[Show abstract][Hide abstract] ABSTRACT: There is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimer's disease (AD) and their function as a seed for the aggregation of Aβ, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aβ42, AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD-like model mice on high-AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aβ42 and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aβ42 and regulates its transport across the blood–brain barrier, suggesting a mediating pathway. Because exposure to AGEs can be diminished, these insights provide an important simple noninvasive potential therapeutic strategy for alleviating a major lifestyle-linked disease epidemic.
[Show abstract][Hide abstract] ABSTRACT: Obesity and type 2 diabetes are associated with increased risk of breast cancer incidence and mortality. Common features of obesity and type 2 diabetes are insulin resistance and hyperinsulinemia. A mammary tumor promoting effect of insulin resistance and hyperinsulinemia was demonstrated in the transgenic female MKR mouse model of pre-diabetes inoculated with mammary cancer cells. Interestingly, in MKR mice, as well as in other diabetic mouse models, males exhibit severe hyperglycemia, while females display insulin resistance and hyperinsulinemia with only a mild increase in blood glucose levels. This gender-specific protection from hyperglycemia may be attributed to estradiol, a key player in the regulation of the metabolic state, including obesity, glucose homeostasis, insulin resistance, and lipid profile. The aim of this study was to investigate the effects of ovariectomy (including the removal of endogenous estradiol) on the metabolic state of MKR female mice and subsequently on the growth of Mvt-1 mammary cancer cells, inoculated into the mammary fat pad of ovariectomized mice, compared with sham-operated mice. The results showed an increase in body weight, accompanied by increased fat mass, elevated blood glucose levels and hypercholesterolemia in ovariectomized MKR mice. In addition, mammary tumor growth was significantly higher in these mice. The results suggest that ovarian hormone deficiency may promote impaired metabolic homeostasis in the hyperinsulinemic MKR female mice, which in turn is associated with increased growth of mammary tumors.
No preview · Article · Sep 2015 · Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Intrauterine HIV/antiretroviral (ARV) and postnatal ARVs are known to perturb energy metabolism and could have permanent effects on future metabolic health. Such maladaptive effects could be mediated by changes in mitochondrial function and intermediary metabolism due to fetal and early-life ARV exposure in HIV/ARV-exposed uninfected (HEU) infants.
To understand the relationship(s) between mitochondrial fuel utilization [assessed via acylcarnitines (ACs) and branched-chain amino acids (BCAAs)] and pre-prandial insulin in infants exposed to in utero HIV/ARV plus postnatal zidovudine (AZT) or nevirapine (NVP) compared to HIV /ARV-unexposed uninfected (HUU) infants.
Prospective cohort study with 3 groups: 1) intrauterine HIV/ARV/postnatal AZT-exposed (HEU-A), 2) intrauterine HIV/ARV/postnatal NVP-exposed (HEU-N), and 3) HUU infants. Principal component analysis and linear regression modeling were performed to assess the association between in utero HIV/ARV exposure and infant insulin.
Cameroonian urban antenatal centers.
HIV-infected and -uninfected pregnant woman/infant dyads.
Of 366 infants, 38 were HEU-A, 118 HEU-N. Forty intermediary metabolites were consolidated into seven principal components. In multivariate analysis, both HEU-A (β=-0.116, p=0.012) and HEU-N (β=-0.070,p=0.022) demonstrated lower insulin compared to HUU infants. However, at high levels of plasma metabolites, HEU-A (β=0.027,p=0.050) exhibited higher insulin levels than HEU-N or HUU infants. A unique array of short-chain ACs (β=0.044, p=0.001) and BCAAs (β=0.033, p=0.012) were associated with insulin.
HEU-A and HEU-N infants have lower preprandial insulin levels at 6 weeks of age and appear to utilize metabolic fuel substrates differently than HUU infants. Future studies are warranted to determine whether observed differences have lasting metabolic implications, such as later insulin resistance.
