Cell Reports Medicine
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2025
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IF 10.6
Jianhai Chen,Jianwei Tan,Nannan Wang,Hui Li,Wenxiang Cheng,Jian Li,Benguo Wang,Adam C. Sedgwick,Zhitong Chen,Guojun Chen,Peng Zhang,Wei Zheng,Chengbo Liu,Jingqin Chen
Rheumatoid arthritis (RA) is the most prevalent inflammatory arthritis with unknown etiology, characterized by synovial inflammation and articular bone erosion. Studies have highlighted that inhibiting macrophage-induced osteoclastogenesis holds promise in mitigating bone destruction. However, specifically halting this pathological cascade remains a challenge for the management of RA. Here, initially, we identify that Ras homolog gene family member A ( RhoA ) is a pivotal target in inducing osteoclastogenesis of macrophages. Subsequently, we develop a strategy termed specific macrophages RhoA targeting (SMART), in which phosphatidylserine (PS)-enriched macrophage membranes are engineered to deliver macrophage-specific promoter-containing CRISPR-Cas9 plasmids (SMART-Cas9), enabling targeted editing of RhoA in RA joint macrophages. Multiscale imaging techniques confirm the highly specific targeted effect of SMART-Cas9 on the macrophages of inflamed joints. SMART-Cas9 successfully reduces osteoclastogenesis by macrophages, thus mitigating bone erosion by modulating cytoskeletal dynamics and immune balance in inflammatory arthritis, representing a therapeutic avenue for RA and other inflammatory bone diseases.
研究领域:
免疫学
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分子生物学
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风湿病学
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PubMed
高影响因子
Scientific Reports
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2016
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IF 5.228
Hengli Zhao,Xuan Zhang,Zhiqiang Dai,Yang Feng,Qiang Li,John H. Zhang,Xin Liu,Yujie Chen,Hua Feng
Blockading P2X7 receptor(P2X7R) provides neuroprotection toward various neurological disorders, including stroke, traumatic brain injury, and subarachnoid hemorrhage. However, whether and how P2X7 receptor suppression protects blood-brain barrier(BBB) after intracerebral hemorrhage(ICH) remains unexplored. In present study, intrastriatal autologous-blood injection was used to mimic ICH in rats. Selective P2X7R inhibitor A438079, P2X7R agonist BzATP, and P2X7R siRNA were administrated to evaluate the effects of P2X7R suppression. Selective RhoA inhibitor C3 transferase was administered to clarify the involvement of RhoA. Post-assessments, including neurological deficits, Fluoro-Jade C staining, brain edema, Evans blue extravasation and fluorescence, western blot, RhoA activity assay and immunohistochemistry were performed. Then the key results were verified in collagenase induced ICH model. We found that endogenous P2X7R increased at 3 hrs after ICH with peak at 24 hrs, then returned to normal at 72 hrs after ICH. Enhanced immunoreactivity was observed on the neurovascular structure around hematoma at 24 hrs after ICH, along with perivascular astrocytes and endothelial cells. Both A438079 and P2X7R siRNA alleviated neurological deficits, brain edema, and BBB disruption after ICH, in association with RhoA activation and down-regulated endothelial junction proteins. However, BzATP abolished those effects. In addition, C3 transferase reduced brain injury and increased endothelial junction proteins' expression after ICH. These data indicated P2X7R suppression could preserve BBB integrity after ICH through inhibiting RhoA activation.
研究领域:
神经科学
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药理学
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分子生物学
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PubMed
高影响因子
ACS Applied Materials & Interfaces
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2025
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IF 8.2
Longwu Xu,Lin Ma,Xiufeng Xu,Yifan Wang,Qiuhong Jiao,Shulan Pang,Yuying Wang,Weiwei Yang,Shuai Mao,Yudan Zhao,Jie Hao,Tao Huang,Peikang Dong,Yingshuai Wang,Tao Wang
Aortic dissection (AD) is a life-threatening condition with a high mortality rate. Oxidative stress and endothelial and vascular smooth muscle cell migration contribute to AD pathogenesis. Herein, we investigated the therapeutic potential of hydrogen (H2), delivered via magnesium diboride nanosheets (MBNs), in a murine model of β-aminopropionitrile-induced AD. This treatment significantly improved survival rate and reduced AD progression, as evidenced by improved aortic wall structure and reduced false lumen formation. Transcriptomic analysis indicated modulation of the RhoA/ROCK pathway, confirmed using Western blotting, immunohistochemistry, and immunofluorescence, which showed significant downregulation of RhoA and ROCK2 after 28 days of treatment (P < 0.05). These findings suggest that hydrogen released from MBNs attenuates AD progression through reactive oxygen species scavenging and RhoA/ROCK pathway inhibition.
