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Model for the role of the RhoA-ROCK pathway in the pathogenesis of TBI. The small GTPase RhoA is activated by RhoA-GEFs in response to various extracellular signals triggered by injury. Active GTP-bound RhoA binds to and stimulates the activity of the serine/threonine kinase ROCK1/2. Through phosphorylation of downstream effectors such as PTEN, LIMK, MLC, and CRMP-2, ROCK initiates signaling cascades that induce cytoskeletal remodeling underlying dendrite/axon retraction and synapse/spine loss as well as cell death, which together contribute to functional deficits. Inhibition of ROCK (e.g., Fasudil, Y-27632) or RhoA rescues these TBI-induced deficits. ROCK: Rho Kinase, GEF: guanine nucleotide exchange factor, GAP: GTPase-activating protein, GDI: Guanine nucleotide dissociation inhibitor, PTEN: phosphatase and tensin homolog, LIMK: LIM kinase, MLC: myosin light chain, CRMP2: collapsin response mediator protein 2, MAG: myelin-associated glycoprotein, OMgp: oligodendrocyte-myelin glycoprotein, NgR: nogo receptor, PTPσ: protein tyrosine phosphate σ, NgR1/3: nogo receptor 1 and 3, LAR: leukocyte common antigen-related phosphatase, CSPG: chondroitin sulfate proteoglycans.
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Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. TBIs, which range in severity from mild to severe, occur when a traumatic event, such as a fall, a traffic accident, or a blow, causes the brain to move rapidly within the skull, resulting in damage. Long-term consequences of TBI can include motor and cognitive defic...
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... small GTPases (e.g., RhoA, Rac1, Cdc42) are key regulators of cytoskeletal and cell adhesion dynamics that control a wide range of cellular processes, including morphogenesis, migration, proliferation, and survival [9]. Rho GTPases regulate these processes by functioning as molecular switches, cycling between an active GTP-bound state and an inactive GDP-bound state (Figure 1). This cycling is precisely controlled in space and time by the opposing actions of guanine nucleotide-exchange factors (GEFs), which activate Rho GTPases by facilitating GTP-GDP exchange, and GTPase-activating proteins (GAPs), which inhibit Rho GTPases by catalyzing GTP hydrolysis [10,11]. ...
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... their GTP-bound state, Rho GTPases interact with and activate downstream effector proteins, initiating intracellular signaling cascades that affect cell behavior and morphology [9]. A major downstream effector for RhoA is the serine-threonine kinase ROCK1/2 [12,13] (Figure 1). Following RhoA activation, ROCK promotes actomyosin contractile force generation by increasing the phosphorylation of myosin light chain (MLC), a subunit of the actin-based motor protein myosin II [14]. ...
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... ROCK phosphorylates and stimulates the activity of the dual protein/lipid phosphatase PTEN (phosphatase and tensin homolog), a tumor suppressor that inhibits cell growth and survival [19]. Collectively, these actions of RhoA-ROCK signaling drive actin cytoskeletal remodeling, cell contractility, and cell death (Figure 1). Figure 1. ...
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... these actions of RhoA-ROCK signaling drive actin cytoskeletal remodeling, cell contractility, and cell death (Figure 1). Figure 1. Model for the role of the RhoA-ROCK pathway in the pathogenesis of TBI. ...
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... we found that TBI disrupted contextual fear discrimination in mice, impairing their ability to distinguish between a fearful and a non-fearful environment, and that inhibiting RhoA genetically (RhoA fl/fl , CamKIIα-Cre mice) or ROCK pharmacologically (fasudil) protected mice against this hippocampal-dependent memory deficit [43]. Together, these findings indicate that blocking RhoA-ROCK signaling alleviates TBI-induced motor and cognitive impairments and thus enhances functional recovery after TBI (Figure 1). Moreover, since genetically ablating RHOA and pharmacologically inhibiting ROCK produced similar results, it is likely that ROCK is the primary mediator of TBI-induced deficits rather than other RhoA effector pathways. ...
