JOURNAL OF FOOD AND DRUG ANALYSIS
·
2024
·Vol. 32
·期 4
·506
·
IF 2.6
Tian-Shuang Xia,Sheng-Yan Xu,Li-Yong Lai,Yi-Ping Jiang,Na-Ni Wang,Hai-Liang Xin
Bitter acids (BA) are main component of Humulus lupulus L. (hops). They are known for beer brewing and have various biological and pharmacological properties, especially the bone-protective effect confirmed by our previous in vivo study. Here we aimed to elucidate the anti-senior osteoporosis (SOP) effect of BA on osteoblasts and explore its underlying mechanism. In vitro SOP model was established by D-galactose (D-gal) injured osteoblasts, and the bone formation markers and apoptosis level were measured. mCherry-EGFP-LC3 adenovirus infection and autophagic markers including beclin1 and LC3 proteins were detected to investigate the autophagy level in osteoblasts. To further verify whether BA play the bone-protective role through regulating autophagy, the autophagy inhibitor 3-MA was used, and the cell proliferation, ALP activity, bone mineralization, apoptosis rate and SA-β-gal staining areas were measured. Finally, the protein expressions of AKT/mTOR signaling pathway were detected by Western blotting, and AKT agonist SC79 and mTOR agonist MHY1485 were used to further study the mechanism of BA on AKT/mTOR-mediated autophagy. The results showed that BA stimulated osteoblastic differentiation and inhibited apoptosis proteins Bcl-2/Bax in D-gal-treated osteoblasts. BA also increased the expression of autophagic markers beclin1 and LC3-II/LC3-I in D-gal-treated osteoblasts. mCherry-EGFP-LC3 autophagic double fluorescent adenovirus showed BA promoted the generation of autolysosomes and autophagosomes in D-gal-injured osteoblasts, indicating that BA might prevent osteoblastic bone loss through activating autophagy. Autophagy inhibitor 3-MA was used to further verify whether BA played the bone-protective role via regulating autophagy. The results revealed the promotion effects of BA on proliferation, ALP activity, and mineralized nodule formation in D-gal-injured osteoblasts were eliminated after autophagy blocking with 3-MA, and the inhibitory effects of BA on apoptosis rate and SA-β-gal staining areas were also eliminated. Moreover, BA reduced the phosphorylation levels of AKT, mTOR, p70S6K, and 4EBP in AKT/mTOR pathway, and the promotion of BA on the autophagic markers was blocked after the activation of AKT and mTOR by SC79 and MHY1485. In conclusion, it was the first time to demonstrate that BA improved cell activities and bone formation in aging osteoblasts, and revealed the mechanism of BA against SOP in osteoblasts was activating AKT/mTOR-mediated autophagy.
研究领域:
药理学
·
细胞生物学
·
分子生物学
·
老年医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Zengyu Zhang,Shanshan Huang,Yong Wang,Zhiwen Jiang,Zhuohang Liu,Chenran Wang,Rong Ji,Yiwen Yuan,Xueyu Mao,Kaicheng Yang,Huicong Niu,Yanqin Gao,Jing Zhao
Microglial metabolic/inflammatory reprogramming critically influences stroke outcomes, yet its mechanisms remain poorly understood. Lysine lactylation, an epigenetic modification in which lactate-derived lactyl groups modify lysine residues, regulates immune and neurological processes. Here, lysine lactylation is identified as a key link between ischemic metabolic stress and microglial dysfunction. Stroke-induced lactate accumulation drives microglial protein lactylation, which correlates with poor neurological outcomes. Proteomics identified that methyl-CpG binding protein 2 (MeCP2) is lactylated at lysine 210 (K210), enhancing its transcriptional activation of glycolytic/inflammatory genes, especially hexokinase 2 (HK2). HK2 overexpression mimics lactylation-induced pathology (mitochondrial dysfunction, glycolytic shift, inflammation), while knockdown reverses these effects. Lactylated MeCP2 impairs mitochondrial respiration, disrupts metabolic signaling (leading to dysregulated activation of the mammalian target of rapamycin (mTOR)/AMPK pathway), and sustains neuroinflammation. Genetic ablation of MeCP2-K210 lactylation (via K210R mutation), pharmacological inhibition of lactyltransferase p300, or HK2 inhibition with lonidamine restores mitochondrial function, attenuates neuroinflammation, and improves neurofunctional recovery. The findings establish MeCP2-K210 lactylation as a critical metabolic-epigenetic switch driving microglial activation via the HK2/mTOR axis, identifying a therapeutic target for postischemic neuroinflammation.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Jianfa Wu,Lingli Jiang,Sihong Wang,Lei Peng,Rong Zhang,Zhou Liu
