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Keywords = RhoA-ROCK

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16 pages, 2654 KB  
Article
Differential Sensitivity to MEK Inhibitors Highlights Distinct Entosis Mechanisms in BxPC3 and MCF7 Cells
by Paweł Tyrna, Julia Kostro, Monika Olszanecka, Piotr Szukało and Izabela Młynarczuk-Biały
Cells 2025, 14(19), 1500; https://doi.org/10.3390/cells14191500 - 25 Sep 2025
Viewed by 322
Abstract
Entosis is a form of cell-in-cell interaction observed in epithelial cancers, characterized by the internalization of one cell into another. This process is initiated by cell detachment, cadherin-mediated homotypic adhesion, and the formation of an entotic vacuole. Mechanistically, entosis is driven by Rho/ROCK [...] Read more.
Entosis is a form of cell-in-cell interaction observed in epithelial cancers, characterized by the internalization of one cell into another. This process is initiated by cell detachment, cadherin-mediated homotypic adhesion, and the formation of an entotic vacuole. Mechanistically, entosis is driven by Rho/ROCK signaling and actomyosin contractility in the invading (inner) cell, which becomes stiffer and is pulled into the softer host (outer) cell. A functional assay using differently stained cell populations allows for the assessment of pharmacological interventions on either the inner or outer cell during entosis. In this study, we investigated the impact of MEK pathway inhibition on entosis in two epithelial cancer cell lines, BxPC3 (pancreatic cancer) and MCF7 (breast cancer). BxPC3 cells, which rely on adhesion, exhibited a significant reduction in entotic index upon MEK inhibition. In contrast, MCF7 cells showed no selectivity of entosis to three different MEK inhibitors. These findings suggest cell-type-specific regulation of entosis, potentially linked to differences in protrusion formation mechanisms and upstream Ras signaling pathways previously implicated in cancer cell motility. Full article
(This article belongs to the Topic Kinases in Cancer and Other Diseases, 2nd Edition)
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18 pages, 1192 KB  
Review
Active Endothelial Inactivation of Hyperpermeability: The Role of Nitric Oxide-Driven cAMP/Epac1 Signaling
by Mauricio A. Lillo, Pía C. Burboa and Walter N. Durán
J. Cardiovasc. Dev. Dis. 2025, 12(9), 361; https://doi.org/10.3390/jcdd12090361 - 17 Sep 2025
Viewed by 527
Abstract
Endothelial hyperpermeability is a hallmark of diverse inflammatory and vascular pathologies, including sepsis, acute respiratory distress syndrome (ARDS), ischemia–reperfusion injury, and atherosclerosis. Traditionally considered a passive return to baseline following stimulus withdrawal, barrier recovery is now recognized as an active, endothelial-driven process. Earlier [...] Read more.
Endothelial hyperpermeability is a hallmark of diverse inflammatory and vascular pathologies, including sepsis, acute respiratory distress syndrome (ARDS), ischemia–reperfusion injury, and atherosclerosis. Traditionally considered a passive return to baseline following stimulus withdrawal, barrier recovery is now recognized as an active, endothelial-driven process. Earlier work identified individual components of this restorative phase, such as cyclic adenosine monophosphate (cAMP)/exchange protein directly activated by cAMP 1 (Epac1) signaling, Rap1/Rac1 activation, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, and targeted cytoskeletal remodeling, as well as kinase pathways involving PKA, PKG, and Src. However, these were often regarded as discrete events lacking a unifying framework. Recent integrative analyses, combining mechanistic insights from multiple groups, reveal that nitric oxide (NO) generated early during hyperpermeability can initiate a delayed cAMP/Epac1 cascade. This axis coordinates Rap1/Rac1-mediated cortical actin polymerization, VASP-driven junctional anchoring, retro-translocation of endothelial nitric oxide synthase (eNOS) to caveolar domains, PP2A-dependent suppression of actomyosin tension, and Krüppel-like factor 2 (KLF2)-driven transcriptional programs that sustain endothelial quiescence. Together, these pathways form a temporally orchestrated, multi-tiered “inactivation” program capable of restoring barrier integrity even in the continued presence of inflammatory stimuli. This conceptual shift reframes NO from solely a barrier-disruptive mediator to the initiating trigger of a coordinated, pro-resolution mechanism. The unified framework integrates cytoskeletal dynamics, junctional reassembly, focal adhesion turnover, and redox/transcriptional control, providing multiple potential intervention points. Therapeutically, Epac1 activation, Rap1/Rac1 enhancement, RhoA/ROCK inhibition, PP2A activation, and KLF2 induction represent strategies to accelerate endothelial sealing in acute microvascular syndromes. Moreover, applying these mechanisms to arterial endothelium could limit low-density lipoprotein (LDL) entry and foam cell formation, offering a novel adjunctive approach for atherosclerosis prevention. In this review, we will discuss both the current understanding of endothelial hyperpermeability mechanisms and the emerging pathways of its active inactivation, integrating molecular, structural, and translational perspectives. Full article
(This article belongs to the Section Electrophysiology and Cardiovascular Physiology)
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15 pages, 1970 KB  
Article
Role of RhoGEFs or RhoGAPs in Pyk2-Mediated RhoA Activation in Depolarization-Induced Contraction of Rat Caudal Arterial Smooth Muscle
by Kazuki Aida, Mitsuo Mita and Reiko Ishii-Nozawa
Int. J. Mol. Sci. 2025, 26(17), 8676; https://doi.org/10.3390/ijms26178676 - 5 Sep 2025
Viewed by 924
Abstract
It has previously been reported that the RhoA/Rho-associated kinase (ROCK) pathway is involved in depolarization-induced contraction triggered by high [K+] stimulation in rat caudal arterial smooth muscle. Furthermore, we reported that activation of the upstream Ca2+-dependent proline-rich tyrosine kinase [...] Read more.
