Autophagic down-regulation in motor neurons remarkably prolongs the survival of ALS mice

Hsueh, Kuo Wei; Chiou, Tzyy Wen; Chiang, Shu‐Fen; Yamashita, Toru; Abe, Kōji; Borlongan, Cesar V.; Sanberg, Paul R.; Huang, Angelayu Hsuan; Lin, Shinn Zong; Harn, Horng Jyh

doi:10.1016/j.neuropharm.2016.03.035

Cited by 47 publications

(35 citation statements)

References 22 publications

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“…BP has been reported to prolong the survival of ALS mice by down-regulating autophagy and upregulating mTOR expression [26]. Combining bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) with two main components of Radix Angelica Sinensis, BP and sodium ferulate (SF), contribute to angiogenesis after cerebral ischemia which is associated with AKT/mTOR signaling activation [27].…”

Section: Discussionmentioning

confidence: 99%

Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition

Liao

Chiu

Huang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Radix Angelica Sinensis (danggui in Chinese) is widely used in traditional chinese medicine (TCM). N-butylidenephthalide (BP), a bioactive compound in danggui, is a potential antitumor agent for various cancer types. However, its clinical effect and mechanism in the treatment of gastric cancer remain undetermined. Methods: The in vivo protective effect of danggui in patients with gastric cancer were validated using data from Taiwan’s National Health Insurance Research Database (NHIRD). The genes induced by BP-treatment were analyzed by whole transcriptome RNA sequencing (RNA-seq) and validated by real-time PCR, western blot and siRNA transfection. The effect of BP on AGS cell migration and invasion was evaluated in transwell assays. The antitumor effects of BP were evaluated in vivo in an AGS xenograft animal model. Results: Danggui users were found to have an increased survival rate when compared with danggui nonusers (log-rank test p = 0.002) . The use of danggui highly associated with decreased mortality (the adjusted hazard ratio (HR) of danggui user was 0.72 [95 % CI, 0.57-0.92] (p = 0.009). The in vitro results showed that BP inhibited gastric cancer cell proliferation, and triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Using RNA-seq analysis we found that REDD1 was the highest transcript induced by BP in gastric cancer cells. BP induce an increase of REDD1 expression that inhibits mTOR signaling, thus inhibiting gastric cancer growth. We used RNA interference to demonstrate that the knock-down of REDD1 attenuated the BP-induced mTORC1 activation and growth inhibition. BP suppressed the growth of AGS xenografts tumor in vivo. Conclusion: Danggui can prolong the survival rate of gastric cancer patients in Taiwan. BP caused gastric cancer cell death through the activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in gastric cancer cells. BP inhibited the in vivo growth of AGS xenograft tumors. These results may provide the basis for a new therapeutic approach toward the treatment of gastric cancer progression.

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Section: Discussionmentioning

confidence: 99%

Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition

Liao

Chiu

Huang

et al. 2018

Cell Physiol Biochem

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“…For instance, progesterone or trehalose have shown therapeutic efficacy in ALS models by activating autophagy but, on the other hand, a recent paper has demonstrated a remarkable increase in mice life span by down-regulating autophagy in motor neurons with n -butylidenephthalide [43]. In addition, rapamycin and lithium both enhancing autophagy have failed to ameliorate ALS disease [22, 30]; hence, the precise role of autophagy in ALS is still to be resolved.…”

Section: Discussionmentioning

confidence: 99%

Actions of the antihistaminergic clemastine on presymptomatic SOD1-G93A mice ameliorate ALS disease progression

Apolloni

Fabbrizio

Amadio

et al. 2016

J Neuroinflammation

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BackgroundAmyotrophic lateral sclerosis (ALS) is a disease with a strong neuroinflammatory component sustained by activated microglia contributing to motoneuron death. However, how to successfully balance neuroprotective versus neurotoxic actions by the use of antinflammatory agents is still under scrutiny. We have recently shown that the antihistamine clemastine, an FDA-approved drug, can influence the M1/M2 switch occurring in SOD1-G93A ALS microglia.MethodsHere, we have chronically treated female SOD1-G93A mice with clemastine, evaluated disease progression and performed mice lumbar spinal cord analysis at symptomatic and end stage of the disease. Moreover, we have studied the mechanism of action of clemastine in primary adult spinal SOD1-G93A microglia cultures and in NSC-G93A motor neuron-like cells.ResultsWe found that a short treatment with clemastine (50 mg/kg) from asymptomatic (postnatal day 40) to symptomatic phase (postnatal day 120) significantly delayed disease onset and extended the survival of SOD1-G93A mice by about 10 %. Under these conditions, clemastine induced protection of motor neurons, modulation of inflammatory parameters, reduction of SOD1 protein levels and SQSTM1/p62 autophagic marker, when analysed immediately at the end of the treatment (postnatal day 120). A long treatment with clemastine (from asymptomatic until the end stage) instead failed to ameliorate ALS disease progression. At the end stage of the disease, we found that clemastine short treatment decreased microgliosis and SOD1 protein and increased LC3-II autophagic marker, while the long treatment produced opposite effects. Finally, in spinal microglia cultures from symptomatic SOD1-G93A mice clemastine activated inflammatory parameters, stimulated autophagic flux via the mTOR signalling pathway and decreased SOD1 levels. Modulation of autophagy was also demonstrated in NSC34 SOD1-G93A motor neuron-like cells.ConclusionsBy gaining insights into the ameliorating actions of an antihistaminergic compound in ALS disease, our findings might represent an exploitable therapeutic approach for familial forms of ALS.

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“…Although key details remain to be addressed, autophagy is co-substantial to skeletal muscle maintenance and adaptation and has already been targeted to ameliorate disease (Raben et al 2010; Carmignac et al 2011; Grumati et al 2010, 2011 Bhuiyan et al 2013; Cabet et al 2015; Chrisam et al 2015; Hidvegi et al 2015; Hsueh et al 2016; Whitehead et al 2015; Foltz et al 2016). A greater understanding of tension-induced autophagy systems may help to elucidate connections between protein unfolding and mTOR-dependent or mTOR-independent hypertrophic responses.…”

Section: Discussionmentioning

confidence: 99%

Disrupted autophagy undermines skeletal muscle adaptation and integrity

Jokl

Blanco

2016

Mamm Genome

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This review assesses the importance of proteostasis in skeletal muscle maintenance with a specific emphasis on autophagy. Skeletal muscle appears to be particularly vulnerable to genetic defects in basal and induced autophagy, indicating that autophagy is co-substantial to skeletal muscle maintenance and adaptation. We discuss emerging evidence that tension-induced protein unfolding may act as a direct link between mechanical stress and autophagic pathways. Mechanistic links between protein damage, autophagy and muscle hypertrophy, which is also induced by mechanical stress, are still poorly understood. However, some mouse models of muscle disease show ameliorated symptoms upon effective targeting of basal autophagy. These findings highlight the importance of autophagy as therapeutic target and suggest that elucidating connections between protein unfolding and mTOR-dependent or mTOR-independent hypertrophic responses is likely to reveal specific therapeutic windows for the treatment of muscle wasting disorders.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-016-9659-2) contains supplementary material, which is available to authorized users.

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Autophagic down-regulation in motor neurons remarkably prolongs the survival of ALS mice

Cited by 47 publications

References 22 publications

Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition

Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition

Actions of the antihistaminergic clemastine on presymptomatic SOD1-G93A mice ameliorate ALS disease progression

Disrupted autophagy undermines skeletal muscle adaptation and integrity

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