The Alzheimer＇s disease （AD） is one of the common cognitive disorders in the elderly. AD shares some similar pathological characters with diabetes mellitus （DM）, suggesting potential application of anti-diabetic agents, such as vanadyl complexes, in therapeutic treatment of AD. In the present work, we studied the effects of vanadyl acetylacetonate （VO（acac）2） and cinnamaldehyde （CA） on an AD model based on SH-SY5Y neural cells. The experimental results showed that VO（acac）2 at sub-micromolar concentrations could improve the viability of neural cells with or without increased β-amyloid （Aβ） burden; and the combination of VO（acac）2 and CA showed an additive cell protection effects. Further investigation revealed that for SH-SY5Y neural cells, VO（acac）2 could activate PPART-AMPK signal transduction and inhibit GSK 3β, one of the major kinases for Tau hyperphosphorylation. Meanwhile, CA could correct the abnormal mitochondrial morphology due to Aβ-induced excessive mitochondrial fission, thus restoring/enhancing the mitochondrial function. In addition, both VO（acac）2 and CA decreased intracellular reactive oxygen species （ROS） level and inhibited formation of toxic Aβ oligomers. Overall, VO（acac）2 might work with CA in improving the neural cell viability under the Aβ burden, suggesting application of vanadium metallodrugs in AD treatment.
Cinnamon and its major active component, cinnamaldehyde, have been shown to be neuroprotective in models of Alzheimer＇s disease （AD）. To further investigate the mechanism of cinnamaldehyde, we investigated the effects of cinnamaldehyde focusing on mitochondrial function in SH-SYSY neural cells. The results demonstrated that cinnamaldehyde could enhance neural cell viability with or without increased Aβ levels. Cinnamaldehyde facilitated the maintenance of normal mitochondrial morphology, preserved the mitochondrial membrane potential （ATm）, and reduced production of reactive oxygen species （ROS）. Cinnamaldehyde also decreased the expression of dynamin-related protein 1 （Drpl）, a protein critically involved in mitochondrial dynamics. In addition, cinnamaldehyde inhibited Aβ oligomerization, but it had no effects on Tau phosphorylation. In overall, cinnamaldehyde promoted mitochondrial function and inhibited Aβ toxicity, and these two properties may both contribute to the neuroprotective effect. These results suggest that cinnamaldehyde could be a potential nutriceutical in the prevention and even therapeutic treatment of AD as well as other aging-related metabolic syndromes.
Lidan BaiXue LiQing ChangRui WUJing ZhangXiaoda Yang
Vanadium compounds are promising anti-diabetic agents. However, the concern in the toxicity, especially the long-term renal side effect along with diabetic status, is restricting the further development of this metal drug. Recently, we have prepared a bis（（5-hydroxy-4-oxo-4H-pyran-2-yl） methyl 2-hydroxy-benzoatato） oxovanadium（BSOV）, which exhibited excellent hypoglycemic effect with low acute toxicity. In order to facilitate the development of anti-diabetic vanadium complexes, especially BSOV, we studied the long-term toxicity and hypoglycemic effect of BSOV in comparison with bis（maltolato） oxovanadium（BMOV） on both non-diabetic and type II diabetic mice. The experiments confirmed a stable hypoglycemic effect for both the vanadium complexes over the testing period（6–7 months）. However, the chronic administration of vanadium compounds slightly increased oxidative stress in ICR mice and the induced renal interstitial edema（RIE） in a part of the diabetic animals associated with low levels of serum albumin. The use of an antioxidant dietary supplement（a combination of vitamin C and Zinc gluconate） could prevent vanadium-induced oxidative stress but have marginal effect on RIE. However, BSOV caused much lower incidence of RIE than BMOV did, suggesting that BSOV is an important step towards the successful development of anti-diabetic vanadium drugs.
The tight junction disorder plays an important role in the pathological process of many chronic diseases, and is becoming a major concern for the clinical application of metal drugs, i.e. anti-diabetic vanadium compounds. The development of novel tight junction protecting agents has thus been a major research focus. Since oxidative stress is the primary cause for vanadium toxicity, the present work tested the protective effects of zinc gluconate （Zn2＋） alone and when combined with vitamin C （VC） on the vanadium compound （VO（acac）z.）-mediated paracellular leakage of MDCK cells. The experimental results showed that VO（acac）2_ treatment significantly increased the paracellular permeability of MDCK monolayer. Zn2＋ alone showed no protective effects and VC ameliorated tight junction leakage of MDCK cells when given in the basal chamber. Interestingly, unilateral treatment with the combination of Zn2＋ and VC effectively prevented the increase of paracellular permeability. In addition, the combination of zinc and VC down-regulated the levels of reactive oxygen species in both the control and VO（acac）2-treated MDCK cells and caused the elevation of intracellular Ca2＋; both effects were beneficial for the maintenance of integrity of intercellular tight junction. Our results provided a simple but very effective method of preventing the metal toxicity for clinical aoNication of anti-diabetic vanadium compounds.
Vanadium compounds are promising anti-diabetic agents. However, the underlying mechanisms have not been fully elucidated. Inflammation and auto-immune disorders play important roles in the progresses of both type Ⅰ and type Ⅱ diabetes, in which heat shock protein 60 （HSP60） is an important endogenous inflammatory mediator. In the present work, we investigated the effects of vanadium compounds （vanadyl sulfate and sodium metavanadate） on the IL-6 production in RAW264.7 cells upon HSP60 stimulation. Our data revealed that both vanadyl ions regulated the IL-6 expression in a concentration-dependent manner. However, the two common NF-κB and PPAR-γ, signal pathways were not involved in this process. Further works are needed to elucidate the underlying mechanism and significance of the immuno-modification actions for the pharmacological applications of anti-diabetic vanadium compounds.
