MICROBIAL PATHOGENESIS
·
2025
·
IF 3.5
Kai Liu,Hong Sun,Hong Wang,Junbo Zheng,Xiuzhen Wang,Xin Wang,Yeting Hou,Qian Ye,Ji Li
Sepsis is a systemic inflammatory response syndrome triggered by infection. Severe sepsis is associated with dysbiosis of the intestinal flora and impaired intestinal function. Ellagic acid (EA) is a natural compound known for its ability to inhibit bacteria and viruses, thereby preventing infections. However, it remains unclear whether EA mitigates intestinal barrier dysfunction. In this work, BALB/c mice were administered doses of EA via gavage, followed by an injection of lipopolysaccharide (LPS) to induce sepsis. Fecal samples, serum, and ileum tissues were collected for molecular or pathological analysis. The intestinal contents underwent 16S rRNA sequencing and targeted metabolomics for short-chain fatty acids (SCFAs) detection. Additionally, an in vitro injury model was established using IEC6 cells treated with LPS; subsequent changes in inflammation and oxidative stress were assessed following EA treatment. The results indicated that EA reduced inflammation and oxidative stress as well as ameliorated intestinal lesions and enhanced intestinal barrier function in both mouse and cell models. Moreover, EA inhibited the signaling of nuclear factor kappa-light-chain-enhancer of activated B cells/myosin light chain kinase/myosin light chain (NF-κB/MLCK/MLC) pathway. Besides, EA also rectified genomic and metabolomic disturbances within the gut microbiota caused by sepsis. In conclusion, EA mitigates sepsis-induced intestinal injury through modulation of gut microbiota composition and inhibition of NF-κB-mediated MLCK/MLC signaling pathway. Thus, EA might represent a promising therapeutic agent for addressing intestinal injuries associated with sepsis.
研究领域:
药理学
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微生物学
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免疫学
·
分子生物学
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重症医学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
CURRENT NEUROVASCULAR RESEARCH
·
2025
·Vol. 22
·期 1
·70-85
·
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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产品关联
DOI
PubMed
高影响因子
Animal Models and Experimental Medicine
·
2024
·
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
·
中医学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2020
·Vol. 11
·期 4
·3741-3748
·
IF 4.171
Wei Li,Mingbo Gao,Ting Han
Impairment of the intestinal barrier often occurs in inflammatory bowel diseases, and pro-inflammatory factors play a vital role in the pathogenesis of intestinal diseases. In our study, the potential protective effects of Lycium barbarum polysaccharides (LBP) against intestinal barrier dysfunction evoked by pro-inflammatory factors and its anti-inflammatory effects were investigated. Caco-2 cells were stimulated with or without tumor necrosis factor (TNF)-α in the presence or absence of LBP. Our findings showed that LBP assuaged the increase of paracellular permeability and the decrease of transepithelial electrical resistance (TER) in Caco-2 cells. In addition, LBP also prevented the secretion of pro-inflammatory markers (IL-8, IL-6, ICAM-1 and MCP-1) in TNF-α-challenged Caco-2 cells. Moreover, LBP inhibited the overexpression of tight junction (TJ) proteins (claudin-1, ZO-3, and occludin) and the increase of MLCK, pMLC, p-IκBα and NFκBp65 protein expression evoked by TNF-α was suppressed by LBP pre-incubation. This finding indicated that LBP improve TNF-α-evoked intestinal barrier dysfunction via suppressing the MLCK-MLC signaling pathway mediated by NFκB.
研究领域:
药理学
·
胃肠病学
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细胞生物学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 23
·12810
·
IF 4.9
Xiaoyu Gao,Kaifeng Guo,Shuangfeng Liu,Weixing Yang,Jun Sheng,Yang Tian,Lei Peng,Yan Zhao
Vidarabine (VID) is an antiviral medication that is commonly utilized to treat conditions such as hand, foot, and mouth disease and herpes. Constipation is a prevalent complication of these diseases. Could VID treat these diseases by influencing defecation behavior? To date, no studies have been conducted on the potential of VID to relieve constipation. Therefore, a systematic investigation was conducted into the laxative effects and mechanisms of VID using loperamide-induced functional constipated mice. The findings indicate that the oral administration of VID promoted gastrointestinal peristalsis, improved fecal properties, facilitated defecation, and demonstrated a significant laxative effect on functional constipated mice. It has been demonstrated that VID may increase the water content of feces by regulating the expression of aquaporins (AQP3, AQP4, andAQP8) in the colon and promote intestinal motility by regulating the expression of neurotransmitters (AChE and VIP) and the adenosine A2A receptor–myosin light chain (A2AR-MLC) signaling pathway in constipated mice. Concurrently, VID may also reduce colonic inflammation in constipated mice, reinforce the gut barrier function, and alter the composition and structure of the gut microbial community. Some microbial taxa, including Firmicutes andLactobacillus, were found to be associated with the alleviation of constipation, while other taxa, including Bacteroidetes, Proteobacteria, Muribaculaceae,Muribaculum,norank__f__Desulfovibrionaceae, andParasutterella, were found to be associated with constipation. These results indicate that the gut microbiota may play a significant role in the alleviation of constipation by VID. These findings confirm the efficacy of VID in a constipated animal model, which justifies further investigation into its potential clinical applications.