研究领域:
医学
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分子生物学
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Chenjiao Miao,Zuoyao Wu,Yafei Sun,Zheng Cao
Deoxynivalenol (DON) poses a serious global food safety risk due to its high toxicity and contamination rate. It disrupts the intestinal epithelial barrier, allowing exogenous toxins to enter the circulation and resulting in sepsis and systemic toxicity. In this research, 32 male Kunming mice and Porcine Small Intestinal Epithelial (IPEC-J2) cells were treated with DON at 0–4.8 mg/kg (7 d) and 0–12 μM (24 h), respectively. Histopathological results revealed that DON disrupted the intestinal epithelial barrier, causing apoptosis and tight junction (TJ) injury. Immunofluorescence and protein expression results showed that DON-induced p53-dependent mitochondrial pathway apoptosis and fibrillar actin (F-actin)-associated TJ injury and that the RhoA/ROCK pathway were activated in mice jejunal tissue and IPEC-J2 cells. Pretreatment with RhoA or ROCK inhibitors (Rosin or Y-27632) maintained DON-induced apoptosis and F-actin-associated TJ injury in IPEC-J2 cells. Thus, DON induces damage to the intestinal epithelial barrier through the RhoA/ROCK pathway-mediated apoptosis and F-actin-associated TJ disruption.
CAS / MDL:
研究领域:
毒理学
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细胞生物学
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食品科学
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PubMed
高影响因子
FITOTERAPIA
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2025
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IF 2.6
Xuan Zhang,Jie Weng,Yi Luo,Hongcun Liu,Jing Yan,Zhiqiang Gong,Chaonan Kong,Xue Li,Lifang Yang,Mingguo Jiang
To elucidate the efficacy and potential molecular mechanisms underlying the therapeutic effects of Spatholobi Caulis flavonoids (SCF) in the treatment of primary dysmenorrhea (PD). The present study established oxytocin-induced uterine contractions in vitro and a model of PD in rats evoked by estradiol benzoate and oxytocin. The uterine contraction experiments demonstrated that SCF significantly inhibited uterine smooth muscle tone by 62.07 %. SCF effectively attenuated the torsional response in PD rats, normalised the PGF2α/PGE2 ratio, and reduced NO and Ca 2+ levels. The constituents of SCF were evaluated by using a Liquid Chromatograph Mass Spectrometer(LC-MS) method, and 11 flavonoid components were preliminarily deduced. Network pharmacology and molecular docking (MD) techniques were used to predict therapeutic targets, with the former suggesting key targets such as RhoA, VEGFA, and PIK3CA, while the latter indicated that 10 compounds had a strong binding affinity for RhoA. The expression of CALM, RhoA, ROCK1, PIK3CA, and AKT was down-regulated at both the protein and mRNA levels. Additionally, the expression levels of genes associated with VEGFA, IP3R, MLCK and NOS3 were found to be regulated. The collective evidence from this study suggests that SCF may attenuate uterine spasm by inhibiting the RhoA/ROCK signaling pathway, decreasing the levels of PGF2α, NO and Ca 2+ , and increasing the content of PGE2. This study provides a theoretical basis for the application of SCF in the treatment of PD.
研究领域:
药理学
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分子生物学
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PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2025
·Vol. 63
·期 1
·199
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IF 4.3
Yang Huijie,Wang Fangyu,Li Qian,Li Tiange,Zhang Bei,Song Lianjun,Huang Xianqing,Liu Shuyang,Galaverna Gianni,Zhao Peijun,Bakry Ibrahim A.,Li Ning
Lead (Pb) exposure is a major environmental risk factor for neurodegenerative diseases. This study investigates the neuroprotective effects of black soybean peptides (BSPs), particularly BSP1, BSP3, and BSP4, against Pb-induced toxicity in HT22 mouse hippocampal neuron cells, with a mechanistic focus on the RhoA/MAPK signaling pathway. The rationale for targeting RhoA/MAPK stems from their established roles in mediating oxidative stress and apoptosis in Pb-related pathology. Pretreatment with BSP1 or BSP4 (200 µM) increased cell viability by approximately 35% relative to the Pb-only group. At the same time, BSPs also decreased intracellular reactive oxygen species (ROS) levels by up to 40% and malondialdehyde (MDA) by 30%. Antioxidant enzyme activities, including superoxide dismutase (SOD) and catalase (CAT), were restored to near-control levels; for example, SOD activity increased 1.8-fold compared with the Pb group. Western blot and immunofluorescence confirmed that BSPs reduced the Pb-triggered activation of RhoA, ROCK1/2, and MAPK proteins (p38, JNK, ERK). These findings demonstrate that BSPs mitigate Pb-induced neurotoxicity by enhancing antioxidant activity and targeting RhoA/MAPK signaling, highlighting their potential as functional food ingredients or therapeutic agents for neuroprotection.
