TRC 051384

Target: Hsp70

IC50: N/A

TRC 051384, belonging to substituted 2-propen-1-one class, is a potent inducer of heat shock protein 70 (HSP70) [1]. Induction of HSP70 is a natural response of stressed cells that protects neuronal cells from a variety of insults including acute ischemia. Therefore, induction of HSP70 provides a potential target for the treatment of stroke [1].

In vitro: Induction of HSP70 by TRC 051384 (6.25, and 12.5 μM) involved heat shock factor-1 (HSF1) activation in HeLa cells and led to increasing chaperone and anti-inflammatory activity [1]. Moreover, TRC 051384 (10-50 μM) dose-dependently induced HSPA1B overexpression in endothelial cells as well as leucocyte origin [2].

In vivo: TRC 051384 (9 mg/kg, intra-peritoneal administration) treatment significantly decreased stroke-associated neuronal injury, disability, and increased survival in a rat model of transient ischemic stroke [1]. In addition, TRC 051384 (9 mg/kg, intra-peritoneal administration) delayed thrombus formation without increasing bleeding risk in WT mice [2].

References:
1.  Mohanan A, Deshpande S, Jamadarkhana PG, Kumar P, Gupta RC, Chauthaiwale V, et al. Delayed intervention in experimental stroke with TRC 051384--a small molecule HSP70 inducer. Neuropharmacology. 2011;60(6):991-9.
2.  Allende M, Molina E, Guruceaga E, Tamayo I, Gonzalez-Porras JR, Gonzalez-Lopez TJ, et al. Hsp70 protects from stroke in atrial fibrillation patients by preventing thrombosis without increased bleeding risk. Cardiovasc Res. 2016;110(3):309-18.

Construction of Conveniently Screening pLKO.1-TRC Vector Tagged with TurboGFP.[Pubmed:27730520]

Appl Biochem Biotechnol. 2017 Feb;181(2):699-709.

The pLKO.1-TRC plasmid has been a popular and widely used vector due to its simple handling and stability. The huge RNAi database, a TRC library, has been established based on this vector. However, this plasmid only has a puromycin-resisted gene for selecting, which limits its application in microscopy and fluorescence-activated cell sorting (FACS). In the present work, PCR, restriction endonuclease digestion and molecular cloning techniques were used to insert the gene decoding green fluorescent protein (GFP) without changing the structure of original plasmid to extend its application. To demonstrate the function of new plasmid, we constructed shNC and shGAPDH plasmids based on newly constructed pLKO-TurboGFP-TRC (pLKOG) and original pLKO plasmids, and then packaged lentivirus particles by 293T cells. The supernatant containing lentiviral particles was collected and then incubated with RAW264.7 cells for infection. After selection for 7 days by using puromycin, the cells were harvested. RT-qPCR and Western blotting were used to detect the target gene expression. FACS was used to detect the green fluorescent of cells. Our results showed that the newly constructed pLKOG plasmid, as a lentiviral vector carrying shRNA, could knock down the target gene expression efficiently and express TurboGFP protein efficiently in the host cells. We conclude that the new plasmid is a convenient vector for selecting positive cells with shRNA by using fluorescent microscope and FACS.

[Status of cardiac resynchronization therapy in Catalonia, Spain: Results of the prospective multicentric study TRC-CAT].[Pubmed:26869206]

Med Clin (Barc). 2016 May 20;146(10):423-8.

