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Responses to Muscular Exercise, Heat Shock Proteins as Regulators of Inflammation, and Mitochondrial Quality Control
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Alex T. Von Schulze, Paige C. Geiger
HSPs have the additional ability to tag and initiate the degradation of damaged proteins via the UPS. The UPS tags damaged or aggregated proteins with ubiquitin to target them for degradation via the proteasome (22). HSP70 and HSP90 are linked to the UPS via the co-chaperone carboxyl terminus of Hsc70 interacting protein (CHIP) and ubiquitin conjugating enzyme E2 N (UBE2N) (20, 98). CHIP, an E3 ubiquitin ligase, contains N-terminal binding domains for both HSP70 and HSP90. Upon HSP70 or HSP90 binding with the damaged target protein, the protein-bound HSP complexes are recruited to CHIP (12). This CHIP:HSP:Protein complex then interacts with the UBEN2, allowing for the transfer and ligation of ubiquitin onto target proteins (98). Once the substrate protein is tagged with ubiquitin, the nucleotide exchange factor, Bcl‐2‐associated athanogene 1 (BAG1), binds to the CHIP:HSP:Protein-ub complex allowing for proteasomal recruitment and eventual substrate release (54). In this way, HSP40, HSP70, and HSP90 work with CHIP synergistically to degrade proteins that are beyond repair.
Skeletal Muscle
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
Muscle spindles contain three types of muscle fibers, described as: nuclear bag1 fibers, nuclear bag2 fibers, and nuclear chain fibers, collectively referred to as intrafusal fibers. This is to distinguish them from the muscle fibers proper of the muscle itself, which are referred to in the same context as extrafusal fibers. Nuclear bag1 fibers are also termed dynamic bag1 fibers (DB1) and nuclear bag2 fibers are termed static bag2 fibers (SB2) for reasons that will become apparent shortly. The intrafusal fibers are illustrated in Figure 9.12, where the nuclear chain fibers are denoted by Ch. Some of the nuclear chain fibers are longer than the other chain fibers.
Anti-Cancer Agents from Natural Sources
Published in Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg, Promising Drug Molecules of Natural Origin, 2020
Debasish Bandyopadhyay, Felipe Gonzalez
The study identified the protein, responsible for apoptosis by aloe-emodin, was p38. Lee et al. (2001) conducted a study to investigate to evaluate the impact of aloe-emodin on the pharmacodynamics of CH27 (human lung squamous cell carcinoma) cells. The reported mechanism was like that of Yeh et al. CH27 experienced apoptosis through alteration of expression of the proteins BCLX(L), Bak, & Bag-1. These modifications are due to the translocation of Bax and Bak from the previous cytosolic to a particulate fraction. This could potentially cause an activation of capase-3, -8 and -9, which could conclude that apoptosis was initiated through the Bax pathway. In a recent report (Ren et al., 2018) showed chrysophanol-induced apoptosis in MCF-7 and MDA-MB-231 cells. Cell growth was inhibited by chrysophanol’s potential to inhibit the NF-κB activity. The protein which was down-regulated was Bcl-2, and the crucial transcription factors p65 and IκB phosphorylation. An increase in paclitaxel potential (synergy) was observed with chrysophanol in both the cell lines. Moreover, the effects of chrysophanol-induced apoptosis could be notably reduced by NF-κB inhibition with ammonium pyrrolidine dithiocarbonate.
