Promising Strategy For Effective Treatment Research Articles

Implantation with SHED sheet induced with homogenate protein of spinal cord promotes functional recovery from spinal cord injury in rats.

Introduction: After spinal cord injury (SCI) occurs, the lesion is in a growth inhibitory microenvironment that severely hinders neural regeneration. In this microenvironment, inhibitory factors are predominant and factors that promote nerve regeneration are few. Improving neurotrophic factors in the microenvironment is the key to treating SCI. Methods: Based on cell sheet technology, we designed a bioactive material with a spinal cord-like structure -SHED sheet induced with homogenate protein of spinal cord (hp-SHED sheet). Hp-SHED sheet was implanted into the spinal cord lesion for treating SCI rats with SHED suspensions as a control to investigate the effects on nerve regeneration. Results: Hp-SHED sheet revealed a highly porous three-dimensional inner structure, which facilitates nerve cell attachment and migration. Hp-SHED sheet in vivo restored sensory and motor functions in SCI rats by promoting nerve regeneration, axonal remyelination, and inhibiting glial scarring. Discussion: Hp-SHED sheet maximally mimics the microenvironment of the natural spinal cord and facilitate cell survival and differentiation. Hp-SHED sheet could release more neurotrophins and the sustained action of neurotrophins improves the pathological microenvironment, which effectively promotes nerve regeneration, axonal extension, and inhibits glial scarring, thereby promoting the in situ centralis neuroplasticity. Hp-SHED sheet therapy is a promising strategy for effective treatment of SCI based on neurotrophins delivery.

Transplantation of Human Mesenchymal Stem-Cell-Derived Exosomes Immobilized in an Adhesive Hydrogel for Effective Treatment of Spinal Cord Injury.

Spinal cord injury is among the most fatal diseases. The complicated inhibitory microenvironment requires comprehensive mitigation. Exosomes derived from mesenchymal stem cells (MSCs) are natural biocarriers of cell paracrine secretions that bear the functions of microenvironment regulation. However, the effective retention, release, and integration of exosomes into the injured spinal cord tissue are poorly defined. Herein, an innovative implantation strategy is established using human MSC-derived exosomes immobilized in a peptide-modified adhesive hydrogel (Exo-pGel). Unlike systemic admistration of exosomes, topical transplantation of the Exo-pGel provides an exosome-encapsulated extracellular matrix to the injured nerve tissue, thereby inducing effecient comprehensive mitigation of the SCI microenvironment. The implanted exosomes exhibit efficient retention and sustained release in the host nerve tissues. The Exo-pGel elicits significant nerve recovery and urinary tissue preservation by effectively mitigating inflammation and oxidation. The Exo-pGel therapy presents a promising strategy for effective treatment of central nervous system diseases based on exosome implantation.

Multifunctional PEI-entrapped gold nanoparticles enable efficient delivery of therapeutic siRNA into glioblastoma cells.

RNA interference (RNAi) has been considered as a promising strategy for effective treatment of cancer. However, the easy degradation of small interfering RNA (siRNA) limits its extensive applications in gene therapy. For safe and effective delivery of siRNA, a novel vector system possessing excellent biocompatibility, highly efficient transfection efficiency and specific targeting properties has to be considered. In this study, we report the use of polyethyleneimine (PEI)-entrapped gold nanoparticles (Au PENPs) modified with an arginine-glycine-aspartic (Arg-Gly-Asp, RGD) peptide via a poly(ethylene glycol) (PEG) spacer as a vector for Bcl-2 (B-cell lymphoma-2) siRNA delivery to glioblastoma cells. The synthesized Au PENPs were well characterized. The efficiency of siRNA delivery was appraised by flow cytometry, confocal microscopy imaging, and the protein expression level. Our results revealed that the Au PENPs were capable of delivering Bcl-2 siRNA to glioblastoma cells with an excellent transfection efficiency, leading to specific gene silencing in the target cells (22% and 25.5% Bcl-2 protein expression in vitro and in vivo, respectively) thanks to the RGD peptide-mediated targeting pathway. The designed RGD-targeted Au PENPs may hold great promise to be used as a novel vector for specific cancer gene therapy applications.

