NEUROSCIENCE
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2024
·
IF 2.9
Xinyue Zhang,Xiao Wang,Le Yin,Dan Wang,Hong Jiao,Xiaodan Liu,Jiaolin Zheng
HECT domain and Ankyrin repeat-containing E3 ubiquitin protein ligase 1 (HACE1) is an E3 ubiquitin ligase involving oxidative stress, an important contributor in cerebral ischemia–reperfusion injury (CIRI). It was proposed to be associated with the PI3K/AKT pathway and Nrf2 nuclear translocation, which are important players of oxidative stress. Therefore, we supposed that HACE1 might affect CIRI by regulating the PI3K/AKT/Nrf2 pathway. Here, we used the transient middle cerebral artery occlusion-reperfusion (tMCAO/R) model to induce CIRI in rats and found lower HACE1 expression in ischemic rats compared with the control. To explore the exact role of HACE1, the lentivirus vector carrying the HACE1 sequence was administrated to rats by intracerebroventricular injection (1 × 10 9 TU/mL, 9 μL) one week before tMCAO/R operation. HACE1 overexpression alleviated tMCAO/R-induced brain damage in rats. Further studies revealed that it reduced oxidative stress via activating the PI3K/AKT/Nrf2 pathway, thereby inhibiting neuronal apoptosis in the ischemic penumbra of rats with CIRI. Then, differentiated PC12 cells were cultured in oxygen-glucose deprivation-reoxygenation (OGD/R) conditions (OGD: 1 % O 2 , 94 % N2, and 5 % CO 2 ; R: normal atmosphere) to simulate CIRI in vitro . Similarly, HACE1 overexpression inhibited neuronal apoptosis caused by OGD/R treatment. The PI3K inhibitor LY294002 reversed the inhibitory effects of HACE1 overexpression on oxidative stress in OGD/R-injured cells, accompanied by the inactivated AKT/Nrf2 pathway. Altogether, our results suggest that HACE1 protects against oxidative stress-induced neuronal apoptosis in CIRI by activating the PI3K/AKT/Nrf2 pathway, providing a new insight into the CIRI treatment.
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FOOD AND CHEMICAL TOXICOLOGY
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2025
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IF 3.5
Ziyang Huang,Ruijia Xu,Zhongjun Wan,Chao Liu,Jinquan Li,Jun He,Li Li
Cadmium (Cd) is a prevalent heavy metal pollutant known to cause lung damage. However, the mechanisms underlying Cd-induced lung injury and the associated therapeutic strategies remain unclear. By establishing Cd-induced lung damage models both in vivo and in vitro , we observed that Cd inhibited the Nrf2/HO-1 signaling pathway, disrupted the redox balance in lung tissue, accelerated endoplasmic reticulum (ER) stress, and promoted ferroptosis, ultimately leading to lung injury. Melatonin (Mel), a potent reactive oxygen species (ROS) inhibitor with high antioxidative efficacy, mitigated the increasing in ROS and the decreasing in superoxide dismutase levels induced by Cd, as well as the upregulation of PERK-eIF2α-ATF4 signaling associated with ER stress, through the activation of the Nrf2/HO-1 signaling pathway. Furthermore, Mel administration not only prevented Cd-induced iron overload but also reduced lipid peroxidation levels, thereby improving mitochondrial morphological alterations. Collectively, our results demonstrated that Mel treatment alleviated Cd-induced lung injury by inhibiting oxidative stress, which in turn ameliorated ER stress and ferroptosis through the activation of the Nrf2/HO-1 pathway.
