|Year : 2017 | Volume
| Issue : 49 | Page : 123-128
Vincamine alleviates amyloid-β 25-35 peptides-induced cytotoxicity in PC12 cells
Jianfeng Han1, Qiumin Qu1, Jin Qiao1, Jie Zhang2
1 Department of Neurology, The First Clinical Hospital of Xian Jiaotong University, Xian 710061, P.R. China
2 Institute of Liver Disease, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
|Date of Submission||28-Aug-2015|
|Date of Acceptance||14-Oct-2015|
|Date of Web Publication||06-Jan-2017|
Dr. Jie Zhang
Institute of Liver Disease, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: Vincamine is a plant alkaloid used clinically as a peripheral vasodilator that increases cerebral blood flow and oxygen and glucose utilization by neural tissue to combat the effect of aging. The main purpose of the present study is to investigate the influence of vincamine on amyloid-β 25-35 (Aβ25-35) induced cytotoxicityto gain a better understanding of the neuroprotective effects of this clinically used anti-Alzheimer's disease drug. Materials and Methods: Oxidative stress was assessed by measuring malondialdehydeglutathioneand superoxide dismutase (SOD) levels. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell apoptosis detection was performed using an Annexin-V-FITC Apoptosis Detection Kit. The production of reactive oxygen species (ROS) was determined using an ROS Assay Kit. Western blot detection was carried out to detect the protein expression. Results: Our studies showed that pretreatment with vincamine could reduce Aβ25-35 induced oxidative stress. Vincamine markedly inhibited cell apoptosis dose-dependently. More importantlyvincamine increased the phosphatidylinositol-3 kinase (PI3K)/Akt and Bcl-2 family protein ratios on preincubation with cells for 2 h. Conclusion: Above observation led us to assume that one possible mechanism of vincamine protects Aβ25-35-induced cell death could be through upregulation of SOD and activation of the PI3K/Akt pathway.
Abbreviation used: Aβ25-35: Amyloid-β 25-35; AD: Alzheimer's disease; BCA: Bicinchoninic acid; GSH: glutathione; PBS: Phosphate buffered solution; SDS: Sodium dodecylsulphate; SOD: Superoxide dismutase
Keywords: Alzheimer′s diseaseamyloid-βPC12 cellsphosphatidylinositol-3 kinase/Akt pathwayvincamine
|How to cite this article:|
Han J, Qu Q, Qiao J, Zhang J. Vincamine alleviates amyloid-β 25-35 peptides-induced cytotoxicity in PC12 cells. Phcog Mag 2017;13:123-8
|How to cite this URL:|
Han J, Qu Q, Qiao J, Zhang J. Vincamine alleviates amyloid-β 25-35 peptides-induced cytotoxicity in PC12 cells. Phcog Mag [serial online] 2017 [cited 2022 Aug 10];13:123-8. Available from: http://www.phcog.com/text.asp?2017/13/49/123/196309
- Vincamine ameliorates amyloid-β 25-35 (Ab25-35) peptides induced cytotoxicity in PC12 cells
- Vincamine reduces Aβ 25-35 peptides induced apoptosis of PC12 cells
- Vincamine activates the phosphatidylinositol-3 kinase/Akt pathway
- Vincamine up-regulates the superoxide dismutase.
| Introduction|| |
The number of people suffering from Alzheimer's disease (AD) increases as the world population agescreating a huge socioeconomic burden. AD is the crucial cause of dementia in people over the age of 60,, which is mainly characterized by three pathological hallmarks: Cholinergic system dysfunctionthe amyloid-β (Aβ) peptide depositionand the Tau protein hyperphosphorylation., The intercellular transfer of Aβ and tau proteins has received increasing attention in AD. Although the link of Aβ or tau protein to brain degeneration has remained elusivethe Aβ cascade hypothesis remains as one of the dominant hypotheses for AD etiology. Neverthelesswith the fact that many therapeutic approaches toward Aβ lowering/clearing fail to gain anticipated benefits in the clinical trials,, it is of great importance to further understand and analyze the essence of Aβ cascade theory. Currentlythe extracellular deposit of insoluble Aβ is no longer considered as the major contributor for AD pathogenesis, whereas supports from numerous experimental paradigms have implicated the ab normal accumulation of intracellular Aβ oligomers is responsible for the manifestations of AD pathology., Growing researches have been focused on studying the association between the intracellular Aβ cascade and the dysfunction of subcellular organellesespecially mitochondria.,, More interestinglyit is reported that mitochondrial Aβ levels were positively correlated with the extent of mitochondrial dysfunction in different brain regions in APP or APP/PS1 transgenic miceand the degree of cognitive impairment in AD transgenic mice could be linked to the extent of synaptic mitochondrial dysfunction and mitochondrial Aβ levels., Hencetargeting Aβ-associated mitochondrial dysfunctionespecially blocking mitochondrial Aβ accumulation is expected as a promising approach for AD-modifying.
