Molecular Chaperones: Molecular Assembly Line Brings Metabolism and Immunity in Shape

Zhao, Haoxin; Raines, Lydia; Huang, Stanley Ching-Cheng

doi:10.3390/metabo10100394

Cited by 15 publications

(8 citation statements)

References 202 publications

(214 reference statements)

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“…Heat shock proteins (Hsp) are molecular chaperones that play a key role in maintaining protein homeostasis in the cell (protostasis) [1]. They prevent protein misfolding and aggregation, which is achieved through their action on folding intermediates [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

The Correlation between Extracellular Heat Shock Protein 70 and Lipid Metabolism in a Ruminant Model

et al. 2021

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Metabolic stress in early lactation cows is characterized by lipolysis, ketogenesis, insulin resistance and inflammation because of negative energy balance and increased use of lipids for energy needs. In this study the relationship between lipid metabolite, lipid-based insulin resistance, and hepatocyte functionality indexes and tumor necrosis factor alpha (TNF-α) with extracellular heat shock protein 70 (eHsp70) was investigated. The experiment included 50 cows and all parameters were measured in blood serum. In cows with a more pronounced negative energy balance, the following was determined: a higher concentration of eHsp70, TNF-α, non-esterified fatty acid (NEFA), beta-hydroxybutyrate (BHB), NEFA to insulin and NEFA to cholesterol ratio and lower concentration of cholesterol, very low-density lipoproteins (VLDL), low density lipoproteins (LDL) and liver functionality index (LFI). The eHsp70 correlated negatively with the values of cholesterol, VLDL, LDL, and triglycerides, while correlated positively with the level of NEFA and BHB. A higher concentration of eHsp70 suggests the development of fatty liver (due to a higher NEFA to cholesterol ratio and lower LFI) and insulin resistance (due to a lower revised quantitative insulin sensitivity check index RQUICKI-BHB and higher NEFA to insulin ratio). The eHsp70 correlated positively with TNF-α. Both TNF-α and eHsp70 correlated similarly to lipid metabolites. In cows with high eHsp70 and TNF-α values we found higher concentrations of NEFA, BHB, NEFA to insulin and NEFA to cholesterol ratio and a lower concentration of triglycerides and VLDL cholesterol compared to cows that had only high TNF-α values. Based on the positive correlation between eHsp70 and TNF-α, their similar relations, and the additional effect of eHsp70 (high TNF-α + eHsp70 values) on lipid metabolites we conclude that eHsp70 has pro-inflammatory effects implicating lipolysis, fatty liver, and fat tissue insulin resistance.

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Section: Introductionmentioning

confidence: 99%

The Correlation between Extracellular Heat Shock Protein 70 and Lipid Metabolism in a Ruminant Model

et al. 2021

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“…Histones can disrupt cell membranes, cause oxidative stress, and activate intracellular signaling pathways that promote cell death. Excessive histone release has been shown to induce the production of interleukin-8 in ARPE-19 cells, and at concentrations more than 20 μg/mL is toxic to cells [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

RNA-Seq Analysis of Trans-Differentiated ARPE-19 Cells Transduced by AAV9-AIPL1 Vectors

Galieva,

Egorov,

Malogolovkin

et al. 2023

IJMS

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Inherited retinal disorders (IRD) have become a primary focus of gene therapy research since the success of adeno-associated virus-based therapeutics (voretigene neparvovec-rzyl) for Leber congenital amaurosis type 2 (LCA2). Dozens of monogenic IRDs could be potentially treated with a similar approach using an adeno-associated virus (AAV) to transfer a functional gene into the retina. Here, we present the results of the design, production, and in vitro testing of the AAV serotype 9 (AAV9) vector carrying the codon-optimized (co) copy of aryl hydrocarbon receptor-interacting protein like-1 (AIPL1) as a possible treatment for LCA4. The pAAV-AIPL1co was able to successfully transduce retinal pigment epithelium cells (ARPE-19) and initiate the expression of human AIPL1. Intriguingly, cells transduced with AAV9-AIPL1co showed much less antiviral response than AAV9-AIPL1wt (wild-type AIPL1) transduced. RNA-sequencing (RNA-seq) analysis of trans-differentiated ARPE-19 cells transduced with AAV9-AIPL1co demonstrated significant differences in the expression of genes involved in the innate immune response. In contrast, AAV9-AIPL1wt induced the prominent activation of multiple interferon-stimulated genes. The key part of the possible regulatory molecular mechanism is the activation of dsRNA-responsive antiviral oligoadenylate synthetases, and a significant increase in the level of histone coding genes’ transcripts overrepresented in RNA-seq data (i.e., H1, H2A, H2B, H3, and H4). The RNA-seq data suggests that AAV9-AIPL1co exhibiting less immunogenicity than AAV9-AIPL1wt can be used for potency testing, using relevant animal models to develop future therapeutics for LCA4.

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“…A recent study has shown that short and non-toxic treatment of epithelial cells with thapsigargin triggers ER stress, which appears to be responsible for inducing a spectrum of host antiviral defenses [ 57 ]. This thapsigargin-elicited ER stress was also associated with the induction of heat-shock proteins known to promote DC maturation [ 58 ]. However, whether ER stress is the driver of the LAD2 MC-mediated maturation of DCs remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Thapsigargin-Stimulated LAD2 Human Mast Cell Line Is a Potent Cellular Adjuvant for the Maturation of Monocyte-Derived Dendritic Cells for Adoptive Cellular Immunotherapy

Taborska

Stakheev

Bartůňková

et al. 2021

IJMS

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The preparation of dendritic cells (DCs) for adoptive cellular immunotherapy (ACI) requires the maturation of ex vivo-produced immature(i) DCs. This maturation ensures that the antigen presentation triggers an immune response towards the antigen-expressing cells. Although there is a large number of maturation agents capable of inducing strong DC maturation, there is still only a very limited number of these agents approved for use in the production of DCs for ACI. In seeking novel DC maturation agents, we used differentially activated human mast cell (MC) line LAD2 as a cellular adjuvant to elicit or modulate the maturation of ex vivo-produced monocyte-derived iDCs. We found that co-culture of iDCs with differentially activated LAD2 MCs in serum-containing media significantly modulated polyinosinic:polycytidylic acid (poly I:C)-elicited DC maturation as determined through the surface expression of the maturation markers CD80, CD83, CD86, and human leukocyte antigen(HLA)-DR. Once iDCs were generated in serum-free conditions, they became refractory to the maturation with poly I:C, and the LAD2 MC modulatory potential was minimized. However, the maturation-refractory phenotype of the serum-free generated iDCs was largely overcome by co-culture with thapsigargin-stimulated LAD2 MCs. Our data suggest that differentially stimulated mast cells could be novel and highly potent cellular adjuvants for the maturation of DCs for ACI.

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Molecular Chaperones: Molecular Assembly Line Brings Metabolism and Immunity in Shape

Cited by 15 publications

References 202 publications

The Correlation between Extracellular Heat Shock Protein 70 and Lipid Metabolism in a Ruminant Model

The Correlation between Extracellular Heat Shock Protein 70 and Lipid Metabolism in a Ruminant Model

RNA-Seq Analysis of Trans-Differentiated ARPE-19 Cells Transduced by AAV9-AIPL1 Vectors

Thapsigargin-Stimulated LAD2 Human Mast Cell Line Is a Potent Cellular Adjuvant for the Maturation of Monocyte-Derived Dendritic Cells for Adoptive Cellular Immunotherapy

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