The markedly higher circulating concentrations of biologically active (unconjugated) genistein in certain strains of mice cast doubt on the value of the use of these rodents for gaining insight into the effects of isoflavones in humans, especially with regard to the effects on breast tissue.
The soy isoflavone metabolite, S-(-)equol, has selective affinity for estrogen receptor (ER)beta and also antagonizes in vivo the action of dihydrotestosterone. It is therefore of interest as a potential new therapeutic agent in hormone-dependent conditions and is under development as a nutraceutical. Our objective in this study was to define the pharmacokinetics of natural S-(-)equol after administration of SE5-OH, a newly developed S-(-)equol supplement made by incubation of the equol-producing bacterium Lactococcus garvieae with soy germ isoflavones. In a single-center, open-label, randomized, 2-period crossover design study, the pharmacokinetics of S-(-)equol administered as single-bolus oral doses of 10 and 30 mg in the form of SE5-OH tablets was determined in 12 healthy postmenopausal women. S-(-)equol was measured in plasma and urine collected at timed intervals over a 48-h period postdosing using tandem MS. Equol-producer status was also determined after a soymilk challenge conducted after the pharmacokinetic sampling was complete. S-(-)equol was rapidly absorbed after oral administration and attained high plasma concentrations, with a plasma elimination half-life of 8 h. The maximum plasma concentration/dose, area under the plasma concentration-time curve from time 0 to infinity/dose, and the fraction of dose excreted in urine (%f(e,u)) were similar for the 2 doses, indicating a dose-proportional response in total S-(-)equol pharmacokinetics. The systemic bioavailability of S-(-)equol was very high, as the %f(e,u) was 82% for both doses, which is greater than published data for the soy isoflavones daidzein and genistein. Three participants were determined to be equol-producers, representing a 25% frequency, and equol-producer status had no effect on natural S-(-)equol pharmacokinetics.
The high bioavailability of both diastereoisomers contrasts with previous findings for the soy isoflavones daidzein and genistein, both of which have relatively poor bioavailability, and suggests that low doses of equol taken twice daily may be sufficient to achieve biological effects.
Mobilization of hematopoietic stem cells (HSCs) from bone marrow (BM) to peripheral blood (PB) by cytokine granulocyte colony-stimulating factor (G-CSF) or the chemical antagonist of CXCR4, AMD3100, is important in the treatment of blood diseases. Due to clinical conditions of each application, there is a need for continued improvement of HSC mobilization regimens. Previous studies have shown that genetic ablation of the Rho GTPase Cdc42 in HSCs results in their mobilization without affecting survival. Here we rationally identified a Cdc42 activity-specific inhibitor (CASIN) that can bind to Cdc42 with submicromolar affinity and competitively interfere with guanine nucleotide exchange activity. CASIN inhibits intracellular Cdc42 activity specifically and transiently to induce murine hematopoietic stem/progenitor cell egress from the BM by suppressing actin polymerization, adhesion, and directional migration of stem/progenitor cells, conferring Cdc42 knockout phenotypes. We further show that, although, CASIN administration to mice mobilizes similar number of phenotypic HSCs as AMD3100, it produces HSCs with better long-term reconstitution potential than that by AMD3100. Our work validates a specific small molecule inhibitor for Cdc42, and demonstrates that signaling molecules downstream of cytokines and chemokines, such as Cdc42, constitute a useful target for long-term stem cell mobilization.