Herbal medicines have been proven to be a major source of novel agents with various pharmaceutical activities.,,,,, Natural products have provided a rich source of drugs for many diseasesincluding AD. Vincamine [Figure 1] is an alkaloid of clinical use against the brain sclerosisas well as in postoperative states of the central nervous system. It is employed today in the therapy of cerebral metabolic and circulatory disorders since it combines cerebrometabolic and hemodynamic properties.,,, Twenty years beforeit was used as a drug for treating memory impairments. Vinpocetinea vincamine derivativeefficiently protects cells from reactive oxygen species (ROS) attack. Recentlythe protective effect of vinpocetine was demonstrated using in vitro models of oxidative stress induced by the oxidant pair ascorbate/Fe2+ and by synthetic peptides of the AD-associated Aβ. Results obtained from these in vitro experiences support that additional clinical trials should be carried out using vincamineor vincamine derivativesto test its therapeutic or preventive effects in AD.
To the best of our knowledgein the present studywe demonstrated for the first time that vincamine could alleviate Aβ25-35 induced cytotoxicity in PC12 cellsthus providing basis for clinical application of vincamine in AD cases.
| Materials and Methods|| |
Chemicals and preparation
Vincamine was purchased from Sigma Chemical Co.(St. LouisMOUSA) and was dissolved with deionized water as stock solution. The drug stock solution was further diluted with deionized water to proper concentrations before usage. Unless otherwise statedall other chemicals were purchased from Sigma (MOUSA).
Preparation and treatment with amyloid-β 25-35
Aβ25-35 peptide (GenScriptPiscatawayNJUSA) stock solutions were freshly prepared before each treatment at 1 mM in double distilled deionized waterconsidered the soluble form. The cells were then treated with Aβ25-35 peptide in a range of 0-80 mM in serum-free medium containing 1% PS for 24 h. Thenthe cells were incubated at 37°C in a humidified and sterile atmosphere containing 5% CO2 for 2448and 72 h.
Oxidative stress assays
Oxidative stress was assessed by measuring malondialdehyde (MDA)glutathione (GSH)and superoxide dismutase (SOD) levels. PC12 cells cultured in 6-well plates (4 × 104 cells/well) for 24 h were treated with various concentrations of vincamine for 3 h before the addition of 30 μM Aβ25-35 and further 24 h incubation. Cells were then digested with trypsin and washed twice in phosphate buffered solution (PBS). Thereaftercells were suspended in 500 μl of PBS and lysed by ultrasonication in the presence of protease inhibitor before centrifugation at 4000 rpm for 5 min. The supernatant was collected for analysis. Supernatant protein concentrations were measured using a Bradford protein assay kit from Key Gen Biotech (NanjingChina). The levels of MDAGSHand SOD were measured using appropriate kits purchased from Key Gen Biotech following the manufacturer's instructions.
Detection of reactive oxygen species
PC12 cells were cultured and treated as per the oxidative stress assays. The production of ROS was determined using an ROS Assay Kit in accordance with the manufacturer's instructions (BeyotimeShanghaiChina).
