PMID- 27929536
OWN - NLM
STAT- MEDLINE
DCOM- 20170918
LR  - 20211204
IS  - 2041-4889 (Electronic)
VI  - 7
IP  - 12
DP  - 2016 Dec 8
TI  - Hyperhomocysteinemia causes ER stress and impaired autophagy that is reversed by 
      Vitamin B supplementation.
PG  - e2513
LID - 10.1038/cddis.2016.374 [doi]
AB  - Hyperhomocysteinemia (HHcy) is a well-known risk factor for stroke; however, its 
      underlying molecular mechanism remains unclear. Using both mouse and cell culture 
      models, we have provided evidence that impairment of autophagy has a central role 
      in HHcy-induced cellular injury in the mouse brain. We observed accumulation of 
      LC3B-II and p62 that was associated with increased MTOR signaling in human and 
      mouse primary astrocyte cell cultures as well as a diet-induced mouse model of 
      HHcy, HHcy decreased lysosomal membrane protein LAMP2, vacuolar ATPase 
      (ATP6V0A2), and protease cathepsin D, suggesting that lysosomal dysfunction also 
      contributed to the autophagic defect. Moreover, HHcy increased unfolded protein 
      response. Interestingly, Vitamin B supplementation restored autophagic flux, 
      alleviated ER stress, and reversed lysosomal dysfunction due to HHCy. 
      Furthermore, the autophagy inducer, rapamycin was able to relieve ER stress and 
      reverse lysosomal dysfunction caused by HHcy in vitro. Inhibition of autophagy by 
      HHcy exacerbated cellular injury during oxygen and glucose deprivation and 
      reperfusion (OGD/R), and oxidative stress. These effects were prevented by 
      Vitamin B co-treatment, suggesting that it may be helpful in relieving 
      detrimental effects of HHcy in ischemia/reperfusion or oxidative stress. 
      Collectively, these findings show that Vitamin B therapy can reverse defects in 
      cellular autophagy and ER stress due to HHcy; and thus may be a potential 
      treatment to reduce ischemic damage caused by stroke in patients with HHcy.
FAU - Tripathi, Madhulika
AU  - Tripathi M
AD  - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders 
      Program, Duke-NUS Medical School, Singapore 169857, Singapore.
AD  - Stroke Trial Unit, Department of Neurology, Singapore General Hospital, Outram 
      Road, Singapore 169608, Singapore.
AD  - National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, 
      Singapore.
FAU - Zhang, Cheng Wu
AU  - Zhang CW
AD  - National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, 
      Singapore.
FAU - Singh, Brijesh Kumar
AU  - Singh BK
AD  - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders 
      Program, Duke-NUS Medical School, Singapore 169857, Singapore.
FAU - Sinha, Rohit Anthony
AU  - Sinha RA
AD  - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders 
      Program, Duke-NUS Medical School, Singapore 169857, Singapore.
FAU - Moe, Kyaw Thu
AU  - Moe KT
AD  - Newcastle University Medicine Malaysia (NUMed, Malaysia) No. 1 Jalan Sarjana, 
      Iskandar Puteri (formerly Nusajaya), Johor 179200, Malaysia.
FAU - DeSilva, Deidre Anne
AU  - DeSilva DA
AD  - Stroke Trial Unit, Department of Neurology, Singapore General Hospital, Outram 
      Road, Singapore 169608, Singapore.
AD  - National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, 
      Singapore.
FAU - Yen, Paul Michael
AU  - Yen PM
AD  - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders 
      Program, Duke-NUS Medical School, Singapore 169857, Singapore.
LA  - eng
PT  - Journal Article
DEP - 20161208
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Map1lc3b protein, mouse)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Sequestosome-1 Protein)
RN  - 0 (Sqstm1 protein, mouse)
RN  - 935E97BOY8 (Folic Acid)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - IY9XDZ35W2 (Glucose)
RN  - P6YC3EG204 (Vitamin B 12)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Animals
MH  - Astrocytes/drug effects/metabolism/pathology
MH  - Autophagy/*drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Diet
MH  - *Dietary Supplements
MH  - Endoplasmic Reticulum Stress/*drug effects
MH  - Folic Acid/pharmacology
MH  - Glucose/deficiency
MH  - Humans
MH  - Hyperhomocysteinemia/drug therapy/*pathology
MH  - Lysosomes/drug effects/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microtubule-Associated Proteins
MH  - Models, Biological
MH  - Oxidative Stress/drug effects
MH  - Oxygen
MH  - Reperfusion Injury/pathology
MH  - Sequestosome-1 Protein/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Vitamin B 12/*pharmacology/therapeutic use
PMC - PMC5260994
EDAT- 2016/12/09 06:00
MHDA- 2017/09/19 06:00
PMCR- 2016/12/01
CRDT- 2016/12/09 06:00
PHST- 2016/08/28 00:00 [received]
PHST- 2016/10/11 00:00 [revised]
PHST- 2016/10/11 00:00 [accepted]
PHST- 2016/12/09 06:00 [entrez]
PHST- 2016/12/09 06:00 [pubmed]
PHST- 2017/09/19 06:00 [medline]
PHST- 2016/12/01 00:00 [pmc-release]
AID - cddis2016374 [pii]
AID - 10.1038/cddis.2016.374 [doi]
PST - epublish
SO  - Cell Death Dis. 2016 Dec 8;7(12):e2513. doi: 10.1038/cddis.2016.374.