BACKGROUNDNecroptosis, a newly defined regulatable necrosis with membrane disruption, has been demonstrated to participate in trauma brain injury (TBI) related neuronal cell death. Heat shock protein 70 (HSP70) is a stress protein with neuroprotective activity, but the potential protective mechanisms are not fully understood.METHODS AND RESULTSHere, we investigated the effects of HSP70 regulators in a cellular TBI model induced by traumatic neuronal injury (TNI) and glutamate treatment. We found that necroptosis occurred in cortical neurons after TNI and glutamate treatment. Neuronal trauma markedly upregulated HSP70 protein expression within 24 h. The results of immunostaining and lactate dehydrogenase release assay showed that necroptosis following neuronal trauma was inhibited by HSP70 activator TRC051384 (TRC), but promoted by the HSP70 inhibitor 2-phenylethyenesulfonamide (PES). In congruent, the expression and phosphorylation of receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) were differently regulated by HSP70. Furthermore, the expression of HSP90α induced by neuronal trauma was further promoted by PES but decreased by TRC. The data obtained from western blot showed that the phosphorylation of RIPK3 and MLKL induced by HSP70 inhibition were reduced by RIPK3 inhibitor GSK-872 and HSP90α inhibitor geldanamycin (GA). Similarly, inhibition of HSP90α with GA could partially prevented the increased necroptosis induced by PES.CONCLUSIONSTaken together, HSP70 activation exerted protective effects against neuronal trauma via inhibition of necroptosis. Mechanistically, the HSP90α-mediated activation of RIPK3 and MLKL is involved in these effects.

01 May 2021·Molecular and Cellular BiochemistryQ3 · BIOLOGY

Activation of HSP70 impedes tert-butyl hydroperoxide (t-BHP)-induced apoptosis and senescence of human nucleus pulposus stem cells via inhibiting the JNK/c-Jun pathway

Q3 · BIOLOGY

Article

Author: Wang, Peng ; Wang, Baichuan ; Hu, Binwu ; Zhang, Shuo ; Lv, Xiao ; Chen, Songfeng ; Shao, Zengwu ; Liu, Weijian

The endogenous repair failure of degenerated intervertebral disk (IVD) is highly related to the exhaustion of nucleus pulposus stem cells (NPSCs). Excessive oxidative stress could induce apoptosis and senescence of NPSCs, thus, declining the quantity and quality of NPSCs. Heat shock protein 70 (HSP70) is a family of cytoprotective and antioxidative proteins. However, there is no report on the protective effects of HSP70 on oxidative stress-induced NPSC impairments and underlying mechanisms. In the present study, we treated NPSCs with tert-butyl hydroperoxide (t-BHP) in vitro to simulate an oxidative stress condition. HSP70 inducer TRC051384 was used to evaluate the cytoprotective effects of HSP70. The results suggested that HSP70 impeded t-BHP-mediated cell viability loss and protected the ultrastructure of NPSCs. Moreover, t-BHP could induce mitochondrial apoptosis and p53/p21-mediated senescence of NPSCs, both of which were significantly inhibited in HSP70 activation groups. Excessive oxidative stress and mitochondrial dysfunction reinforced each other and contributed to the cellular damage processes. HSP70 decreased reactive oxygen species (ROS) production, rescued mitochondrial membrane potential (MMP) collapse, and blocked ATP depletion. Finally, our data showed that HSP70 downregulated the JNK/c-Jun pathway. Taken together, activation of HSP70 could protect against t-BHP-induced NPSC apoptosis and senescence, thus, improving the quantity and quality of NPSCs. Therefore, HSP70 may be a promising therapeutic target for IVD degeneration.

01 Jun 2016·Cardiovascular ResearchQ1 · MEDICINE

Hsp70 protects from stroke in atrial fibrillation patients by preventing thrombosis without increased bleeding risk

Q1 · MEDICINE

Article

Author: González-Porras, José Ramón ; Oyarzabal, Julen ; Allende, Mikel ; Tamayo, Ibai ; Toledo, Estefanía ; Rivera, José ; Gonzalez-López, Tomás José ; Ugarte, Ana ; Montes, Ramón ; Molina, Eva ; Roldán, Vanesa ; Guruceaga, Elisabet ; Rabal, Obdulia ; Hermida, José

AIMSAtrial fibrillation (AF) is a major risk factor for cardio-embolic stroke. Anticoagulant drugs are effective in preventing AF-related stroke. However, the high frequency of anticoagulant-associated major bleeding is a major concern. This study sought to identify new targets to develop safer antithrombotic therapies.METHODS AND RESULTSHere, microarray analysis in peripheral blood cells in eight patients with AF and stroke and eight AF subjects without stroke brought to light a stroke-related gene expression pattern. HSPA1B, which encodes for heat-shock protein 70 kDa (Hsp70), was the most differentially expressed gene. This gene was down-regulated in stroke subjects, a finding confirmed further in an independent AF cohort of 200 individuals. Hsp70 knock-out mice subjected to different thrombotic challenges developed thrombosis significantly earlier than their wild-type (WT) counterparts. Remarkably, the tail bleeding time was unchanged. Accordingly, both TRC051384 and tubastatin A, i.e. two Hsp70 inducers via different pathways, delayed thrombus formation in WT mice, the tail bleeding time still being unaltered. Most interestingly, Hsp70 inducers did not increase the bleeding risk even when aspirin was concomitantly administered. Hsp70 induction was associated with an increased vascular thrombomodulin expression and higher circulating levels of activated protein C upon thrombotic stimulus.CONCLUSIONSHsp70 induction is a novel approach to delay thrombus formation with minimal bleeding risk, and is especially promising for treating AF patients and in other situations where there is also a major bleeding hazard.

100 Deals associated with TRC-051384

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Indication	Highest Phase	Country/Location	Organization	Date
Ischemic stroke	Preclinical	IN	Torrent Pharmaceuticals Ltd.	16 Dec 2010

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