BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH
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2024
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IF 1.9
Zheng Delu,Cui Chenli,Ye Chengsong,Shao Chen,Zha Xiujing,Xu Ying,Liu Xu,Wang Can
Coenzyme Q10 (CoQ10) is a potent antioxidant that is implicated in the inhibition of osteoclastogenesis, but the underlying mechanism has not been determined. We explored the underlying molecular mechanisms involved in this process. RAW264.7 cells received receptor activator of NF-κB ligand (RANKL) and CoQ10, after which the differentiation and viability of osteoclasts were assessed. After the cells were treated with CoQ10 and/or H2O2 and RANKL, the levels of reactive oxygen species (ROS) and proteins involved in the PI3K/AKT/mTOR and MAPK pathways and autophagy were tested. Moreover, after the cells were pretreated with or without inhibitors of the two pathways or with the mitophagy agonist, the levels of autophagy-related proteins and osteoclast markers were measured. CoQ10 significantly decreased the number of TRAP-positive cells and the level of ROS but had no significant impact on cell viability. The relative phosphorylation levels of PI3K, AKT, mTOR, ERK, and p38 were significantly reduced, but the levels of FOXO3/LC3/Beclin1 were significantly augmented. Moreover, the levels of FOXO3/LC3/Beclin1 were significantly increased by the inhibitors and mitophagy agonist, while the levels of osteoclast markers showed the opposite results. Our data showed that CoQ10 prevented RANKL-induced osteoclastogenesis by promoting autophagy via inactivation of the PI3K/AKT/mTOR and MAPK pathways in RAW264.7 cells.
研究领域:
细胞生物学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2022
·
IF 4.319
Lei Lei,Jing Zhao,Xue-Qi Liu,Juan Chen,Xiang-Ming Qi,Ling-Ling Xia,Yong-Gui Wu
Introduction Kidney tubular epithelial injury is one of the key factors in the progression of diabetic nephropathy (DN). Wogonin is a kind of flavonoid, which has many pharmacological effects, such as anti-inflammation, anti-oxidation and anti-fibrosis. However, the effect of wogonin in renal tubular epithelial cells during DN is still unknown.Materials and Methods STZ-induced diabetic mice were given doses of wogonin (10, 20, and 40 mg/kg) by intragastric administration for 16 weeks. The metabolic indexes from blood and urine and pathological damage of renal tubules in mice were evaluated. Human tubular epithelial cells (HK-2) were cultured in high glucose (HG) condition containing wogonin (2μM, 4μM, 8μM) for 24 h. Tubular epithelial cell inflammation and autophagic dysfunction both in vivo and in vitro were assessed by Western blot, qRT-PCR, IHC, and IF analyses.Results The treatment of wogonin attenuated urinary albumin and histopathological damage in tubulointerstitium of diabetic mice. We also found that wogonin down-regulated the expression of pro-inflammatory cytokines and autophagic dysfunction in vivo and in vitro. Molecular docking and Cellular Thermal Shift Assay (CETSA) results revealed that mechanistically phosphoinositide 3-kinase (PI3K) was the target of wogonin. We then found that inhibiting PI3K eliminated the protective effect of wogonin. Wogonin regulated autophagy and inflammation via targeting PI3K, the important connection point of PI3K/Akt/NF-κB signaling pathway.Conclusion Our study is the first to demonstrate the novel role of wogonin in mitigating tubulointerstitial fibrosis and renal tubular cell injury via regulating PI3K/Akt/NF-κB signaling pathway-mediated autophagy and inflammation. Wogonin might be a latent remedial drug against tubular epithelial injury in DN by targeting PI3K.