Cell apoptosis assay
Cell apoptosis detection was performed using an Annexin-V-FITC Apoptosis Detection Kit (BD CompanyUSA) as described elsewhere., In brief24 h after Aβ25-35 exposurethe PC12 cultures were washed with warm (37°C) Krebs-Ringer solution and fixed with 4% (w) paraformaldehyde in PBS for 30 min at room temperature. For vincamine-treated groupcells were collected after 24 h treatment with vincamine. The cells were washed twice with cold PBS then resuspended in 1× binding buffer at a concentration of 1 × 106 cells/ml. Then 500 μl cell suspension was incubated with 5 μl Annexin-V-FITC and 10 μl propidium iodide (PI) for 15 min in the dark and analyzed by a FACS calibur instrument (Becton DickinsonSan JoseUSA) within 1 h. Apoptotic cells were those stained with Annexin V+/PI- (early apoptosis) plus Annexin V+/PI+ (late apoptosis).
Western blot analysis
Western blot detection was carried out to detect the protein expression., Brieflyfollowing treatment of PC12 cells with vincamine at the corresponding concentration and for the indicated timecells were harvested using trypsin ethylenediaminetetraacetic acid (EDTA)washed twice with PBSand stored at -80°C. Cells were lysed in lysis buffer (1 mM EDTA150 mM NaCl100 μg/ml phenyl methylsulfonyl fluoride 50 mM Tris-HClpH 7.5) for 30 min on ice and then a particle-free supernatant solution was obtained by centrifugation at 14,000 g for 15 min. All operations were at 0-4°C. A sample was taken for measurement of protein content by a bicinchoninic acid assay (Pierce). Equal amounts of protein were heated in sodium dodecylsulphate (SDS) sample buffer (Laemmli) for 15 min at 95°Cseparated on an 8-12% SDS-polyacrylamide gel and transferred onto polyvinylidene fluoride membranes. Membranes blocked with 5% nonfat milk powder (w/v) in TBST (10 mM Tris10 mM NaCl0.1% Tween 20) for 2-4 h at room temperature to prevent nonspecific antibody bindingand incubated with the corresponding primary antibody diluted in blocking buffer overnight at 4°C. After 3 min × 10 min washes in TBSTblots were incubated for 1 h with corresponding peroxidase conjugated secondary antibody and developed employing a commercial kit (West Pico chemiluminescent substrate). Blots were reprobed with an antibody against β-actin or GAPDH as control of protein loading and transfer.
Data were expressed as mean ± standard error of mean Student's t-test was applied in the comparisons between two groups. Multiple comparisons between model group and different concentrations of vincamine-treated groups were analyzed by one-way ANOVAfollowed by Dunnett test. Differences were considered significant at P < 0.05.
| Results|| |
Determination of amyloid-β 25-35 cytotoxicity to PC12 cells
The relative survival rate of PC12 cells treated with Aβ25-35 for 24 h decreased with increasing concentration of Aβ25-35 [Figure 2]. The relative survival rate was 97.6% with 1 μM Aβ25-35 and 25.8% with 80 μM Aβ25-35. The survival rate was approximately 50% with exposure to 30 μM Aβ25-35; hencethis concentration was chosen in all subsequent experiments for the determination of survival in response to different treatments.
|Figure 2: Effect of amyloid-β 25-35 on cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in PC12 cells. (a) Cells treated with amyloid-β 25-35 (0-80 μM) for 24 h. (b) Cells treated with 30 μM amyloid-β 25-35 for 01224364860 and 72 h. All results are expressed as mean ± standard deviation (n = 3). *P < 0.05**P < 0.01***P < 0.001 as compared with the control group|
Click here to view
Vincamine alleviated amyloid-β 25-35 induced cytotoxicity in PC12 cells
The relative survival rate of Aβ25-35-treated PC12 cells pretreated with vincamine increased with increasing vincamine concentration [Figure 3]. The relative survival rate was 43.5% without vincamine and 83.6% with 80 μM vincamine (P < 0.01).
