Delayed intervention in experimental stroke with TRC051384 – A small molecule HSP70 inducer

Mohanan, Anookh; Deshpande, Shailesh; Jamadarkhana, Prashant; Kumar, Prabhat; Gupta, Ramesh C.; Chauthaiwale, Vijay; Dutt, Chaitanya

doi:10.1016/j.neuropharm.2010.12.003

Cited by 16 publications

(7 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Each group was injected with relevant cells via tail vein according to the preimplantation experiment. The next day those which bore PCSK9 shRNA SGC-7901 cells were treated with physiological saline or TRC051384 intraperitoneally at a dose of 9 mg/kg as first dose and then 4.5 mg/kg every 12 h thereafter for 10 days, as previously described ( 19 ). Four weeks later, the mice were subjected to 18 F-FDG positron emission tomography (PET) scan (MedicLab PET/MR, Madic Technology Co. Ltd, Shandong, China) to show a rough picture of tumor metastasis.…”

Section: Methodsmentioning

confidence: 99%

Proprotein Convertase Subtilisin/Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apoptosis by Facilitating MAPK Signaling Pathway Through HSP70 Up-Regulation

Fang

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

ObjectiveTo examine the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) on gastric cancer (GC) progression and prognosis, and to explore the underlying mechanism.MethodsPCSK9 expression levels in human GC tissues were determined by quantitative real-time PCR, western blotting, and immunohistochemical assay. PCSK9 serum levels were detected by enzyme-linked immunosorbent assay. The relationships of PCSK9 and GC progression and survival were analyzed using the Chi-square test, Kaplan-Meier analysis, and Cox proportional hazards model. The effect of PCSK9 on cell invasion, migration, and apoptosis were determined in human GC cell lines and mouse xenograft model separately using PCSK9 knockdown and overexpression strategies. The PCSK9 interacting molecules, screened by co-immunoprecipitation combined with LC-MS/MS, were identified by immunofluorescence localization and western blotting. Additionally, the mitogen-activated protein kinase (MAPK) pathway was assessed by western blotting.ResultsPCSK9 mRNA and protein levels were significantly elevated in GC tissues compared with the paired normal tissues at our medical center (P < 0.001). Notably, the up-regulation of PCSK9 expression in GC tissues was related to tumor progression and poor survival. GC patients had higher serum levels of PCSK9 than the age-matched healthy controls (P < 0.001); PCSK9 promoted invasive and migratory ability and inhibited apoptosis in GC cells with no apparent affection in cell proliferation. The silencing of PCSK9 reversed these effects, suppressing tumor metastasis in vitro and in vivo. Furthermore, PCSK9 maintained these functions through up-regulating heat shock protein 70 (HSP70), ultimately facilitating the mitogen-activated protein kinase (MAPK) pathway.ConclusionCollectively, our data revealed that high PCSK9 expression levels in GC tissue were correlated with GC progression and poor prognosis and that PCSK9 could promote GC metastasis and suppress apoptosis by facilitating MAPK signaling pathway through HSP70 up-regulation. PCSK9 may represent a novel potential therapeutic target in GC.

show abstract

Section: Methodsmentioning

confidence: 99%

Proprotein Convertase Subtilisin/Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apoptosis by Facilitating MAPK Signaling Pathway Through HSP70 Up-Regulation

Fang

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…Most recently neural precursor cells transduced with TAT-Hsp70 have been shown to protect against experimental focal cerebral ischemia better than the precursor cells alone [23]. In addition, a small molecule inducer of Hsp70 given after stroke has also been shown to be protective, avoiding the problem of extracellular Hsp70 administration [24]. Given the mounting literature on Hsp70 induced neuroprotection, one wonders if it is not time to begin to consider this approach for human stroke trials.…”

Section: Hsp70 Defines the Brain Ischemic Penumbra And Is Neuroprotecmentioning

confidence: 99%

Heat Shock Proteins in the Brain: Role of Hsp70, Hsp 27, and HO-1 (Hsp32) and Their Therapeutic Potential

Sharp

Zhan

Liu

2013

Transl. Stroke Res.

