Impact of Serum Calcium Levels on Alzheimer's Disease: A Mendelian Randomization Study.

BACKGROUND: Altered calcium homeostasis is hypothesized to underlie Alzheimer's disease (AD). However, it remains unclear whether serum calcium levels are genetically associated with AD risk. OBJECTIVE: To develop effective therapies, we should establish the causal link between serum calcium levels and AD. METHODS: Here, we performed a Mendelian randomization study to investigate the causal association of increased serum calcium levels with AD risk using the genetic variants from a large-scale serum calcium genome-wide association study (GWAS) dataset (61,079 individuals of European descent) and a large-scale AD GWAS dataset (54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Here, we selected the inverse-variance weighted (IVW) as the main analysis method. Meanwhile, we selected other three sensitivity analysis methods to examine the robustness of the IVW estimate. RESULTS: IVW analysis showed that the increased serum calcium level (per 1 standard deviation (SD) increase 0.5 mg/dL) was significantly associated with a reduced AD risk (OR = 0.57, 95% CI 0.35-0.95, p = 0.031). Meanwhile, all the estimates from other sensitivity analysis methods were consistent with the IVW estimate in terms of direction and magnitude. CONCLUSION: In summary, we provided evidence that increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be conducted to clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.

Circulating serum vitamin D levels and total body bone mineral density: A Mendelian randomization study.

Until recently, randomized controlled trials have not demonstrated convincing evidence that vitamin D, or vitamin D in combination with calcium supplementation could improve bone mineral density (BMD), osteoporosis and fracture. It remains unclear whether vitamin D levels are causally associated with total body BMD. Here, we performed a Mendelian randomization study to investigate the association of vitamin D levels with total body BMD using a large-scale vitamin D genome-wide association study (GWAS) dataset (including 79 366 individuals) and a large-scale total body BMD GWAS dataset (including 66,628 individuals). We selected three Mendelian randomization methods including inverse-variance weighted meta-analysis (IVW), weighted median regression and MR-Egger regression. All these three methods did not show statistically significant association of genetically increased vitamin D levels with total body BMD. Importantly, our findings are consistent with recent randomized clinical trials and Mendelian randomization study. In summary, we provide genetic evidence that increased vitamin D levels could not improve BMD in the general population. Hence, vitamin D supplementation alone may not be associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture.

Enhanced Therapeutic Potential of Nano-Curcumin Against Subarachnoid Hemorrhage-Induced Blood-Brain Barrier Disruption Through Inhibition of Inflammatory Response and Oxidative Stress.

Curcumin and nano-curcumin both exhibit neuroprotective effects in early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH). However, the mechanism that whether curcumin and its nanoparticles affect the blood-brain barrier (BBB) following SAH remains unclear. This study investigated the effect of curcumin and the poly(lactide-co-glycolide) (PLGA)-encapsulated curcumin nanoparticles (Cur-NPs) on BBB disruption and evaluated the possible mechanism underlying BBB dysfunction in EBI using the endovascular perforation rat SAH model. The results indicated that Cur-NPs showed enhanced therapeutic effects than that of curcumin in improving neurological function, reducing brain water content, and Evans blue dye extravasation after SAH. Mechanically, Cur-NPs attenuated BBB dysfunction after SAH by preventing the disruption of tight junction protein (ZO-1, occludin, and claudin-5). Cur-NPs also up-regulated glutamate transporter-1 and attenuated glutamate concentration of cerebrospinal fluid following SAH. Moreover, inhibition of inflammatory response and microglia activation both contributed to Cur-NPs' protective effects. Additionally, Cur-NPs markedly suppressed SAH-mediated oxidative stress and eventually reversed SAH-induced cell apoptosis in rats. Our findings revealed that the strategy of using Cur-NPs could be a promising way in improving neurological function in EBI after experimental rat SAH.

Induction of S-Phase Arrest in Human Glioma Cells by Selenocysteine, a Natural Selenium-Containing Agent Via Triggering Reactive Oxygen Species-Mediated DNA Damage and Modulating MAPKs and AKT Pathways.