Abstract 112: FTY720-P is a potent inhibitor of class I histone deacetylases that enhances histone acetylation, reactivates ERα expression, and increases hormonal therapeutic sensitivity of breast cancer

Abstract Hormonal therapies, including ovarian ablation, ER antagonists, and aromatase inhibitors, are the standards of care for treatment of ERα positive breast cancer. However, development of resistance to hormone therapies in advanced breast cancer is a major obstacle. Moreover, estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and does not respond to conventional estrogen targeted therapies. Strategies that lead to re-expression of ERα could sensitize breast cancers to selective ER modulators. FTY720/Fingolimod, a sphingosine analog, is an FDA-approved pro-drug for treatment of multiple sclerosis that also has anticancer actions that are not yet well understood. We have now found that FTY720 is phosphorylated in breast cancer cells by nuclear sphingosine kinase 2 and accumulates there. Nuclear FTY720-P in turn is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and gene expression independently of its known effects on canonical signaling through sphingosine-1-phosphate receptors. In ERα negative human and murine breast cancer cells, FTY720 reactivated expression of silenced ERα and sensitized them to tamoxifen. Moreover, oral administration of clinically relevant doses of FTY720 to mice bearing ERα negative syngeneic breast tumors also re-expressed ERα and increased therapeutic sensitivity to tamoxifen in vivo more potently than a known HDAC inhibitor. Our work suggests that FTY720 is a promising strategy for effective treatment of conventional hormonal therapy-resistant breast cancer and triple-negative breast cancer. Supported by NIH grant RO1CA061774 and the Department of Defense BCRP program award W81XWH-14-1-0086 (S. Spiegel). Citation Format: Nitai C. Hait, Dorit Avni, Akimitsu Yamada, Sheldon Milstien, Kazuaki Takabe, Sarah Spiegel. FTY720-P is a potent inhibitor of class I histone deacetylases that enhances histone acetylation, reactivates ERα expression, and increases hormonal therapeutic sensitivity of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 112. doi:10.1158/1538-7445.AM2015-112

Activation of NK1 receptors in the locus coeruleus induces analgesia through noradrenergic‐mediated descending inhibition in a rat model of neuropathic pain

The locus coeruleus (LC) is a major source of noradrenergic projections to the dorsal spinal cord, and thereby plays an important role in the modulation of nociceptive information. The LC receives inputs from substance P (SP)-containing fibres from other regions, and expresses the NK(1) tachykinin receptor, a functional receptor for SP. In the present study, we investigated the roles of SP in the LC in neuropathic pain. Chronic constriction injury (CCI) of the left sciatic nerve was performed in rats to induce neuropathic pain. After development of neuropathic pain, SP was injected into the LC and the nocifensive behaviours were assessed. The involvement of noradrenergic descending inhibition in SP-induced analgesia was examined by i.t. administration of yohimbine, an α(2) -adrenoceptor antagonist. NK(1) receptor expression in the LC was examined by immunohistochemistry. In CCI rats, mechanical allodynia was alleviated by SP injection into the LC. These effects were abolished by prior injection of WIN 51708, an NK(1) receptor antagonist, into the LC or i.t. treatment with yohimbine. NK(1) receptor-like immunoreactivity was observed in noradrenergic neurons throughout the LC in intact rats, and remained unchanged after CCI. SP in the LC exerted analgesic effects on neuropathic pain through NK(1) receptor activation and resulted in facilitation of spinal noradrenergic transmission. Accordingly, manipulation of the SP/NK(1) receptor signalling pathway in the LC may be a promising strategy for effective treatment of neuropathic pain.