miRNA-based therapeutic potential of stem cell-derived extracellular vesicles: a safe cell-free treatment to ameliorate radiation-induced brain injury

Leavitt, Ron; Limoli, Charles L.; Baulch, Janet E.

doi:10.1080/09553002.2018.1522012

Cited by 37 publications

(35 citation statements)

References 104 publications

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“…Some experimental approaches, while difficult to translate into the clinic, have shown promising results 20-22 , but approved clinical treatment options for preventing the late sequelae of cerebral radiotherapy are few and are mostly limited to radiation treatment volume reduction 23 or sparing of critical brain structures from irradiation 24 . Previous pharmacological radioprotection studies using e.g.…”

Section: Introductionmentioning

confidence: 99%

1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine Treatment After Brain Irradiation Preserves Cognitive Function in Mice

Bhat

Medina

et al. 2020

Preprint

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AbstractBackgroundNormal tissue toxicity to the CNS is an inevitable consequence of a successful radiotherapy of brain tumors or cancer metastases to the CNS. Cranial irradiation commonly leads to neurocognitive deficits that manifest months or years after treatment. Mechanistically, radiation-induced loss of neural stem/progenitor cells, neuro-inflammation and de-myelinization are contributing factors that lead to progressive cognitive decline.MethodsThe effects of Compound #5 on irradiated murine neurospheres, microglia cells and patients-derived gliomaspheres were assessed in sphere-formation assays, flow cytometry and IL-6 ELISAs, Activation of the Hedgehog pathway was studied by qRT-PCR. The in vivo effects of Compound #5 were analyzed using flow cytometry, sphere-formation assays, immune-histochemistry, behavioral testing and an intracranial mouse model of glioblastoma.ResultsWe report that 1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine (Compound #5) mitigates radiation-induced normal tissue toxicity in the brains of mice. Compound #5 treatment significantly increased the number of neural stem/progenitor cells after brain irradiation in female animals, inhibited radiation-induced microglia activation and expression of the pro-inflammatory cytokine interleukin-6. Behavioral testing revealed that treatment with Compound #5 after radiotherapy successfully mitigates radiation-induced decline in motor, sensory and memory function of the brain. In mouse models of glioblastoma, Compound #5 showed no toxicity and did not interfere with the growth-delaying effects of radiation.ConclusionsWe conclude that Compound #5 has the potential to mitigate cognitive decline in patients undergoing partial or whole brain irradiation without promoting tumor growth and that the use of this compound as a radiation mitigator of radiation late effects on the CNS warrants further investigation.Importance of the StudySuccessful radiotherapy of CNS malignancies inevitably lead to cognitive decline in cancer survivors and treatment options to mitigate this side effect are limited. We present evidence that a piperazine compound can prevent cognitive decline in mice after total brain irradiation without compromising the antitumor effect of radiation, suggesting that this compound could be used to mitigate radiation side effects in brain tumor patients undergoing radiotherapy.

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Section: Introductionmentioning

confidence: 99%

1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine Treatment After Brain Irradiation Preserves Cognitive Function in Mice

Bhat

Medina

et al. 2020

Preprint

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“…The composition of exosomes is influenced by a variety of factors, especially dependent on the origin of the cells from which they are released [22]. Depending on the nature of exosomes, they may have many roles in different physiological and pathological settings, with beneficial or detrimental activity [23,24].Exosomes have emerged as important mediators of intercellular communication with the ability to shuttle bioactive molecules (e.g., microRNAs [miRNAs] and proteins) between neighboring and distant cells, modulating the biological activities such as immune response, cell proliferation, and cell signaling pathways of the recipient cells. In this review, we highlight the role of exosomes in intercellular signaling in the nervous system and discuss the existing evidence on the relationships of exosomes in cancer-related symptoms, with a focus on CRCI and its potential value in CRCI research.…”

