The Effect of Oxidized Fish Oil on the Spleen Index, Antioxidant Activity, Histology and Transcriptome in Juvenile Hybrid Grouper (♀ Epinephelus fuscoguttatus × ♂ Epinephelus lanceolatus)

The spleen is an important organ in the immune function of fish, and it is also important for hematogenesis and antibody and granulocyte production. However, the effect of oxidized fish oil on the spleen of hybrid grouper (♀ Epinephelus fuscoguttatus × ♂ Epinephelus lanceolatus) is unknown. In this study, hybrid groupers were fed with oxidized fish oil and the spleen index, antioxidant ability, histology and transcriptome were investigated. Oxidized fish oil did not affect the spleen index. Levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in the spleen were significantly increased as the amount of oxidized fish oil in the diet increased, but the vitamin E concentration was significantly decreased. The morphological organization of the spleen was damaged with increased oxidative stress. And the spleen reacted to oxidative stress by platelet activation, FOXO and notch signaling pathways, which involved amyloid beta precursor protein binding family B member 1 interacting protein (APBB1IP) gene, glucose-6-phosphatase (G6PC) gene, histone acetyltransferase p300 (EP300) gene, insulin gene and notch 2 gene. In conclusion, the oxidized fish oil caused oxidative stress and damaged its structure. Additionally, oxidized fish oil changed the transcription profile of the spleen.

Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model

Chaperone-mediated autophagy (CMA) is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. However, the mechanisms that regulate CMA are not fully understood. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Importantly, we find that in the APP/PS1 mouse model of Alzheimer’s disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.

The amyloid beta precursor protein is differentially expressed in lymph node metastasis in human breast cancer.

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). Between the breast and the brain reside the secondary lymphoid organ, the lymph nodes. We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with metastasis to the lymph nodes in humans with metastatic breast cancer. We found that amyloid beta precursor protein, APP, was among the genes whose expression was most different in the lymph node metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. APP mRNA was present at decreased quantities in lymph node metastases as compared to primary tumors of the breast. Importantly, expression of APP in primary tumors of the breast was correlated with patient recurrence-free survival, in lymph node negative patients but not in lymph node positive patients. Modulation of APP expression may be relevant to the biology by which tumor cells metastasize from the breast to the lymph nodes and the brain in humans with metastatic breast cancer.

The Essentials of Biochemistry of the Proteins as Related to Alzheimer’s Disease: A Review

Amyloid plaques and Tau tangles, constitute the pathological hallmarks of the brains of the patients suffering from Alzheimer’s disease. They are identified as far back as 1996 by Alois Alzheimer, a German psychiatrist and neuropathologist, but till this date, how they produce neuronal death remained an enigma. The amyloid cascade theory held its sway until recent times until the emphasis is shifted to the metabolites of amyloid Beta precursor protein (APP). Several metabolites of APP are formed depending on by which pathway, the APP is metabolized, either by the non -amyloidogenic pathway (forming α-C terminal fragment -CTFα / C83 and the N-terminal fragment sAPPα / P3 and the APP intracellular domain AICD). Or amyloidogenic pathways. (Forming extracellular Aβ and APP intracellular domain -AICD). The hyperphosphorylation is held responsible for the tau protein tangles. The over activity of the tau kinases or the failure of inhibition by the tau phosphatases is implicated, in tau tangle deposits. These biochemical aspects of AD assumed importance in connection with the interventional therapeutic strategies that are developed in the years bygone, as well as those still are in the developing stage. In keeping with this fact, it is attempted to review the essentials of the biochemical aspects of the involved proteins, as related to AD, in this article.