It has previously been reported that the RhoA/Rho-associated kinase (ROCK) pathway is involved in depolarization-induced contraction triggered by high [K+] stimulation in rat caudal arterial smooth muscle. Furthermore, we reported that activation of the upstream Ca2+-dependent proline-rich tyrosine kinase 2 (Pyk2) leads to phosphorylation of myosin targeting subunit of myosin light chain phosphatase (MYPT1) and 20 kDa myosin light chain (LC20). These findings suggest that Rho guanine nucleotide exchange factors (RhoGEFs) or Rho GTPase-activating proteins (RhoGAPs) may mediate RhoA activation downstream of Pyk2, thereby contributing to depolarization-induced contraction. However, it remains unclear whether Pyk2 directly interacts with RhoGEFs or RhoGAPs. In this study, we investigated the interaction between Pyk2 and RhoGEFs or RhoGAPs during depolarization stimulation of rat caudal arterial smooth muscle. We examined the interaction between Pyk2 and RhoGEFs or RhoGAPs, which previously were identified in smooth muscle, specifically in rat caudal arterial smooth muscle, in response to 60 mM K+ stimulation by immunoprecipitation analysis. ArhGEF11, ArhGEF12, phosphorylated ArhGAP42 at Tyr792 (pTyr792-ArhGAP42) and phosphorylated ArhGAP42 at Tyr376 (pTyr376-ArhGAP42) co-immunoprecipitated with Pyk2. The co-immunoprecipitation of pTyr792-ArhGAP42, but not pTyr376-ArhGAP42, with Pyk2 was inhibited by a Pyk2 inhibitor, sodium salicylate. Furthermore, 60 mM K+ stimulation increased ArhGAP42 phosphorylation at Tyr792, which was also suppressed by sodium salicylate. These findings indicate that Pyk2-mediated phosphorylation of ArhGAP42 at Tyr792 may play a role in depolarization-induced contraction of rat caudal arterial smooth muscle. Full article
(This article belongs to the Special Issue Smooth Muscle Cells in Vascular Disease)
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15 pages, 3753 KB  
Article
Dual-Targeting of ATOX1 and ROCK1: A Potent Strategy to Potentiate the Inhibition of Lung Adenocarcinoma Proliferation
by Sailong Ma, Changqing Peng, Qi Xiong, Liying Yang, Pengcheng Yan, Zitian Huo and Guoping Wang
Cancers 2025, 17(17), 2887; https://doi.org/10.3390/cancers17172887 - 2 Sep 2025
Viewed by 642
Abstract
Background: Lung adenocarcinoma (LUAD), the most prevalent and malignant form of lung cancer subtypes, is in urgent need of additional therapeutic targets and prognostic indicators. Antioxidant 1 (ATOX1) copper chaperone and RhoA/Rho kinase 1 (ROCK1) are novel anti-tumour targets in cancers. However, their [...] Read more.
