Hydroximic Acid Derivatives: Pleiotropic Hsp Co-Inducers Restoring Homeostasis and Robustness

Crul, Tim; Tóth, Noémi; Piotto, Stefano; Literati-Nagy, Peter; Tory, Kálmán; Haldimann, Pierre; Kalmár, Bernadett; Greensmith, Linda; Török, Zsolt; Balogh, Gábor; Gombos, Imre; Campana, F.; Concilio, Simona; Gallyas, Ferenc; Nagy, Gábor; Berente, Zoltán; Güngör, Burçin; Makk, Péter; Glatz, Attila; Hunya, Ákos; Literati-Nagy, Zsuzsanna; Hoogstra-Berends, Femke; Heeres, André; Kuipers, Irma; Loen, Lizette; Seerden, Jean-Paul G.; Zhang, Deli; Meijering, Roelien A. M.; Henning, Robert H.; Brundel, Bianca J. J. M.; Kampinga, Harm H.; Korányi, László; Szilvássy, Zoltán; Mandl, József; Sümegi, Balázs; Febbraio, Mark A.; Horváth, Ibolya; Hooper, Philip L.; Vigh, László Gergely

doi:10.2174/1381612811306030309

Cited by 16 publications

(30 citation statements)

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“…BGP-15 had previously been shown to facilitate the actions of membrane-localized receptor proteins via enhancing membrane fluidity 34 , including increased phosphorylation of the insulin receptor in kidney and adipose cells 12 . Thus, we turned our attention to IGF1R, an insulin receptor family member, which protects the heart in settings of cardiac disease 19 .…”

Section: Discussionmentioning

confidence: 99%

“…BGP-15 is administered orally and has been shown to have an excellent safety profile in multiple human clinical trials in healthy individuals 9,10 and insulin-resistant nondiabetic patients 11 . The initial rationale for assessing the therapeutic potential of BGP-15 in an animal model with a failing heart and increased susceptibility to AF was related to its role as a co-inducer of the stress inducible form of heat-shock protein 70 (HSP70/72) 12 . Studies in animal models and/or humans suggested that elevated levels of HSP70 (endogenous, genetically manipulated, drug-induced or hyperthermia-induced) were protective against the development of AF, and/or cardiac pathology in settings of ischaemia [13][14][15][16][17][18] .…”

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confidence: 99%

“…6). In addition to acting as a HSP-coinducer, BGP-15 has also been shown to enhance the actions of membrane-localized receptor proteins, including the insulin receptor 12,34 . Accordingly, we next assessed the phosphorylation of the IGF1R, an insulin receptor family member known to mediate protection in the heart 19 .…”

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confidence: 99%

“…To help understand the association between increased phosphorylation of IGF1R with BGP-15 treatment and potential downstream signalling events, we conducted cell culture experiments, assessed circulating IGF1 levels in mice, performed lipid analyses of atrial tissue, and undertook further protein analyses in ventricular and atrial tissue. First, we examined whether BGP-15 had the potential to enhance the phosphorylation of the IGF1R, as reported for the insulin receptor 12 . For this purpose, neonatal rat ventricular myocytes (NRVMs) were stimulated with IGF1 in the absence and presence of BGP-15 for 48 h. Treatment with IGF1 induced a significant phosphorylation of the IGF1R and this was enhanced in the presence of BGP-15 (Fig.…”

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confidence: 99%

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The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

et al. 2014

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Heart failure (HF) and atrial fibrillation (AF) share common risk factors, frequently coexist and are associated with high mortality. Treatment of HF with AF represents a major unmet need. Here we show that a small molecule, BGP-15, improves cardiac function and reduces arrhythmic episodes in two independent mouse models, which progressively develop HF and AF. In these models, BGP-15 treatment is associated with increased phosphorylation of the insulin-like growth factor 1 receptor (IGF1R), which is depressed in atrial tissue samples from patients with AF. Cardiac-specific IGF1R transgenic overexpression in mice with HF and AF recapitulates the protection observed with BGP-15. We further demonstrate that BGP-15 and IGF1R can provide protection independent of phosphoinositide 3-kinase-Akt and heat-shock protein 70; signalling mediators often defective in the aged and diseased heart. As BGP-15 is safe and well tolerated in humans, this study uncovers a potential therapeutic approach for HF and AF.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

