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1.
FASEB J ; 38(9): e23654, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38717442

RESUMO

Heart failure and cardiac remodeling are both characterized by mitochondrial dysfunction. Healthy mitochondria are required for adequate contractile activity and appropriate regulation of cell survival. In the mammalian heart, enhancement of the mitochondrial unfolded protein response (UPRmt) is cardioprotective under pressure overload conditions. We explored the UPRmt and the underlying regulatory mechanism in terms of hypertension-induced cardiac remodeling and the cardioprotective effect of metformin. Male spontaneously hypertensive rats and angiotensin II-treated neonatal rat cardiomyocytes were used to induce cardiac hypertrophy. The results showed that hypertension induced the formation of aberrant mitochondria, characterized by a reduced mtDNA/nDNA ratio and swelling, as well as lower levels of mitochondrial complexes I to V and inhibition of the expression of one protein subunit of each of complexes I to IV. Such changes eventually enlarged cardiomyocytes and increased cardiac fibrosis. Metformin treatment increased the mtDNA/nDNA ratio and regulated the UPRmt, as indicated by increased expression of activating transcription factor 5, Lon protease 1, and heat shock protein 60, and decreased expression of C/EBP homologous protein. Thus, metformin improved mitochondrial ultrastructure and function in spontaneously hypertensive rats. In vitro analyses revealed that metformin reduced the high levels of angiotensin II-induced mitochondrial reactive oxygen species in such animals and stimulated nuclear translocation of heat shock factor 1 (HSF1). Moreover, HSF1 small-interfering RNA reduced the metformin-mediated improvements in mitochondrial morphology and the UPRmt by suppressing hypertrophic signals and cardiomyocyte apoptosis. These results suggest that HSF1/UPRmt signaling contributes to the beneficial effects of metformin. Metformin-mediated targeting of mitochondrial protein homeostasis and modulation of HSF1 levels have potential therapeutic implications in terms of cardiac remodeling.


Assuntos
Fatores de Transcrição de Choque Térmico , Metformina , Miócitos Cardíacos , Resposta a Proteínas não Dobradas , Animais , Masculino , Ratos , Angiotensina II/farmacologia , Cardiomegalia/metabolismo , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Fatores de Transcrição de Choque Térmico/efeitos dos fármacos , Fatores de Transcrição de Choque Térmico/metabolismo , Hipertensão/metabolismo , Hipertensão/tratamento farmacológico , Metformina/farmacologia , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
2.
Addict Biol ; 26(2): e12939, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32720424

RESUMO

Ethanol consumption impairs learning and memory through disturbances of NMDA-type glutamate receptor-dependent synaptic plasticity (long-term depression [LTD] and long-term potentiation [LTP]) in the hippocampus. Recently, we demonstrated that two ethanol binge-like episodes in young adult rats selectively blocked NMDA-LTD in hippocampal slices, increased NMDA receptor sensitivity to a GluN2B subunit antagonist, and induced cognitive deficits. Here, using knockout adult mice, we show that a stress-responsive transcription factor of the heat shock factor family, HSF2, which is involved in the perturbation of brain development induced by ethanol, participates in these processes. In the absence of ethanol, hsf2-/- mice show a selective loss of LTD in the hippocampus, which is associated with an increased sensitivity of NMDA-field excitatory postsynaptic potentials (fEPSPs) to a GluN2B antagonist, compared with wild-type (WT) mice. These results suggest that HSF2 is required for proper glutamatergic synaptic transmission and LTD plasticity. After 1 month of chronic ethanol consumption in a two-bottle choice paradigm, WT mice showed an increase in hippocampal synaptic transmission, an enhanced sensitivity to GluN2B antagonist, and a blockade of LTD. In contrast, such modulation of synaptic transmission and plasticity were absent in hsf2-/- mice. We conclude that HSF2 is an important mediator of both glutamatergic neurotransmission and synaptic plasticity in basal conditions and also mediates ethanol-induced neuroadaptations of the hippocampus network after chronic ethanol intake.