研究领域:
药理学
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肾病学
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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
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
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IF 8.5
Meng-xiao Wang,Ke-ke Luo,Meng-yao Tian,Wen-ya Gao,Shan Jiang,Yan Zhang,Jian Yang,Nan Si,Shi-lan Ding,Xiao-lu Wei,Yu-yang Liu,Bao-lin Bian,Yan-yan Zhou,Hong-jie Wang
The diagnosis and treatment of chronic glomerulonephritis (CGN) during childhood pose distinct challenges. Acteoside (ACT) is the primary active ingredient extracted from the leaves of Rehmannia glutinosa by our research group, accounting for 2.15 %, which possess multiple biological activities, especially for nephropathy treatment. However, its mechanism intervention on CGN in children remains obscure. In this study, we established a model of purinomycin aminonucleoside (PAN)-induced CGN in childhood rats to assess the potential therapeutic effect and underlying mechanisms of ACT. Leveraging network pharmacology and multi-omics technology, we delved into the effects and mechanisms of ACT intervention on CGN. And these findings were further corroborated through qRT-PCR, western blot and targeted metabolomics. Our results demonstrated that ACT had significantly efficient in the treatment of CGN in childhood rats by improving the key indicators and pathological changes. Further, ACT could significantly regulate differences in endogenous small molecules and genes based on non-target metabolomics and transcriptomics. Meanwhile, target capture analysis found the crucial targets of ACT treatment in CGN. Integrated analysis of multi-omics study indicated that PI3K/Akt signaling pathway and its downstream amino acid metabolism were significantly enriched, hinting at the essential regulatory pathway for ACT in treating of CGN. Finally, through qRT-PCR, western blot and targeted metabolomics, it was verified that ACT could ameliorate CGN through Cxcr4-PI3K-Akt-eNOS signaling pathway, thereby regulating amino acid metabolism. The collective results were consistent with those of multi-omics analysis. Our study illuminated that ACT had notable curative effect on CGN rats, and preliminarily elucidated its mechanism of action. Our research will provide solid basis for the treatment of chronic glomerulonephritis in children with ACT and developing it into innovative traditional Chinese medicine.
研究领域:
药理学
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分子生物学
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
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IF 6.1
Leisheng Wang,Yifei Fu,Shiwei Xu,Enhong Chen,Shuo Zhang,Dongjie Yang,Youzhao He,Yuanlong Gu,Yong Mao,Fenglai Yuan,Hao Hu
6PPD-quinone (6PPDQ), a derivative of the antioxidant 6PPD used in the rubber industry, has been implicated in environmental and public health risks. To explore its impact on metabolic and cognitive functions, we orally administered 6PPDQ to mice and assessed its effects. Our results show that 6PPDQ induces a dose-dependent increase in body weight, elevated fasting blood glucose, insulin resistance, and other hallmarks of metabolic syndrome. Furthermore, cognitive tests revealed significant impairments in learning and memory in 6PPDQ-treated mice. Transcriptomic and Western blot analyses suggest that 6PPDQ disrupts insulin signaling through inhibition of the PI3K-AKT pathway, leading to metabolic and cognitive dysfunction. Notably, treatment with the PI3K-AKT agonist SC79 partially alleviated these effects. These findings highlight the health risks of 6PPDQ exposure and suggest potential avenues for preventive and therapeutic strategies.
研究领域:
环境毒理学
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神经科学
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代谢性疾病
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信号转导
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药理学
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公共卫生
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产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2020
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IF 5.076
Dengwen Zhang,Li Mei,Ruichun Long,Can Cui,Yi Sun,Sheng Wang,Zhengyuan Xia
Background. Cerebral ischemic stroke is a refractory disease which seriously endangers human health. Remote ischemic perconditioning (RiPerC) by which the sublethal ischemic stimulus is administered during the ischemic event is beneficial after an acute stroke. However, the regulatory mechanism of RiPerC that relieves cerebral ischemic injury is still not completely clear. Methods. In the present study, we investigated the regulatory mechanism of RiPerC in a rat model of ischemia induced by the middle cerebral artery occlusion (MCAO). Forty-eight adult male Sprague-Dawley (SD) rats were injected intracerebroventricularly with miR-98 agomir, miR-98 antagomir, or their negative controls (agomir-NC, antagomir-NC) 2 h before MCAO or MCAO+RiPerC followed by animal behavior tests and infraction volume measurement at 24 h after MCAO. The expression of miR-98, PIK3IP1, and tight junction proteins in rat hippocampus and cerebral cortex tissues was detected by quantitative polymerase chain reaction (qPCR) and Western blot (WB). Enzyme-linked immunosorbent assay (ELISA) was used to assess the IL-1β, IL-6, and TNF-α levels in the rat serum. Results. The results showed that in MCAO group, the expression of PIK3IP1 was upregulated, but decreased after RiPerC treatment. Then, we found that PIK3IP1 was a potential target of miR-98. Treatment with miR-98 agomir decreased the infraction volume, reduced brain edema, and improved neurological functions compared to control rats. But treating with miR-98 antagomir in RiPerC group, the protective effect on cerebral ischemia injury was canceled. Conclusion. Our finding indicated that RiPerC inhibited the MCAO-induced expression of PIK3IP1 through upregulated miR-98, thereby reducing the apoptosis induced by PIK3IP1 through the PI3K/AKT signaling pathway, thus reducing the cerebral ischemia-reperfusion injury.