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confidence: 99%

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confidence: 99%

Role of Exosomes in Cancer-Related Cognitive Impairment

Koh

Tan

Toh

et al. 2020

IJMS

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A decline in cognitive function following cancer treatment is one of the most commonly reported post-treatment symptoms among patients with cancer and those in remission, and include memory, processing speed, and executive function. A clear understanding of cognitive impairment as a result of cancer and its therapy can be obtained by delineating structural and functional changes using brain imaging studies and neurocognitive assessments. There is also a need to determine the underlying mechanisms and pathways that impact the brain and affect cognitive functioning in cancer survivors. Exosomes are small cell-derived vesicles formed by the inward budding of multivesicular bodies, and are released into the extracellular environment via an exocytic pathway. Growing evidence suggests that exosomes contribute to various physiological and pathological conditions, including neurological processes such as synaptic plasticity, neuronal stress response, cell-to-cell communication, and neurogenesis. In this review, we summarize the relationship between exosomes and cancer-related cognitive impairment. Unraveling exosomes' actions and effects on the microenvironment of the brain, which impacts cognitive functioning, is critical for the development of exosome-based therapeutics for cancer-related cognitive impairment.Int. J. Mol. Sci. 2020, 21, 2755 2 of 16 attention, learning, and executive function [10]. CRCI adversely affects cancer patients and survivors, causing distress and reduced quality of life, and impacts many facets of their daily lives [11]. CRCI is complicated by many factors including the direct effects of cancer, genetic predisposition (e.g., carrier of apolipoprotein E type epsilon 4 allele [12] and brain-derived neurotrophic factor Met allele [13]), comorbidities independent of the actual disease, and/or treatments or combinations of treatments administered for the disease [14].Efforts to better understand cancer-and cancer-therapy-associated cognitive impairment have relied on methods ranging from cognitive functioning assessment to imaging technologies on brain structure and function (e.g., magnetic resonance imaging scan). However, these approaches may be limited to help us understand the etiology and pathophysiology of cognitive dysfunction. The emerging application of the use of liquid biopsies (e.g., plasma and cerebrospinal fluid) as a strategy for biomarker discovery to detect, assess and monitor CRCI is fast-expanding and evolving [15,16]. In published literature, studies have revealed that genetics and neurobiological and immunological mechanisms may be involved in the biogenesis and development of CRCI. Preclinical studies have also provided insights into the pathophysiological mechanisms underlying CRCI, including neurotoxicity and inflammatory factors, which were shown to be responsible for CRCI [17]. Nevertheless, the underlying mechanisms of CRCI have yet to be established. While the role of exosomes in cancer has been well-documented [18][19][20], the role of cancer exosomes and their ability ...

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“…Many studies have shown that MVs delivering miRNAs are involved in the occurrence and development of many diseases . As a strategy to alter the type and quantity of extracellular miRNAs to gain therapeutic advantage, specific miRNAs or their inhibitors can be added to specific MVs . Future studies may focus on tailored recombinant MVs with unique cassettes of miRNAs for therapeutic benefits …”

Section: Existing Problems Of Mvs and The Clinical Prospectsmentioning

confidence: 99%

“…131,138,139 As a strategy to alter the type and quantity of extracellular miRNAs to gain therapeutic advantage, specific miRNAs or their inhibitors can be added to specific MVs. 140 Future studies may focus on tailored recombinant MVs with unique cassettes of miRNAs for therapeutic benefits. 141…”

Section: The Clinical Prospect Of Mvsmentioning

confidence: 99%

The role of microvesicles containing microRNAs in vascular endothelial dysfunction

Shu

Tan

Miao

et al. 2019

J Cellular Molecular Medi

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Many studies have shown that endothelial dysfunction is associated with a variety of cardiovascular diseases. The endothelium is one of the primary targets of circulating microvesicles. Besides, microRNAs emerge as important regulators of endothelial cell function. As a delivery system of microRNAs, microvesicles play an active and important role in regulating vascular endothelial function. In recent years, some studies have shown that microvesicles containing microRNAs regulate the pathophysiological changes in vascular endothelium, such as cell apoptosis, proliferation, migration and inflammation. These studies have provided some clues for the possible roles of microvesicles and microRNAs in vascular endothelial dysfunction‐associated diseases, and opened the door towards discovering potential novel therapeutic targets. In this review, we provide an overview of the main characteristics of microvesicles and microRNAs, summarizing their potential role and mechanism in endothelial dysfunction, and discussing the clinical application and existing problems of microvesicles for better translational applications.

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miRNA-based therapeutic potential of stem cell-derived extracellular vesicles: a safe cell-free treatment to ameliorate radiation-induced brain injury

Cited by 37 publications

References 104 publications

1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine Treatment After Brain Irradiation Preserves Cognitive Function in Mice

1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine Treatment After Brain Irradiation Preserves Cognitive Function in Mice

Role of Exosomes in Cancer-Related Cognitive Impairment

The role of microvesicles containing microRNAs in vascular endothelial dysfunction

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