Also, Gi and Ggust proteins, which usually couple to T2R receptors, are expressed in these cells. Finally, we demonstrated for the first time that bitter compounds can exert pro-tumor actions that should be taken into account as side effects when they are used as nutraceuticals.     

Risk prediction measures for case-cohort and nested case-control designs: an application to cardiovascular disease

Case-cohort and nested case-control designs are often used to select an appropriate subsample of individuals from prospective cohort studies. Despite the great attention that has been given to the calculation of association estimators, no formal methods have been described for estimating risk prediction measures from these 2 sampling designs. Using real data from the Swedish Twin Registry (2004-2009), the authors sampled unstratified and stratified (matched) case-cohort and nested case-control subsamples and compared them with the full cohort (as "gold standard"). The real biomarker (high density lipoprotein cholesterol) and simulated biomarkers (BIO1 and BIO2) were studied in terms of association with cardiovascular disease, individual risk of cardiovascular disease at 3 years, and main prediction metrics. Overall, stratification improved efficiency, with stratified case-cohort designs being comparable to matched nested case-control designs. Individual risks and prediction measures calculated by using case-cohort and nested case-control designs after appropriate reweighting could be assessed with good efficiency, except for the finely matched nested case-control design, where matching variables could not be included in the individual risk estimation. In conclusion, the authors have shown that case-cohort and nested case-control designs can be used in settings where the research aim is to evaluate the prediction ability of new markers and that matching strategies for nested case-control designs may lead to biased prediction measures.     

Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer’s disease and apoE TR mouse cortex

The apolipoprotein E4 allele (APOE4) contributes to Alzheimer's disease (AD) risk and APOE2 is protective, but the relevant cellular mechanisms are unknown. We have used flow cytometry analysis to measure apolipoprotein E (apoE) and amyloid beta peptide (Aβ) levels in large populations of synaptic terminals from AD and aged cognitively normal controls, and demonstrate that modest but significant increases in soluble apoE levels accompany elevated Aβ in AD cortical synapses and in an APP/PS1 rat model of AD. Dual labeling experiments document co-localization of apoE and Aβ in individual synapses with concentration of Aβ in a small population of apoE-positive synapses in both AD and controls. Consistent with a clearance role, the apoE level was higher in Aβ-positive synapses in control cases. In aged targeted replacement mice expressing human apoE, apoE2/4 synaptic terminals demonstrated the highest level of apoE and the lowest level of Aβ compared to apoE3/3 and apoE4/4 lines. In apoE2/4 terminals, the pattern of immunolabeling for apoE and Aβ closely resembled the pattern in human control cases, and elevated apoE was accompanied by elevated free cholesterol in apoE2/4 synaptic terminals. These results are consistent with a role for APOE in Aβ clearance in AD synapses, and suggest that optimal lipidation of apoE2 compared to E3 and E4 makes an important contribution to Aβ clearance and synaptic function.     

Prostate cancer chemoprevention in men of African descent: current state of the art and opportunities for future research

Prostate cancer is the most frequently diagnosed malignancy in men. However, African American/Black men are 60 % more likely to be diagnosed with and 2.4 times more likely to die from prostate cancer, compared to Non-Hispanic White men. Despite the increased burden of this malignancy, no evidence-based recommendation regarding prostate cancer screening exists for the high-risk population. Moreover, in addition to screening and detection, African American men may constitute a prime population for chemoprevention. Early detection and chemoprevention may thus represent an integral part of prostate cancer control in this population. Importantly, recent research has elucidated biological differences in the prostate tumors of African American compared to European American men. The latter may enable a more favorable response in African American men to specific chemopreventive agents that target relevant signal transduction pathways. Based on this evolving evidence, the aims of this review are threefold. First, we aim to summarize the biological differences that were reported in the prostate tumors of African American and European American men. Second, we will review the single- and multi-target chemopreventive agents placing specific emphasis on the pathways implicated in prostate carcinogenesis. And lastly, we will discuss the most promising nutraceutical chemopreventive compounds. Our review underscores the promise of chemoprevention in prostate cancer control, as well as provides justification for further investment in this filed to ultimately reduce prostate cancer morbidity and mortality in this high-risk population of African American men.     

New cell therapy using bone marrow-derived stem cells/endothelial progenitor cells to accelerate neovascularization in healing of experimental ulcerative colitis

Inflammatory bowel disease (IBD): ulcerative colitis (UC) and Crohn disease (CD) are characterized by recurrent inflammation and ulceration of intestinal and/or colonic mucosa and an inappropriate and delayed healing. Current therapies with, e.g., anti-TNFα antibody (infliximab) and other anti-inflammatory drugs (e.g., mesalamine) do not induce sustained remission, complete healing or prevent recurrence of UC. Although the pathogenesis of UC is not fully understood, pathologic angiogenesis has been postulated as a critical pathogenic component in UC. Recent studies demonstrated that the poor healing, chronic inflammation in colon of UC could be the result of microvascular dysfunction and endothelial barrier defect, resulting in sustained tissue hypoperfusion and ischemia in the colon. Previously, regeneration of injured endothelium and neovascularization were believed to rely solely on the migration and proliferation of neighboring endothelial cells from existing blood vessels. However, accumulating evidence shows that additional mechanisms may exist, and may be mediated by the circulating pool of bone marrow-derived endothelial progenitor cells (BMD-EPC). Furthermore, stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 have been demonstrated to play an important role in the "homing" of BMD-EPC to injured sites and neovascularization in tissue repair. Recent studies by others and us showed reduced BMD-EPC levels in the circulation of IBD patients and rats with experimental UC. However, the potential therapeutic effect of BMD-EPC on neovascularization and colonic mucosal repair in UC has not been elucidated. In this review, we discussed the possibility that impaired contribution of BMD-EPC (i.e., decreased release of BMD-EPC from bone marrow to circulation and/or blocked/impaired homing of BMD-EPC to colonic lesions) may be a critical component of mechanisms in the incomplete/delayed healing of UC, and may offer a novel form of cell therapy for IBD.     

Major histocompatibility complex class I-mediated inhibition of neurite outgrowth from peripheral nerves

Studies of mice deficient in classical major histocompatability complex class I (MHCI) revealed that MHCI plays an important role in neurodevelopment in the central nervous system. We previously studied the effects of recombinant MHCI molecules on wildtype retina explants and observed that MHCI can inhibit retina neurite outgrowth, with self-MHCI molecules having greater inhibitory effect than non-self MHCI molecules. Here, we examined classical MHCI's effects on axon outgrowth from neurons of the peripheral nervous system (PNS). We used the embryonic dorsal root ganglia (DRG) explant model since their neurons express MHCI and because DRG explants have been widely used to assess the effects of molecules on axonal outgrowth from PNS neurons. We observed that picomolar levels of a recombinant self-MHCI molecule, but not non-self MHCI molecules, inhibited axon outgrowth from DRG explants. This differential sensitivity to self- vs. non-self MHCI suggests that early in development, self-MHCI may "educate" PNS neurons to express appropriate MHCI receptors, as occurs during natural killer cell development. Furthermore, we observed that a MHCI tetramer stained embryonic DRG neurons, indicating the expression of classical MHCI receptors. These results suggest that MHCI and MHCI receptors play roles during early stages of PNS development and may provide new targets of therapeutic strategies to promote neuronal outgrowth after PNS injury.