研究领域:
神经科学
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分子生物学
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中风研究
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神经保护
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Pin Gong,Xufeng Wang,Yewen Han,Hui Long,Wenjuan Yang,Fuxin Chen,Mengjiao Cui,Wenjun Zhai,Benzhong Zheng,Xuefeng Chen
This study devised optimal conditions to extract Eucommia ulmoides leaf (EUL) polysaccharides using a cellulase and pectinase composite enzyme system based on one-way experiments and response surface methodology. Crude EUL polysaccharides (EULPs) were extracted and purified using a DEAE chromatography column. The polysaccharides EUL-w, EUL1, EUL2, and EUL3 were obtained by elution with water, 0.1 mol/L NaCl, 0.2 mol/L NaCl, and 0.3 mol/L NaCl, respectively. The EUL-w fraction had the highest hypoglycemic activity based on its α-amylase and α-glucosidase activities. The preliminary structure of purified EUL-w1 was elucidated. In vitro hypoglycemic activity studies and metabolomics analyses suggested that EUL-w1 modulated glucose metabolism by mediating the AMPK/PI3K/Akt signaling pathway. Our findings provide novel insights and data support for the utilization of EULPs as an emerging food resource in functional foods.
研究领域:
药理学
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生物化学
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细胞生物学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
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2025
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IF 1.7
Sun Jingchi,Zheng Zhousong
Activated microglia are considered to be closely related to brain senescence and the pathogenesis of neurodegenerative diseases. Ginkgo biloba extract (GBE) is widely used to treat cognitive impairment and Alzheimer's disease (AD). This study aims to investigate the active ingredients of GBE and the underlying molecular mechanisms. The active ingredients of GBE in AD treatment were first analyzed by network pharmacology, culminating in the identification of the key ingredient, quercetin, and its targeted protein, NQO1. GO function enriched the oxidative stress pathway, while KEGG enriched the PI3K/Akt/mTOR pathway. Quercetin binding to NQO1 was verified by molecular docking and DARTS analysis. Cytotoxicity assay revealed no significant toxicity of GBE (0–1 mg/mL) and quercetin (0–0.4 μM) over 48 h. Subsequently, we constructed the microglial injury model by H 2 O 2 -induced HMC3 and BV2 cell lines. GBE and quercetin suppressed the senescence characteristics in H 2 O 2 -induced microglia. Further investigation revealed that the expression of NQO1 was downregulated in the injury model, and treatment with GBE and quercetin facilitated the protein expression of NQO1. In addition, silencing NQO1 reduced the promoting effect of quercetin on microglia viability and phosphorylation levels of PI3K, Akt, and mTOR. At the same time, it significantly increased the levels of p53, p21, p16 and β-galactosidase (SA-β-gal). Collectively, GBE mitigated H 2 O 2 -induced microglial injury, which activated the PI3K/Akt/mTOR pathway through the quercetin/NQO1 axis. These findings highlight quercetin/NQO1 signaling as a possible therapeutic target for senescence-related neurodegeneration.