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... we found that TBI disrupted contextual fear discrimination in mice, impairing their ability to distinguish between a fearful and a non-fearful environment, and that inhibiting RhoA genetically (RhoA fl/ fl , CamKII-Cre mice) or ROCK pharmacologically (fasudil) protected mice against this hippocampal-dependent memory deficit [43]. Together, these findings indicate that blocking RhoA-ROCK signaling alleviates TBI-induced motor and cognitive impairments and thus enhances functional recovery after TBI (Figure 1). Moreover, since genetically a How might inhibiting RhoA-ROCK signaling protect against injury-related brain damage and/or promote repair? ...
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... of CNS regeneration include myelin-associated inhibitors, glial scar-associated inhibitors, and repulsive axon guidance molecules [44]. Notably, many of these growth inhibitory molecules mediate their effects via activating RhoA-ROCK signaling (Figure 1). For instance, in an injured CNS, myelin-derived axon growth inhibitors such as myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), and Nogo bind to the Nogo receptor (NgR1), which in cooperation with receptors such as p75 NTR and LINGO-1 activates RhoA-ROCK signaling, resulting in growth cone collapse and axon growth inhibition [29,45,46]. ...
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... instance, in an injured CNS, myelin-derived axon growth inhibitors such as myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), and Nogo bind to the Nogo receptor (NgR1), which in cooperation with receptors such as p75 NTR and LINGO-1 activates RhoA-ROCK signaling, resulting in growth cone collapse and axon growth inhibition [29,45,46]. Likewise, repulsive axon guidance molecules such as ephrinB3 and semaphorin 4D and glial scar components such as chondroitin sulfate proteoglycans (CSPGs) trigger activation of RhoA-ROCK signaling, resulting in axon outgrowth inhibition [29] (Figure 1). Abrogating RhoA-ROCK signaling can reverse the inhibitory effects of these molecules on axon outgrowth and sprouting, which may help promote functional recovery in animal models of CNS injury such as TBI. ...
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... of CNS regeneration include myelin-associated inhibitors, glial scar-associated inhibitors, and repulsive axon guidance molecules [44]. Notably, many of these growth inhibitory molecules mediate their effects via activating RhoA-ROCK signaling (Figure 1). For instance, in an injured CNS, myelin-derived axon growth inhibitors such as myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), and Nogo bind to the Nogo receptor (NgR1), which in cooperation with receptors such as p75 NTR and LINGO-1 activates RhoA-ROCK signaling, resulting in growth cone collapse and axon growth inhibition [29,45,46]. ...
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... instance, in an injured CNS, myelin-derived axon growth inhibitors such as myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), and Nogo bind to the Nogo receptor (NgR1), which in cooperation with receptors such as p75 NTR and LINGO-1 activates RhoA-ROCK signaling, resulting in growth cone collapse and axon growth inhibition [29,45,46]. Likewise, repulsive axon guidance molecules such as ephrinB3 and semaphorin 4D and glial scar components such as chondroitin sulfate proteoglycans (CSPGs) trigger activation of RhoA-ROCK signaling, resulting in axon outgrowth inhibition [29] (Figure 1). Abrogating RhoA-ROCK signaling can reverse the inhibitory effects of these molecules on axon outgrowth and sprouting, which may help promote functional recovery in animal models of CNS injury such as TBI. ...
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... addition to synapse loss, spines remodel in response to TBI, resulting in a reduction in large mushroom-shaped spines and a corresponding increase in immature filopodia-like structures, compared to sham animals [43,64,68]. Excessive activation of RhoA-ROCK signaling could drive this TBI-induced synaptic remodeling since this pathway is known to promote spine retraction and synapse loss through modulation of the actin cytoskeleton [69] (Figure 1). Indeed, previous work in the retina has shown that ROCK inhibition preserves rod-bipolar synapses after retinal detachment [70]. ...