Vitamin D has endocrine function as a key regulator of calcium absorption and bone homeostasis and also has intracrine function as an immunomodulator. Vitamin D deficiency before hematopoietic stem cell transplantation (HSCT) has been variably associated with higher risks of graft-versus-host disease (GVHD) and mortality. Children are at particular risk of growth impairment and bony abnormalities in the face of prolonged deficiency. There are few longitudinal studies of vitamin D deficient children receiving HSCT, and the prevalence and consequences of vitamin D deficiency 100 days after transplant has been poorly studied. Serum samples from 134 consecutive HSCT patients prospectively enrolled into an HSCT sample repository were tested for 25-hydroxy (25 OH) vitamin D levels before starting HSCT (baseline) and at 100 days after transplantation. Ninety-four of 134 patients (70%) had a vitamin D level < 30 ng/mL before HSCT, despite supplemental therapy in 16% of subjects. Post-transplant samples were available in 129 patients who survived to day 100 post-transplant. Vitamin D deficiency persisted in 66 of 87 patients (76%) who were already deficient before HSCT. Moreover, 24 patients with normal vitamin D levels before HSCT were vitamin D deficient by day 100. Overall, 68% of patients were vitamin D deficient (<30 ng/mL) at day 100, and one third of these cases had severe vitamin D deficiency (<20 ng/mL). Low vitamin D levels before HSCT were not associated with subsequent acute or chronic GVHD, contrary to some prior reports. However, severe vitamin D deficiency (<20 ng/mL) at 100 days post-HSCT was associated with decreased overall survival after transplantation (P = .044, 1-year rate of overall survival: 70% versus 84.1%). We conclude that all pediatric transplant recipients should be screened for vitamin D deficiency before HSCT and at day 100 post-transplant and that aggressive supplementation is needed to maintain sufficient levels.
Tay-Sachs disease (TSD) is a lethal lysosomal storage disease (LSD) caused by mutations in the HexA gene, which can lead to deficiency of β-hexosaminidase A (HexA) activity and consequent accumulation of its substrate, GM2 ganglioside. Recent reports that progranulin (PGRN) functions as a chaperone of lysosomal enzymes and its deficiency is associated with LSDs, including Gaucher Disease and neuronal ceroid lipofuscinosis, prompted us to screen the effects of recombinant PGRN on lysosomal storage in fibroblasts from 11 patients affected by various LSDs, which led to the isolation of TSD in which PGRN demonstrated the best effects in reducing lysosomal storage. Subsequent in vivo studies revealed significant GM2 accumulation and the existence of typical TSD cells containing zebra-bodies in both aged and ovalbuminchallenged adult PGRN deficient mice. In addition, HexA, but not HexB, was aggregated in PGRN deficient cells. Furthermore, recombinant PGRN significantly reduced GM2 accumulation and lysosomal storage in these animal models. Mechanistic studies indicated that PGRN bound to HexA through granulin G and E domain, and increased the enzymatic activity and lysosomal delivery of HexA. More importantly, Pcgin, an engineered PGRN derivative bearing the granulin E domain, also effectively bound to HexA and reduced the GM2 accumulation. Collectively, these studies not only provide new insights into the pathogenesis of TSD, but may also have implications for developing PGRN-based therapy for this lifethreatening disorder.
We describe for the first time the chemopreventive effects of S-(-)equol and R-(+)equol, diastereoisomers with contrasting affinities for estrogen receptors (ERs). S-(-)equol, a ligand for ERbeta, is an intestinally derived metabolite formed by many humans and by rodents consuming diets containing soy isoflavones. Whether the well-documented chemopreventive effect of a soy diet could be explained by equol's action was unclear because neither diastereoisomers had been tested in animal models of chemoprevention. Sprague-Dawley rats (n = 40-41 per group) were fed a soy-free AIN-93G diet or an AIN-93G diet supplemented with 250 mg/kg of S-(-)equol or R-(+)equol beginning day 35. On day 50, mammary tumors were induced by dimethylbenz[a]anthracene and thereafter, animals were palpated for number and location of tumors. On day 190, animals were killed and mammary tumors were removed and verified by histology, and the degree of invasiveness and differentiation was determined. S-(-)equol and R-(+)equol plasma concentrations measured on days 35, 100 and 190 by tandem mass spectrometry confirmed diet compliance and no biotransformation of either diastereoisomer. In this model, S-(-)equol had no chemopreventive action, nor was it stimulatory. In contrast, R-(+)equol compared with Controls reduced palpable tumors (P = 0.002), resulted in 43% fewer tumors (P = 0.004), increased tumor latency (88.5 versus 66 days, P = 0.003), and tumors were less invasive but showed no difference in pattern grade or mitosis. Both enantiomers had no effect on absolute uterine weight but caused a significant reduction in body weight gain. In conclusion, the novel finding that the unnatural enantiomer, R-(+)equol, was potently chemopreventive warrants investigation of its potential for breast cancer prevention and treatment.
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