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International Journal of Nanomedicine
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2024
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IF 6.6
Tingting Chen,Zimei Wu,Qiaodan Hou,Yixin Mei,Kunkun Yang,Jing Xu,Lin Wang
Purpose Given the escalating prevalence of diabetes, the demand for specific bone graft materials is increasing, owing to the greater tendency towards bone defects and more difficult defect repair resulting from diabetic bone disease (DBD). Melatonin (MT), which is known for its potent antioxidant properties, has been shown to stimulate both osteogenesis and angiogenesis.Methods MT was formulated into MT@PLGA nanoparticles (NPs), mixed with sodium alginate (SA) hydrogel, and contained within a 3D printing polycaprolactone/β-Tricalcium phosphate (PCL/β-TCP) scaffold. The osteogenic capacity of the MT nanocomposite scaffold under diabetic conditions was demonstrated via in vitro and in vivo studies and the underlying mechanisms were investigated.Results Physicochemical characterization experiments confirmed the successful fabrication of the MT nanocomposite scaffold, which can achieve long-lasting sustained release of MT. The in vitro and in vivo studies demonstrated that the MT nanocomposite scaffold exhibited enhanced osteogenic capacity, which was elucidated by the dual angiogenesis effects activated through the NF-E2–related factor 2/Heme oxygenase 1 (Nrf2/HO-1) signaling pathway, including the enhancement of antioxidant enzyme activity to reduce the oxidative stress damage of vascular endothelial cells (VECs) and directly stimulating vascular endothelial growth factor (VEGF) production, which reversed the angiogenesis-osteogenesis uncoupling and promoted osteogenesis under diabetic conditions.Conclusion This study demonstrated the research prospective and clinical implications of the MT nanocomposite scaffold as a novel bone graft for treating bone defect and enhancing bone fusion in diabetic individuals.
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ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2024
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IF 3.8
Feng-Xia Qu,Xiao Guo,Xiao-Jun Liu,Shu-Wen Zhang,Yue Xin,Jing-Yuan Li,Rong Wang,Chen-Ji Xu,Hai-Ying Li,Chang-Hong Lu
Myocardial infarction (MI) is the primary source of death in cardiovascular diseases. Myricitrin (MYR) is a phenolic compound known for its antioxidant properties. This study aimed to investigate the impact of MYR alone or combined with exercise on a rat model of MI and its underlying mechanism. Sprague-Dawley rats were randomized into 5 groups: sham-operated (Sham), MI-sedentary (MI-Sed), MI-exercise (MI-Ex), MI-sedentary + MYR (MI-Sed-MYR) and MI-exercise + MYR (MI-Ex-MYR). MI was induced through ligation of left anterior descending coronary artery. The treatment with exercise or MYR (30 mg/kg/d) gavage began one week after surgery, either individually or in combination. After 8 weeks, the rats were assessed for cardiac function. Myocardial injuries were estimated using triphenyltetrazolium chloride, sirius red and Masson staining. Changes in reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔΨm), apoptosis and Nrf2/HO-1 pathway were analyzed by ROS kit, JC-1 kit, TUNEL assay, western blot and immunohistochemistry. Both MYR and exercise treatments improved cardiac function, reduced infarct size, suppressed collagen deposition, and decreased myocardial fibrosis. Additionally, both MYR and exercise treatments lowered ROS production induced by MI, restored ΔΨm, and attenuated oxidative stress and apoptosis in cardiomyocytes. Importantly, the combination of MYR and exercise showed greater efficacy compared to individual treatments. Mechanistically, the combined intervention activated the Nrf2/HO-1 signaling pathway. These findings suggest that the synergistic effect of MYR and exercise may offer a promising therapeutic approach for alleviating MI.
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JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Song-Xue Yang,Wei-Lie Xiao,Xing-Jie Zhang
Ethnopharmacological relevance The root of Saposhnikovia divaricata has been traditionally used in Chinese medicine to treat inflammation and immune related skin diseases, such as skin allergy and itchy rash. However, scientific research supporting its efficacy, particularly in curing inflammation from acne, is still scarce. Aim of the study To evaluate the therapeutic effects of essential oil of Saposhnikovia divaricata (EOSD) on Cutibacterium acnes ( C. acnes )-induced acne and investigate its mechanisms. Materials and Methods An acute acne model was established by injecting C. acnes into mouse ears, followed by topical EOSD treatment (0.25 %, 0.5 % and 1 %). Ear tissues were analyzed 24 hours post-treatment. In vitro, C. acnes -stimulated J774A.1 macrophages were treated with EOSD (3, 10 and 30 μg/ml) to assess mitochondrial damage, oxidative stress, and inflammatory responses. Key markers were analyzed using electron microscopy, real-time PCR, immunoblotting, ELISA, and immunofluorescence. Nrf2 knockdown was achieved via siRNA transfection. Results C. acnes suppressed Nrf2 activation, increased ROS levels, and triggered NLRP3 inflammasome activation, leading to inflammation. EOSD restored Nrf2 activity, reduced ROS levels, and inhibited NLRP3 activation. In vitro, EOSD disrupted Nrf2/Keap1 interaction, enhanced Nrf2 nuclear translocation, reduced mitochondrial damage, and suppressed pyroptosis by downregulating IL-1β, Caspase-1, GSDMD, and NF-κB signaling. These effects were reversed by Nrf2 knockdown. Conclusion EOSD alleviates oxidative stress and modulates NLRP3 inflammasome activation through upregulating Nrf2 pathway and inhibiting NF-κB pathway, as well as improving mitochondrial homeostasis and inflammatory responses in acne. These findings suggest that EOSD may be a promising therapeutic agent for the treatment of acne vulgaris.