研究领域:
药理学
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胃肠病学
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微生物学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2021
·Vol. 23
·期 5
·1-9
·
IF 2.952
Yang Yao,Ranyuan Luo,Shu Xiong,Chang Zhang,Yukun Zhang
Intestinal inflammation frequently occurs alongside dysmotility, which is characterized by altered myosin light chain phosphorylation levels. Curcumin, an active component from the ginger family, is reported to confer anti‑inflammatory effects. However, the effects of curcumin on both diarrhea and constipation associated inflammation remains to be elucidated. The present study was designed to investigate the effects of curcumin on diarrhea and constipation and to determine the related mechanisms. Sprague‑Dawley rats were used to establish diarrhea and constipation models via intracolonic acetic acid (4%) instillation or cold water gavage for 2 weeks, respectively. Blood samples were collected to measure the serum levels of the cytokines TNF‑α and IL‑1β using ELISA kits. Western blotting was performed to measure NF‑κB, RhoA, Rho‑related kinase 2, phosphorylated MLC20, phosphorylated myosin phosphorylated target subunit 1, 130k Da‑MLC kinase (MLCK), c‑kit tyrosine kinase protein expression, and reverse transcription‑quantitative PCR was conducted to measure MLCK expression levels. The results indicated that curcumin reversed the elevations in the pro‑inflammatory cytokines IL‑1β and TNF‑α by inhibiting the NF‑κB pathway in rats with diarrhea and constipation. The results also indicated that myosin light chain (MLC) phosphorylation in intestinal smooth muscle was positively and negatively associated with the motility of inflammation‑related diarrhea and constipation in rats, respectively. Curcumin significantly reversed the increased MLC phosphorylation in the jejunum of the rats with diarrhea, significantly enhanced the reductions in inflammatory mediators, including TNF‑α and IL‑1β, of rats with constipation and significantly ameliorated the related hyper‑motility and hypo‑motility in rats with both diarrhea and constipation. In conclusion, the potential roles of the MLC kinase, c‑kit tyrosine and Rho A/Rho‑associated kinase 2 pathways, which are involved in curcumin‑induced amelioration of inflammation‑related diarrhea and constipation, were explored in the present study. Results from the present study suggested that curcumin has potential therapeutic value for treating intestinal inflammation and inflammation‑related motility disorders.
研究领域:
药理学
·
胃肠病学
·
炎症
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2021
·
IF 3.575
Dequan Kong,Baoying Xie,Yuhang Li,Yaping Xu
Palmitoylethanolamide (PEA) offers a strong protection against BBB disruption and neurological deficits after cerebral ischaemic/reperfusion (I/R) injury. To date, these BBB protective effects of PEA are mainly attributed to PPARα-mediated actions. However, whether PEA protects against BBB disruption through direct regulation of cytoskeletal microfilaments remains unknown. Here, we identified PEA as a Rho-associated protein kinase (ROCK2) inhibitor (IC 50 = 38.4 ± 4.8 μM). In vitro data suggested that PEA reduced the activation of ROCK/MLC signaling and stress fiber formation within microvascular endothelial cells (ECs) after oxygen-glucose deprivation (OGD), and consequently attenuated early (0–4 h) EC barrier disruption. These actions of PEA could not be blocked by the PPARα antagonist GW6471. In summary, the present study described a previously unexplored role of PEA as a ROCK2 inhibitor, and propose a PPARα-independent mechanism for pharmacological effects of PEA.