Background: Lung adenocarcinoma (LUAD), the most prevalent and malignant form of lung cancer subtypes, is in urgent need of additional therapeutic targets and prognostic indicators. Antioxidant 1 (ATOX1) copper chaperone and RhoA/Rho kinase 1 (ROCK1) are novel anti-tumour targets in cancers. However, their prognostic value and synergistic inhibitory effect remain unclear in LUAD. Methods: We re-analyzed the open-access proteomic landscape study of LUAD in 2019 and investigated the prognostic value of ATOX1/ROCK1 expression patterns. Then we verified it immunohistochemically using an independent cohort from our hospital enrolling 35 patients with TNM stage III/IV LUAD. In vitro, double fluorescence was used to confirm the co-expression and location of ATOX1/ROCK1. The CCK—8 assay and Transwell assay were carried out to assess the changes in proliferation and migration of Lewis lung carcinoma (LLC) cells following treatment with ATOX1/ROCK1 si-RNA or inhibitory drugs. Western blot was used to confirm protein expression after si-RNA transfection. Moreover, ATOX1/ROCK1-targeted drugs’ therapeutic effects were further investigated in the LLC allogeneic transplantation model and MNU-induced tumour model. Results: Firstly, according to the ATOX1/ROCK1 expression pattern derived from proteomic data, double-low expression of ATOX1/ROCK1 indicated a better Disease Free Survival (DFS) (log-rank test p = 0.01) and Overall Survival (OS) (log-rank test p = 8.2 × 10−3), whose expression was also correlated with the lower expression of MCM family proteins. Further, we verified this prognostic correlation in our cohort. The IHC-defined ATOX1/ROCK1 low subtype also had the best OS (log-rank test p = 2.4 × 10−3). In vitro, double fluorescence confirmed that ATOX1/ROCK1 was highly expressed together in Lewis cells. Co-inhibition of ATOX1 and ROCK1 either by siRNA transfection or inhibitory drugs could lead to a significant decrease in tumour proliferation. Interestingly, transcriptional inhibition of ATOX1 can lead to the up-regulation of ROCK1, while inhibition of ROCK1 resulted in the promotion of ATOX1. Moreover, in the analysis of migration ability, a similar synergistic effect from the co-inhibition of ATOX1/ROCK1 was also observed. Finally, the Lewis and Mnu-induced allogeneic transplantation model also demonstrated a greatly improved therapeutic effect by combining targeting ATOX1 and ROCK1. Conclusions: Collectively, our results suggest that a low expression pattern of ATOX1/ROCK1 can predict better clinical outcomes in LUAD. Combining the inhibition of these two targets can reach a significantly better therapeutic effect than targeting either alone. Full article
(This article belongs to the Section Molecular Cancer Biology)
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10 pages, 209 KB  
Review
RhoKinase (ROCK) Inhibition as a Therapeutic Strategy for Pseudophakic Bullous Keratopathy: A Comprehensive Review
by Anđela Jukić, Josip Pavan, Biljana Đapic Ivančić, Miro Kalauz, Rajka Kasalica Žužul and Tomislav Jukić
J. Clin. Med. 2025, 14(17), 6093; https://doi.org/10.3390/jcm14176093 - 28 Aug 2025
Viewed by 638
Abstract
Pseudophakic bullous keratopathy (PBK) is a vision-threatening corneal complication following cataract surgery, characterised by progressive endothelial cell loss, persistent corneal oedema, and painful epithelial bullae, leading to impaired vision. Corneal transplantation, either penetrating or endothelial keratoplasty, remains the primary treatment but faces challenges [...] Read more.
Pseudophakic bullous keratopathy (PBK) is a vision-threatening corneal complication following cataract surgery, characterised by progressive endothelial cell loss, persistent corneal oedema, and painful epithelial bullae, leading to impaired vision. Corneal transplantation, either penetrating or endothelial keratoplasty, remains the primary treatment but faces challenges such as donor tissue shortages, graft rejection, and limited graft longevity. Recently, Rho-kinase (ROCK) inhibitors have emerged as promising pharmacological alternatives. These agents enhance corneal endothelial cell proliferation, migration, and adhesion, suppress apoptosis, and promote corneal deturgescence and wound healing. Several preclinical and clinical studies have demonstrated the efficacy of ROCK inhibitors in improving corneal clarity, endothelial function, and visual acuity in PBK. Their use has been associated with reductions in corneal oedema, improved endothelial cell density, and delayed or prevented the need for corneal transplantation. A systematic literature search of PubMed, Scopus, and Web of Science databases was conducted, restricted to peer-reviewed English-language articles, ensuring comprehensive coverage. ROCK inhibitors represent a novel pharmacological strategy for PBK prevention and management, potentially reducing dependency on donor grafts. Further research is needed to determine long-term safety, optimal dosing, and efficacy. Full article
(This article belongs to the Section Ophthalmology)
6 pages, 3814 KB  
Case Report
Effect of Netarsudil 0.02% on a Patient with Fuchs Corneal Dystrophy and Radial Keratotomy
by Praneetha Thulasi, Shae Chambers and Soroosh Behshad
J. Clin. Transl. Ophthalmol. 2025, 3(3), 17; https://doi.org/10.3390/jcto3030017 - 15 Aug 2025
Viewed by 693
Abstract
This study reports an unusual case of dramatic change in visual acuity, pachymetry, and corneal topography in a patient with a history of Fuchs dystrophy and radial keratotomy following the use of Rho-kinase (ROCK) inhibitor. A patient with a history of 8-cut radial [...] Read more.