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高影响因子
Toxicology Research
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2024
·Vol. 13
·期 2
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IF 2.2
Niu Junjie,Hu Jinyang,Wang Zhu
BackgroundTriple-negative breast cancer (TNBC) lacks effective therapeutic targets. Scutellaria barbata D.Don (SB) has been revealed to have anti-breast cancer (BC) effect, but the effect of SB extract in TNBC is still unclear. Herein, this research delves into the underlying mechanism.MethodsSB was extracted by solvent extraction, and the main components were identified using an Agilent 6,520 HPLC-Chip/Q-TOF (Chip/Q-TOF) MS system. In vitro cell experiments were conducted. The effects of SB extract alone, SB extract plus EGF, GSK alone, GSK plus Ezrin overexpression, or SB extract plus Ezrin overexpression on cell viability, invasion, migration, and apoptosis were examined by cell function experiments. The apoptosis- and RhoA/ROCK1 pathway-related protein levels were analyzed by western blot assay.ResultsMass spectrometry analysis exhibited that SB extract mainly contains long-chain fatty acids and ursolic acid. SB extract mitigated TNBC cell biological phenotypes, apoptosis- and RhoA/ROCK1 pathway-related marker expressions, which were reversed by EGF. The further results found that GSK obviously weakens TNBC cell biological behaviors, apoptosis- and RhoA/ROCK1 signaling-related protein levels, while oe-Ezrin treatment reverses the effect of GSK on TNBC cells. Moreover, SB extract regulated Ezrin-mediated function of TNBC cells by impeding the RhoA/ROCK1 pathway.ConclusionOur findings demonstrated that SB extract regulated Ezrin-mediated proliferation, migration, invasion, and apoptosis of TNBC cells via suppressing the RhoA /ROCK1 signaling. Our results offer the experimental foundation for further investigation of the anti-cancer role of SB in TNBC cells.HighlightsSB extract inhibits the biological phenotypes of TNBC cells.SB extract inhibits the biological behaviors of TNBC cells through the RhoA/ROCK1 pathway.SB extract modulates Ezrin-mediated TNBC cell proliferation, migration, invasion, and apoptosis via restraining the RhoA/ROCK1 signaling.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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PubMed
高影响因子
PHYTOMEDICINE
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2022
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IF 6.656
Di Zhang,Bei Jing,Zhenni Chen,Xin Li,Huimei Shi,Yachun Zheng,Shiquan Chang,Guoping Zhao
Background Nonsteroidal anti-inflammatory drugs are used to relieve sciatica, but their effects are not satisfactory. Purpose This study aimed to explore the therapeutic effects of ferulic acid on sciatica. Methods Thirty-two SD rats were randomly divided into 4 groups, i.e., sham operation group, chronic constriction injury (CCI) group, mecobalamin group, and ferulic acid group. We conducted behavioural tests, ELISA, PCR, Western blots, and immunofluorescence analysis. Specific inhibitors were used in cell experiments to explore the related mechanisms. Results Thermal hyperalgesia was induced after CCI operation, and ferulic acid relieved thermal hyperalgesia. In addition, ferulic acid decreased the IL1β, IL6, TNF-α, and CRP mRNA levels; the IBA-1, iNOS, IL1β, RhoA, RhoA-GTP, COX2, Rock1, TRPV1, TRPA1, and p-p38MAPK levels in dorsal root ganglion (DRG) neurons; and the LPS, CRP, substance P (SP), and prostaglandin E2 (PGE2) levels in serum, and these levels were higher in the CCI group. In the cell experiments, LPS induced M1 polarization of GMI-R1 cells via the RhoA/Rock pathway. Ferulic acid attenuated LPS-induced M1 polarization by decreasing the levels of M1 polarization markers, including IL1β, IL6, TNF-α, iNOS, and CD32, and increased M2 polarization by increasing the levels of M2 polarization markers, including CD206 and Arg-1. LPS treatment clearly increased the iNOS, IL1β, RhoA, Rock1, Rock2 and p-p38 MAPK levels and reduced Arg-1 expression, and ferulic acid reversed these changes. Conclusion Ferulic acid can inhibit peripheral sensitization by reducing the levels of inflammatory factors, TRPA1 and TRPV1 through the RhoA/p38 MAPK pathway to alleviate sciatica.