研究领域:
神经科学
·
药理学
·
细胞生物学
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DOI
PubMed
高影响因子
MEDIATORS OF INFLAMMATION
·
2021
·
IF 4.711
Huan Lan,Lu-Ying Zhang,Wen He,Wan-Ying Li,Zhen Zeng,Bo Qian,Chengqiang Wang,Jia-Le Song
The integrity and permeability of the intestinal epithelial barrier are important indicators of intestinal health. Impaired intestinal epithelial barrier function and increased intestinal permeability are closely linked to the onset and progression of various intestinal diseases. Sinapic acid (SA) is a phenolic acid that has anti-inflammatory, antihyperglycemic, and antioxidant activities; meanwhile, it is also effective in the protection of inflammatory bowel disease (IBD), but the specific mechanisms remain unclear. Here, we evaluated the anti-inflammatory of SA and investigated its potential therapeutic activity in LPS-induced intestinal epithelial barrier and tight junction (TJ) protein dysfunction. SA improved cell viability; attenuated epithelial permeability; restored the protein and mRNA expression of claudin-1, ZO-1, and occludin; and reversed the redistribution of the ZO-1 and claudin-1 proteins in LPS-treated Caco-2 cells. Moreover, SA reduced the inflammatory response by downregulating the activation of the TLR4/NF-κB pathway and attenuated LPS-induced intestinal barrier dysfunction by decreasing the activation of the MLCK/MLC pathway. This study demonstrated that SA has strong anti-inflammatory activity and can alleviate the occurrence of high intercellular permeability in Caco-2 cells exposed to LPS.
研究领域:
药理学
·
免疫学
·
细胞生物学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
·
2023
·Vol. 14
·期 14
·6482-6495
·
IF 6.1
Wei Liu,Yuan-Yuan Liu,Meng-Qiu Zhang,Miao-Zhen Qin,Yuan-Yuan Yang,Bi-Wen Liu,Dong-Jian Zhang,Cui-Hua Jiang,Zhi-Qi Yin,Min Lu,Jian-ping Shen,Jian Zhang
As a dietary supplement, hyaluronic acid (HA) has exhibited appreciable immunomodulatory activity and an ameliorative effect on rodent colitis. However, its high viscosity is not only refractory to absorb through the gut, but also causes flatulence. In contrast to HA, hyaluronic acid oligosaccharides (o-HAs) can overcome the above-mentioned constraints, but their treatment effect still remains ill-defined contemporarily. Herein, the current study intends to compare the modulatory effects of HA and o-HA on colitis and assess the underlying molecular mechanism. We first showed that o-HA had a better preventive effect than HA in alleviating colitis symptoms, as evidenced by lower body weight loss, lower disease activity index scores, a lower inflammatory response (TNF-α, IL-6, IL-1β, p-NF-κB), and more intact colon epithelial integrity in vivo. The best efficiency was observed in the o-HA treated group with a dosage of 30 mg kg−1. In an in vitro barrier function assay, o-HA exerted a better protective effect on the transepithelial electrical resistance (TEER), FITC permeability, and wound healing and modulated the expression of tight junction (TJ) proteins (ZO-1, occludin) in lipopolysaccharide (LPS)-stimulated Caco-2 cells. In summary, both HA and o-HA showed the potential to reduce inflammation and ameliorate intestinal damage in DSS-induced colitis and LPS-induced inflammation, but o-HA had improved outcomes. The results also provided a glimpse of the latent mechanism by which HA and o-HA enhanced intestinal barrier function via MLCK/p-MLC signaling pathway suppression.
研究领域:
药理学
·
免疫学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2016
·Vol. 37
·期 8
·1091-1100
·
IF 3.166
Xiong Yong-jian,Chu Hong-wei,Lin Yuan,Han Fang,Li Ya-chan,Wang Ai-guo,Wang Fu-jin,Chen Da-peng,Wang Jing-yu
Aim: Postoperative ileus (POI) is a postoperative dysmotility disorder of gastrointestinal tract, which remains one of the most perplexing problems in medicine. In the present study we investigated the effects of hesperidin, a major flavonoid in sweet oranges and lemons, on POI in rats. Methods: SD rats were administered hesperidin (5, 20, and 80 mg·kg −1 ·d −1 , ig) for 3 consecutive days. POI operation (gently manipulating the cecum for 1 min) was performed on d 2. The gastrointestinal motility and isolated intestinal contraction were examined 1 d after the operation. Then the myosin phosphorylation and inflammatory responses in cecum tissue were assessed. Smooth muscle cells were isolated from rat small intestine for in vitro experiments. Results: The gastric emptying and intestinal transit were significantly decreased in POI rats, which were reversed by administration of hesperidin. In ileum and cecum preparations of POI rats in vitro , hesperidin (2.5–160 μmol/L) dose-dependently increased the spontaneous contraction amplitudes without affecting the contractile frequency, which was blocked by the myosin light chain kinase (MLCK) inhibitor ML-7 or verapamil, but not by TTX. Furthermore, administration of hesperidin increased the phosphorylation of MLC 20 in the cecum tissue of POI rats. Moreover, administration of hesperidin reversed the increased levels of inflammatory cytokines, iNOS and COX-2 in cecum tissue of POI rats. In freshly isolated intestinal smooth muscle cells, hesperidin (5–80 μmol/L) dose-dependently increased the intracellular Ca 2+ concentration as well as the phosphorylation of MLC 20 , which was abrogated by ML-7 or siRNA that knocked down MLCK. Conclusion: Oral administration of hesperidin effectively alleviates rat POI through inhibition of inflammatory responses and stimulation of Ca 2+ -dependent MLC phosphorylation.