This study reports an unusual case of dramatic change in visual acuity, pachymetry, and corneal topography in a patient with a history of Fuchs dystrophy and radial keratotomy following the use of Rho-kinase (ROCK) inhibitor. A patient with a history of 8-cut radial keratotomy (RK), astigmatic keratotomy (AK), and Fuchs dystrophy showed dramatic changes in visual acuity, pachymetry, and corneal topography after using one drop of netarsudil 0.02%. The dramatic effect of netarsudil in our patient may be due to increased penetration of a rho-kinase inhibitor from the corneal incisions, facilitating the effect on corneal endothelium, resulting in a dramatic improvement in corneal pachymetry. This suggests a potential role for corneal incisions to improve the effectiveness of rho-kinase inhibitors in patients with Fuchs dystrophy. Full article
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28 pages, 690 KB  
Review
A Comprehensive Review of the Role of Rho-Kinase Inhibitors in Corneal Diseases
by Elizabeth Y. X. Leong, Jianbin Ding, Duoduo Wu, Blanche X. H. Lim, Andrea Ang, Evan Wong, Nigel Morlet, Jodhbir S. Mehta and Chris H. L. Lim
Life 2025, 15(8), 1283; https://doi.org/10.3390/life15081283 - 13 Aug 2025
Cited by 1 | Viewed by 1685
Abstract
There is growing interest in the application of Rho-associated protein kinase (ROCK) inhibitors (ROCKI) to the treatment of corneal diseases. ROCK is a key regulator of several cellular processes in the cornea, including cytoskeletal organization, cell proliferation, migration, inflammation, and wound healing. ROCKI, [...] Read more.
There is growing interest in the application of Rho-associated protein kinase (ROCK) inhibitors (ROCKI) to the treatment of corneal diseases. ROCK is a key regulator of several cellular processes in the cornea, including cytoskeletal organization, cell proliferation, migration, inflammation, and wound healing. ROCKI, such as ripasudil and netarsudil, enhances endothelial cell migration, and promotes repair in conditions characterized by endothelial dysfunction. These agents also exert anti-inflammatory, anti-angiogenic, and anti-fibrotic effects for wound healing. As such, ROCKI demonstrate promise as therapeutic options for conditions such as Fuchs’ endothelial corneal dystrophy, pseudophakic bullous keratopathy, and iridocorneal endothelial syndrome. Emerging data further supports ROCKI’s potential in managing corneal neovascularization and supporting recovery following cataract surgery and keratoplasty, reducing the need for donor tissue. This narrative review provides a comprehensive evaluation of ROCKI’s mechanism of action, pharmacological properties, safety profile, applications in corneal disease management, emerging clinical trials, and novel approaches. We emphasize both preclinical and clinical findings, highlight existing evidence gaps, and outline future research priorities. Full article
(This article belongs to the Section Physiology and Pathology)
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13 pages, 611 KB  
Review
Rho-Kinase Inhibitors: The Application and Limitation in Management of Glaucoma
by Yuan-Ping Chao, Ta-Hung Chiu and Da-Wen Lu
Biomedicines 2025, 13(8), 1871; https://doi.org/10.3390/biomedicines13081871 - 1 Aug 2025
Viewed by 1399
Abstract
Glaucoma is recognized as a progressive optic neuropathy and a leading cause of irreversible blindness worldwide. While intraocular pressure (IOP) is considered the only modifiable risk factor, current medical treatments are challenged by issues such as inadequate IOP control and ocular side effects. [...] Read more.
Glaucoma is recognized as a progressive optic neuropathy and a leading cause of irreversible blindness worldwide. While intraocular pressure (IOP) is considered the only modifiable risk factor, current medical treatments are challenged by issues such as inadequate IOP control and ocular side effects. Rho kinase (ROCK) inhibitors have been developed as a novel pharmacologic class targeting the trabecular meshwork to enhance conventional aqueous humor outflow. In this review, the pharmacokinetics and IOP-lowering efficacy of key ROCK inhibitors are summarized. Beyond IOP reduction, ROCK inhibitors exhibit neuroprotective, anti-inflammatory, antifibrotic, and ocular perfusion-enhancing effects. Finally, we analyzed the limitations and future prospects of ROCK inhibitors in the management of glaucoma. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Ophthalmic Diseases)
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18 pages, 6694 KB  
Article
Effects of a ROCK Inhibitor on Retinal Ganglion Cells In Vivo and In Vitro
by Wanjing Chen, Yoko Iizuka, Fumihiko Mabuchi and Kenji Kashiwagi
J. Clin. Med. 2025, 14(15), 5344; https://doi.org/10.3390/jcm14155344 - 29 Jul 2025
Viewed by 666
Abstract
Objective: To investigate the neuroprotective effects of a Rho-associated kinase (ROCK) inhibitor on retinal ganglion cells (RGCs) in vitro and in vivo. Methods: For in vivo studies, a unilateral optic nerve crush mouse model was established. Then, 100 mM Y-27632 (a [...] Read more.
