RESUMO
Hyperglycemia has various adverse health effects, some of which are due to chronic oxidative and inflammatory impairment of bone marrow (BM), hematopoietic stem cells (HSCs), and mesenchymal stem cells (MSCs). Astaxanthin (ASTX) has been shown to ameliorate hyperglycemia-associated systemic complications and acute mortality, and this effect is partially associated with restoration of normal hematopoiesis. Here, the effects of ASTX on diabetes-induced complications in BM and BM stem cells were investigated, and the underlying molecular mechanisms were elucidated. Ten-week-old C57BL/6 mice received a single intraperitoneal injection of streptozotocin (STZ; 150 mg/kg) in combination with oral gavage of ASTX (12.5 mg/kg) for 30 or 60 consecutive days. Supplemental ASTX ameliorated acute mortality and restored the STZ-impaired bone mass accrual and BM microenvironment in STZ-injected mice. Oral gavage of ASTX suppressed osteoclast formation in the BM of STZ-injected mice. Specifically, supplementation with ASTX inhibited oxidative stress and senescence induction of BM HSCs and MSCs and ameliorated hematopoietic disorders in STZ-injected mice. These effects of ASTX were associated with BM restoration of angiopoietin 1, stromal cell-derived factor 1, ß-catenin, and Nrf2. Long-term ASTX gavage also recovered the STZ-induced dysfunction in migration, colony formation, and mineralization of BM-derived stromal cells. Further, a direct addition of ASTX exhibited direct and dose-dependent inhibition of osteoclastic activation without cytotoxic effects. Collectively, these results indicate that ASTX protects against diabetes-induced damage in the BM microenvironment in BM, HSCs, and MSCs and restores normal hematopoiesis and bone accrual in STZ-injected mice.
RESUMO
OBJECTIVE: To examine the association of vitamin D receptor (VDR) gene polymorphisms of the Fok1 locus on bone mass accrual in Indian girls used to a low calcium intake. METHODS: An intervention trial was undertaken in 102 girls aged 8-16 y, attending a state run school in Pune city, India. All girls received 500 mg calcium daily and 30,000 IU of vitamin D3 quarterly for one year. Dietary calcium intake was evaluated. Bone mineral content (BMC), bone area (BA) and bone mineral density (BMD) were measured at total body using Dual Energy X-ray Absorptiometry (Lunar DPX-PRO). Polymorphisms of the Fok1 locus of the vitamin D Receptor (VDR) gene were detected using SYBR Green quantitative polymerase chain reaction. RESULTS: The prevalence of Fok1 polymorphism was 43.1% (Ff), 9.8% (ff) and 47.1% (FF). At baseline, FF genotype had significantly lower BMD as compared to ff and Ff genotype (p < 0.05). At baseline, majority of girls (82.4%) were hypocalcemic with low calcium intake. Post-supplementation, FF genotype had significantly lower bone mass as compared to ff and Ff genotype. Significant increase in BMC [Ff (17.9%); ff (18.1%); FF (17.4%)], and BMD [Ff (5.4 %); ff (6.3%); FF (4.8%)] was observed post supplementation (p value < 0.05), though percentage increase in BMC and BMD was similar for three Fok1 polymorphisms (p > 0.1). CONCLUSIONS: VDR gene polymorphism, as defined by Fok1 genotype had no positive influence on bone mass accrual in response to calcium supplementation.