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MOLECULAR NEUROBIOLOGY
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2024
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IF 4.6
Xu Yao,Liu Yongsheng,Wu Yan,Sun Jingshan,Lu Xiaocheng,Dai Kun,Zhang Yiting,Luo Chengliang,Zhang Jian
Early brain injury caused by subarachnoid hemorrhage (SAH) is associated with inflammatory response and ferroptosis. Curcumin alleviates neuroinflammation and oxidative stress by as yet unknown neuroprotective mechanisms. The objective of this study was to investigate the impact of curcumin on neuronal ferroptosis and microglia-induced neuroinflammation following SAH. By examining Nrf2/HO-1 expression levels and ferroptosis biomarkers expression both in vitro and in vivo, it was demonstrated that curcumin effectively suppressed ferroptosis in neurons after SAH through modulation of the Nrf2/HO-1 signaling pathway. Furthermore, by analyzing the expression levels of Nrf2, HO-1, p-p65, and inflammation-related genes, it was confirmed that curcumin could prevent the upregulation of pro-inflammatory factors following SAH by regulating the Nrf2/HO-1/NF-κB signaling pathway in microglia. The ability of curcumin to reduce neuronal damage and cerebral edemas after SAH in mice was validated using TUNEL staining, Nissl staining, and measurement of brain tissue water content. Additionally, through implementation of the modified Garcia test, open field test, and Y-maze test, it was established that curcumin ameliorated neurobehavioral impairments in mice post-SAH. Taken together, these data suggest that curcumin may offer a promising therapeutic approach for improving outcomes following SAH by concurrently attenuating neuronal ferroptosis and reducing neuroinflammation. Graphical Abstract
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Antioxidants
·
2020
·Vol. 9
·期 9
·783
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IF 5.014
Bowen Sun,Xifan Wang,Xiaoxue Liu,Longjiao Wang,Fazheng Ren,Xiaoyu Wang,Xiaojing Leng
Chronic kidney disease (CKD) is characterized by the accumulation of protein-bound uremic toxins (PBUTs), which play a pathophysiological role in renal fibrosis (a common pathological process resulting in CKD progression). Accumulation of the PBUT hippuric acid (HA) is positively correlated with disease progression in CKD patients, suggesting that HA may promote renal fibrosis. Oxidative stress is the most important factor affecting PBUTs nephrotoxicity. Herein, we assessed the ability of HA to promote kidney fibrosis by disrupting redox homeostasis. In HK-2 cells, HA increased fibrosis-related gene expression, extracellular matrix imbalance, and oxidative stress. Additionally, reactive oxygen species (ROS)-mediated TGFβ/SMAD signaling contributed to HA-induced fibrotic responses. HA disrupted antioxidant networks by decreasing the levels of nuclear factor erythroid 2-related factor 2 (NRF2), leading to ROS accumulation and fibrotic responses, as evidenced by NRF2 activation and knockdown. Moreover, NRF2 levels were reduced by NRF2 ubiquitination, which was regulated via increased interactions of Kelch-like ECH-associated protein 1 with Cullin 3 and NRF2. Finally, renal fibrosis and redox imbalance promoted by HA were confirmed in rats. Importantly, sulforaphane (NRF2 activator) reversed HA-promoted renal fibrosis. Thus, HA promotes renal fibrosis in CKD by disrupting NRF2-driven antioxidant system, indicating that NRF2 is a potential therapeutic target for CKD.Keywords:hippuric acid;protein-bound uremic toxin;renal fibrosis;oxidative stress;antioxidation;NRF2;NRF2 ubiquitination
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ACS Applied Materials & Interfaces
·
2023
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IF 9.5
Fengxian Luo,Beiwei Zhu,Di Wu,Yu Xu,Tao Chen,Yanfei Li,Jiangning Hu
Acute liver injury (ALI) is a severe health condition with limited treatment options. Phlorotannin (PT), a natural compound extracted from seaweeds, has shown potential in improving liver function. However, its poor stability and bioavailability have limited its applications in vivo. In this study, we developed PT-based nanoparticles (NPs) through a Mannich reaction with glycine, which exhibited good biocompatibility and prolonged circulation time in vivo. Our results revealed that the PT NPs possess strong free radical scavenging ability, effectively reducing reactive oxygen species (ROS) and alleviating oxidative stress and proinflammatory responses in the H2O2-induced oxidative damage model of HepG2 cells. Furthermore, the PT NPs effectively attenuated oxidative stress and inflammation in the liver tissue of carbon tetrachloride (CCl4)-induced liver injury mice by regulating the Nrf2/HO-1 signaling pathway. In summary, our results suggested that the PT NPs could serve as a promising nano-therapeutic strategy for alleviating ALI.