Citations
... The Rho GTPases are inhibited by catalyzing GTP hydrolysis. When Rho is GTP-bound, it interacts with downstream effector proteins, such as Rho-associated Kinase-1 (ROCK1), Rho-associated Kinase-2 (ROCK2), and DIAPH1 [154,158]. ROCK is a serine-threonine kinase that promotes actomyosin contractile force generation [159][160][161]. ROCK does this by increasing myosin light chain, a subunit of motor protein myosin II, phosphorylation. ...
... Rho GTPases regulate cytoskeletal and cell adhesion dynamics [154][155][156]. They are involved in cell morphogenesis, cell survival, cell proliferation, and cell migration ( Figure 2). ...
... The Rho GTPases are inhibited by catalyzing GTP hydrolysis. When Rho is GTPbound, it interacts with downstream effector proteins, such as Rho-associated Kinase-1 (ROCK1), Rho-associated Kinase-2 (ROCK2), and DIAPH1 [154,158]. ROCK is a serinethreonine kinase that promotes actomyosin contractile force generation [159][160][161]. ROCK does this by increasing myosin light chain, a subunit of motor protein myosin II, phosphorylation. ...
Parkinson’s disease (PD), a progressive neurodegenerative disease, has no cure, and current therapies are not effective at halting disease progression. The disease affects mid-brain dopaminergic neurons and, subsequently, the spinal cord, contributing to many debilitating symptoms associated with PD. The GTP-binding protein, Rho, plays a significant role in the cellular pathology of PD. The downstream effector of Rho, Rho-associated kinase (ROCK), plays multiple functions, including microglial activation and induction of inflammatory responses. Activated microglia have been implicated in the pathology of many neurodegenerative diseases, including PD, that initiate inflammatory responses, leading to neuron death. Calpain expression and activity is increased following glial activation, which triggers the Rho-ROCK pathway and induces inflammatory T cell activation and migration as well as mediates toxic α-synuclein (α-syn) aggregation and neuron death, indicating a pivotal role for calpain in the inflammatory and degenerative processes in PD. Increased calpain activity and Rho-ROCK activation may represent a new mechanism for increased oxidative damage in aging. This review will summarize calpain activation and the role of the Rho-ROCK pathway in oxidative stress and α-syn aggregation, their influence on the neurodegenerative process in PD and aging, and possible strategies and research directions for therapeutic intervention.
... The RhoA/ROCK pathway emerges as a pivotal player in ischemic stroke, orchestrating diverse cellular responses that contribute to both injury and repair processes. Activation of RhoA triggers downstream signaling cascades mediated by ROCK, culminating in cytoskeletal rearrangements, cell contraction, and inflammation [158,159]. Despite its central role, targeting this pathway presents a double-edged sword, with both neuroprotective and detrimental effects observed. ...
Ischemic stroke triggers a complex cascade of cellular and molecular events leading to neuronal damage and tissue injury. This review explores the potential therapeutic avenues targeting cellular signaling pathways implicated in stroke pathophysiology. Specifically, it focuses on the articles that highlight the roles of RhoA/ROCK and mTOR signaling pathways in ischemic brain injury and their therapeutic implications. The RhoA/ROCK pathway modulates various cellular processes, including cytoskeletal dynamics and inflammation, while mTOR signaling regulates cell growth, proliferation, and autophagy. Preclinical studies have demonstrated the neuroprotective effects of targeting these pathways in stroke models, offering insights into potential treatment strategies. However, challenges such as off-target effects and the need for tissue-specific targeting remain. Furthermore, emerging evidence suggests the therapeutic potential of MSC secretome in stroke treatment, highlighting the importance of exploring alternative approaches. Future research directions include elucidating the precise mechanisms of action, optimizing treatment protocols, and translating preclinical findings into clinical practice for improved stroke outcomes.