研究领域:
神经生物学
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药理学
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分子医学
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老年医学
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神经退行性疾病
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天然药物化学
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细胞信号转导
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
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IF 5.988
Wenbin Luo,Yu Tao,Shengnan Chen,Hao Luo,Xiaoping Li,Shuang Qu,Ken Chen,Chunyu Zeng
Pulmonary ischemia/reperfusion (IR) injury is the leading cause of acute lung injury, which is mainly attributed to reactive oxygen species (ROS) induced cell injuries and apoptosis. Since rosmarinic acid (RA) has been identified as an antioxidant natural ester, this natural compound might protect against pulmonary IR injury. In this study, the mice were given RA daily (50, 75, or 100 mg/kg) by gavage for 7 days before the pulmonary IR injury. We found that hypoxemia, pulmonary edema, and serum inflammation cytokines were aggravated in pulmonary IR injury. RA pretreatment (75 and 100 mg/kg) effectively reversed these parameters, while 50 mg/kg RA pretreatment was less pronounced. Our data also indicated RA pretreatment mitigated the upregulation of pro-oxidant NADPH oxidases (NOX2 and NOX4) and the downregulation of anti-oxidant superoxide dismutases (SOD1 and SOD2) upon IR injury. In vitro studies showed RA preserved the viability of anoxia/reoxygenation (AR)-treated A549 cells (a human lung epithelial cell line), and the results showed the protective effect of RA started at 5 μM concentration, reached its maximum at 15 μM, and gradually decreased at 20-25 μM. Besides, RA pretreatment (15 μM) greatly reduced the lactate dehydrogenase release levels subjected to AR treatment. Moreover, the results of our research revealed that RA eliminated ROS production and reduced alveolar epithelial cell apoptosis through activating the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway, which was supported by using wortmannin, because in the presence of wortmannin, the RA-mediated protection was blocked. Meanwhile, wortmannin also reversed the protective effects of RA in mice. Together, our results demonstrate the beneficial role of RA in pulmonary IR injury via PI3K/Akt-mediated anti-oxidation and anti-apoptosis, which could be a promising therapeutic intervention for pulmonary IR injury.
研究领域:
药理学
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肺科学
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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
International Journal of Biological Sciences
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2019
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IF 4.067
Haotian Li,Xinran Zhang,Xi Qi,Xu Zhu,Liming Cheng
Endoplasmic reticulum (ER) stress-induced neuronal apoptosis is a crucial pathological process of spinal cord injury (SCI). In our previous study, icariin (ICA) showed neuroprotective effects in SCI. However, the relationships between ER stress and ICA in SCI are unclear yet. Therefore, whether ICA could ameliorate SCI via attenuating ER stress was investigated in vitro and in vivo . Adult mice were established SCI model and received vehicle solution or ICA by gavage once per day in vivo . The primary cultured cells were treated with or without thapsigargin (TG), ICA or LY294002 to induce ER stress in vitro . Motor dysfunction, neuronal apoptosis, tissue damage and inhibition of PI3K/AKT pathway were induced by ER stress after SCI. But ICA administration significantly enhanced motor recovery and protected spinal cord tissues against infraction and hemorrhage, etc. post injury. Meanwhile, the expression of ER stress markers ATF6, IRE1α, GRP78, XBP1 and eIF2α was decreased, while the level of p-AKT/AKT was increased by ICA. Furthermore, ICA significantly inhibited the expression of ER stress apoptotic proteins caspase-12, CHOP, Bax/Bcl-2, caspase-9 and caspase-3. Moreover, immunofluorescence double staining indicated that ICA reduced GRP78, CHOP and TUNEL positive neurons following SCI. However, this beneficial effect of ICA was abolished by PI3K/AKT inhibitor LY294002 in vitro . Finally, ICA preserved the ultra-structure of ER by transmission electron microscope histologically. This study suggested that the neuroprotective effect of ICA on motor recovery and neuronal survival was related to attenuating ER stress via PI3K/AKT signaling pathway after SCI.
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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病理生理学
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产品关联
DOI
PubMed
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2023
·Vol. 46
·期 6
·764-772
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IF 2
Xin Zhang,Zhifang Liang,Ying Zhou,Fang Wang,Shan Wei,Bing Tan,Yujie Guo
Diabetic peripheral neuropathy (DPN) is an early developing complication of diabetes mellitus associated with nerve dysfunction. Artesunate (ART), a natural compound extracted from the herb Artemisia annua L., was reported to benefit neural injury. However, whether ART has a role in preventing DPN is still unknown. In this study, a rat model of DPN with a high fat diet feeding and streptozotocin (STZ) injection was established. The findings indicated that ART treatment significantly ameliorated hyperglycemia-induced hot plate reaction latency (HPRL) decline, cold sensitivity and mechanical allodynia, and nerve injury by inhibiting sciatic nerve apoptosis. Further, ART restored high glucose (HG)-induced elevated apoptosis and deficient survival in rat neuronal Schwann cells, RSC96 cells. We demonstrated that ART promoted protein kinase B (AKT) phosphorylation as well as its downstream factor mammalian target of rapamycin (mTOR) in vivo and in vitro. Of note, the protective effects of ART in RSC96 cells under HG condition could be counteracted by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor. Taken together, ART mitigated hyperglycemia-induced nerve injury by suppressing apoptosis and promoting the viability of Schwann cells via the PI3K/AKT/mTOR signaling pathway.
