Nasal delivery of Fasudil‐modified immune cells exhibits therapeutic potential in experimental autoimmune encephalomyelitis

Guo, Shang-De; Liu, Chunyun; Yu, Jingwen; Chai, Zhi; Wang, Qing; Mi, Xi-Ting; Song, Guobin; Li, Yanhua; Yang, Peng-Wei; Li, Feng; Xiao, Bao‐Guo; Ma, Cun‐Gen

doi:10.1111/cns.13111

Cited by 12 publications

(5 citation statements)

References 60 publications

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“…It was indicated that endogenous and exogenous IL-10 could directly or indirectly inhibit the production of pro-inflammatory factors, such as IL-1β, and the proliferation of T cells, thus blocking elicitation of the immune response and reducing inflammatory damage in a severe colitis mouse model [ 3 ]. Subsequently, CD4 + IL-10 + T cells were shown to exert immunosuppressive effects in various disease models, such as inflammatory bowel disease (IBD) and experimental autoimmune encephalomyelitis (EAE) [ 4 , 5 ]. Our previous results showed that hPMSCs could alleviate GVHD symptoms by maintaining the balance of CD4 + IL-10 + T cells and Th17 subsets [ 6 ]; however, the specific mechanism by which hPMSCs regulate the generation of CD4 + IL-10 + T cells remains unclear.…”

Section: Introductionmentioning

confidence: 99%

hPMSCs inhibit the expression of PD-1 in CD4+IL-10+ T cells and mitigate liver damage in a GVHD mouse model by regulating the crosstalk between Nrf2 and NF-κB signaling pathway

Zhang

et al. 2021

Stem Cell Res Ther

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Background The activation of T cells and imbalanced redox metabolism enhances the development of graft-versus-host disease (GVHD). Human placenta-derived mesenchymal stromal cells (hPMSCs) can improve GVHD through regulating T cell responses. However, whether hPMSCs balance the redox metabolism of CD4+IL-10+ T cells and liver tissue and alleviate GVHD remains unclear. This study aimed to investigate the effect of hPMSC-mediated treatment of GVHD associated with CD4+IL-10+ T cell generation via control of redox metabolism and PD-1 expression and whether the Nrf2 and NF-κB signaling pathways were both involved in the process. Methods A GVHD mouse model was induced using 6–8-week-old C57BL/6 and Balb/c mice, which were treated with hPMSCs. In order to observe whether hPMSCs affect the generation of CD4+IL-10+ T cells via control of redox metabolism and PD-1 expression, a CD4+IL-10+ T cell culture system was induced using human naive CD4+ T cells. The percentage of CD4+IL-10+ T cells and their PD-1 expression levels were determined in vivo and in vitro using flow cytometry, and Nrf2, HO-1, NQO1, GCLC, GCLM, and NF-κB levels were determined by western blotting, qRT-PCR, and immunofluorescence, respectively. Hematoxylin-eosin, Masson’s trichrome, and periodic acid-Schiff staining methods were employed to analyze the changes in hepatic tissue. Results A decreased activity of superoxide dismutase (SOD) and a proportion of CD4+IL-10+ T cells with increased PD-1 expression were observed in GVHD patients and the mouse model. Treatment with hPMSCs increased SOD activity and GCL and GSH levels in the GVHD mouse model. The percentage of CD4+IL-10+ T cells with decreased PD-1 expression, as well as Nrf2, HO-1, NQO1, GCLC, and GCLM levels, both in the GVHD mouse model and in the process of CD4+IL-10+ T cell generation, were also increased, but NF-κB phosphorylation and nuclear translocation were inhibited after treatment with hPMSCs, which was accompanied by improvement of hepatic histopathological changes. Conclusions The findings suggested that hPMSC-mediated redox metabolism balance and decreased PD-1 expression in CD4+IL-10+ T cells were achieved by controlling the crosstalk between Nrf2 and NF-κB, which further provided evidence for the application of hPMSC-mediated treatment of GVHD.