|Figure 3: Effect of vincamine on cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in amyloid-β 25-35-treated PC12 cells. The results are expressed as mean ± standard deviation (n = 3). *P < 0.05**P < 0.01 as compared with the amyloid-β 25-35-treated group|
Click here to view
Vincamine decreased amyloid-β 25-35 induced oxidative stress
Intracellular MDA concentrations were significantly increased in Aβ25-35-treated cells compared with the negative control group cells (P < 0.05) [Table 1]. Vincamine decreased intracellular MDA concentrations in Aβ25-35-treated cells in a dose-dependent manner [Table 1]. The MDA concentrations in the vincamine-treated groups were significantly lower than the concentration in the model control group (P < 0.05). Intracellular GSH concentrations were significantly decreased in Aβ25-35-treated cells compared with the negative control group cells (P < 0.05) [Table 1]. Vincamine increased intracellular GSH concentrations in Aβ25-35-treated cells in a dose-dependent manner [Table 1]. The GSH concentrations in the vincamine-treated groups were significantly higher than the concentration in the model control group (P < 0.05). Intracellular SOD concentrations were significantly decreased in Aβ25-35-treated cells compared with the negative control group cells (P < 0.05) [Table 1]. Vincamine increased intracellular SOD concentrations in Aβ25-35-treated cells in a dose-dependent manner [Table 1]. The SOD concentrations in the vincamine-treated groups were significantly lower than the concentration in the model control group (P < 0.05).
Vincamine reduced reactive oxygen species levels
ROS levels were significantly increased in Aβ25-35-treated cells (667.5 vs. 192.6 fluorescence intensity unitsP < 0.05) [Figure 4]. Vincamine significantly reduced ROS level in a dose-dependent manner [Figure 4]. ROS levels in the vincamine 40 and 80 μM groups were significantly lower than the level in the model control group (365.2 and 286.6 vs. 667.5 fluorescence intensity unitsP < 0.05).
|Figure 4: Intracellular reactive oxygen species produced after amyloid-β 25-35 induced oxidative stress in PC12 cells with and without vincamine. Student's t-test was performed to evaluate the significance of the results. *P < 0.05, **P < 0.01, vincamine-treated cells compared with respective control. Results are mean ± standard deviation (n = 3)|
Click here to view
Anti-apoptotic effect of vincamine
An Annexin V-FITC and PI double stain were used to evaluate the percentages of apoptosis. The rate of apoptosis was significantly increased in Aβ25-35-treated cells compared with the negative control group cells (75.8 vs. 4.8%P < 0.05) [Figure 5]. Vincamine significantly reduced the rate of apoptosis in a dose-dependent manner [Figure 5]. The rate of apoptosis in the three vincamine groups was significantly lower than the rate in the model control group (57.335.6and 25.3 vs. 75.8%P < 0.05).
|Figure 5: Vincamine attenuated amyloid-β 25-35 induced neurotoxicity in PC12 cells. (A) Apoptosis analysis of PC12 cells treated with amyloid-β 25-35, vincamine, or a combination of them. (a) Untreated cells; (b) 30 μM amyloid-β 25-35-treated cells; (c) 30 μM amyloid-β 25-35 + 20 μM vincamine-treated cells; (d) 30 μM amyloid-β 25-35 + 40 μM vincamine-treated cells; (e) 30 μM amyloid-β 25-35 + 80 μM vincamine-treated cells. Cells were exposed for 48 h. Double staining was used to distinguish between viable (lower left quadrant, annexin V-negative, propidium iodide-negative), early apoptosis (lower right quadrant, annexin V-positive, propidium iodide-negative), late apoptosis and necrotic (upper right quadrant, annexin V-positive, propidium iodide-positive) and cell debris (upper left quadrant). Statistical analysis is shown in (B). *P < 0.05, **P < 0.01, amyloid-β 25-35, vincamine or both treated cells compared with untreated control cells. #P < 0.05, ##P < 0.01, vincamine-treated cells compared with 30 μM amyloid-β 25-35-treated cells. Results are mean ± standard deviation (n = 3)|
Click here to view
Vincamine regulated Akt and phospho-Akt levels in PC12 cells
To gain a better insight into anti-apoptotic effect of vincaminewe detected protein expression of apoptosis marker molecular. Aktand phospho-Akt were examined by Western blotting. Results showed that Aβ25-35 increased the phospho-Akt/Akt ratio. Vincamine (2040and 80 μM) increased the phospho-Akt/Akt ratio after preincubation for 2 h. These data suggested that vincamine could provide neuroprotection from Aβ25-35 induced PC12 apoptosis through the phosphatidylinositol-3 kinase/Akt signaling pathway [Figure 6]a.