研究领域:
神经学
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药理学
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糖尿病
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细胞生物学
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信号传导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Inflammation Research
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2025
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IF 4.1
Haiou Wang,Wenkang Huang,Xiaoya Pan,Meizi Tian,Jiahui Chen,Xiaotong Liu,Qin Li,Jianhua Qi,Yiping Ye,Lijuan Gao
Purpose To explore the protective effect and underlying mechanism of Quzhou Aurantii Fructus flavonoids (QAFF) on Ulcerative colitis (UC).Methods The constituents of QAFF were accurately determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The therapeutic impacts of QAFF were assessed in dextran sulfate sodium (DSS)-induced UC mice, focusing on the changes in body weight, disease activity index (DAI), colon length, histological assessment of colonic tissues, levels of pro-inflammatory cytokines, and expression of tight junction proteins. Western blotting confirmed key regulatory proteins within the differential signaling pathways, guided by transcriptome analysis. Additionally, the influence of QAFF on the gut microbiome was explored through 16S ribosomal RNA (rRNA) sequencing. The alterations in endogenous metabolites were detected by untargeted metabolomics, and their potential correlation with intestinal flora was then examined utilizing Spearman correlation analysis. Subsequently, the regulation of gut microbiome by QAFF was validated by fecal microbiota transplantation (FMT).Results Eleven flavonoids, including Naringin and hesperidin, were initially identified from QAFF. In vivo experiments demonstrated that QAFF effectively ameliorated colitis symptoms, reduced IL-6, IL-1β, and TNF-α levels, enhanced intestinal barrier integrity, and downregulated PI3K/AKT pathway activation. Furthermore, QAFF elevated the levels of beneficial bacteria like Lachnospiraceae_NK4A136_group and Alloprevotella and concurrently reduced the pathogenic bacteria such as Escherichia-Shigella, [Eubacterium]_siraeum_group, and Parabacteroides. Metabolomics analysis revealed that 34 endogenous metabolites exhibited significant alterations, predominantly associated with Glycerophospholipid metabolism. These metabolites were significantly correlated with those differential bacteria modulated by QAFF. Lastly, the administration of QAFF via FMT ameliorated the colitis symptoms.Conclusion QAFF could ameliorate inflammatory responses and intestinal barrier dysfunction in DSS-induced UC mice probably by modulating the PI3K/AKT signaling pathway and gut microbiome, offering promising evidence for the therapeutic potential of QAFF in UC treatment.
研究领域:
药理学
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分子生物学
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微生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2023
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IF 3.1
Yong-xin Chen,Hong Yang,Da-song Wang,Yu-ting Yao,Ting-ting Chen,Ling Tao,Yan Chen,Xiang-chun Shen
Vascular dementia (VaD), the second most common type of dementia, is attributed to lower cerebral blood flow. To date, there is still no available clinical treatment for VaD. The phenolic glucoside gastrodin (GAS) is known for its neuroprotective effects, but the role and mechanisms of action on VD remains unclear. In this study, we aim to investigate the neuroprotective role and underlying mechanisms of GAS on chronic cerebral hypoperfusion (CCH)-mediated VaD rats and hypoxia-induced injury of HT22 cells. The study showed that GAS relieved learning and memory deficits, ameliorated hippocampus histological lesions in VaD rats. Additionally, GAS down-regulated LC3II/I, Beclin-1 levels and up-regulated P62 level in VaD rats and hypoxia-injured HT22 cells. Notably, GAS rescued the phosphorylation of PI3K/AKT pathway-related proteins expression , which regulates autophagy. Mechanistic studies verify that YP-740, a PI3K agonist, significantly resulted in inhibition of excessive autophagy and apoptosis with no significant differences were observed in the YP-740 and GAS co-treatment. Meantime, we found that LY294002 , a PI3K inhibitor, substantially abolished GAS-mediated neuroprotection. These results revealed that the effects of GAS on VaD are related to stimulating PI3K/AKT pathway-mediated autophagy, suggesting a potentially beneficial therapeutic strategy for VaD.
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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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）