INTRODUCTION AND OBJECTIVES: Results of cardiac resynchronization therapy (CRT) have been extensively published. However, there is limited data in unselected populations. The objective of the study was to analyse the efficacy and safety of CRT in Catalonia. METHODS: A prospective study was performed of consecutive patients implanted with CRT over one year in 7 university hospitals in Catalonia, representing 90% of the implanted patients. Echocardiographic reverse remodelling was defined as 5 points improvement in left ventricular ejection fraction and clinical responders were defined as patients with an increase>10% of six-minute walk test or one point of New York Heart Association functional class at 12 months. Patients were followed up for one year and hospital admissions and mortality were analyzed. RESULTS: Of the 200 patients included in the study, 99% met the indications of the current CRT clinical guidelines and 68% received CRT with implantable cardioverter-defibrillator. The rate of complications was 12.5%. During follow-up 16 patients (8%) died. Fifty-two percent (104) of the population was considered to respond clinically and 62% (124) presented improved echocardiographic parameters. Compared to the year prior to implant, hospital admissions decreased by 82% (P<.001). CONCLUSIONS: In an unselected population of Catalonia, we observe that CRT was effective and decreased the number of hospital admissions.

Clinical importance of a transcription reverse-transcription concerted (TRC) diagnosis using peritoneal lavage fluids obtained pre- and post-lymphadenectomy from gastric cancer patients.[Pubmed:26272486]

Surg Today. 2016 Jun;46(6):654-60.

PURPOSE: Our previous study demonstrated that a transcription reverse-transcription concerted (TRC) diagnosis using peritoneal lavage fluids at laparotomy was a potential prognostic factor for gastric cancer patients; however, the clinical importance of a TRC diagnosis from peritoneal lavage fluids after lymphadenectomy remains unclear. METHODS: TRC amplification targeting CEA mRNA was utilized to detect free cancer cells before and after lymphadenectomy during gastric cancer resection. Of 120 patients who underwent curative gastrectomy for cT2-T4 gastric cancer, 38 whose peritoneal lavage samples were collected pre- and post-lymphadenectomy were eligible for analysis. RESULTS: Six (16.0 %) patients had CEA positivity before lymphadenectomy (pre-CEA), whereas nine (23.7 %) had CEA positivity after lymphadenectomy (post-CEA). Post-CEA was significantly correlated with higher pathological N-stage. Moreover, the positive post-CEA group had significantly worse relapse-free survival than the negative post-CEA group (p = 0.001). Cox multivariate analysis revealed that post-CEA positivity was a significant predictor of poor relapse-free survival (p = 0.012). It was also a predictor of distant metastasis, but not specific for peritoneal recurrence. CONCLUSIONS: These findings demonstrated that post-CEA positivity in a TRC diagnosis was a potential predictor of disease recurrence, but not a specific predictor of peritoneal recurrence.

Delayed intervention in experimental stroke with TRC051384--a small molecule HSP70 inducer.[Pubmed:21167846]

Neuropharmacology. 2011 May;60(6):991-9.

Induction of HSPs is a natural response of stressed cells that protects against many insults including acute ischemia. TRC051384, a novel compound belonging to substituted 2-propen-1-one class is a potent inducer of heat shock protein 70 (HSP70). The aim of this study was to investigate the ability of TRC051384 in reducing neuronal injury and disability upon delayed treatments (4 and 8 hours post ischemia onset) in a rat model of transient cerebral ischemia. Focal cerebral ischemia was produced in rats by occluding the MCA using the intra luminal suture technique. Rats subjected to 2 hours focal cerebral ischemia were administered by intra-peritoneal route, TRC051384 or vehicle every 2 hours for 48 hours, from 4th hour or 8th hour after onset of ischemia. Progression of infarct and edema was assessed up to 48 hours post ischemic insult using magnetic resonance imaging and the neurological disability and survival studied till 7 days. Here we show for the first time that treatment with TRC051384 significantly reduces stroke associated neuronal injury (87% reduction in area of penumbra recruited to infarct, and 25% reduction in brain edema) and disability in a rat model of transient ischemic stroke even when administered 8 hours post onset of ischemia. Significant improvement in survival (50% by day 2 and 67.3% by day 7) was observed with TRC051384 treatment initiated at 4 hours after ischemia onset. Induction of HSP70 by TRC051384 involves HSF1 activation and results in elevated chaperone and anti-inflammatory activity. These results show that TRC051384 has the potential to be developed as a novel pharmacological agent for the treatment of ischemic stroke.