|Figure 6: Phosphatidylinositol-3 kinase/Akt pathway was involved in the anti-apoptotic effects of vincamine. (a) PC12 cells were treated with vincamine for 2 h. Akt and its phosphorylation were detected by Western blotting. β-actin served as a control for loading. (b) Protein expression of Bcl-2, Bax in PC12 cells after indicated treatments was also measured by Western blots. GAPDH served as a control for loading|
Click here to view
Bcl-2 family proteins were involved with the anti-apoptotic effect of vincamine
We next investigated the expression of Bcl-2 familieswhich regulated mitochondrial apoptosis and could be separated into pro-survival members (such as Bcl-2BclxLand Mcl-1)as well as pro-apoptotic proteins (such as Bax). As shown in [Figure 6]b after vincamine treatmentBcl-2 was upregulated significantly and Bax was downregulated on the contrary. These results are consisted with the general notion that Bcl-2 and Bax play pivotal role in regulating mitochondrial apoptosis pathway.
| Discussion|| |
AD, the most prevalent form of dementia in older adultsis a chronic progressive neurodegenerative disorder. AD patients have severe progressive cognitive dysfunctionmemory impairmentbehavioral symptoms and loss of independence. According to AD Internationalat least 35.6 million people had dementia in 2010with the numbers nearly doubling every 20 years. Many factors contribute to the etiology of ADelevated Aβ and loss of nicotinic acetylcholine receptors being prominent. Although the neuroprotective effects of vincamine have attracted intense interest in recent yearsthe exact molecular mechanisms underlying have not yet been clarified. The major impressive characteristics of the present study are novel anti-apoptotic and antioxidant effects of vincamine.
Aβ plays a pivotal role in the mitochondrial dysfunctions because mitochondrial deficits like oxidative stressenergy deficiencyand mitochondrial depolarization were frequently seen in Aβ-treated cell models and Aβ over expression animal models.,, Thereforereversing Aβ-associated oxidative stress may provide an opportunity to recover AD.
In the current studywe found that vincamine administration could effectively reduce Aβ induced cytotoxicitywhich is the first report of vincamine reducing Aβ induced cytotoxicity to our knowledge. Vincamine has been reported to probably hydrolyze in the rat plasma into vincamic acid (a hydroxycarboxylic acid) that could possibly form a complex with Fe and excreted in urine and subsequently the Fe level reduced in the brain. Vincamine was completely metabolized and excreted in urine as sulfates and glucuronide conjugates. Vincamine could be useful in aged people because it reduces the brain Fe concentration and subsequently prevents the oxidative damage of Fe on neural cells. Vincamine has been reported to cross the blood-brain barrierand its antioxidant scavenging capacity to inactivate hydroxyl free radicals was actually ranked in part with Vitamin E. Iron is believed to accumulate in high concentration in neurodegenerative diseases such as Parkinson's Alzheimer's and Huntington's diseases and contribute to oxidative stress and subsequently lead to neuronal death.
Dietary phytochemicals consist of a wide variety of biologically active compounds that are ubiquitous in plantsmany of which have been reported to have pharmaceutical properties. Epidemiological studies have shown that natural components may play an important role in preventing human diseases.,,,, Among themvincaminewhich is abundant in Vinca minor L.has been reported to have therapeutic potential for treating many human diseases.,
In addition to looking at indicators of oxidative damagewe also examined the concentrations of several important antioxidantsGSHand SOD. In keeping with oxidative stress findingswe found that concentrations of both GSH and SOD were significantly increased in PC12 cells pretreated with vincamine before Aβ25-35 treatment. This is an important findinggiven that decreases in the expression of both GSH and SOD have been implicated in the development of AD and other neurological diseases.,
Unsurprisinglygiven the decreased oxidative damage and higher concentrations of antioxidantswe found that survival was significantly increased and apoptosis was significantly decreased in PC12 cells pretreated with vincamine before Aβ25-35 treatment compared with PC12 cells treated with Aβ25-35 alone. Our data showed that pretreatment with vincamine markedly increased the survival percentage of PC12 cells subsequently treated with Aβ25-35. The finding of decreased apoptosis is noteworthy because increased apoptotic signaling/neuronal death is thought to contribute to the pathology of neurodegenerative disordersincluding AD.
| Conclusion|| |
Our research for the first time found that vincaminea natural alkaloidameliorated the deleterious effects of Aβ25-35 in PC12 cells. Specificallyvincamine increased cell survivaldecreased apoptosis and cytotoxicityand decreased the concentrations/activities of a variety of indicators of oxidative stress. We believe that these are promising findings that support the continued investigation of vincamine as a potential treatment for AD. Our data might shed more light on the clinical benefits gained by vincamine and provide useful clues for future AD drug developmenthoweverthe precise mechanisms underlying the beneficial effect of the drug needs further investigation.