Full-text · Article · Jul 2015 · The Journal of Clinical Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: CD24 is an anchored cell surface marker that is highly expressed in cancer cells (Lee et al., 2009) and its expression is associated with poorer outcome of cancer patients (Kristiansen et al., 2003). Phenotype comparison between two subpopulations derived from the Mvt1 cell line, CD24− cells (with no CD24 cell surface expression) and the CD24+ cells, identified high tumorigenic capacity for the CD24+ cells. In order to reveal the transcripts that support the CD24+ aggressive and invasive phenotype we compared the gene profiles of these two subpopulations. mRNA profiles of CD24− and CD24+ cells were generated by deep sequencing, in triplicate, using an Illumina HiSeq 2500. Here we provide a detailed description of the mRNA-seq analysis from our recent study (Rostoker et al., 2015). The mRNA-seq data have been deposited in the NCBI GEO database (accession number GSE68746).
[Show abstract][Hide abstract] ABSTRACT: Estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and does not respond to conventional hormonal therapies. Strategies that lead to re-expression of ERα could sensitize ERα-negative breast cancers to selective ER modulators. FTY720 (fingolimod, Gilenya), a sphingosine analog, is the Food and Drug Administration (FDA)-approved prodrug for treatment of multiple sclerosis that also has anticancer actions that are not yet well understood. We found that FTY720 is phosphorylated in breast cancer cells by nuclear sphingosine kinase 2 and accumulates there. Nuclear FTY720-P is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and regulates expression of a restricted set of genes independently of its known effects on canonical signaling through sphingosine-1-phosphate receptors. High-fat diet (HFD) and obesity, which is now endemic, increase breast cancer risk and have been associated with worse prognosis. HFD accelerated the onset of tumors with more advanced lesions and increased triple-negative spontaneous breast tumors and HDAC activity in MMTV-PyMT transgenic mice. Oral administration of clinically relevant doses of FTY720 suppressed development, progression and aggressiveness of spontaneous breast tumors in these mice, reduced HDAC activity and strikingly reversed HFD-induced loss of estrogen and progesterone receptors in advanced carcinoma. In ERα-negative human and murine breast cancer cells, FTY720 reactivated expression of silenced ERα and sensitized them to tamoxifen. Moreover, treatment with FTY720 also re-expressed ERα and increased therapeutic sensitivity of ERα-negative syngeneic breast tumors to tamoxifen in vivo more potently than a known HDAC inhibitor. Our work suggests that a multipronged attack with FTY720 is a novel combination approach for effective treatment of both conventional hormonal therapy-resistant breast cancer and triple-negative breast cancer.
[Show abstract][Hide abstract] ABSTRACT: Breast tumors are comprised of distinct cancer cell populations which differ in their tumorigenic and metastatic capacity. Characterization of cell surface markers enables investigators to distinguish between cancer stem cells and their counterparts. CD24 is a well-known cell surface marker for mammary epithelial cells isolation, recently it was suggested as a potential prognostic marker in a wide variety of malignancies. Here, we demonstrate that CD24(+) cells create intra-tumor heterogeneity, and display highly metastatic properties.
The mammary carcinoma Mvt1 cells were sorted into CD24(-) and CD24(+) cells. Both subsets were morphologically and phenotypically characterized, and tumorigenic capacity was assessed via orthotopic inoculation of each subset into the mammary fat pad of wild-type and MKR mice. The metastatic capacity of each subset was determined with the tail vein metastasis assay. The role of CD24 in tumorigenesis was further examined with shRNA technology. GFP-labeled cells were monitored in-vivo for differentiation. The genetic profile of each subset was analyzed using RNA sequencing.
CD24(+) cells displayed a more spindle-like cytoplasm. The cells formed mammospheres in high efficiency and CD24(+) tumors displayed rapid growth in both WT and MKR mice, and were more metastatic than CD24- cells. Interestingly, CD24-KD in CD24+ cells had no effect both in-vitro and in-vivo on the various parameters studied. Moreover, CD24(+) cells gave rise in-vivo into the CD24(-) that comprised the bulk of the tumor. RNA-seq analysis revealed enrichment of genes and pathways of the extracellular matrix in the CD24(+) cells.
CD24(+) cells account for heterogeneity in mammary tumors. CD24 expression at early stages of the cancer process is an indication of a highly invasive tumor. However, CD24 is not a suitable therapeutic target; instead we suggest here new potential targets accounting for early differentiated cancer cells tumorigenic capacity.