... Novel therapies targeting a variety of the pathophysiological processes in neurotrauma remain a significant area of research, as comprehensively described elsewhere [16,43,69,162]. These are summarised in Table 2. Whilst a number of biological targets have proven promising in pre-clinical studies, translational success has often proven challenging [49,83,106,107,[163][164][165][166][167][168][169][170][171][172][173][174][175][176][177]. Interventional studies continue to investigate novel targets and approaches but have thus far failed to prove efficacious in improving functional outcomes [16,69,178,179]. ...
... NGF = nerve growth factor; BDNF = brain-derived neurotrophic factor; IGF-1 = insulin-like growth factor 1; CS = chondroitin sulphates; PEDF = pigment epithelium-derived factor; Rho-A = Ras homolog family member A; mTOR = mammalian target of rapamycin; chk2 = checkpoint kinase 2; NgR = Nogo-66 receptor; AQP-4 = aquaporin 4; mPTP = mitochondrial permeability transition pore; ADSCs = adipose-derived stem cells; DPSCs = dental pulp stem cells; ESC = embryonic stem cells; IL-6 = interleukin-6; iPSC = induced pluripotent stem cells; NSC = neural stem cells; NPC = neural progenitor cells; MSC = mesenchymal stem cells; nNOS = neuronal nitric oxide synthase; OPC = oligodendrocyte progenitor cells; PLGA = poly (lactic-co-glycolic acid); siRNA = small interfering ribonucleic acid; HDAC = histone deacetylase; Uqcr11 = ubiquinol-cytochrome c reductase, complex III subunit XI. [172], BDNF [173], PEDF [135] and IGF-1 delivery via nanofibrous dural substitutes [197] Caspases [174], Rho-A [175], mTOR [176], chk2 [177], Rab [198] and transglutaminases [199] Caspases [174], Bcl-2 [200], imipramine [201], cyclosporin A [202] and statins [203] NgR [107], glutamate [163] and endothelin [204] AQP-4 [83], Ca 2+ channel inhibitors [164] and mPTP [165] Immunomodulation [166], gangliosides [49,167], HDAC inhibitors [205] and bexarotene [206] Mitochondria-endoplasmic reticulum contact sites [207] Antioxidants [168], ROS scavenger materials [170,171,208,209] and Uqcr11 overexpression [210] Chondroitinase ABC [169,170], decorin [106,171] and 4-methylumbelliferone [211] Neuronal differentiation [43,212] HSPs [213] Progesterone [214], erianin [215] Hydrogen sulphide [216], tetramethylpyrazine [217], zinc [218], probucol [219], phenserine tartrate [220] and hyperbaric oxygen [221] Cell therapies Stem cells ...
Traumatic injury to the brain and spinal cord (neurotrauma) is a common event across populations and often causes profound and irreversible disability. Pathophysiological responses to trauma exacerbate the damage of an index injury, propagating the loss of function that the central nervous system (CNS) cannot repair after the initial event is resolved. The way in which function is lost after injury is the consequence of a complex array of mechanisms that continue in the chronic phase post-injury to prevent effective neural repair. This review summarises the events after traumatic brain injury (TBI) and spinal cord injury (SCI), comprising a description of current clinical management strategies, a summary of known cellular and molecular mechanisms of secondary damage and their role in the prevention of repair. A discussion of current and emerging approaches to promote neuroregeneration after CNS injury is presented. The barriers to promoting repair after neurotrauma are across pathways and cell types and occur on a molecular and system level. This presents a challenge to traditional molecular pharmacological approaches to targeting single molecular pathways. It is suggested that novel approaches targeting multiple mechanisms or using combinatorial therapies may yield the sought-after recovery for future patients.
... Our results revealed that ROCK was a direct target of miR-124-3p and that ROCK inhibitor Fasudil exerted a similar neuroprotective role as M2-EXOs alone. It has been demonstrated that Rho/ROCK signaling serves an important therapeutic target in the pathogenesis of cerebral injury [44]. Our previous studies confirmed that in the sepsis rat model, since the activation of Rho/ROCK pathway induces the occurrence of SAE, the application of ROCK inhibitor Fasudil can significantly improve the brain injury and cognitive impairment [22]. ...
