Strategies to neutralize RhoA/ROCK pathway after spinal cord injury

Roy, Abhishek; Pathak, Zarna; Kumar, Hemant

doi:10.1016/j.expneurol.2021.113794

Cited by 17 publications

(18 citation statements)

References 144 publications

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“…Differentially expressed genes with vital biological functions, such as ASK1, MKK3, MLC, ERK, Tau, and ATF-2, have been identified. The RhoA/ROCK signaling pathway is a classic signaling that controls various biological behaviors of cells [ 26 ]. The functional diversity of RhoA is closely related to the diversity of its downstream effector molecules [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Echinococcus multilocularis drives the polarization of macrophages by regulating the RhoA-MAPK signaling pathway and thus affects liver fibrosis

et al. 2022

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Echinococcus multilocularis is a small parasite that causes alveolar echinococcosis. It primarily induces liver disorder, such as liver fibrosis and even liver cancer, which severely endangers human lives. This study aims to explore the efficacy of Echinococcus multilocularis soluble antigen in preventing and alleviating alveolar echinococcosis-induced liver fibrosis and determine the underlying mechanism. We first identified the optimal dose and time of Echinococcus multilocularis soluble antigen. The protein levels of key genes in the RhoA-MAPK signaling pathway were remarkably upregulated in RAW264.7 and Ana-1 cells induced with 80 μg/mL Echinococcus multilocularis soluble antigen for 8 h. Interestingly, the upregulated expression levels were remarkably reversed by the RhoA, JNK, ERK, or p38 inhibitor, confirming the significance of the RhoA-MAPK signaling pathway. In addition, the relative contents of M2 polarization markers IL-10 and Arg-1 in macrophages induced with 80 μg/mL Echinococcus multilocularis soluble antigen for 8 h increased, whereas those of M1 polarization markers IL-12 and NOS-2 decreased. Mouse hepatic stellate cells were the key components of the hepatocellular carcinoma tumor microenvironment. Hepatic stellate cells were activated by Echinococcus multilocularis soluble antigen and transformed into the morphology of myofibroblasts in response to liver disorders. By detecting the marker of myofibroblast formation, RhoA inhibitor remarkably reduced the positive expression of α-SMA in mouse hepatic stellate cells induced with Echinococcus multilocularis soluble antigen. Therefore, Echinococcus multilocularis soluble antigen remarkably activated the RhoA-MAPK pathways in macrophages, further inducing the polarization of macrophages and ultimately causing liver fibrosis. Hypothesis: We hypothesize that infection with Echinococcus multilocularis activates the RhoA-MAPK signaling pathway and subsequently induces macrophage polarization to promote hepatic stellate cells activation leading to liver fibrosis. Aims: To investigate the mechanism by which soluble antigen of Echinococcus multilocularis affects liver fibrosis through the RhoA-MAPK pathway driving polarization of macrophages. Goals: To identify new pathways of intervention and drug targets for the regulation of macrophage polarity phenotype switching and the attenuation or inhibition of the development and treatment of liver fibrosis caused by Echinococcus multilocularis infection.

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Section: Discussionmentioning

confidence: 99%

Echinococcus multilocularis drives the polarization of macrophages by regulating the RhoA-MAPK signaling pathway and thus affects liver fibrosis

et al. 2022

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“…Poor neuronal differentiation has been reported as a significant limitation of NPC transplantation approaches; we now report a one-step priming procedure to partially overcome this problem, avoid in vivo application of PGA-SS-FAS, and reduce the potential side effects on host tissue. The convergence RhoA/ROCK pathway becomes activated by inhibitory molecules within the SCI milieu and plays a central role in inflammation, apoptosis, neuronal degeneration, and axon retraction [ 56 ]. Given the importance of these processes to SCI pathogenesis and the impairment of functional recovery, several pharmacological strategies have been developed to prevent cell death and promote axonal regeneration and functional recovery after SCI [ 57 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

Transplantation of Human-Fetal-Spinal-Cord-Derived NPCs Primed with a Polyglutamate-Conjugated Rho/Rock Inhibitor in Acute Spinal Cord Injury

