Cell-penetrating artificial mitochondria-targeting peptide-conjugated metallothionein 1A alleviates mitochondrial damage in Parkinson’s disease models

Kang, Yuna; Son, Minuk; Kang, Sung Un; Im, Suyeol; Piao, Ying; Lim, Kyutae; Song, Min Young; Park, Kang Sik; Kim, Yong Hee; Pak, Youngmi Kim

doi:10.1038/s12276-018-0124-z

Cited by 50 publications

(31 citation statements)

References 51 publications

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“…Moreover, two metallothionein genes, MT1A and MT1X, presented higher expression in progressive MS CP than in control CP. Metallothioneins are antioxidant metal binding molecules recently explored as therapeutic agents [31]. The increased MT1X expression in progressive MS CP may be caused by hypoxia [68,75], or by the higher copper levels present in the CSF of MS patients relative to healthy subjects [50].…”

Section: Discussionmentioning

confidence: 99%

Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis

Rodríguez‐Lorenzo

Francisco

Vos

et al. 2020

acta neuropathol commun

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The choroid plexus (CP) is a key regulator of the central nervous system (CNS) homeostasis through its secretory, immunological and barrier properties. Accumulating evidence suggests that the CP plays a pivotal role in the pathogenesis of multiple sclerosis (MS), but the underlying mechanisms remain largely elusive. To get a comprehensive view on the role of the CP in MS, we studied transcriptomic alterations of the human CP in progressive MS and non-neurological disease controls using RNA sequencing. We identified 17 genes with significantly higher expression in progressive MS patients relative to that in controls. Among them is the newly described long non-coding RNA HIF1A-AS3. Next to that, we uncovered disease-affected pathways related to hypoxia, secretion and neuroprotection, while only subtle immunological and no barrier alterations were observed. In an ex vivo CP explant model, a subset of the upregulated genes responded in a similar way to hypoxic conditions. Our results suggest a deregulation of the Hypoxia-Inducible Factor (HIF)-1 pathway in progressive MS CP. Importantly, cerebrospinal fluid levels of the hypoxia-responsive secreted peptide PAI-1 were higher in MS patients with high disability relative to those with low disability. These findings provide for the first time a complete overview of the CP transcriptome in health and disease, and suggest that the CP environment becomes hypoxic in progressive MS patients, highlighting the altered secretory and neuroprotective properties of the CP under neuropathological conditions. Together, these findings provide novel insights to target the CP and promote the secretion of neuroprotective factors into the CNS of progressive MS patients.

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Section: Discussionmentioning

confidence: 99%

Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis

Rodríguez‐Lorenzo

Francisco

Vos

et al. 2020

acta neuropathol commun

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“…CPPs were effective tools for drug brain delivery against Parkinson's disease. Kang et al synthesized a fusion CPP using TAT and mitochondria-targeting sequence (YGRKKRRQRRR LLRAALR-KAAL) named CAMP, and used it to deliver the antioxidant protein human metallothionein 1A (hMT1A) into mitochondria to target ROS damage for preventing Parkinson's disease (Kang et al, 2018). CAMP-hMT1A could effectively rescue movement impairment in a mouse model of Parkinson's disease.…”

Section: Application Of Cpps In Central Nervous System Disordersmentioning

confidence: 99%

“…These results show that mtCPP-1 is a mitochondrial CPP. Kang et al (2018) developed a cellpenetrating artificial mitochondria-targeting peptide (CAMP), which could conjugate the antioxidant protein human metallothionein 1A (hMT1A) to form CAMP-hMT1A successfully localized to the mitochondria. CAMP-hMT1A restored mitochondrial activity, tyrosine hydroxylase production, and inhibited ROS release after treating a cell Parkinson's disease model.…”

Section: Organelle-specific Delivery: Mitochondrial Deliverymentioning

confidence: 99%

Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application

et al. 2020

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Cell-penetrating peptides (CPPs) are short peptides (fewer than 30 amino acids) that have been predominantly used in basic and preclinical research during the last 30 years. Since they are not only capable of translocating themselves into cells but also facilitate drug or CPP/cargo complexes to translocate across the plasma membrane, they have potential applications in the disease diagnosis and therapy, including cancer, inflammation, central nervous system disorders, otologic and ocular disorders, and diabetes. However, no CPPs or CPP/cargo complexes have been approved by the US Food and Drug Administration (FDA). Many issues should be addressed before translating CPPs into clinics. In this review, we summarize recent developments and innovations in preclinical studies and clinical trials based on using CPP for improved delivery, which have revealed that CPPs or CPP-based delivery systems present outstanding diagnostic therapeutic delivery potential.

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“… 93 MPPs have been confirmed to delocalize lipophilic cations to deliver bioactive compounds to the Mc. 94–97 MPPs usually have positively charged (lysine, arginine) and lipophilic (isoleucine, phenylalanine, tyrosine) amino acids. 98 , 99 For example, the aromatic cation-containing Szeto-Schiller (SS) peptide 100 was mainly designed to deliver tyrosine or dimethyl tyrosine as an antioxidant motif to the Mc.…”

Section: Targeting Characteristics Of St-mc-ddssmentioning

confidence: 99%

Smart Stimuli-Responsive and Mitochondria Targeting Delivery in Cancer Therapy

Huang

Wang

Tan

et al. 2021

IJN

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Dysfunction in the mitochondria (Mc) contributes to tumor progression. It is a major challenge to deliver therapeutic agents specifically to the Mc for precise treatment. Smart drug delivery systems are based on stimuli-responsiveness and active targeting. Here, we give a whole list of documented pathways to achieve smart stimuli-responsive (St-) and Mc-targeted DDSs (St-Mc-DDSs) by combining St and Mc targeting strategies. We present the formulations, targeting characteristics of St-Mc-DDSs and clarify their anti-cancer mechanisms as well as improvement in efficacy and safety. St-Mc-DDSs usually not only have Mc-targeting groups, molecules (lipophilic cations, peptides, and aptamers) or materials but also sense the surrounding environment and correspondingly respond to internal biostimulators such as pH, redox changes, enzyme and glucose, and/or externally applied triggers such as light, magnet, temperature and ultrasound. St-Mc-DDSs exquisitely control the action site, increase therapeutic efficacy and decrease side effects of the drug. We summarize the clinical research progress and propose suggestions for follow-up research. St-Mc-DDSs may be an innovative and sensitive precision medicine for cancer treatment.

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Cell-penetrating artificial mitochondria-targeting peptide-conjugated metallothionein 1A alleviates mitochondrial damage in Parkinson’s disease models

Cited by 50 publications

References 51 publications

Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis

Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis

Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application

Smart Stimuli-Responsive and Mitochondria Targeting Delivery in Cancer Therapy

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