Mitochondrial Dysfunction | Mitochondria and Disease

Autism - Sulforaphane
Sulforaphane induces Autophagy

http://www.ncbi.nlm.nih.gov/pubmed/24952354

FEBS Lett. 2014 Aug 25;588(17):3081-8. doi: 10.1016/j.febslet.2014.06.036. Epub 2014 Jun 18.

Sulforaphane induces autophagy through ERK activation in neuronal cells.

Jo C1, Kim S2, Cho SJ2, Choi KJ3, Yun SM2, Koh YH2, Johnson GV4, Park SI5.

Abstract

Sulforaphane (SFN), an activator of nuclear factor E2-related factor 2 (Nrf2), has been reported to induce autophagy in several cells. However, little is known about its signaling mechanism of autophagic induction.
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Here, we provide evidence that SFN induces autophagy with increased levels of LC3-II through extracellular signal-regulated kinase (ERK) activation in neuronal cells. Pretreatment with NAC (N-acetyl-l-cysteine), a well-known antioxidant, completely blocked the SFN-induced increase in LC3-II levels and activation of ERK. Knockdown or overexpression of Nrf2 did not affect autophagy.
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Together, the results suggest that SFN-mediated generation of reactive oxygen species (ROS) induces autophagy via ERK activation, independent of Nrf2 activity in neuronal cells.

http://www.ncbi.nlm.nih.gov/pubmed/26586127

Mini Rev Med Chem. 2015 Nov 19. [Epub ahead of print]

Hormetic potential of Sulforaphane (SFN) in switching cells' fate towards survival or death.

Pal S, Konkimalla VB1.

Abstract

Epidemiological evidences establish sulforaphane (SFN), a hormetic dietary isothiocyanate to be a promising chemopreventive, anti-inflammatory and anti-cancer agent. Beyond a concentration threshold SFN exerts pro-death activities (cell cycle arrest, epigenetic modifications and apoptosis) and below the threshold it either promotes pro-survival autophagy or remains latent. There is a significant lacuna in understanding the underpinning dynamic molecular networks that alternate the pharmacological responses with respect to the intracellular concentration and exposure time that renders SFN to be a characteristic hormetic molecule (display characteristic biphasic dose response curve).

Unraveling this multi-targeted SFN triggered molecular interplay between apoptosis and pro-survival autophagy may have great therapeutic implications. From the available literature, here we present a review that illustrates the existence of a hormetic window and briefly discussed its role in the spectrum of activity of SFN in different pathological conditions (cancer and immune-mediated diseases). Further, we hypothesize a hormetic signaling event on how SFN triggers mutually exclusive molecular pathways such as cell survival or death signals depending on its pathophysiological environment, exposure time and in vitro working concentrations.

By better understanding these altered events and underpinning mechanisms in different combinations such as concentrations and time a proper therapeutic can be designed.

http://www.ncbi.nlm.nih.gov/pubmed/26108801

Mol Nutr Food Res. 2015 Oct;59(10):1954-61.

Analysis of autophagic flux in response to sulforaphane in metastatic prostate cancer cells.

Watson GW1,2, Wickramasekara S3, Fang Y4, Palomera-Sanchez Z2, Maier CS3, Williams DE5,6, Dashwood RH7,8,9,10, Perez VI6,11, Ho E2,6.

Abstract

SCOPE:

The phytochemical sulforaphane (SF) has been shown to decrease prostate cancer metastases in a genetic mouse model of prostate carcinogenesis, though the mechanism of action is not fully known. SF has been reported to stimulate autophagy, and modulation of autophagy has been proposed to influence SF cytotoxicity; however, no conclusions about autophagy can be drawn without assessing autophagic flux, which has not been characterized in prostate cancer cells following SF treatment.

METHODS AND RESULTS:

We conducted an investigation to assess the impact of SF on autophagic flux in two metastatic prostate cancer cell lines at a concentration shown to decrease metastasis in vivo. Autophagic flux was assessed by multiple autophagy related proteins and substrates. We found that SF can stimulate autophagic flux and cell death only at high concentrations, above what has been observed in vivo.

CONCLUSION:

These results suggest that SF does not directly stimulate autophagy or cell death in metastatic prostate cancer cells under physiologically relevant conditions, but instead supports the involvement of in vivo factors as important effectors of SF-mediated prostate cancer suppression.

http://www.ncbi.nlm.nih.gov/pubmed/25130556

Neuroscience. 2014 Oct 10;278:31-9. doi: 10.1016/j.neuroscience.2014.07.072. Epub 2014 Aug 15.

Sulforaphane-induced autophagy flux prevents prion protein-mediated neurotoxicity through AMPK pathway.

Lee JH1, Jeong JK1, Park SY2.

Abstract

Prion diseases are neurodegenerative and infectious disorders that involve accumulation of misfolded scrapie prion protein, and which are characterized by spongiform degeneration. Autophagy, a major homeostatic process responsible for the degradation of cytoplasmic components, has garnered attention as the potential target for neurodegenerative diseases such as prion disease. We focused on protective effects of sulforaphane found in cruciferous vegetables on prion-mediated neurotoxicity and the mechanism of sulforaphane related to autophagy.

In human neuroblastoma cells, sulforaphane protected prion protein (PrP) (106-126)-mediated neurotoxicity and increased autophagy flux marker microtubule-associated protein 1 light chain 3-II protein levels, following a decrease of p62 protein level. Pharmacological and genetical inhibition of autophagy by 3MA, wortmannin and knockdown of autophagy-related 5 (ATG5) led to block the effect of sulforaphane against PrP (106-126)-induced neurotoxicity. Furthermore we demonstrated that both sulforaphane-induced autophagy and protective effect of sulforaphane against PrP (106-126)-induced neurotoxicity are dependent on the AMP-activated protein kinase (AMPK) signaling.

The present results indicated that sulforaphane of cruciferous vegetables enhanced autophagy flux led to the protection effects against prion-mediated neurotoxicity, which was regulated by AMPK signaling pathways in human neuron cells. Our data also suggest that sulforaphane has a potential value as a therapeutic tool in neurodegenerative disease including prion diseases.

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