Selenocysteine (SeC) a natural available selenoamino acid exhibits novel anticancer activities against human cancer cell lines. However, the growth inhibitory effect and mechanism of SeC in human glioma cells remain unclear. The present study reveals that SeC time- and dose-dependently inhibited U251 and U87 human glioma cells growth by induction of S-phase cell cycle arrest, followed by the marked decrease of cyclin A. SeC-induced S-phase arrest was achieved by inducing DNA damage through triggering generation of reactive oxygen species (ROS) and superoxide anion, with concomitant increase of TUNEL-positive cells and induction of p21waf1/Cip1 and p53. SeC treatment also caused the activation of p38MAPK, JNK and ERK, and inactivation of AKT. Four inhibitors of MAPKs and AKT pathways further confirmed their roles in SeC-induced S-phase arrest in human glioma cells. Our findings advance the understanding on the molecular mechanisms of SeC in human glioma management.

Beneficial effects of Yerba Mate tea (Ilex paraguariensis) on hyperlipidemia in high-fat-fed hamsters.

Yerba Mate tea (Mate), an infusion made from the leaves of the tree Ilex paraguariensis, is a widely consumed beverage in South America. Mate has previously been shown to have hypolipidemic effects. However, its mechanism of action is not well understood. This study was conducted to determine the effect of Mate on hyperlipidemia induced in hamsters by a high-fat diet, as well as its mechanism of action. Fifty male hamsters were randomly assigned to normal control, high-fat control, and high-fat with Mate tea aqueous extract (1%, 2% or 4% w/v) groups. We evaluated the effects of Mate aqueous extract on body weight, serum lipids, antioxidant enzyme activity, lipoprotein metabolism enzyme activity, and gene expression involved in lipid metabolism in hyperlipidemic hamsters. Mate aqueous extract significantly decreased body-weight gain and lowered serum lipid levels in the hyperlipidemic hamster model. Meanwhile, Mate treatment increased antioxidant enzyme activity, improved lipoprotein lipase (LPL) and hepatic lipase (HL) activities in serum and liver, upregulated mRNA expression of peroxisome proliferator-activated receptor α and low density lipoprotein receptor, and downregulated mRNA expression of sterol regulatory element-binding protein 1c and acetyl CoA carboxylase in the liver. The results indicate that Mate tea ameliorates hyperlipidemia partly by reducing lipid peroxidation, improving endothelial function and LPL and HL activities, and modulating the expression levels of genes involved in lipid oxidation and lipogenesis.

Extract of Ginkgo biloba promotes the expression of VEGF following subarachnoid hemorrhage in rats.

The study aimed to investigate the effect of extract of Ginkgo biloba (EGb) on the expression of vascular endothelial growth factor (VEGF) after subarachnoid hemorrhage (SAH). Wistar rats were divided into non-SAH, SAH, vehicle, EGb1 (low-dose), and EGb2 (high-dose) groups. VEGF mRNA and VEGF protein were measured from brain tissues. The expressions of VEGF mRNA in SAH and vehicle groups were enhanced 24 and 72 hr after the establishment of SAH. Increased VEGF positive cells were found in the brain tissues in SAH and vehicle groups. The expressions of VEGF mRNA and VEGF protein were further increased by the pretreatment of EGb. We concluded that EGb exerts protective effects on secondary cerebral ischemic injury after SAH via the promotion of the expression of VEGF.

Effects of extract of ginkgo biloba on intracranial pressure, cerebral perfusion pressure, and cerebral blood flow in a rat model of subarachnoid haemorrhage.

The purpose of this study was to investigate in effect of extract of Ginkgo biloba (EGb) on cerebral blood perfusion in a subarachnoid haemorrhage (SAH) rat model. SAH lead to an increase in intracranial pressure and decrease in cranial perfusion pressure and regional cerebral blood flow in all groups. However, the intracranial pressure increases in EGb groups were less than that of the vehicle group (p < .01), whereas the reduction in cranial perfusion pressure and regional cerebral blood flow in the EGb group was less than that of the vehicle and SAH groups (p < .01). It was concluded that EGb attenuates the increase in intracranial pressure and reduction in cerebral blood perfusion after SAH.