研究领域:
药理学
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纳米技术
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肝病学
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International Journal of Nanomedicine
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2024
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IF 6.6
Zixia Wu,Weibo Xia,Liling Ou,Ling Zheng,Bingying Hou,Tonghe Pan,Wenjie Sun,Leo H Koole,Yongqing Shao,Lei Qi
Purpose Patients afflicted with dry eye disease (DED) experience significant discomfort. The underlying cause of DED is the excessive accumulation of ROS on the ocular surface. Here, we investigated the nitrogen doped-graphene quantum dots (NGQDs), known for their ROS-scavenging capabilities, as a treatment for DED.Methods NGQDs were prepared by using citric acid and urea as precursors through hydrothermal method. The antioxidant abilities of NGQDs were evaluated through: scavenging the ROS both extracellular and intracellular, regulating the nuclear factor-erythroid 2-related factor (Nrf2) antioxidant pathway of human corneal epithelial cells (HCECs) and their transcription of inflammation related genes. Furthermore, NGQDs were modified by Arg-Gly-Asp-Ser (RGDS) peptides to obtain RGDS@NGQDs. In vivo, both the NGQDs and RGDS@NGQDs were suspended in 0.1% Pluronic F127 (w/v) and delivered as eye drops in the scopolamine hydrobromide-induced DED mouse model. Preclinical efficacy was compared to the healthy and DPBS treated DED mice.Results These NGQDs demonstrated pronounced antioxidant properties, efficiently neutralizing free radicals and activating the intracellular Nrf2 pathway. In vitro studies revealed that treatment of H2O2-exposed HCECs with NGQDs induced a preservation in cell viability. Additionally, there was a reduction in the transcription of inflammation-associated genes. To prolong the corneal residence time of NGQDs, they were further modified with RGDS peptides and suspended in 0.1% Pluronic F127 (w/v) to create RGDS@NGQDs F127 eye drops. RGDS@NGQDs exhibited superior intracellular antioxidant activity even at low concentrations (10 μg/mL). Subsequent in vivo studies revealed that RGDS@NGQDs F127 eye drops notably mitigated the symptoms of DED mouse model, primarily by reducing ocular ROS levels.Conclusion Our findings underscore the enhanced antioxidant benefits achieved by modifying GQDs through nitrogen doping and RGDS peptide tethering. Importantly, in a mouse model, our novel eye drops formulation effectively ameliorated DED symptoms, thereby representing a novel therapeutic pathway for DED management.