This work is supported in part by the National Natural Science Foundation of China (NSFC-2015).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Alzheimer's AssociationAlzheimer's disease facts and figures. Alzheimers Dement 2014;10:e47-92.
Denk J, Boelmans K, Siegismund C, Lassner D, Arlt S, Jahn H, MicroRNA Profiling of CSF reveals potential biomarkers to detect Alzheimer's disease. PLoS One 20 1520;10:e0126423.
Gandy S, DeKosky ST, Toward the treatment and prevention of Alzheimer's disease: Rational strategies and recent progress. Annu Rev Med 2013;64:367-83.
Risacher SL, Saykin AJ, Neuroimaging and other biomarkers for Alzheimer's disease: The changing landscape of early detection. Annu Rev Clin Psychol 2013;9:621-48.
Giacobini E, Gold G, Alzheimer disease therapy – Moving from amyloid-ß to tau. Nat Rev Neurol 2013;9:677-86.
Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M, Alzheimer's disease: Clinical trials and drug development. Lancet Neurol 2010;9:702-16.
Goure WF, Krafft GA, Jerecic J, Hefti F, Targeting the proper amyloid-beta neuronal toxins: A path forward for Alzheimer's disease immunotherapeutics. Alzheimers Res Ther 2014;6:42-
Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al.
Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 2008;14:837-42.
Benilova I, Karran E, De Strooper B, The toxic Aßoligomer and Alzheimer's disease: An emperor in need of clothes. Nat Neurosci 2012;15:349-57.
Narayan P, Holmström KM, Kim DH, Whitcomb DJ, Wilson MR, St George-Hyslop P, et al.
Rare individual amyloid-ßoligomers act on astrocytes to initiate neuronal damage. Biochemistry 2014;53:2442-53.
Dragicevic N, Smith A, Lin X, Yuan F, Copes N, Delic V, et al.
Green tea epigallocatechin-3-gallate (EGCG) and other flavonoids reduce Alzheimer's amyloid-induced mitochondrial dysfunction. J Alzheimers Dis 2011;26:507-21.
Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, et al.
Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat Med 2008;14:1097-105.
Takuma K, Yao J, Huang J, Xu H, Chen X, Luddy J, et al.
ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB J 2005;19:597-8.
Dragicevic N, Mamcarz M, Zhu Y, Buzzeo R, Tan J, Arendash GW, et al.
Mitochondrial amyloid-beta levels are associated with the extent of mitochondrial dysfunction in different brain regions and the degree of cognitive impairment in Alzheimer's transgenic mice. J Alzheimers Dis 2010;20:S535-50.
Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH, Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: Implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 2006;15:1437-49.
Nie F, Liang Y, Xun H, Sun J, He F, Ma X, Inhibitory effects of tannic acid in the early stage of 3T3-L1 preadipocytes differentiation by down-regulating PPARg expression. Food Funct 2015;6:894-901.
Jiang HZ, Quan XF, Tian WX, Hu JM, Wang PC, Huang SZ, et al.
Fatty acid synthase inhibitors of phenolic constituents isolated from Garcinia mangostana
. Bioorg Med Chem Lett 2010;20:6045-7.
Quan X, Wang Y, Ma X, Liang Y, Tian W, Ma Q, et al.
α-Mangostin induces apoptosis and suppresses differentiation of 3T3-L1 cells via inhibiting fatty acid synthase. PLoS One 2012;7:e33376-
Liang Y, Tian W, Ma X, Inhibitory effects of grape skin extract and resveratrol on fatty acid synthase. BMC Complement Altern Med 2013;13:361-
Zhao YX, Liang WJ, Fan HJ, Ma QY, Tian WX, Dai HF, et al.
