BHBA对HT22细胞中ACE表达的影响
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摘要
生酮饮食(KD)已被证实具有神经保护作用,但其机制尚不明确。本试验以小鼠海马神经元HT22为细胞模型,利用2 mmol/Lβ-羟基丁酸酯(BHBA)对HT22细胞进行处理,通过荧光定量PCR,免疫蛋白印迹和信号通路阻断试验,观察BHBA对HT22细胞ACE表达的影响,并探讨参与调控的信号通路。结果表明,2 mmol/L BHBA可通过激活HT22细胞内GPR109A受体和ERK1/2信号通路进而增加HT22细胞中ACE的表达。
To reveal the mechanism of BHBA on protecting neurodegeneration,HT22 cells were cultured as hippocampal cell model which was treated with 2 mmol/L BHBA.The effects of BHBA on ACE expression in HT22 cells and regulatory signaling pathways involved in were investigated by RT-PCR,western blot and pathway blockage.The results showed that 2 mmol/L BHBA increased the expression of ACE in HT22 cells by activating GPR109 A receptor and ERK1/2 signaling pathways.
To reveal the mechanism of BHBA on protecting neurodegeneration,HT22 cells were cultured as hippocampal cell model which was treated with 2 mmol/L BHBA.The effects of BHBA on ACE expression in HT22 cells and regulatory signaling pathways involved in were investigated by RT-PCR,western blot and pathway blockage.The results showed that 2 mmol/L BHBA increased the expression of ACE in HT22 cells by activating GPR109 A receptor and ERK1/2 signaling pathways.
引文
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[2] NUSSBAUM R L,ELLIS C E.Alzheimer's disease and parkinson?s disease[J].N Engl J Med,2003,348(14):1356-1364.
[3] GOEDERT M,SPILLANTINI M G.A century of alzheimer's disease[J].Science,2006,314(5800):777-781.
[4] BRAAK H,BRAAK E.Neuropathological stageing of alzheimer-related changes[J].Acta Neuropathol,1991,82(4):239-259.
[5] SELKOE D J.Physiological production of the beta-amyloid protein and the mechanism of alzheimer's disease[J].Trends Neurosci,1993,16(10):403-409.
[6] MANGIALASCHE F,SOLOMON A,WINBLAD B,et al.Alzheimer's disease:Clinical trials and drug development[J].Lancet Neurol,2010,9(7):702-716.
[7] KEHOE P G,MINERS S,LOVE S.Angiotensins in alzheimer's disease - friend or foe? [J].Trends Neurosci,2009,32:619-628.
[8] HEMMING M L,SELKOE D J.Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ace) and elevated by an ace inhibitor[J].J Biol Chem,2005,280(45):37644-37650.
[9] BERNSTEIN K E,KORONYO Y,SALUMBIDES B C,et al.Angiotensin-converting enzyme overexpression in myelomonocytes prevents alzheimer's-like cognitive decline[J].J Clin Invest,2014,124(3):1000-1012.
[10] KORONYO-HAMAOUI M,SHAH K,KORONYO Y,et al.Ace overexpression in myelomonocytic cells:Effect on a mouse model of alzheimer's disease[J].Curr Hypertens Rep,2014,16(7):444.
[11] NEI M,NGO L,SIRVEN J I,et al.Ketogenic diet in adolescents and adults with epilepsy[J].Seizure,2014,23(6):439-442.
[12] CROSS H.Epilepsy:Behavioural,psychological,and ketogenic diet treatments[J].BMJ Clin Evid,2015,2015:1214.
[13] AUGUSTIN K,KHABBUSH A,WILLIAMS S,et al.Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders[J].Lancet Neurol,2018,17(1):84-93.
[14] YAMANASHI T,IWATA M,KAMIYA N,et al.Beta-hydroxybutyrate,an endogenic nlrp3 inflammasome inhibitor,attenuates stress-induced behavioral and inflammatory responses[J].Sci Rep,2017,7(1):7677.
[15] FU S P,WANG J F,XUE WJ,et al.Anti-inflammatory effects of bhba in both in vivo and in vitro parkinson’s disease models are mediated by gpr109a-dependent mechanisms[J].J Neuroinflammation,2015;12:9.
[16] FU S P,LI S N,WANG J F,et al.Bhba suppresses lps-induced inflammation in bv-2 cells by inhibiting nf-κb activation[J].Mediators Inflamm,2014,2014:983401.
[17] RAHMAN M,MUHAMMAD S,KHAN M A,et al.The β-hydroxybutyrate receptor hca2 activates a neuroprotective subset of macrophages[J].Nat Commun,2014,5:3944.
[18] KOSSOFF E H,RHO J M.Ketogenic diets:Evidence for short- and long-term efficacy[J].Neurotherapeutics,2009,6(2):406-414.
[19] KRIKORIAN R,SHIDLER M D,DANGELO K,et al.Dietary ketosis enhances memory in mild cognitive impairment[J].Neurobiol Aging,2012,33(2):425.
[20] HENDERSON S T,VOGEL J L,BARR L J,et al.Study of the ketogenic agent ac-1202 in mild to moderate alzheimer's disease:A randomized,double-blind,placebo-controlled,multicenter trial[J].Nutr Metab,2009,6:31.
[21] GOLDBERG E L,ASHER J L,MOLONY R D,et al.Β-hydroxybutyrate deactivates neutrophil nlrp3 inflammasome to relieve gout flares[J].Cell Rep,2017,18(9):2077-2087.
[22] NAKAMURA K,TONOUCHI H,SASAYAMA A,et al.A ketogenic formula prevents tumor progression and cancer cachexia by attenuating systemic inflammation in colon 26 tumor-bearing mice[J].Nutrients,2018,10(2):E206.
[23] LIM S,CHESSER A S,GRIMA J C,et al.D-β-hydroxybutyrate is protective in mouse models of huntington's disease[J].Plos One,2011,6(9):e24620.
[24] MCGEER P L,MCGEER E G.The amyloid cascade-inflammatory hypothesis of alzheimer disease:Implications for therapy[J].Acta Neuropathol,2013,126(4):479-497.
[25] KEHOE P G,RUSS C,MCILORY S,et al.Variation in dcp1,encoding ace,is associated with susceptibility to alzheimer disease[J].Nat Genet,1999,21(1):71-72.
[26] BERTRAM L,MCQUEEN M B,MULLIN K,et al.Systematic meta-analyses of alzheimer disease genetic association studies:The alzgene database[J].Nat Genet,2007,39(1):17-23.
[27] LEHMANN D J,CORTINA-BORJA M,WARDEN D R,et al.Large meta-analysis establishes the ace insertion-deletion polymorphism as a marker of alzheimer?s disease[J].Am J Epidemiol,2005,162(4):305-317.
[28] BERNSTEIN K E,GONZALEZ-VILLALOBOS R A,GIANI J F,et al.Angiotensin-converting enzyme overexpression in myelocytes enhances the immune response[J].Biol Chem,2014,395(10):1173-1178.
[29] FENG W,WU Y,CHEN G,et al.Sodium butyrate attenuates diarrhea in weaned piglets and promotes tight junction protein expression in colon in a gpr109a-dependent manner[J].Cell Physiol Biochem,2018,47:1617-1629.
[30] WALTERS R W,SHUKLA A K,KOVACS J J,et al.Beta-arrestin1 mediates nicotinic acid-induced flushing,but not its antilipolytic effect,in mice[J].J Clin Invest,2009,119(5):1312-1321.