Geranylgeranyl Transferase-I Knockout Inhibits Oxidative Injury of Vascular Smooth Muscle Cells and Attenuates Diabetes-Accelerated Atherosclerosis.

The proliferation of vascular smooth muscle cells (VSMCs) induced by oxidative injury is one of the main features in diabetes-accelerated atherosclerosis. Geranylgeranyl transferase-I (GGTase-I) is an essential enzyme mediating posttranslational modification, especially the geranylgeranylation of small GTPase, Rac1. Our previous studies found that GGTase-I played an important role in diabetes-accelerated atherosclerosis. However, its exact role is largely unclear. In this study, mouse conditional knockout of VSMC GGTase-I (Pggt1b Δ/Δ mice) was generated using the CRISPR/Cas9 system. The mouse model of diabetes-accelerated atherosclerosis was induced by streptozotocin injections and an atherogenic diet. We found that GGTase-I knockout attenuated diabetes-accelerated atherosclerosis in vivo and suppressed high-glucose-induced VSMC proliferation in vitro. Moreover, after a 16-week duration of diabetes, Pggt1b Δ/Δ mice exhibited lower α-smooth muscle actin (α-SMA) and nitrotyrosine level, Rac1 activity, p47phox and NOXO1 expression, and phospho-ERK1/2 and phosphor-JNK content than wild-type mice. Meanwhile, the same changes were found in Pggt1b Δ/Δ VSMCs cultured with high glucose (22.2 mM) in vitro. In conclusion, GGTase-I knockout efficiently blocked diabetes-accelerated atherosclerosis, and this protective effect must be related to the inhibition of VSMC proliferation. The potential mechanisms probably involved interfering Rac1 geranylgeranylation, inhibiting the assembly of NADPH oxidase cytosolic regulatory subunits, reducing oxidative injury, and decreasing ERK1/2 and JNK phosphorylation.

PPWD1 is associated with the occurrence of postmenopausal osteoporosis as determined by weighted gene co­expression network analysis.

Postmenopausal osteoporosis (PMO) is the most common type of primary osteoporosis (OP), a systemic skeletal disease. Although many factors have been revealed to contribute to the occurrence of PMO, specific biomarkers for the early diagnosis and therapy of PMO are not available. In the present study, a weighted gene co­expression network analysis (WGCNA) was performed to screen gene modules associated with menopausal status. The turquoise module was verified as the clinically significant module, and 12 genes (NUP133, PSMD12, PPWD1, RBM8A, CRNKL1, PPP2R5C, RBM22, PIK3CB, SKIV2L2, PAPOLA, SRSF1 and COPS2) were identified as 'real' hub genes in both the protein­protein interaction (PPI) network and co­expression network. Furthermore, gene expression analysis by microarray in blood monocytes from pre­ and post­menopausal women revealed an increase in the expression of these hub genes in postmenopausal women. However, only the expression of peptidylprolyl isomerase domain and WD repeat containing 1 (PPWD1) was correlated with bone mineral density (BMD) in postmenopausal women. In the validation set, a similar expression pattern of PPWD1 was revealed. Functional enrichment analysis revealed that the fatty acid metabolism pathway was significantly abundant in the samples that exhibited a higher expression of PPWD1. Collectively, PPWD1 is indicated as a potential diagnostic biomarker for the occurrence of PMO.

[Effects of alendronate on bone mineral density, cytokines and indices of bone metabolism in postmenopausal osteoporotic patients].

OBJECTIVE: To observe the effects of alendronate on bone mineral density (BMD), cytokines and indices of bone metabolism in postmenopausal osteoporotic (PMO) patients. METHODS: 185 PMO patients, aged from 55 to 60 years, were randomized into three groups. All of them received a kind of calcium preparation, 1.0 g/d. Group A, 69 patients, received alendronate, 10 mg/d; group B, 66 patients, received tibolone 1.25 mg/d. The remaining patients, group C, received calcium preparation only. 20 women of 55 - 60 (57.4 +/- 3.5) years old were taken as normal controls. Dual-energy X-ray absorptiometry and measurement of a series of biochemical indices were carried out before and after medication at 24th and 48th week. RESULTS: After medication, BMD increased in alendronate and tibolone group. The increment in spine BMD was 2.53% and 3.65% (P < 0.05) and that in nondominant proximal femur BMD was 7.17% and 3.01% (P < 0.001). In the tibolone group, the levels of estradiol (E(2)) increased rapidly (P < 0.01), but those of IL-6, TNFalpha and type I collagen cross-linked N-telopeptides (NTX) decreased (P < 0.01). In the alendronate group, no change of levels of E(2) happened, while levels of alkaline phosphatase (ALP) and osteocalcin (BGP) increased (P < 0.05) and levels of NTX decreased (P < 0.05). There was no change of the levels of other parameters. In the calcium preparation group and control group, the levels of BMD, E(2), ALP, BGP and insulin-like growth factor I decreased (P < 0.05), while those of IL-6, TNFalpha and NTX increased (P < 0.05). CONCLUSION: Alendronate can significantly improve BMD as tibolone do. Thus it plays an important role in the treatment of osteoporosis. However calcium tablet can not prevent the loss of bone.