Bactericidal/Permeability-Increasing Protein Improves Cognitive Impairment in Diabetic Mice via Blockade of the LPS-LBP-TLR4 Signaling Pathway
Authors: Shaoping Deng
Yamei Li
Min Zhang
Lingling Wei
Qin Sun
Tingxin Li
Journal: Frontiers in Physiology (2021)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: bactericidal/permeability-increasing protein; cognitive impairment; diabetes; high-fat diet; lipopolysaccharide-lipopolysacharide-binding protein-toll-like receptor 4 signaling pathway.
Affiliations: School of Medicine, University of Electronic Science and Technology of China, Chengdu, China., Health Management Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China., Center of Diabetes Mellitus, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.

Abstract:  Emerging evidence suggests that the bactericidal/permeability-increasing protein (BPI) is involved in the process of cognitive impairment in diabetes. However, its underlying mechanism remains elusive. In this study, we found that BPI affects cognitive impairment due to diabetes through the lipopolysaccharide (LPS)-lipopolysacharide-binding protein (LBP)-toll-like receptor 4 (TLR4) signaling pathway. We examined the expression of BPI, LPS, LBP, CD14, and TLR4 in established mouse models of diabetes induced by high-fat diet (HFD) in combination with streptozotocin (STZ). Diabetic mice were then injected with adeno-associated-virus carrying BPI overexpression vectors and LPS. Fasting blood glucose, plasma insulin, and serum levels of inflammatory factors were examined. Then, glucose tolerance and, insulin resistance tests were used to measure systemic insulin sensitivity. Next, hippocampal tissue injury and cell apoptosis were examined by hematoxylin-eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. Diabetic mice displayed increased LPS expression and activation of the LPS-CD14-TLR4 signaling pathway. HFD mice following LPS treatment showed significantly increased serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, and expressions of Bcl-2-associated X protein (Bax) and Aβ but decreased expression of Bcl-2 in hippocampal tissues, as well as enhanced fasting blood glucose, plasma insulin, glucose tolerance, insulin tolerance, cell apoptosis, aggravated hippocampal tissue injury and, ultimately, cognitive impairment. However, overexpression of BPI was able to rescue the aforementioned phenotypes driven by LPS treatment. Taken together, BPI could potentially provide relief from cognitive impairment in diabetic mice by disrupting the LPS-LBP-TLR4 signaling pathway, underscoring a possible alternative therapeutic strategy against the cognitive impairment associated with diabetes. 

Retracted: Yes

PubPeer comments:
 Retracted [28 December 2021] . H t [RetractionWatch] . -------------------------------- The journal and Chief Editors retract the 11 February 2021 article cited above. Following publication, concerns were raised regarding the validity of the data in the article. The authors failed to provide the raw data or a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers policies. Given the concerns, and the lack of raw data, the editors no longer have confidence in the findings presented in the article. This retraction was approved by the Chief Editors of Frontiers in Physiology and the Chief Executive Editor of Frontiers. The authors agreed with this retraction. ------------------------------------------- I am puzzled that this paper was ever accepted for publication, when the authors explicitly note in an Acknowledgement sentence that **someone else did the work**.  Acknowledgement. The experiments were conducted in the Cloud-Clone Corp., Wuhan, China It is nice that the outside researchers were acknowledged, but if I were the authors I would be seeking my money back. , 
 In their resemblance to rows of bow-ties, the Western Blots in this paper conform to a style used by recent products of the  contractor papermill. ![file] Here is a montage that I prepared earlier. Clockwise from upper left: - [Wang et al (2020)] - [Gao et al (2021)] - [Chen et al (2020)] - [He et al (2021)] . ![file] In addition, WBs from [Lv et al (2020)] *[retracted]* ![] Also the WBs from [Gao, Feng Tan (2019)] *[retracted]*. ![] , 
 - *[left]* Fig 2C from  Up-regulation of microRNA-223 inhibits brain injury and hippocampal neuron apoptosis of rats after febrile seizure through the NLRP3-Caspase-1 signaling pathway ([Wang et al 2019] ). - *[right]* Fig 2I. Flipped through 180 deg for ease of comparison. ![file] , 
 - *[left]* Fig 2I. - *[right]* Fig 3 from  Effects of CREB1 gene silencing on cognitive dysfunction by mediating PKA-CREB signaling pathway in mice with vascular dementia ([Han et al 2018] ). ![file] ,