Assuntos
Etanol/farmacologia , Fatores de Transcrição de Choque Térmico/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , N-Metilaspartato/efeitos dos fármacos , Adolescente , Adulto , Fatores Etários , Animais , Hipocampo/efeitos dos fármacos , Humanos , Camundongos
3.
Biosci Rep ; 40(3)2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32110802

RESUMO

Heat shock factor 1 (HSF1) is a powerful multifaceted oncogenic modifier that plays a role in maintaining the protein balance of cancer cells under various stresses. In recent studies, there have been reports of increased expression of HSF1 in colorectal cancer (CRC) cells, and the depletion of the HSF1 gene knockdown has inhibited colon cancer growth both in vivo and in vitro. Therefore, HSF1 is a promising target for colon cancer treatment and chemoprevention. In the present study, we found that Schizandrin A (Sch A) significantly inhibited the growth of CRC cell lines by inducing cell cycle arrest, apoptosis and death. Through HSE luciferase reporter assay and quantitative PCR (qPCR), we identified Sch A as a novel HSF1 inhibitor. In addition, Sch A could effectively inhibit the induction of HSF1 target proteins such as heat-shock protein (HSP) 70 (HSP70) and HSP27, whether in heat shock or normal temperature culture. In the Surface Plasmon Resonance (SPR) experiment, Sch A showed moderate affinity with HSF1, further confirming that Sch A might be a direct HSF1 inhibitor. The molecular docking and molecular dynamic simulation results of HSF1/Sch A suggested that Sch A formed key hydrogen bond and hydrophobic interactions with HSF1, which may contribute to its potent HSF1 inhibition. These findings provide clues for the design of novel HSF1 inhibitors and drug candidates for colon cancer treatment.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Ciclo-Octanos/farmacologia , Fatores de Transcrição de Choque Térmico/metabolismo , Lignanas/farmacologia , Compostos Policíclicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , China , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Ciclo-Octanos/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP70/genética , Fatores de Transcrição de Choque Térmico/efeitos dos fármacos , Fatores de Transcrição de Choque Térmico/genética , Humanos , Lignanas/metabolismo , Simulação de Acoplamento Molecular , Compostos Policíclicos/metabolismo , Fatores de Transcrição/genética
4.
Auris Nasus Larynx ; 45(4): 680-685, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29042071

RESUMO

OBJECTIVE: The objective of this study was to investigate the influence of Ginkgo Biloba in early treatment of noise induced hearing loss on expression of IL-6, IL-1 Beta, TNF-alfa, HSP-70, HSF-1 and COX-2 in the rat cochlea. METHODS: Thirty two female rats were randomly divided into four groups (Acoustic Trauma, Ginkgo Biloba, Acoustic Trauma+Ginkgo Biloba, Non Treatment). Auditory brainstem response (ABR) was applied in all the groups. At the end of the study, IL-1Beta, IL-6, TNF-alpha, HSP-70, HSF-1 and COX-2 were studied in cochlear tissue with ELISA and Western blot analysis. RESULTS: There were significant increases in ABR values measured at days 1 and 7 compared to baseline values in Group 3. IL-1 Beta, IL-6 and TNF-alpha values were significantly higher in Group 1 than in the other groups. Whereas HSP-70 and HSF-1 values were found to be significantly lower in Group 1 compared to those in Group 2 and Group 3. COX-2 of Group 1 was significantly higher than the other groups. CONCLUSION: Ginkgo Biloba is helpful in the treatment of noise induced hearing loss and exerts its effect by inhibiting expression of IL-1 Beta, IL-6, TNF-alpha and COX-2 and increasing HSP-70 and HSF-1 values in rat cochlea.


Assuntos
Cóclea/efeitos dos fármacos , Ciclo-Oxigenase 2/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/efeitos dos fármacos , Fatores de Transcrição de Choque Térmico/efeitos dos fármacos , Ruído , Extratos Vegetais/farmacologia , Animais , Western Blotting , Cóclea/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Ginkgo biloba , Proteínas de Choque Térmico HSP70/metabolismo , Perda Auditiva Provocada por Ruído/metabolismo , Perda Auditiva Provocada por Ruído/fisiopatologia , Fatores de Transcrição de Choque Térmico/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Distribuição Aleatória , Ratos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
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