Objective: To investigate the neuroprotective effects of a Rho-associated kinase (ROCK) inhibitor on retinal ganglion cells (RGCs) in vitro and in vivo. Methods: For in vivo studies, a unilateral optic nerve crush mouse model was established. Then, 100 mM Y-27632 (a ROCK inhibitor) or saline was applied to the experimental eyes once a day for 14 days. The effects of the ROCK inhibitor were evaluated by counting the surviving RGCs in the enucleated flat retina tissues and measuring the inner retinal thickness using optical coherence tomography (OCT), the amplitude of the electroretinogram (ERG), and the change in intraocular pressure (IOP). For the in vitro study, RGCs were isolated from five-day-old mice using a modified immunopanning method with magnetic beads. The isolated RGCs were incubated for 72 h with various concentrations of Y-27632, after which TUNEL assays were performed to determine the number of surviving RGCs. Results: Y-27632 has neuroprotective effects, as it significantly increased the number of surviving RGCs by approximately 6.3%. OCT and ERG data also revealed that Y-27632 induced neuroprotective effects in vivo; furthermore, Y-27632 reduced IOP by approximately 18.3%. The in vitro study revealed the dose-dependent neuroprotective effects of Y-27632, with the highest dose of Y-27632 (1000 nM) increasing the RGC survival rate after 72 h of incubation compared with that of the control. Conclusions: The ROCK inhibitor Y-27632 may exert some neuroprotective effects on RGCs when it is used as an eye drop through an IOP-independent mechanism. Full article
(This article belongs to the Section Ophthalmology)
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25 pages, 12149 KB  
Article
Total Flavones of Rhododendron Protect Against Ischemic Cerebral Injury by Regulating the Phosphorylation of the RhoA-ROCK2 Pathway via Endothelial-Derived H2S
by Xiaoqing Sun, Xingyu Zhang, Yuwen Li, Jiyue Wen, Zhiwu Chen and Shuo Chen
Curr. Issues Mol. Biol. 2025, 47(7), 513; https://doi.org/10.3390/cimb47070513 - 3 Jul 2025
Viewed by 611
Abstract
This study aims to investigate the mechanism by which the total flavones of Rhododendron (TFR) protect against cerebral ischemic injury through the endothelial-derived H2S-mediated regulation of RhoA phosphorylation at the Ser188 and Rho kinase 2 (ROCK2) phosphorylation at Thr436. [...] Read more.
This study aims to investigate the mechanism by which the total flavones of Rhododendron (TFR) protect against cerebral ischemic injury through the endothelial-derived H2S-mediated regulation of RhoA phosphorylation at the Ser188 and Rho kinase 2 (ROCK2) phosphorylation at Thr436. For experimental design, mouse or rat cerebrovascular endothelial cells (ECs) were cultured with or without neurons and subjected to hypoxia/reoxygenation (H/R) injury. The vasodilation of the cerebral basilar artery was assessed. Cerebral ischemia/reperfusion (I/R) injury was induced in mice by bilateral carotid artery ligation, followed by Morris water maze and open field behavioral assessments. The protein levels of cystathionine-γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3-MST), RhoA, ROCK2, p-RhoA (RhoA phosphorylated at Ser188), and p-ROCK2 (ROCK2 phosphorylated at Thr436) were quantified. Additionally, the activities of RhoA and ROCK2 were measured. Notably, TFR significantly inhibited H/R-induced H2S reduction and suppressed the increased expression and activity of RhoA and ROCK2 in ECs, effects attenuated by CSE or 3-MST knockout. Moreover, TFR-mediated cerebrovascular dilation was reduced by RhoA or ROCK2 inhibitors, while the protective effect of TFR against cerebral I/R injury in mice was markedly attenuated by the heterozygous knockout of ROCK2. In the ECs-co-cultured neurons, the inhibition of TFR on H/R-induced neuronal injury and decrease in H2S level in the co-culture was attenuated by the knockout of CSE or 3-MST in the ECs. TFR notably inhibited the H/R-induced upregulation of neuronal RhoA, ROCK2, and p-ROCK2 protein levels, as well as the activities of RhoA and ROCK2, while reversing the decrease in p-RhoA. However, the