Expression of the receptors of VEGF and the influence of extract of Ginkgo biloba after cisternal injection of autologus arterial hemolysate in rats.

The study was aimed to investigate the alterations of vascular endothelial growth factor (VEGF) receptors and the influence of extract of Ginkgo biloba (EGb) after subarachnoid hemorrhage (SAH). Wistar rats were divided into non-SAH, SAH, vehicle, EGb1 (lower dose), and EGb2 (higher dose) groups. Autologus arterial hemolysate was injected into cisterna magna to induce SAH. The non-SAH rats received cisternal injection of saline instead. Rats underwent RT-PCR determination of one of the VEGF receptors flt-1mRNA, and immunohistochemistry for VEGF receptors Flt-1 and Flk-1. The results revealed that there was only slight expression of flt-1mRNA in the brain tissue in non-SAH rats. The expression in SAH group was enhanced 24 hours and 72 hours after cisternal injection. No Flt-1 and Flk-1 positive cell was observed in the brain in non-SAH group. A good few Flt-1 and Flk-1 positive cells were found in cortex and other regions of the brain in SAH group. The expression of flt-1mRNA, Flt-1 and Flk-1 proteins were increased by the use of two doses of EGb. It was concluded that the up-regulated expression of the two kinds of VEGF receptors may be an intrinsic protective mechanism in the process of SAH, which can be enhanced by EGb.

Effects of extract of Ginkgo biloba on spasms of the basilar artery and cerebral microcirculatory perfusion in rats with subarachnoid hemorrhage.

This study was aimed at investigating the effects of extract of Ginkgo biloba (EGb) on cerebral vasospasm and microcirculatory perfusion after subarachnoid hemorrhage (SAH). An endovascular piercing method was used to induce Wistar rat SAH models, and animals were divided into sham-operated, vehicle controls, and EGb-treated groups. EGb was injected intraperitoneally 30 minutes before operation and was repeated every 6 hours, with a single dose of 15 mg/kg bw. Diameters of basilar arteries before and after operation were measured. Microcirculatory blood perfusion of parietal lobe cortex was detected using a laser Doppler flow-meter probe within 24 hours. Endothelin-1 levels in both plasma and brain tissue were detected at different time points. The results showed that SAH caused an immediate drop in microcirculatory blood flow in vehicle controls, which persisted for 24 hours. Endothelin-1 levels in both plasma and brain tissue increased after SAH. EGb partly reversed spasms of the basilar artery and antagonized a drop in microcirculatory blood flow. EGb also prevented an increase in endothelin-1 both in plasma and in brain tissue. In conclusion, EGb, by antagonizing the overproduction of endo- thelin-1, partly reverses cerebral vasospasm and improves microcirculation, and thus relieves secondary ischemic brain injury after experimental SAH.

The effects of nimodipine on regional cerebral blood flow, brain water and electrolyte contents in rats with subarachnoid hemorrhage.

Secondary cerebral ischemic injury is a major cause of mortality and disability from subarachnoid hemorrhage (SAH). In this study, the protective effects of nimodipine were investigated. Rat SAH models were divided into a sham-operated group, a saline-controlled, and a nimodipine-treated group by an endovascular piercing method. Nimodipine, 100 microg/kg BW was injected intraperitoneally 30 minutes before operation and was repeated every 6 hours. Dynamic changes in cortical regional cerebral blood flow (rCBF) using a laser Doppler flow-meter probe, and somatosensory evoked potentials (SEP) were estimated. Brain water content, sodium, potassium and calcium contents at different time points were determined. rCBF, latency of SEP, brain water and electrolyte contents did not statistically change in sham-operated rats. In saline-controlled rats, rCBF decreased immediately after SAH, and stabilized at low levels within 24 hours. The latency of SEP delayed gradually after SAH. Brain water and sodium increased, while potassium decreased at 6 hours and 24 hours. Brain calcium content increased significantly from 1 hour to 24 hours after induction of SAH. Extents of alterations of the above parameters caused by SAH in the nimodipine-treated group were less than those in the saline-controlled group, statistically. In conclusion, nimodipine partly prevents a decrease in cerebral blood supply and attenuates secondary cerebral ischemic injury after SAH.