研究领域:
药理学
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神经科学
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免疫学
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分子生物学
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PubMed
高影响因子
Current Research in Toxicology
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2024
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IF 2.9
Yan Ma,Honggang Chen,Yuxin Jiang,Diya Wang,Michael Aschner,Wenjing Luo,Peng Su
Elevated manganese (Mn) exposure has been implicated in a broad spectrum of neurological disorders, including motor dysfunction and cognitive deficits. Previous studies have demonstrated that Mn induces neurotoxicity by disrupting the integrity of the blood–brain barrier (BBB), a critical regulator in maintaining central nervous system homeostasis and a contributing factor in the pathogenesis of numerous neurological disorders. However, the precise molecular mechanisms underlying Mn-induced BBB disruption and its role in facilitating neurotoxicity remain incompletely understood. The primary objectives of this study were to elucidate the mechanisms underlying the relationship between Mn exposure and BBB tight junction proteins (TJPs), and to further investigate potential neuroprotective strategies for mitigating Mn-induced cognitive impairments. In this investigation, we developed Mn exposure models utilizing both murine subjects and cell culture systems to elucidate the mechanisms underlying TJPs involvement and to assess the potential neuroprotective effects of gastrodin (GAS), a bioactive compound extracted from traditional Chinese medicine. Our findings revealed a significant reduction in TJPs expression, both in vivo and in vitro , in Mn-induced BBB disruption. The overexpression of Occludin (OCLN), a crucial component of TJPs, mitigated Mn-induced BBB damage. GAS administration effectively attenuated Mn-induced disruption of the BBB, enhanced the expression of TJPs, and mitigated Mn-induced cognitive dysfunctions, potentially through the modulation of the RhoA/ROCK2 signaling pathway. This research sought to advance our understanding of the molecular pathways involved in Mn-mediated BBB disruption and to identify novel therapeutic approaches for mitigating the deleterious effects of Mn exposure on cognitive function.
研究领域:
神经科学
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毒理学
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药理学
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PubMed
高影响因子
Pharmacognosy Magazine
·
2023
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IF 0.7
Guiyuan Liu,Yinliang Bai,Guangxian Leng,Hanwei Ma,Yin Kong,Liuqing Guo,Fahong Wu,Fengxian Wei,Yi Pang,Youcheng Zhang
Background:Leakage of the alveolar epithelial barrier can lead to pulmonary oedema, leading to organ dysfunction.Objectives:Combination anthraquinone (CA) and free anthraquinone (FA) were extracted from Rhubarb, and the prevention and therapeutic effects of Rhubarb anthraquinones (RA) on lipopolysaccharide (LPS)-induced lung injury were investigated.Materials and Methods:The CA and FA were extracted from Rhubarb by water solvent extraction and ethanol solvent extraction. The extracted RA content was determined using spectrophotometry and high-performance liquid chromatography (HPLC). A mouse model of inflammatory lung injury was established by LPS induction to study the mechanism of RA activity. Inflammatory factors were measured using an enzyme-linked immunosorbent assay. Changes in alveolar epithelial leakage were assessed using a permeability assay. Changes in lung injury were evaluated by histopathological and ultrastructural observations. Tight junction (TJ) markers and Ras homolog gene family member A (RhoA)/Rho-associated protein kinase 1 (ROCK1) pathway-related proteins were measured using immunohistochemistry and Western blotting. As an agonist of RhoA/Rock signalling, U46619 was used to further verify whether RA acts through this pathway.Results:RA could inhibit pulmonary inflammation by decreasing the level of inflammatory factors. The alveolar epithelial permeability was reduced, and the pathological injury of the lung tissue was alleviated after administration with RA. Furthermore, the expression of TJ proteins was up regulated and RhoA/ROCK1 signalling was inhibited in the presence of RA. The effects of RA on TJ proteins were partially reversed by U46619.Conclusion:RA effectively protects mice against inflammatory lung injury by enhancing alveolar epithelial TJ via RhoA/ROCK1 signalling.
