Neuroprotective effect of ginkgetin in experimental cerebral ischemia/reperfusion via apoptosis inhibition and PI3K/Akt/mTOR signaling pathway activation
Authors: Zhaohua Tian
Congyao Tang
Zhigang Wang
Journal: Journal of Cellular Biochemistry (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: apoptosis; ginkgetin; ischemia/reperfusion; phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin.
Affiliations: Emergency Department, Shenzhen Longgang District Hospital of Traditional Chinese Medicine, Shenzhen, P.R. China.

Abstract:  Background: Ginkgetin, extracted from Ginkgo biloba L leaves, has been demonstrated to have potential anti-inflammatory and immune-suppressive properties. But the neuroprotective effect and potential mechanisms of ginkgetin on cerebral ischemia/reperfusion (IR) injury remain unclear. Methods: In this research, we studied the neuroprotective effect of ginkgetin in the middle part of the middle cerebral artery occlusion/reperfusion rat model, by analyzing the apoptosis of brain tissues harvested from treatment groups and control groups using the terminal deoxynucleotidyl transferase dUTP nick-end labeling and apoptosis assays. In addition, we detected the association of the neuroprotective effect of ginkgetin with apoptosis inhibition via the activation of the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway using Western blot analysis. Results: Our results showed that administration of ginkgetin remarkably reduced brain infarction volumes and neurologic deficits; in addition, reducing apoptotic cell numbers, downregulating the levels of cleaved caspase-3 and Bax, and upregulating the level of Bcl-2 in rats subjected to IR injury in a dose-dependent manner. Moreover, high-dose ginkgetin treatment (100 mg/kg) significantly increased the phosphorylations of Akt and mTOR. Blocking of PI3K by LY294002 clearly decreased its antiapoptotic effect and reduced both Akt and mTOR phosphorylation levels. Conclusions: Taken together, these results for the first time suggest that ginkgetin antagonizes cerebral IR-induced injury by inhibiting apoptosis in rats, and this effect was attenuated by the activation of PI3K/Akt/mTOR signaling pathway. 

Retracted: No

PubPeer comments:
 This paper is part of a set of 7 papers that all have the following ethics statement:  *The present study was approved by the Ethics Committee of the Maternity and Child Care Center of Liuzhou. The research has been carried out in accordance with the World Medical Association Declaration of Helsinki. All patients and healthy volunteers provided written informed consent prior to their inclusion within the study.* However, none of these 7 studies were performed at the Liuzhou hospital and none of the authors are affiliated with that hospital. The 7 papers and their affiliations are the following: * Ye Han, Chunying Liu, Ming Lei, Shaosong Sun, Wenkui Zheng, Yanan Niu, Xi Xia, LncRNA TUG1 was upregulated in osteoporosis and regulates the proliferation and apoptosis of osteoclasts, Journal of Orthopaedic Surgery and Research (2019) 14:416, DOI: 10.1186 s13018-019-1430-4, Department of Orthopaedics, Baoding First Central Hospital, Baoding City * Yunyong Liu, Mengdan Li, Huihui Yu, Haozhe Piao, LncRNA SRA1 is down-regulated in HPV-negative cervical squamous cell carcinoma and regulates cancer cell behaviors, Bioscience Reports (2019) 39 BSR20191226, DOI: 10.1042 BSR20191226, Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang City * Min Hu, Yaowu Han, Ying Zhang, Yuanfeng Zhou, Lin Ye, lncRNA TINCR sponges miR-214-5p to upregulate ROCK1 in hepatocellular carcinoma, BMC Medical Genetics (2020) 21:2, DOI: 10.1186 s12881-019-0940-6, Department of Pathology, Anhui University of Chinese Medicine, Hefei * Yu Fu, Limin Cai, Xuexue Lei, Dunwei Wang, Circular RNA ABCB10 promotes hepatocellular carcinoma progression by increasing HMG20A expression by sponging miR-670-3p, Cancer Cell Int (2019) 19:338, DOI: 10.1186 s12935-019-1055-z, Department of Anesthesiology, The First Hospital of Jilin University, Jilin * Zhaohua Tian, Congyao Tang, Zhigang Wang, Neuroprotective effect of ginkgetin in experimental cerebral ischemia reperfusion via apoptosis inhibition and PI3K Akt mTOR signaling pathway activation, J Cell Biochem. 2019;1-9, DOI: 10.1002 jcb.29169, Emergency Department, Shenzhen Longgang District Hospital of Traditional Chinese Medicine, Shenzhen * Qing-an-zi Wang, Yongxiu Yang, Xiaolei Liang, LncRNA CTBP1-AS2 sponges miR-216a to upregulate PTEN and suppress endometrial cancer cell invasion and migration, Journal of Ovarian Research (2020) 13:37, DOI: 10.1186 s13048-020-00639-2, Department of Obstetrics and Gynecology, Key Laboratory for Gynecologic Oncology Gansu Province, the First Hospital of Lanzhou University, Lanzhou City, Gansu Province * Ding Zhu, Xueshuang Huang, Fang Liang, Lijing Zhao, LncRNA miR503HG interacts with miR-31- 5p through multiple ways to regulate cancer cell invasion and migration in ovarian cancer, Journal of Ovarian Research (2020) 13:3, DOI: 10.1186 s13048-019-0599-9, Biomedical Research Center, Hunan University of Medicine, Huaihua City, Hunan Province The textual similarities of the Ethics Statement, and the listing of a very different hospital suggest that the writing of the paper might have been outsourced. This, together with e.g. very small standard deviations in several graphs, makes me concerned about the data as well. Could the authors share the raw data of this study, please? , 
 For this particular paper, the Ethics Statement is especially surprising, because only animal experiments, no human subjects, were described. Also for this particular paper, the Western blots look similar to those found in the so-called Tadpole Paper mill, described here: * https: scienceintegritydigest.com 2020 02 21 the-tadpole-paper-mill * https: febs.onlinelibrary.wiley.com doi full 10.1002 1873-3468.13201 * https: forbetterscience.com 2020 01 24 the-full-service-paper-mill-and-its-chinese-customers Could the authors please provide the uncropped blots? Here are Figures 3B and 4, for example, made a bit lighter to bring out the background.  , 
 #2  Patients with a history of family heart disease were excluded from the study.  . Good to know that only healthy rats took part. , 
 #3 I read through the methods section and did not see how the family medical history questionnaire was completed. This may be a breakthrough for animal studies if it can be replicated. Could the authors provide details? , 
 #2 To my mind these WB simulations are more characteristic of the  Contractor papermill, with [products tabulated here] . Figs 3B and 4 again:  For comparison, Figures2B, 5D from [Wang et al (2019)] .  A montage of similar figures:  ,