Giraldo

Bonilla

Mellado-López

et al. 2022

Cells

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Neural precursor cell (NPC) transplantation represents a promising therapy for treating spinal cord injuries (SCIs); however, despite successful results obtained in preclinical models, the clinical translation of this approach remains challenging due, in part, to the lack of consensus on an optimal cell source for human neuronal cells. Depending on the cell source, additional limitations to NPC-based therapies include high tumorigenic potential, alongside poor graft survival and engraftment into host spinal tissue. We previously demonstrated that NPCs derived from rat fetal spinal cords primed with a polyglutamate (PGA)-conjugated form of the Rho/Rock inhibitor fasudil (PGA-SS-FAS) displayed enhanced neuronal differentiation and graft survival when compared to non-primed NPCs. We now conducted a similar study of human-fetal-spinal-cord-derived NPCs (hfNPCs) from legal gestational interruptions at the late gestational stage, at 19–21.6 weeks. In vitro, expanded hfNPCs retained neural features, multipotency, and self-renewal, which supported the development of a cell banking strategy. Before transplantation, we established a simple procedure to prime hfNPCs by overnight incubation with PGA-SS-FAS (at 50 μM FAS equiv.), which improved neuronal differentiation and overcame neurite-like retraction after lysophosphatidic-acid-induced Rho/Rock activation. The transplantation of primed hfNPCs into immune-deficient mice (NU(NCr)-Foxn1nu) immediately after the eighth thoracic segment compression prompted enhanced migration of grafted cells from the dorsal to the ventral spinal cord, increased preservation of GABAergic inhibitory Lbx1-expressing and glutamatergic excitatory Tlx3-expressing somatosensory interneurons, and elevated the numbers of preserved, c-Fos-expressing, activated neurons surrounding the injury epicenter, all in a low percentage. Overall, the priming procedure using PGA-SS-FAS could represent an alternative methodology to improve the capabilities of the hfNPC lines for a translational approach for acute SCI treatment.

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“…Myelin associated glycoproteins present in the scar are: NogoA, MAG, and OMgp, a GPI-linked glycoprotein ( Yang et al, 2020 ; Roy et al, 2021 ). The myelin proteins bind to the Nogo receptors NgR1&R2 ( Figure 4 ).…”

Section: Barriers For Central Nervous System Regeneration: Intrinsic ...mentioning

confidence: 99%

Bridging the gap of axonal regeneration in the central nervous system: A state of the art review on central axonal regeneration

et al. 2022

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Neuronal regeneration in the central nervous system (CNS) is an important field of research with relevance to all types of neuronal injuries, including neurodegenerative diseases. The glial scar is a result of the astrocyte response to CNS injury. It is made up of many components creating a complex environment in which astrocytes play various key roles. The glial scar is heterogeneous, diverse and its composition depends upon the injury type and location. The heterogeneity of the glial scar observed in different situations of CNS damage and the consequent implications for axon regeneration have not been reviewed in depth. The gap in this knowledge will be addressed in this review which will also focus on our current understanding of central axonal regeneration and the molecular mechanisms involved. The multifactorial context of CNS regeneration is discussed, and we review newly identified roles for components previously thought to solely play an inhibitory role in central regeneration: astrocytes and p75NTR and discuss their potential and relevance for deciding therapeutic interventions. The article ends with a comprehensive review of promising new therapeutic targets identified for axonal regeneration in CNS and a discussion of novel ways of looking at therapeutic interventions for several brain diseases and injuries.

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Strategies to neutralize RhoA/ROCK pathway after spinal cord injury

Cited by 17 publications

References 144 publications

Echinococcus multilocularis drives the polarization of macrophages by regulating the RhoA-MAPK signaling pathway and thus affects liver fibrosis

Echinococcus multilocularis drives the polarization of macrophages by regulating the RhoA-MAPK signaling pathway and thus affects liver fibrosis

Transplantation of Human-Fetal-Spinal-Cord-Derived NPCs Primed with a Polyglutamate-Conjugated Rho/Rock Inhibitor in Acute Spinal Cord Injury

Bridging the gap of axonal regeneration in the central nervous system: A state of the art review on central axonal regeneration

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