123

View full text Add to dashboard Cite

Heat shock proteins are induced by heat shock via HSF proteins binding to heat shock elements in their promoters. Hsp70 is massively induced in response to misfolded proteins following cerebral ischemia in all cell types, but is induced mainly in neurons in the ischemic penumbra. Over expression of Hsp70 via transgenes and viruses or systemic administration of Hsp70 fusion proteins that allow it to cross the blood brain barrier protect brain against ischemia in most reported studies. Hsp27 can exist as unphosphorylated large oligomers that prevent misfolded protein aggregates and improve cell survival. P-Hsp27 small oligomers bind specific protein targets to improve survival. In brain Protein Kinase D phosphorylates Hsp27 following ischemia which then binds ASK1 to prevent MKK4/7, JNK, Jun induced apoptosis and decrease infarct volumes following focal cerebral ischemia. Heme oxygenase-1 (HO-1) metabolizes heme to carbon monoxide, ferrous ion and biliverdin. CO activates cGMP to promote vasodilation, and biliverdin is converted to bilirubin which can serve as an anti-oxidant both of which may contribute to the reported protective role of HO-1 in cerebral ischemia and subarachnoid hemorrhage. However, ferrous ion can react with hydrogen peroxide to produce pro-oxidant hydroxyl radicals which may explain the harmful role of HO-1 in intracerebral hemorrhage. Heat shock proteins as a class have great potential as treatments for cerebrovascular disease and have yet to be tested in the clinic.

show abstract

“…Therefore, protection of photoreceptor cells may be a useful therapeutic strategy for RDs. Some of the candidate therapeutic agents for RDs are listed in Table []; these agents include therapeutic agents against the early stage of photoreceptor cell death (antioxidants, ROS scavengers, Ca 2+ antagonists and calpain inhibitors), therapeutic agents against the late stage of photoreceptor cell death (cathepsin inhibitors and caspase inhibitors), and HSP70 inducers.…”

Section: Candidate Therapeutic Agents For Rdsmentioning

confidence: 99%

A role of Heat Shock Protein 70 in Photoreceptor Cell Death: Potential as a Novel Therapeutic Target in Retinal Degeneration

Furukawa

Koriyama

2015

CNS Neurosci Ther

View full text Add to dashboard Cite

Retinal degenerative diseases (RDs) such as retinitis pigmentosa (RP) are a genetically heterogeneous group of disorders characterized by night blindness and peripheral vision loss, which caused by the dysfunction and death of photoreceptor cells. Although many causative gene mutations have been reported, the final common end stage is photoreceptor cell death. Unfortunately, no effective treatments or therapeutic agents have been discovered. Heat shock protein 70 (HSP70) is highly conserved and has antiapoptotic activities. A few reports have shown that HSP70 plays a role in RDs. Thus, we focused on the role of HSP70 in photoreceptor cell death. Using the N-methyl-N-nitrosourea (MNU)-induced photoreceptor cell death model in mice, we could examine two stages of the novel cell death mechanism; the early stage, including HSP70 cleavage through protein carbonylation by production of reactive oxygen species, lipid peroxidation and Ca(2+) influx/calpain activation, and the late stage of cathepsin and/or caspase activation. The upregulation of intact HSP70 expression by its inducer is likely to protect photoreceptor cells. In this review, we focus on the role of HSP70 and the novel cell death signaling process in RDs. We also describe candidate therapeutic agents for RDs.

show abstract

Delayed intervention in experimental stroke with TRC051384 – A small molecule HSP70 inducer

Cited by 16 publications

References 41 publications

Proprotein Convertase Subtilisin/Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apoptosis by Facilitating MAPK Signaling Pathway Through HSP70 Up-Regulation

Proprotein Convertase Subtilisin/Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apoptosis by Facilitating MAPK Signaling Pathway Through HSP70 Up-Regulation

Heat Shock Proteins in the Brain: Role of Hsp70, Hsp 27, and HO-1 (Hsp32) and Their Therapeutic Potential

A role of Heat Shock Protein 70 in Photoreceptor Cell Death: Potential as a Novel Therapeutic Target in Retinal Degeneration

Contact Info

Product

Resources

About