Genes involved in glucocorticoid receptor signalling affect susceptibility to mood disorders
Published in The World Journal of Biological Psychiatry, 2021
Dawid Szczepankiewicz, Beata Narożna, Piotr Celichowski, Kosma Sakrajda, Paweł Kołodziejski, Ewa Banach, Przemysław Zakowicz, Ewa Pruszyńska-Oszmałek, Joanna Pawlak, Monika Wiłkość, Monika Dmitrzak-Węglarz, Maria Skibińska, Alicja Bejger, Joanna Twarowska-Hauser, Janusz K. Rybakowski, Leszek Nogowski, Aleksandra Szczepankiewicz
The association of BAG1 variant with bipolar disorder was not reported previously in susceptibility to mood disorders. BAG1 is a chaperone for heat shock protein 70 (HSP70) that participates in the GR-ligand complex translocation to the nucleus. It seems that BAG1 inhibits GR activity by reducing GR complex translocation via binding to the receptor and limiting DNA binding (Schmidt et al. 2003). BAG1 downregulation was previously reported to impair recovery from stress-induced depression-like behaviours (McGuffin et al. 1991), whereas increased expression of BAG1 was observed after mood-stabilizing treatment, both in vitro and in vivo, that contributed to decreased translocation of GR-ligand complex to the nucleus and its reduced biological activity (Zhou et al. 2005). Our results showed decreased expression of BAG1 in the brains of animals with depressive-like behaviour, with the highest decrease observed in the hypothalamus, that indicates abundant GR expression. Thus, these data suggest that decreased BAG1 expression after chronic mild stress may impede GR receptor activity leading to hyperactivity of the HPA axis and disturbed stress response observed in depression (Wang Q et al. 2014).
HSC70 expression is reduced in lymphomonocytes of sporadic ALS patients and contributes to TDP-43 accumulation
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2020
Alessandro Arosio, Riccardo Cristofani, Orietta Pansarasa, Valeria Crippa, Chiara Riva, Riccardo Sirtori, Virginia Rodriguez-Menendez, Nilo Riva, Francesca Gerardi, Christian Lunetta, Cristina Cereda, Angelo Poletti, Carlo Ferrarese, Lucio Tremolizzo, Gessica Sala
Based on the reduction of HSC70 expression observed in patient cells, we decided to evaluate some co-chaperones involved in the autophagic lysosomal pathway (ALP). We assessed levels of the small heat shock protein B8 (HSPB8), which was previously described to protect against protein aggregation in ALS (8,26,27). Unexpectedly, HSPB8 protein was not expressed in PBMC lysates (Figure 6(A)) and its mRNA levels were undetectable by real-time PCR. Then, we analyzed the stress-inducible form of HSC70, HSP70, and no difference was observed in HSP70 protein levels between sALS and controls (Figure 6(B)). Among co-chaperones, two members of Bcl2-associated athanogene (BAG) family play a crucial role in the regulation of HSC70 and in the delivery of the substrate to UPS or autophagy for degradation. Thus, we evaluated the expression of BAG1 (which interacts with HSC70 to drive substrates to UPS degradation) and BAG3 (which together with HSC70 and HSPB8 promotes the substrate degradation via macroautophagy). While BAG1 mRNA levels were significantly reduced in sALS PBMCs (−33%, p < 0.05), protein levels were markedly increased (+336%, p < 0.001) (Figure 7(A,B,E)). BAG3 protein levels were also increased in patient cells (+106%, p < 0.01), with no change in its mRNA levels (Figure 7(C–E)).
The 70-kDa heat shock protein (Hsp70) as a therapeutic target for stroke
Published in Expert Opinion on Therapeutic Targets, 2018
Jong Youl Kim, Yeonseung Han, Jong Eun Lee, Midori A. Yenari
Newly generated Hsp70 protein, in conjunction with ATP, Hsp40 and Hsp90, then binds denatured proteins and act as a molecular chaperone by contributing to repair, refolding and trafficking of damaged proteins within the cell. This chaperone complex goes through several cycles of attempting to refold the proteins. This continues with binding of the Hip protein to the N-terminus and the Hop protein to the C-terminus of Hsp70, and thus, Hsp70 is able to assist in the folding of nascent proteins and the refolding of denatured proteins [26]. When refolding does not occur, Bag-1 binds to the N-terminus of Hsp70, and the E3-ubiquitin ligase CHIP (C-terminus of Hsp70/Hsc70 interacting protein) binds to the C terminus of Hsp70. This complex then interacts with the denatured protein and recruits it to the proteasome where it is ubiquitnated and degraded [27]. Thus, Hsp70 is involved in the refolding of denatured proteins, or the degradation and clearance of damaged proteins.