knockout of CSE or 3-MST in the ECs significantly attenuated the inhibition of TFR on these increases. Furthermore, 3-MST knockout in ECs attenuated the TFR-mediated suppression of p-RhoA reduction. Additionally, CSE or 3-MST knockout in ECs exacerbated H/R-induced neuronal injury, reduced H2S level in the co-culture system, and increased RhoA activity and ROCK2 expression in neurons. In summary, TFR protected against ischemic cerebral injury by endothelial-derived H2S promoting the phosphorylation of RhoA at Ser188 but inhibited the phosphorylation of ROCK2 at Thr436 to inhibit the RhoA-ROCK2 pathway in neurons. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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19 pages, 1241 KB  
Systematic Review
Therapeutic Potential of Rho Kinase Inhibitors in Corneal Disease: A Systematic Review of Preclinical and Clinical Studies
by Laura Andreea Ghenciu, Diana Andrei, Claudia Borza, Roxana Iacob, Emil Robert Stoicescu, Sorin Lucian Bolintineanu, Daniela Iacob and Ovidiu Alin Haţegan
Biomedicines 2025, 13(7), 1602; https://doi.org/10.3390/biomedicines13071602 - 30 Jun 2025
Cited by 1 | Viewed by 1680
Abstract
Background/Objectives: Rho-associated coiled-coil-containing protein kinase inhibitors (ROCKis) have now become known as modulators of corneal endothelial wound repair and cell survival. However, evidence remains fragmented across laboratory and clinical reports. We performed a systematic review to synthesize preclinical and clinical data on ROCKis [...] Read more.
Background/Objectives: Rho-associated coiled-coil-containing protein kinase inhibitors (ROCKis) have now become known as modulators of corneal endothelial wound repair and cell survival. However, evidence remains fragmented across laboratory and clinical reports. We performed a systematic review to synthesize preclinical and clinical data on ROCKis in corneal disease, assess their efficacy and safety, and identify research gaps. Methods: We searched PubMed, Web of Science, Scopus, and Google Scholar (until May 2025) for English-language original studies evaluating ROCKis in corneal models or patients. Inclusion criteria encompassed in vitro, ex vivo, in vivo, and clinical trials reporting functional outcomes (endothelial cell density, wound closure, visual acuity). Results: Thirty-one studies met criteria: 14 preclinical studies and 17 clinical studies. Preclinical models (rabbit, porcine, human explants) uniformly showed ROCKis (Y-27632, Ripasudil, Netarsudil, H-1152) accelerate corneal endothelial cell proliferation, migration, and restoration of a hexagonal monolayer with improved barrier and pump function over days to weeks. In 17 clinical investigations, topical Ripasudil or Netarsudil and cultured cell injections achieved significant corneal thinning, endothelial cell density and central corneal thickness changes, and visual acuity improvements (≥2 lines) with minimal adverse events. Overall bias was moderate in non-randomized studies and low in the RCTs. Conclusions: ROCKis demonstrate consistent pro-regenerative effects on corneal endothelium in multiple models and show promising clinical efficacy in Fuchs endothelial dystrophy and pseudophakic endothelial failure. Future work should explore novel delivery systems and larger controlled trials to optimize dosing, safety, and long-term outcomes. Full article
(This article belongs to the Special Issue Molecular Research in Ocular Pathology)
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54 pages, 2627 KB  
Review
Calcium Signaling Dynamics in Vascular Cells and Their Dysregulation in Vascular Disease
by Chang Dai and Raouf A. Khalil
Biomolecules 2025, 15(6), 892; https://doi.org/10.3390/biom15060892 - 18 Jun 2025
Cited by 5 | Viewed by 2682
Abstract
Calcium (Ca2+) signaling is a fundamental regulatory mechanism controlling essential processes in the endothelium, vascular smooth muscle cells (VSMCs), and the extracellular matrix (ECM), including maintaining the endothelial barrier, modulation of vascular tone, and vascular remodeling. Cytosolic free Ca2+ concentration [...] Read more.