As one of the most serious complications of sepsis, sepsis-associated encephalopathy has not been effectively treated or prevented. Exosomes, as a new therapeutic method, play a protective role in neurodegenerative diseases, stroke and traumatic brain injury in recent years. The purpose of this study was to investigate the role of exosomes in glutamate (Glu)-induced neuronal injury, and to explore its mechanism, providing new ideas for the treatment of sepsis-associated encephalopathy. The neuron damage model induced by Glu was established, and its metabolomics was analyzed and identified. BV2 cells were induced to differentiate into M1 and M2 subtypes. After the exosomes from both M1-BV2 cells and M2-BV2 cells were collected, exosome morphological identification was performed by transmission electron microscopy and exosome-specific markers were also detected. These exosomes were then cocultured with HT22 cells. CCK-8 method and LDH kit were used to detect cell viability and toxicity. Cell apoptosis, mitochondrial membrane potential and ROS content were respectively detected by flow cytometry, JC-1 assay and DCFH-DA assay. MiR-124-3p expression level was detected by qRT-PCR and Western blot. Bioinformatics analysis and luciferase reporter assay predicted and verified the relationship between miR-124-3p and ROCK1 or ROCK2. Through metabolomics, 81 different metabolites were found, including fructose, GABA, 2, 4-diaminobutyric acid, etc. The enrichment analysis of differential metabolites showed that they were mainly enriched in glutathione metabolism, glycine and serine metabolism, and urea cycle. M2 microglia-derived exosomes could reduce the apoptosis, decrease the accumulation of ROS, restore the mitochondrial membrane potential and the anti-oxidative stress ability in HT22 cells induced by Glu. It was also found that the protective effect of miR-124-3p mimic on neurons was comparable to that of M2-EXOs. Additionally, M2-EXOs might carry miR-124-3p to target ROCK1 and ROCK2 in neurons, affecting ROCK/PTEN/AKT/mTOR signaling pathway, and then reducing Glu-induced neuronal apoptosis. M2 microglia-derived exosomes may protect HT22 cells against Glu-induced injury by transferring miR-124-3p into HT22 cells, with ROCK being a target gene for miR-124-3p.
... The Ras homolog gene family protein A (RhoA)/Rhoassociated coil-coil containing protein kinase (ROCK) pathway is involved in various physiological activities of cells, including cytoskeleton reconstruction, contraction, migration, phagocytic adhesion, stress fiber formation, the inflammatory response, and angiogenesis, and recent studies have found it to be closely related to the polarization of microglia [36,37]. Targeting the inhibition of the RhoA/ ROCK signaling pathway has gradually become the most promising direction for the treatment of TBI, and multiple molecules, such as Nogo, CSPG, and glutamate, may be upstream molecules of this pathway [38]. A key study reported that spatial cognition can be improved after TBI by inhibiting ROCK1 upregulation [39]. ...
Traumatic brain injury (TBI) can lead to short-term and long-term physical and cognitive impairments, which have significant impacts on patients, families, and society. Currently, treatment outcomes for this disease are often unsatisfactory, due at least in part to the fact that the molecular mechanisms underlying the development of TBI are largely unknown. Here, we observed significant upregulation of Piezo2, a key mechanosensitive ion channel protein, in the injured brain tissue of a mouse model of TBI induced by controlled cortical impact. Pharmacological inhibition and genetic knockdown of Piezo2 after TBI attenuated neuronal death, brain edema, brain tissue necrosis, and deficits in neural function and cognitive function. Mechanistically, the increase in Piezo2 expression contributed to TBI-induced neuronal death and subsequent production of TNF-α and IL-1β, likely through activation of the RhoA/ROCK1 pathways in the central nervous system. Our findings suggest that Piezo2 is a key player in and a potential therapeutic target for TBI.