Full-text · Article · Jun 2015 · Breast cancer research: BCR
[Show abstract][Hide abstract] ABSTRACT: Obesity is associated with multiple metabolic disorders that drive cardiovascular disease, T2D and cancer. The doubling in the number of obese adults over the past 3 decades led to the recognition of obesity as a "disease". With over 42 million children obese or overweight, this epidemic is rapidly growing worldwide. Obesity and T2D are both associated together and independently with an increased risk for cancer and a worse prognosis. Accumulating evidence from epidemiological studies revealed potential factors that may explain the association between obesity-linked metabolic disorders and cancer risk. Studies based on the insulin resistance MKR mice, highlighted the roe of the insulin receptor and its downstream signaling proteins in mediating hyperinsulinemia's mitogenic effects. Hypercholesterolemia was also shown to promote the formation of larger tumors and enhancement in metastasis. Furthermore, the conversion of cholesterol into 27-Hydroxycholesterol was found to link high fat diet-induced hypercholesterolemia with cancer pathophysiology. Alteration in circulating adipokines and cytokines are commonly found in obesity and T2D. Adipokines are involved in tumor growth through multiple mechanisms including mTOR, VEGF and cyclins. In addition, adipose tissues are known to recruit and alter macrophage phenotype; these macrophages can promote cancer progression by secreting inflammatory cytokines such as TNF-α and IL-6.Better characterization on the above factors and their downstream effects is required in order to translate the current knowledge into the clinic, but more importantly is to understand which are the key factors that drive cancer in each patient. Until we reach this point, policies and activities toward healthy diets and physical activities remain the best medicine.
No preview · Article · Apr 2015 · Handbook of experimental pharmacology
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to investigate whether the association of glycaemic control with cognitive function is modulated by the haptoglobin 1-1 (Hp 1-1) genotype in cognitively normal elderly individuals with type 2 diabetes.
In this cross-sectional study, we examined 793 participants who were genotyped for Hp (80 Hp 1-1 carriers and 713 Hp 1-1 non-carriers) enrolled in the Israel Diabetes and Cognitive Decline (IDCD) study. Glycaemic control was operationally defined by HbA1c level. The outcome measures were performance in four cognitive domains (episodic memory, attention/working memory, language/semantic categorisation, executive function) and overall cognition, a composite of the domains. Effect sizes were obtained from hierarchical linear regression analyses for each outcome measure, controlling for demographics, type 2 diabetes-related characteristics, cardiovascular risk factors, and their interactions with Hp genotype.
Interaction analyses showed significantly stronger associations of HbA1c with poorer cognitive function among Hp 1-1 carriers than non-carriers; attention/working memory (p < 0.001) and overall cognition (p = 0.003). For these two cognitive domains, associations were significant for Hp 1-1 carriers despite the small sample size (p < 0.00001 and p = 0.001, respectively), but not for non-carriers.
Our findings suggest that patients with type 2 diabetes and poor glycaemic control carrying the Hp 1-1 genotype may be at increased risk of cognitive impairment, particularly in the attention/working memory domain. The association of glycaemic control with this domain may indicate cerebrovascular mechanisms.
[Show abstract][Hide abstract] ABSTRACT: Rational: Prior studies have shown an anticancer effect of metformin in patients with breast and colorectal cancer. It is unclear, however, whether metformin has a mortality benefit in lung cancer. Objectives: To compare overall survival of diabetic patients with stage IV non-small cell lung cancer (NSCLC) taking metformin versus those not on metformin. Methods: Using data from the Surveillance, Epidemiology and End Results registry linked to Medicare claims, we identified 750 diabetic patients 65-80 years of age diagnosed with stage IV NSCLC between 2007 and 2009. We used propensity score methods to assess the association of metformin use with overall survival while controlling for potential confounders. Measurements and Main Results: Overall, 61% of patients were on metformin at time of lung cancer diagnosis. Median survival in the metformin group was five months, compared to three months in patients not treated with metformin (p<0.001). Propensity score analyses showed that metformin use was associated with a statistically significant improvement in survival (hazard ratio: 0.80, 95% confidence interval 0.71 to 0.89), after controlling for sociodemographics, diabetes severity, other diabetes medications, cancer characteristics, and treatment. Conclusions: Metformin is associated with improved survival among diabetic patients with stage IV NSCLC suggesting a potential anticancer effect. Further research should evaluate plausible biological mechanisms as well as test the effect of metformin in prospective clinical trials.
No preview · Article · Dec 2014 · American Journal of Respiratory and Critical Care Medicine