研究领域:
药理学
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肺病学
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免疫学
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分子生物学
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高影响因子
CURRENT NEUROVASCULAR RESEARCH
·
2025
·Vol. 22
·期 1
·70-85
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IF 1.7
Ziteng Yang,Yuanqi Zuo,Guangyun Wang,Ning Wang
Introduction: The endothelial barrier is composed of brain microvascular endothelial cells (BMECs) and tight junction (TJ) proteins. Musk is a valuable ingredient in Traditional Chinese Medicine (TCM). It is used in the treatment of stroke because of its ability to induce resuscitation. The core component of musk is muscone. Previous studies have evidenced that muscone may be involved in the treatment of ischemic stroke (IS), but the underlying mechanism is still unclear. The main objective of this study was to explore the protective effect of muscone on OGD/R-induced endothelial barrier disruption and determine its underlying mechanism. Methods: OGD/R-induced damage to BMECs was assessed using the MTT and LDH assays. The apoptosis level in BMECs was determined using western blot and Hoechst staining. Western blot, immunofluorescence, and phalloidin staining were used to assess the expressions of TJ proteins and pathway proteins expression. A monolayer cell barrier was constructed using BMECs in vitro, and the permeability of the barrier was assessed by TEER as well as the transmissivity of sodium fluorescein. Molecular docking, DARTS, and CETSA were used to verify the regulatory effect of muscone on the pathway. Results: Muscone reduced OGD/R-induced apoptosis of BMEC cells, inhibited the degradation of TJ proteins, promoted the coherent expression of ZO-1 on the membrane, and restored TEER. Mechanistic studies showed that H-89 reversed the promoting effects of muscone on pathway proteins and promoted the disassembly of the actin cytoskeleton, which, in turn, promotes BMEC apoptosis and TJ protein degradation, ultimately disrupting the endothelial barrier. Discussion: The inhibition of BMEC apoptosis and improvement of endothelial barrier damage by muscone may be an important mechanism for treating ischemic stroke. Conclusion: We demonstrated that muscone could reduce OGD/R-induced hyperpermeability of the brain endothelial barrier by activating the PKA/RHOA/MLC pathway.
研究领域:
神经科学
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药理学
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中医中药
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Animal Models and Experimental Medicine
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2024
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IF 3.8
Ce Zhang,Jia Zheng,Xueping Yu,Binglin Kuang,Xiaohong Dai,Lei Zheng,Weiwei Yu,Wei Teng,Hongtao Cao,Mingyue Li,Jiayong Yao,Xiaoying Liu,Wei Zou
Background Blocking the RhoA/ROCK II/MLC 2 (Ras homolog gene family member A/Rho kinase II/myosin light chain 2) signaling pathway can initiate neuroprotective mechanisms against neurological diseases such as stroke, cerebral ischemia, and subarachnoid hemorrhage. Nevertheless, it is not clear whether and how disrupting the RhoA/ROCK II/MLC 2 signaling pathway changes the pathogenic processes of the blood–brain barrier (BBB) after intracerebral hemorrhage (ICH). The present investigation included the injection of rat caudal vein blood into the basal ganglia area to replicate the pathophysiological conditions caused by ICH. Methods Scalp acupuncture (SA) therapy was performed on rats with ICH at the acupuncture point “Baihui”-penetrating “Qubin,” and the ROCK selective inhibitor fasudil was used as a positive control to evaluate the inhibitory effect of acupuncture on the RhoA/ROCK II/MLC 2 signaling pathway. Post-assessments included neurological deficits, brain edema, Evans blue extravasation, Western blot, quantitative polymerase chain reaction, and transmission electron microscope imaging. Results We found that ROCK II acts as a promoter of the RhoA/ROCK II/MLC 2 signaling pathway, and its expression increased at 6 h after ICH, peaked at 3 days, and then decreased at 7 days after ICH, but was still higher than the pre-intervention level. According to some experimental results, although 3 days is the peak, 7 days is the best time point for acupuncture treatment. Starting from 6 h after ICH, the neurovascular structure and endothelial cell morphology around the hematoma began to change. Based on the changes in the promoter ROCK II, a 7-day time point was selected as the breakthrough point for treating ICH model rats in the main experiment. The results of this experiment showed that both SA at “Baihui”-penetrating “Qubin” and treatment with fasudil could improve the expression of endothelial-related proteins by inhibiting the RhoA/ROCK II/MLC 2 signaling pathway and reduce neurological dysfunction, brain edema, and BBB permeability in rats. Conclusion This study found that these experimental data indicated that SA at “Baihui”-penetrating “Qubin” could preserve BBB integrity and neurological function recovery after ICH by inhibiting RhoA/ROCK II/MLC 2 signaling pathway activation and by regulating endothelial cell–related proteins.
研究领域:
神经科学
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中医学
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分子生物学
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PubMed
高影响因子
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