... The Ras homolog gene family protein A (RhoA)/Rho-associated coil-coil containing protein kinase (ROCK) pathway is involved in various physiological activities of cells, including cytoskeleton reconstruction, contraction, migration, phagocytic adhesion, stress ber formation, the in ammatory response, and angiogenesis, and recent studies have found it to be closely related to the polarization of microglia [23,24] . Targeting the inhibition of the RhoA/ROCK signaling pathway has gradually become the most promising direction for the treatment of TBI, and multiple molecules, such as Nogo, CSPG, and glutamate, may be upstream molecules of this pathway [25] . A key study reported that spatial cognition can be improved after TBI by inhibiting ROCK1 upregulation [26] . ...
Traumatic brain injury (TBI) can lead to short-term and long-term physical and cognitive impairments, which have significant impacts on patients, families, and society. Currently, treatment outcomes for this disease are often unsatisfactory, due at least in part to the fact that the molecular mechanisms underlying the development of TBI are largely unknown. Here, we observed significant upregulation of Piezo2, a key mechanosensitive ion channel protein, in the injured brain tissue of a mouse model of TBI induced by controlled cortical impact. Pharmacological inhibition and genetic knockdown of Piezo2 after TBI attenuated neuronal death, brain edema, brain tissue necrosis, and deficits in neural function and cognitive function. Mechanistically, the increase in Piezo2 expression contributed to TBI-induced neuronal death and subsequent production of TNF-α and IL-1β, likely through activation of the RhoA/ROCK1 pathways in the central nervous system. Our findings suggest that Piezo2 is a key player in and a potential therapeutic target for TBI.
... Rho is necessary for the stimulation and recruitment of macrophages, and its inhibition hinders their chemotaxis and migration (Nagao et al. 2007). Induction of intracellular proteases, inflammation, the release of excitatory amino acids, and cell death are all secondary harm caused by CNS injury that RhoA is also engaged in (Dubreuil et al. 2003;Mulherkar et al. 2017;Mulherkar and Tolias 2020). Zhang et al. discuss the role of RhoA in TBI and the potential of targeting RhoA as a drug target for neurological disorders. ...
Traumatic brain injury (TBI) is a type of brain injury resulting from a sudden physical force to the head. TBI can range from mild, such as a concussion, to severe, which might result in long-term complications or even death. The initial impact or primary injury to the brain is followed by neuroinflammation, excitotoxicity, and oxidative stress, which are the hallmarks of the secondary injury phase, that can further damage the brain tissue. Dexamethasone (DXM) has neuroprotective effects. It reduces neuroinflammation, a critical factor in secondary injury-associated neuronal damage. DXM can also suppress the microglia activation and infiltrated macrophages, which are responsible for producing pro-inflammatory cytokines that contribute to neuroinflammation. Considering the outcomes of this research, some of the effects of DXM on TBI include: (1) DXM-loaded hydrogels reduce apoptosis, neuroinflammation, and lesion volume and improves neuronal cell survival and motor performance, (2) DXM treatment elevates the levels of Ndufs2, Gria3, MAOB, and Ndufv2 in the hippocampus following TBI, (3) DXM decreases the quantity of circulating endothelial progenitor cells, (4) DXM reduces the expression of IL1, (5) DXM suppresses the infiltration of RhoA + cells into primary lesions of TBI and (6) DXM treatment led to an increase in fractional anisotropy values and a decrease in apparent diffusion coefficient values, indicating improved white matter integrity. According to the study, the findings show that DXM treatment has neuroprotective effects in TBI. This indicates that DXM is a promising therapeutic approach to treating TBI.
... ROCK also phosphorylates myosin light chain (MLC) element, increasing actomyosin contractility. This is accomplished by the ROCK-mediated suppression of MLC phosphatase (MLCP) via phosphorylation of myosin phosphatase-targeting subunit 1 (MYPT1) [18]. mDia, another RhoA effector, is a formin molecule that initiates actin nucleation and polymerization via the actin-binding protein profilin. ...