研究领域:
眼科
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材料科学
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药学
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细胞生物学
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Clinical and Experimental Otorhinolaryngology
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2023
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IF 3
Kunyu Liu,Yu Xu
Objectives. Hypoxia-inducible factor 1α (HIF1α) and Tet methylcytosine dioxygenase 2 (TET2) have been reported to mediate nasal polypogenesis through the epithelial-to-mesenchymal transition (EMT). Additionally, HIF1α can regulate the expression and function of TET2. However, the precise mechanism of how TET2 regulates the EMT through HIF1α mediation in nasal epithelial cells is still poorly understood. Methods. Nasal tissue samples were collected from patients with chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps (CRSsNP), and controls. The expression of HIF1α and TET2 was detected using Western blotting and immunohistochemistry. EMT markers (E-cadherin and vimentin) were also evaluated by immunohistochemistry. Primary human nasal epithelial cells (hNECs) were stimulated with CoCl 2 to mimic hypoxia. Vitamin C (VC), a TET2 non-specific activator, and small interfering RNA (siRNA) transfection of TET2 were used to further determine the role of TET2 in hypoxia-induced EMT. Finally, reactive oxygen species (ROS) and Nrf2 were measured to explore the downstream consequences of TET2 in hypoxic hNECs. Results. TET2 levels were lower in the nasal epithelium of CRSwNP patients and were positively correlated with E-cadherin but negatively correlated with vimentin in CRS. However, HIF1α exhibited the opposite pattern and was negatively correlated with TET2 expression. CoCl 2 -simulated hypoxia led to EMT and increased HIF1α in hNECs in vitro , with simultaneous downregulation of TET2 expression. Addition of VC activated TET2 expression in hNECs, but inhibited EMT and HIF1α expression. Furthermore, siRNA knockdown of TET2 contributed to the EMT in CoCl 2 -simulated hNECs despite the addition of VC. Finally, TET2 regulated the EMT in hypoxic hNECs through Nrf2 expression and ROS generation. Conclusion. TET2 was negatively correlated with HIF1α and EMT in vivo . TET2 was downregulated by HIF1α, resulting in the EMT in CoCl 2 -hypoxic hNECs via regulation of oxidative stress in vitro . Hence, TET2 might provide a new therapeutic approach for CRSwNP
研究领域:
免疫学
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耳鼻喉科学
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分子生物学
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细胞生物学
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NEUROREPORT
·
2020
·Vol. 31
·期 18
·1274-1282
·
IF 1.394
Xi Zhiyu,Chen Xiao,Xu Canxin,Wang Baofeng,Zhong Zhihong,Sun Qingfang,Sun Yuhao,Bian Liuguan
The brain edema following intracerebral hemorrhage (ICH) plays a key role in the recovery process. Protocatechuic acid (PCA) has been proved possessing neuroprotection in ICH. Here we tried to explore its value in brain edema after ICH and reveal underlying mechanisms. ICH model was
created in C57 mice using collagenase IV. PCA was injected intraperitoneally at 30 mg/kg every 24 h in PCA group. On day 3 after ICH, the water content of hemorrhagic ipsilateral hemisphere in PCA group was significantly reduced compared with vehicle group. AQP4, the main water channel, was
remarkably decreased in PCA group. Additionally, ZO-1 and occludin expression were increased in PCA group. The bEnd.3 cells were cultured to understand the effect of PCA on the blood-brain barrier (BBB) integrity. Compare to hemin treated group, plus PCA enhanced the expression of HO-1 and
Nrf2 nuclear translocation. Furtherly, the overexpression of HO-1, ZO-1, occludin, in the PCA treatment group was inhibited after knockdown of Nrf2. Taken together, our results proved PCA alleviated brain edema and BBB disruption in ICH by promoting the Nrf2/HO-1 signaling pathway.
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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Frontiers in Nutrition
·
2026
·
IF 5.5
Maoru Li,Zefeng Wang,Huan Zhai,Jiajiao Li,Ji Ma,Bin Qiu
BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) is a rapidly growing metabolic disorder with no FDA-approved treatment. Pachymic acid (PA; synonym: 3-O-acetyltumulosic acid), a lanostane-type triterpenoid, shows potential for treating MASLD. However, its mechanisms remain underexplored.ObjectiveThis work evaluated the therapeutic efficacy and mechanisms of PA in treating MASLD.MethodsThe high-cholesterol diet (HCD)-induced zebrafish model, high-fat diet induced C57BL/6 mice model and free fatty acid (FFA)-treated BRL-3A cells was used to assess PA’s anti- MASLD effects in vivo and in vitro.ResultsPA improved lipid metabolism disrupted by HCD, reduced hepatic oxidative stress, as indicated by decreased MDA levels and increased SOD activity, and lowered inflammatory markers, including TNF-α, IL-6, and IL-1β. PA also enhanced antioxidant activity by regulating the Keap1-Nrf2-HO-1 pathway. PA decreased Keap1 mRNA expression induced by reactive oxygen species (ROS), upregulated Nrf2 and HO-1 expression, and promoted Nrf2 nuclear translocation. These effects suggest that PA inhibits ROS production by activating the Keap1-Nrf2-HO-1 pathway and possibly by inhibiting Nrf2 degradation.ConclusionPA improves MASLD through lipid metabolism regulation and antioxidant effects, primarily by activating the Keap1-Nrf2-HO-1 pathway. These findings highlight PA’s potential as a therapeutic agent for MASLD.
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