et al. 2014

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“…The BGP-15 activation of HSP expression involved the Rac1 signalling cascade. Presumably via Rac1 (and other, as yet unrevealed signalling pathways, bridging the signalling platforms of surface membranes with hsp genes via heat shock factors, (HSFs)), we demonstrated that BGP-15 is able to inhibit the rapid HSF1 acetylation monitored during the early phase of heat stress, thereby promoting a prolonged duration of HSF1 binding to heat shock elements [46,47]. Modulation of the heat shock protein response via drugs, such as BGP-15 acting on the base of membrane lipid therapy has the potential to be beneficial in a range of disorders, including cancer [36].…”

Section: Membranes Are Key Determinants Of Cellular Stress Adaptationmentioning

confidence: 89%

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

Csoboz

Balogh

Kúsz

et al. 2013

International Journal of Hyperthermia

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Hyperthermia is a promising treatment modality for cancer in combination both with radio-and chemotherapy. In spite of its great therapeutic potential, the underlying molecular mechanisms still remain to be clarified. Due to lipid imbalances and 'membrane defects' most of the tumour cells possess elevated membrane fluidity. However, further increasing membrane fluidity to sensitise to chemo-or radiotherapy could have some other effects. In fact, hyperfluidisation of cell membrane induced by membrane fluidiser initiates a stress response as the heat shock protein response, which may modulate positively or negatively apoptotic cell death. Overviewing some recent findings based on a technology allowing direct imaging of lipid rafts in live cells and lipidomics, novel aspects of the intimate relationship between the 'membrane stress' of tumour cells and the cellular heat shock response will be highlighted. Our findings lend support to both the importance of membrane remodelling and the release of lipid signals initiating stress protein response, which can operate in tandem to control the extent of the ultimate cellular thermosensitivity. Overall, we suggest that the fluidity variable of membranes should be used as an independent factor for predicting the efficacy of combinational cancer therapies.

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The central role of heat shock factor 1 in synaptic fidelity and memory consolidation

Hooper

Durham

Török

et al. 2016

Cell Stress and Chaperones

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Networks of neuronal synapses are the fundamental basis for making and retaining memory. Reduced synapse number and quality correlates with loss of memory in dementia. Heat shock factor 1 (HSF1), the major transcription factor regulating expression of heat shock genes, plays a central role in proteostasis, in establishing and sustaining synaptic fidelity and function, and in memory consolidation. Support for this thesis is based on these observations: (1) heat shock induces improvements in synapse integrity and memory consolidation; (2) synaptic depolarization activates HSF1; (3) activation of HSF1 alone (independent of the canonical heat shock response) augments formation of essential synaptic elementsneuroligands, vesicle transport, synaptic scaffolding proteins, lipid rafts, synaptic spines, and axodendritic synapses; (4) HSF1 coalesces and activates memory receptors in the postsynaptic dendritic spine; (5) huntingtin or α-synuclein accumulation lowers HSF1 while HSF1 lowers huntingtin and α-synuclein aggregation-a potential vicious cycle; and (6) HSF1 agonists (including physical activity) can improve cognitive function in dementia models. Thus, via direct gene expression of synaptic elements, production of HSPs that assure high protein fidelity, and activation of other neuroprotective signaling pathways, HSF1 agonists could provide breakthrough therapy for dementia-associated disease.

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Hydroximic Acid Derivatives: Pleiotropic Hsp Co-Inducers Restoring Homeostasis and Robustness

Cited by 16 publications

References 0 publications

The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

The central role of heat shock factor 1 in synaptic fidelity and memory consolidation

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