研究领域:
药理学
·
胃肠病学
·
外科
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Genjiang Zheng,Chen Yang,Wei Yu,Ye Tian,Zeng Xu,Jia Liu,Shatong He,Yunhao Wang,Zhihao Yue,Xiaodong Wu,Hongyu Zhou,Bo Hu,Wei-En Yuan,Huajiang Chen
Paralysis resulting from spinal cord injury (SCI) arises from the limited regenerative capacity of axons. Mechanical factors have recently emerged as crucial regulators of axon regeneration, complementing or even surpassing chemical cues. In this study, we demonstrated that extracellular matrix stiffness, a key mechanical signal, not only modulated the regenerative capacity of neuronal axons in spinal cord with aging, but significantly fine-tuned axon pathfinding through negative-durotaxis pattern. So, it is imperative to develop a scaffold with biomimetic mechanical guidance properties to promote neural axon regeneration after SCI. Strikingly, inspired by the robust adhesive mechanism of mussels, we developed a facile strategy to synthesize catechol-modified HAMA hydrogel (HAMA@CA) that mimics native spinal cord tissue properties, effectively modulates the biomechanical microenvironment, enhances tissue–implant adhesion, and ultimately promotes spinal cord integration after SCI. Mechanistically, HAMA@CA hydrogel regulates neuronal axon pathfinding following a negative durotaxis pattern, coinciding with changes in mechanosensitive signaling and actomyosin contractility via the Piezo1/RhoA/MLC pathway. RNA-seq analysis also confirms mechanical-mediated SCI repairing by HAMA@CA. These results demonstrates that HAMA@CA rationally combined with mechanical and biochemical cues create promising tissue-engineered strategies to facilitate the repair of SCI. This innovative strategy holds significant promise for future clinical applications in the field.
研究领域:
神经科学
·
生物医学工程
·
组织工程
·
机械生物学
·
再生医学
✓ 已验证
产品关联
DOI
高影响因子
EUROPEAN JOURNAL OF CELL BIOLOGY
·
2024
·
IF 4.5
Yiheng Zhang,Mulan Xing,Fansheng Meng,Ling Zhu,Qingchuan Huang,Tianle Ma,Huihua Fang,Xujing Gu,Suzhou Huang,Xinyu Wu,Gaohong Lv,Jun Guo,Li Wu,Xin Liu,Zhipeng Chen
In the development of chronic liver disease, the hepatic stellate cell (HSC) plays a pivotal role in increasing intrahepatic vascular resistance (IHVR) and inducing portal hypertension (PH) in cirrhosis. Our research demonstrated that HSC contraction, prompted by angiotensin II (Ang II), significantly contributed to the elevation of type I collagen (COL1A1) expression. This increase was intimately associated with enhanced cell tension and YAP nuclear translocation, mediated through α-smooth muscle actin (α-SMA) expression, microfilaments (MF) polymerization, and stress fibers (SF) assembly. Further investigation revealed that the Rho/ROCK signaling pathway regulated MF polymerization and SF assembly by facilitating the phosphorylation of cofilin and MLC, while Ca 2+ chiefly governed SF assembly via MLC. Inhibiting α-SMA-MF-SF assembly changed Ang II-induced cell contraction, YAP nuclear translocation, and COL1A1 expression, findings corroborated in cirrhotic mice models. Overall, our study offers insights into mitigating IHVR and PH through cell mechanics, heralding potential breakthroughs.
研究领域:
肝病学
·
细胞生物学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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