... An important target of RhoA is ROCK, which phosphorylates MYPT of MLCP [26]. The activation of ROCK results in the inhibition of MLCP activity either through direct phosphorylation of MYPT or through other indirect mechanisms [18]. The ROCK-mediated MLCP phosphorylation induces dissociation of the catalytic subunit from MYPT, causing MLCP inactivation. ...
... 328,329 The RhoA/ROCK signaling mediates cell skeleton remodeling, cell contractility, and cell death process in response to multiple biochemical and biomechanical signals. 330 RhoA/ROCK signaling pathway is engaged in many diseases, including osteoarthritis, 331 Alzheimer's disease, 332 ischemic stroke, 333 hepatic and pulmonary fibrosis, 334,335 and cancer. 336 For example, the RhoA/ROCK signaling regulates the cardiac fibroblast-to-myofibroblast transformation (FMT) process. ...
Cellular mechanotransduction, a critical regulator of numerous biological processes, is the conversion from mechanical signals to biochemical signals regarding cell activities and metabolism. Typical mechanical cues in organisms include hydrostatic pressure, fluid shear stress, tensile force, extracellular matrix stiffness or tissue elasticity, and extracellular fluid viscosity. Mechanotransduction has been expected to trigger multiple biological processes, such as embryonic development, tissue repair and regeneration. However, prolonged excessive mechanical stimulation can result in pathological processes, such as multi-organ fibrosis, tumorigenesis, and cancer immunotherapy resistance. Although the associations between mechanical cues and normal tissue homeostasis or diseases have been identified, the regulatory mechanisms among different mechanical cues are not yet comprehensively illustrated, and no effective therapies are currently available targeting mechanical cue-related signaling. This review systematically summarizes the characteristics and regulatory mechanisms of typical mechanical cues in normal conditions and diseases with the updated evidence. The key effectors responding to mechanical stimulations are listed, such as Piezo channels, integrins, Yes-associated protein (YAP) /transcriptional coactivator with PDZ-binding motif (TAZ), and transient receptor potential vanilloid 4 (TRPV4). We also reviewed the key signaling pathways, therapeutic targets and cutting-edge clinical applications of diseases related to mechanical cues.
... ROCK, a previously identified downstream target of Rho, has a relative molecular mass of 160 kDa, a complicated molecular structure, and substantial variation in terms of tissue distribution (Mulherkar and Tolias, 2020). When Rho activates ROCK, ROCK then activates downstream substrates; thus, ROCK functions as a bridge to transmit signals from inside to outside the cell and vice versa (Shinozaki et al., 2019;Lu et al., 2021). ...
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Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system. Macrophage polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis, a traditional experimental model of multiple sclerosis. This study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune encephalomyelitis. We found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type, as shown by reduced expression of inducible nitric oxide synthase/nitric oxide, interleukin-12, and CD16/32 and increased expression of arginase-1, interleukin-10, CD14, and CD206, which was linked to inhibition of Rho kinase activity, decreased expression of toll-like receptors, nuclear factor-κB, and components of the mitogen-activated protein kinase signaling pathway, and generation of the pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6. Crucially, Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis, resulting in later onset of disease, lower symptom scores, less weight loss, and reduced demyelination compared with unmodified macrophages. In addition, Fasudil-modified macrophages decreased interleukin-17 expression on CD4 ⁺ T cells and CD16/32, inducible nitric oxide synthase, and interleukin-12 expression on F4/80 ⁺ macrophages, as well as increasing interleukin-10 expression on CD4 ⁺ T cells and arginase-1, CD206, and interleukin-10 expression on F4/80 ⁺ macrophages, which improved immune regulation and reduced inflammation. These findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response, thereby providing new insight into cell immunotherapy for multiple sclerosis.
