bims-ershed 2023-04-23 papers

J Anim Sci. 2023 Jan 03. pii: skad101. [Epub ahead of print]101

The endoplasmic reticulum stress and B cell lymphoma-2 related ovarian killer participate in docosahexaenoic acid-induced adipocyte apoptosis in grass carp (Ctenopharyngodon idellus).

Xiaocheng Huang, Shanghong Ji, Chenchen Bian, Jian Sun, Hong Ji.

Docosahexaenoic acid (DHA) lessens adipose tissue lipid deposition partly by inducing adipocyte apoptosis in grass carp, but the underlying mechanism remains unclear. Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) is the novel pathway for inducing apoptosis. This study aimed to explore the potential role of ER stress in DHA-induced apoptosis in grass carp (Ctenopharyngodon idellus) adipocytes. DHA induced apoptosis by deforming the nuclear envelope, condensing the chromatin, and increasing the expression of apoptosis-related proteins and genes in vivo and in vitro (P < 0.05). However, the ER stress inhibitor, 4-phenylbutyric acid (4-PBA), effectively suppressed DHA-induced apoptosis (P < 0.05), indicating that ER stress mediates DHA-induced adipocyte apoptosis. Furthermore, we observed that 200 μM DHA significantly up-regulates the transcripts of B cell lymphoma-2 (BCL-2) related ovarian killer (BOK) in vitro (P < 0.05). BOK is a pro-apoptotic protein in the BCL-2 family, which governs the mitochondria apoptosis pathway. Hence, we hypothesized that BOK might be an important linker between ER stress and apoptosis. We cloned and identified two grass carp BOK genes, BOKa and BOKb, which encode peptides of 213 and 216 amino acids, respectively. BOKa primarily localizes in ER and mitochondria in the cytoplasm, while BOKb localizes in the nucleus and cytoplasm of grass carp adipocytes. Moreover, 200 μM DHA treatment up-regulated the mRNA expression of BOKa and BOKb, whereas 4-PBA suppressed the DHA-induced expressions. These results raised the possibility that BOK participates in DHA-induced adipocyte apoptosis through ER stress signaling, in line with its localization in ER and mitochondria. Two UPR branches, the inositol-requiring enzyme 1 (IRE1α) and activating transcription factor 6 (ATF6) signaling pathways, are possibly important in DHA-induced adipocyte apoptosis, unlike protein kinase RNA-activated-like ER kinase. The study also emphasized the roles of BOKa and BOKb in IRE1α- and ATF6-mediated apoptosis. This work is the first to elucidate the importance of the ER stress-BOK pathway during adipocyte apoptosis in teleost.

Keywords: BOK; DHA; apoptosis; endoplasmic reticulum stress; grass carp

DOI: https://doi.org/10.1093/jas/skad101

MicroPubl Biol. 2023 ;2023

Quaternary structure analysis of IRE1.

Samirul Bashir, Debnath Pal, Ozaira Qadri, Mariam Banday, Khalid Fazili.

IRE1 belongs to a type I transmembrane protein family harboring two functional domains, cytoplasmic domain with kinase and RNAse catalytic activity, and the luminal domain, which is involved in the sensing of unfolded proteins. IRE1 molecule undergoes dimerization in the lumenal domain, which functionally activates the catalytic C-terminal domain. IRE1 activation is directly related to transition between monomeric and dimeric forms. We have deduced two quaternary structures from the published crystal structure of IRE1. One structure with a large stable interface that requires large activation and deactivation energy to active IRE1. The other quaternary structure has low dissociation energy and is more suitable for IRE1 oligomeric transition.

DOI: https://doi.org/10.17912/micropub.biology.000763

Rejuvenation Res. 2023 Apr 18.

Kai-Xin-San improves cognitive impairment via Wnt/β-catenin and IRE1/XBP1s signalings in APP/PS1 mice.

Yu-Min Xu, Fang-Mei Lu, Hong-Cai Xu, Jie Zhang, Shang-Yan Hei, Yu-Hui Qiu, Ye-Feng Cai, Shi-Jie Zhang, Min Zhao.

Alzheimer's disease (AD) is the most common type of dementia with an insidious onset and slow progression. Kai-Xin-San (KXS) has been reported to be effective in improving cognitive impairment in AD. However, the mechanism is still confused. In this study, we employed APP/PS1 mice to explore the neuroprotective mechanism of KXS. Forty-eight male APP/PS1 mice were randomly divided into model group, Kai-Xin-San groups (0.7, 1.4 and 2.8 g/kg/d, p.o.) and the wild-type mice were assigned to the normal control group (n=12 in each group). Y-maze and novel object recognition (NOR) tests were carried out after continuous intragastric administration for 2 months. The abilities of learning, memory and new object recognition in the APP/PS1 mice were enhanced significantly after KXS treatment. KXS can reduced the deposition of Aβ40 and Aβ42 in APP/PS1 mice brain. KXS decreased the levels of serum inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). KXS increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) significantly, while inhibited the contents of reactive oxygen species (ROS) and malondialdehyde (MDA) significantly. In addition, we also detected Wnt/β-catenin signaling related proteins, such as Wnt7a, β-catenin, low-density lipoprotein receptor-related protein 6 (LRP6), glycogen synthase kinase-3β (GSK-3β), nuclear factor kappa-B (NF-κB), postsynaptic density 95 (PSD95), microtubule associated protein-2 (MAP-2) and ER stress (IRE1 pathway) related proteins, such as inositol-requiring enzyme 1 (IRE1), phosphorylated IRE1(p-IRE1), spliced X-box-binding protein 1 (XBP1s), immunoglobulin binding protein (BIP), protein disulfide isomerase (PDI) in hippocampus. Results showed that KXS decreased the expressions of GSK-3β, NF-kB, p-IRE1/IRE1 ratio, XBP1s and BIP, increased the expressions of Wnt7a, β-catenin, LRP6, PSD95, MAP2 and PDI. In conclusion, KXS improved cognitive impairment by activating Wnt/β-catenin signaling, inhibiting IRE1/XBP1s pathway in APP/PS1 mice.

DOI: https://doi.org/10.1089/rej.2022.0063