Calcium (Ca2+) signaling is a fundamental regulatory mechanism controlling essential processes in the endothelium, vascular smooth muscle cells (VSMCs), and the extracellular matrix (ECM), including maintaining the endothelial barrier, modulation of vascular tone, and vascular remodeling. Cytosolic free Ca2+ concentration is tightly regulated by a balance between Ca2+ mobilization mechanisms, including Ca2+ release from the intracellular stores in the sarcoplasmic/endoplasmic reticulum and Ca2+ entry via voltage-dependent, transient-receptor potential, and store-operated Ca2+ channels, and Ca2+ elimination pathways including Ca2+ extrusion by the plasma membrane Ca2+-ATPase and Na+/Ca2+ exchanger and Ca2+ re-uptake by the sarco(endo)plasmic reticulum Ca2+-ATPase and the mitochondria. Some cell membranes/organelles are multifunctional and have both Ca2+ mobilization and Ca2+ removal pathways. Also, the individual Ca2+ handling pathways could be integrated to function in a regenerative, capacitative, cooperative, bidirectional, or reciprocal feed-forward or feed-back manner. Disruption of these pathways causes dysregulation of the Ca2+ signaling dynamics and leads to pathological cardiovascular conditions such as hypertension, coronary artery disease, atherosclerosis, and vascular calcification. In the endothelium, dysregulated Ca2+ signaling impairs nitric oxide production, reduces vasodilatory capacity, and increases vascular permeability. In VSMCs, Ca2+-dependent phosphorylation of the myosin light chain and Ca2+ sensitization by protein kinase-C (PKC) and Rho-kinase (ROCK) increase vascular tone and could lead to increased blood pressure and hypertension. Ca2+ activation of matrix metalloproteinases causes collagen/elastin imbalance and promotes vascular remodeling. Ca2+-dependent immune cell activation, leukocyte infiltration, and cholesterol accumulation by macrophages promote foam cell formation and atherosclerotic plaque progression. Chronic increases in VSMCs Ca2+ promote phenotypic switching to mesenchymal cells and osteogenic transformation and thereby accelerate vascular calcification and plaque instability. Emerging therapeutic strategies targeting these Ca2+-dependent mechanisms, including Ca2+ channel blockers and PKC and ROCK inhibitors, hold promise for restoring Ca2+ homeostasis and mitigating vascular disease progression. Full article
(This article belongs to the Special Issue Calcium Signaling in Cell Function and Dysfunction)
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20 pages, 5381 KB  
Article
Role of Central Inflammatory and Oxidative Pathways in the Morphine Exacerbation of Cardiovascular Effects of Sepsis in Rats
by Mohamed Abdelnaby, Marwa Y. Sallam, Mai M. Helmy, Hanan M. El-Gowelli and Mahmoud M. El-Mas
Pharmaceuticals 2025, 18(6), 882; https://doi.org/10.3390/ph18060882 - 12 Jun 2025
Viewed by 839
Abstract
Background/Objectives: Sepsis remains one of the most serious and possibly fatal complications encountered in intensive care units. Considering the frequent use of narcotic analgesics in this setting, we investigated whether the cardiovascular and peripheral and central inflammatory features of sepsis could be modified [...] Read more.
Background/Objectives: Sepsis remains one of the most serious and possibly fatal complications encountered in intensive care units. Considering the frequent use of narcotic analgesics in this setting, we investigated whether the cardiovascular and peripheral and central inflammatory features of sepsis could be modified by morphine. Methods: Rats were instrumented with femoral and intracisternal (i.c.) indwelling catheters and sepsis was induced by cecal ligation and puncture (CLP). Results: The i.v. administration of morphine (3 and 10 mg/kg) significantly and dose-dependently aggravated septic manifestations of hypotension and impaired cardiac autonomic activity, as reflected by the reductions in indices of heart rate variability (HRV). Cardiac contractility (dP/dtmax) was also reduced by morphine in septic rats. The morphine effects were mostly eliminated following (i) blockade of μ-opioid receptors by i.v. naloxone and (ii) inhibition of central PI3K, MAPK-ERK, MAPK-JNK, NADPH oxidase (NADPHox), or Rho-kinase (ROCK) by i.c. wortmannin, PD98059, SP600125, diphenyleneiodonium, and fasudil, respectively. Further, these pharmacologic interventions significantly reduced the heightened protein expression of toll-like receptor 4 (TLR4) and monocyte chemoattractant protein-1 (MCP1) in brainstem rostral ventrolateral medullary (RVLM), but not cardiac, tissues of CLP/morphine-treated rats. Conclusions: Morphine worsens cardiovascular and autonomic disturbances caused by sepsis through a mechanism mediated via μ-opioid receptors and upregulated central inflammatory, chemotactic, and oxidative signals. Clinical studies are warranted to re-affirm the adverse cardiovascular interaction between opioids and the septic challenge. Full article
(This article belongs to the Special Issue Pharmacology and Toxicology of Opioids)
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12 pages, 4686 KB  
Communication
From Quiescence to Activation: The Reciprocal Regulation of Ras and Rho Signaling in Hepatic Stellate Cells
by Saeideh Nakhaei-Rad, Silke Pudewell, Amin Mirzaiebadizi, Kazem Nouri, Doreen Reichert, Claus Kordes, Dieter Häussinger and Mohammad Reza Ahmadian
Cells 2025, 14(9), 674; https://doi.org/10.3390/cells14090674 - 5 May 2025
Viewed by 1218
Abstract
Chronic liver diseases are marked by persistent inflammation and can evolve into liver fibrosis, cirrhosis, and hepatocellular carcinoma. In an affected liver, hepatic stellate cells (HSCs) transition from a quiescent to an activated state and adopt a myofibroblast-like cell phenotype. While these activated [...] Read more.