Fatty acid synthase inhibitors from the hulls of Nephelium lappaceum
L. Carbohydr Res 2011;346:1302-6.
Fan H, Wu D, Tian W, Ma X, Inhibitory effects of tannic acid on fatty acid synthase and 3T3-L1 preadipocyte. Biochim Biophys Acta 2013;1831:1260-6.
Dany F, Liozon F, Goudoud JC, Castel JP, Michel JP, Marsaud P, et al.
Severe ventricular arrhythmia following parenteral administration of vincamine. Predisposing factors in 6 cases. Arch Mal Coeur 1980;73:298-306.
Lim CC, Cook PJ, James IM, The effect of an acute infusion of vincamine and ethyl apovincaminate on cerebral blood flow in healthy volunteers. Br J Clin Pharmacol 1980;9:100-1.
Rassat J, Robenek H, Themann H, Changes in mouse hepatocytes caused by vincamin. A thin-sectioning and freeze-fracture study. Naunyn Schmiedebergs Arch Pharmacol 1982;318:349-57.
Pesce E, Viganò V, Piacenza G, Effect of vincamine on platelet respiration. Farmaco Prat 1978;33:343-50.
Fayed AH, Brain trace element concentration of rats treated with the plant alkaloid, vincamine. Biol Trace Elem Res 2010;136:314-9.
Wang Y, Nie F, Ouyang J, Wang X, Ma X, Inhibitory effects of sea buckthorn procyanidins on fatty acid synthase and MDA-MB-231 cells. Tumour Biol 2014;35:9563-9.
Fan H, Tian W, Ma X, Curcumin induces apoptosis of HepG2 cells via inhibiting fatty acid synthase. Target Oncol 2014;9:279-86.
Li P, Tian W, Wang X, Ma X, Inhibitory effect of desoxyrhaponticin and rhaponticin, two natural stilbene glycosides from the Tibetan nutritional food Rheum tanguticum
Maxim. Ex Balf, on fatty acid synthase and human breast cancer cells. Food Funct 2014;5:251-6.
Li P, Tian W, Ma X, Alpha-mangostin inhibits intracellular fatty acid synthase and induces apoptosis in breast cancer cells. Mol Cancer 2014;13:138-
Small SA, Petsko GA, Retromer in Alzheimer disease, Parkinson disease and other neurological disorders. Nat Rev Neurosci 2015;16:126-32.
Butterfield DA, Di Domenico F, Swomley AM, Head E, Perluigi M, Redox proteomics analysis to decipher the neurobiology of Alzheimer-like neurodegeneration: Overlaps in Down's syndrome and Alzheimer's disease brain. Biochem J 2014;463:177-89.
Tabert MH, Liu X, Doty RL, Serby M, Zamora D, Pelton GH, et al.
A10-item smell identification scale related to risk for Alzheimer's disease. Ann Neurol 2005;58:155-60.
Esmaeili Tazangi P, Moosavi SM, Shabani M, Haghani M, Erythropoietin improves synaptic plasticity and memory deficits by decrease of the neurotransmitter release probability in the rat model of Alzheimer's disease. Pharmacol Biochem Behav 2015;130:15-21.
Gao X, Tang XC, Huperzine A attenuates mitochondrial dysfunction in beta-amyloid-treated PC12 cells by reducing oxygen free radicals accumulation and improving mitochondrial energy metabolism. J Neurosci Res 2006;83:1048-57.
Sarkar P, Zaja I, Bienengraeber M, Rarick KR, Terashvili M, Canfield S, et al.
Epoxyeicosatrienoic acids pretreatment improves amyloid ß-induced mitochondrial dysfunction in cultured rat hippocampal astrocytes. Am J Physiol Heart Circ Physiol 2014;306:H475-84.
Vereczkey L, Tamás J, Czira G, Szporny L, Metabolism of vincamine in the rat in vivo
and in vitro
. Arzneimittelforschung 1980;30:1860-5.
Viganò V, Paracchini S, Piacenza G, Pesce E, Metabolism of vincamine in the rat. Farmaco Sci 1978;33:583-94.
Sprumont P, Lintermans J, Autoradiographic evidence for passage of vincamine through the blood-brain barrier. Arch Int Pharmacodyn Ther 1979;237:42-8.
Fiedler A, Reinert T, Morawski M, Brückner G, Arendt T, Butz T, Intracellular iron concentration of neurons with and without perineuronal nets. Nucl Instrum Methods Phys Res 2007;260:153-8.