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Section: Introductionmentioning

confidence: 99%

hPMSCs inhibit the expression of PD-1 in CD4+IL-10+ T cells and mitigate liver damage in a GVHD mouse model by regulating the crosstalk between Nrf2 and NF-κB signaling pathway

Zhang

et al. 2021

Stem Cell Res Ther

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“…126 Intranasal administration of the entire cells was also attempted with a reported moderate positive effect. [134][135][136] Indeed, cells can migrate in to the CNS after being administered by intranasal delivery. 135 Moreover, a couple of studies reported efficacy of the intranasal microvesicles therapy in a preclinical scenario.…”

Section: Intranasalmentioning

confidence: 99%

“…Production and release of EVs is one of the major modes of action of cells used in cell therapy 126 . Intranasal administration of the entire cells was also attempted with a reported moderate positive effect 134–136 . Indeed, cells can migrate in to the CNS after being administered by intranasal delivery 135 .…”

Section: Alternative Drug Delivery Strategiesmentioning

confidence: 99%

Reconsidering the route of drug delivery in refractory multiple sclerosis: Toward a more effective drug accumulation in the central nervous system

Kalkowski

Walczak

Mycko

et al. 2023

Medicinal Research Reviews

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Multiple sclerosis is a chronic demyelinating disease with different disease phenotypes. The current FDA‐approved disease‐modifying therapeutics (DMTs) cannot cure the disease, but only alleviate the disease progression. While the majority of patients respond well to treatment, some of them are suffering from rapid progression. Current drug delivery strategies include the oral, intravenous, subdermal, and intramuscular routes, so these drugs are delivered systemically, which is appropriate when the therapeutic targets are peripheral. However, the potential benefits may be diminished when these targets sequester behind the barriers of the central nervous system. Moreover, systemic drug administration is plagued with adverse effects, sometimes severe. In this context, it is prudent to consider other drug delivery strategies improving their accumulation in the brain, thus providing better prospects for patients with rapidly progressing disease course. These targeted drug delivery strategies may also reduce the severity of systemic adverse effects. Here, we discuss the possibilities and indications for reconsideration of drug delivery routes (especially for those “non‐responding” patients) and the search for alternative drug delivery strategies. More targeted drug delivery strategies sometimes require quite invasive procedures, but the potential therapeutic benefits and reduction of adverse effects could outweigh the risks. We characterized the major FDA‐approved DMTs focusing on their therapeutic mechanism and the potential benefits of improving the accumulation of these drugs in the brain.

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“…The Fasudil, a potent ROCK inhibitor has been approved for clinical use in Japan for the treatment of subarachnoid hemorrhage, and cerebral vasospasm. It was also shown to increase motor neuron survival, and inhibit axonal degeneration, enhances axonal regeneration, and modulates microglial function in vitro and in vivo (Bandarage et al, 2021;De et al, 2019;Koch et al, 2020;Mietzner et al, 2020;Román-Albasini et al, 2020;Tatenhorst et al, 2016;Wang et al, 2020;Zhao et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Design and development of novel fasudil derivatives as potent antibreast cancer agent that improves intestinal flora and intestinal barrier function in rats

et al. 2021

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This study was conducted to develop novel fasudil derivatives after incorporation of substituted thiazoles as potent anti-breast cancer (BC) agents. The compounds were developed using a facile synthetic route in excellent yields. The entire set of developed compounds was tested for inhibitory activity against rho-associated coiled-coil kinase (ROCK; ROCK1 and ROCK2) kinase, where they exhibit potent and selective inhibition of ROCK1 as compared to ROCK2. The most potent ROCK2 inhibitor, compound 6h significantly inhibited the viability of BC cells (MCF-7). It also causes inhibition of migration and invasion of MCF-7 cells.Moreover, the anti-BC activity of compound 6h was studied in 7,12 dimethyl Benz(a)anthracene (DMBA)-induced BC in female Sprague Dawley rats. Results suggest that it causes significant improvement in the bodyweight of the animals with a reduction in oxidative stress in the liver and mammary tissues of rats. It showed improvement in the intestinal barrier function of rats by restoring the level of Diamine oxidase, d-lactate, and endotoxin. In western blot analysis, it showed improvement in (ZO-1), occludin, and claudin-1 in the colon tissue of the rat as compared to the DMBA group. Our study demonstrated the development of the novel class of fasudil derivatives potent anti-BC agent that improves intestinal flora and intestinal barrier function in rats.

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Nasal delivery of Fasudil‐modified immune cells exhibits therapeutic potential in experimental autoimmune encephalomyelitis

Cited by 12 publications

References 60 publications

hPMSCs inhibit the expression of PD-1 in CD4+IL-10+ T cells and mitigate liver damage in a GVHD mouse model by regulating the crosstalk between Nrf2 and NF-κB signaling pathway

hPMSCs inhibit the expression of PD-1 in CD4+IL-10+ T cells and mitigate liver damage in a GVHD mouse model by regulating the crosstalk between Nrf2 and NF-κB signaling pathway

Reconsidering the route of drug delivery in refractory multiple sclerosis: Toward a more effective drug accumulation in the central nervous system

Design and development of novel fasudil derivatives as potent antibreast cancer agent that improves intestinal flora and intestinal barrier function in rats

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