Chronic liver diseases are marked by persistent inflammation and can evolve into liver fibrosis, cirrhosis, and hepatocellular carcinoma. In an affected liver, hepatic stellate cells (HSCs) transition from a quiescent to an activated state and adopt a myofibroblast-like cell phenotype. While these activated cells play a role in supporting liver regeneration, they can also have detrimental effects on liver function as the disease progresses to fibrosis and cirrhosis. These findings highlight the dynamic switching between different signaling pathways involving Ras, Rho GTPases, and Notch signaling. Notably, two specific members of the Ras and Rho GTPases, Eras and Rnd3, are predominantly expressed in quiescent HSCs, while Mras and Rhoc are more abundant in their activated forms. In addition, this study highlights the critical role of cytosolic Notch1 in quiescent HSCs and Rock in activated HSCs. We hypothesize that distinct yet interdependent intracellular signaling networks regulate HSC fate decisions in two key ways: by maintaining HSC quiescence and homeostasis and by facilitating HSC activation, thereby influencing processes such as proliferation, transdifferentiation, and mesenchymal transition. The proposed signaling model, combined with specific methodological tools for maintaining HSCs in a quiescent state, will deepen our understanding of the mechanisms underlying chronic liver disease and may also pave the way for innovative therapies. These therapies could include small molecule drugs targeting Ras- and Rho-dependent pathways. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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Article
Poria cocos Ethanol Extract Restores MK-801-Induced Cytoskeleton Regulation in Neuro2A and IMR-32 Cells and Locomotor Hyperactivity in C57BL/6 Mice by Modulating the Rho Signaling Pathway
by Ya-Ying Chang, Cheng-Wei Lu, Tzu-Yu Lin, I-Shiang Tzeng, Yi-Chyan Chen and Mao-Liang Chen
Curr. Issues Mol. Biol. 2025, 47(5), 312; https://doi.org/10.3390/cimb47050312 - 28 Apr 2025
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Abstract
Poria cocos extract attenuates MK-801-induced hyperactivity via RhoA/ROCK1 pathway modulation in mice. Background/Objectives: Poria cocos (P. cocos), a traditional East Asian medicinal mushroom, serves as a medicine and nutritional supplement, has been used to improve sleep and mood. Its bioactive compounds [...] Read more.
Poria cocos extract attenuates MK-801-induced hyperactivity via RhoA/ROCK1 pathway modulation in mice. Background/Objectives: Poria cocos (P. cocos), a traditional East Asian medicinal mushroom, serves as a medicine and nutritional supplement, has been used to improve sleep and mood. Its bioactive compounds may regulate calcium signaling and Rho family proteins, which are linked to cytoskeletal remodeling and psychiatric symptoms. This study investigated the effects of P. cocos ethanol extract (PCEE) on Rho signaling, cytoskeleton dynamics, and behavior in MK-801-treated cells and mice. Methods: PCEE components were analyzed using HPLC. IMR-32 and Neuro2A cells were treated with MK-801 and PCEE to assess changes in F-actin (via fluorescence staining), cell migration (wound healing and Transwell assays), and Rho signaling proteins (by immunoblotting). In vivo, C57BL/6 mice received MK-801 to induce hyperactivity, followed by PCEE treatment. RhoA/ROCK1 pathway protein levels in the prefrontal cortex were analyzed. Results: PCEE reversed MK-801-induced inhibition of cell migration, F-actin disruption, and dysregulation of Rho-related proteins (RhoGDI1, RhoA, CDC42, Rac1, ROCK1, MLC2, PFN1). In mice, PCEE significantly reduced MK-801-induced hyperactivity and normalized RhoA/ROCK1 signaling in the brain. Conclusion: PCEE modulates cytoskeletal dynamics by regulating RhoA/ROCK1 signaling and attenuates MK-801-induced behavioral and molecular changes, suggesting its therapeutic potential for psychosis with fewer adverse effects. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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