Wang Y, Tian WX, Ma XF, Inhibitory effects of onion (Allium cepa
L.). extract on proliferation of cancer cells and adipocytes via inhibiting fatty acid synthase. Asian Pac J Cancer Prev 2012;13:5573-9.
Jiang HZ, Ma QY, Fan HJ, Liang WJ, Huang SZ, Dai HF, et al.
Fatty acid synthase inhibitors isolated from Punica granatum
L. J Braz Chem Soc 2012;23:889-93.
Duan C, Wang Y, Ma X, Jiang Y, Liu J, Tu P, A new furostanol glycoside with fatty acid synthase inhibitory activity from Ophiopogon japonicus
. Chem Nat Compd 2012;48:613-5.
Liu Y, Tian W, Ma X, Ding W, Evaluation of inhibition of fatty acid synthase by ursolic acid: Positive cooperation mechanism. Biochem Biophys Res Commun 2010;392:386-90.
Wu D, Ma X, Tian W, Pomegranate husk extract, punicalagin and ellagic acid inhibit fatty acid synthase and adipogenesis of 3T3-L1 adipocyte. J Funct Food 2013;5:633-41.
Springer JE, Azbill RD, Mark RJ, Begley JG, Waeg G, Mattson MP, 4-hydroxynonenal, a lipid peroxidation product, rapidly accumulates following traumatic spinal cord injury and inhibits glutamate uptake. J Neurochem 1997;68:2469-76.
Baldwin SA, Broderick R, Osbourne D, Waeg G, Blades DA, Scheff SW, The presence of 4-hydroxynonenal/protein complex as an indicator of oxidative stress after experimental spinal cord contusion in a rat model. J Neurosurg 1998;88:874-83.
Bains JS, Shaw CA, Neurodegenerative disorders in humans: The role of glutathione in oxidative stress-mediated neuronal death. Brain Res Brain Res Rev 1997;25:335-58.
Maier CM, Chan PH, Role of superoxide dismutases in oxidative damage and neurodegenerative disorders. Neuroscientist 2002;8:323-34.
Mattson MP, Neuronal life-and-death signaling, apoptosis, and neurodegenerative disorders. Antioxid Redox Signal 2006;8:1997-2006.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
|This article has been cited by|
||Neuroprotective role of herbal alternatives in circumventing Alzheimer’s disease through multi-targeting approach - a review
| ||Sunil K Ravi, Balenahalli Narasingappa Ramesh, Shilpa Kj, Jagadesha Poyya, Jyothsna Karanth, N.G Raju, Chandrashekhar G Joshi |
| ||Egyptian Journal of Basic and Applied Sciences. 2022; 9(1): 91 |
|[Pubmed] | [DOI]|
||Vincamine, a safe natural alkaloid, represents a novel anticancer agent
| ||Sarah Al-Rashed, Abu Baker, Syed Sayeed Ahmad, Asad Syed, Ali H. Bahkali, Abdallah M. Elgorban, Mohd Sajid Khan |
| ||Bioorganic Chemistry. 2021; 107: 104626 |
|[Pubmed] | [DOI]|
||Natural products attenuate PI3K/Akt/mTOR signaling pathway: A promising strategy in regulating neurodegeneration
| ||Sajad Fakhri, Amin Iranpanah, Mohammad Mehdi Gravandi, Seyed Zachariah Moradi, Mohammad Ranjbari, Mohammad Bagher Majnooni, Javier Echeverría, Yaping Qi, Mingfu Wang, Pan Liao, Mohammad Hosein Farzaei, Jianbo Xiao |
| ||Phytomedicine. 2021; 91: 153664 |
|[Pubmed] | [DOI]|
||Attenuation of Nrf2/Keap1/ARE in Alzheimer’s Disease by Plant Secondary Metabolites: A Mechanistic Review
| ||Sajad Fakhri, Mirko Pesce, Antonia Patruno, Seyed Zachariah Moradi, Amin Iranpanah, Mohammad Hosein Farzaei, Eduardo Sobarzo-Sánchez |
| ||Molecules. 2020; 25(21): 4926 |
|[Pubmed] | [DOI]|