The involvement of Interferon-stimulated exonuclease gene 20 (ISG20) has been reported in renal clear cell carcinoma, hepatocellular carcinoma, and cervical cancer. However, its role in ovarian cancer chemotherapy remains unclear. In this study, we conducted a comparative analysis of TGF-β1 and ISG20 in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells and tissues using qRT-PCR and a tissue immunofluorescence analysis. We also investigated the impact of ISG20-targeted drugs (IFN-γ) and TGF-β1 inhibitors on cisplatin response both in vivo and in vitro. Additionally, we assessed the effects of TGF-β1 or ISG20 on the polarization of tumor-associated macrophages through flow cytometry and ELISA analysis. Our findings revealed that ISG20 expression was lower in cisplatin-resistant tissues compared to cisplatin-sensitive tissues; however, overexpression of ISG20 sensitized ovarian cancer to cisplatin treatment. Furthermore, activation of ISG20 expression with IFN-γ or TGF-β1 inhibitors enhanced the sensitivity of ovarian cancer cells to cisplatin therapy. Notably, our results demonstrated that TGF-β1 promoted M2-type macrophage polarization as well as PI3K/mTOR pathway activation by suppressing ISG20 expression both in vivo and in vitro. In conclusion, our study highlights the critical role played by ISG20 within the network underlying cisplatin resistance in ovarian cancer. Targeting ISG20 using IFN-γ or TGF-β1 inhibitors may represent a promising therapeutic strategy for treating ovarian cancer.
研究领域:
肿瘤学
·
免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MEDIATORS OF INFLAMMATION
·
2024
·Vol. 2024
·期 1
·4777789
·
IF 4.4
Zheng Liang,Dajin Pi,Jianwei Zhen,Haizhen Yan,Chuiyang Zheng,July Liang Chen,Wen Fan,Qingliang Song,Jinyue Pan,Dongdong Liu,Maoxing Pan,Qinhe Yang,Yupei Zhang
Nonalcoholic steatohepatitis (NASH) is the advanced stage of nonalcoholic fatty liver disease (NAFLD), which is distinguished by the accumulation of fat in the liver, damage to liver cells, and inflammation. Chaihu Shugan powder (CSP), a renowned traditional Chinese medicine (TCM) blend extensively utilized in China to address liver disease, has demonstrated its efficacy in reducing lipid buildup and effectively combating inflammation. Hence, the primary objective of this research is to examine the impacts and possible mechanisms of CSP on NASH through assessments of liver histopathology, lipidomic analysis, and gene expression. To induce a mouse model of NASH, we employed a diet which deficient in methionine and choline, known as methionine–choline deficient (MCD) diet. Initially, we examined the impact of administering CSP to NASH mice by assessing the levels of serum and liver indicators. We found that CSP was able to reduce lipid buildup and inflammation in mice. In addition, a total of 1009 genes exhibited enrichment in both the autophagy and ferroptosis pathways. The liver protein levels of Adenosine monophosphate-activated protein kinase–mammalian target of rapamycin (AMPK–mTOR)-mediated autophagy and ferroptosis markers, such as p-AMPK α /AMPK α , p-mTOR/mTOR, Beclin-1, microtubule associated protein 1 light chain 3 gamma (LC3), p62 (sequestosome 1 [SQSTM1/p62]), Kelch-like ECH-associated protein 1 (KEAP1), nuclear factor erythroid 2-related factor 2 (Nrf-2), ferritin heavy chain 1 (FTH1), and glutathione peroxidase 4 (GPX4), were restored by CSP. Furthermore, our findings indicated that the suppression of autophagy had a repressive impact on the occurrence of ferroptosis in the mouse model, indicating that autophagy activation likely plays a role in mediating ferroptosis in NASH.
研究领域:
药理学
·
肝病学
·
分子生物学
·
中医
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Medical Sciences
·
2020
·
IF 2.523
Zhao Qu,Yushan Lin,Daniel Kam-Wah Mok,Qingya Bian,William Chi-Shing Tai,Sibao Chen
Triple-Negative Breast Cancer (TNBC) is a most dangerous breast cancer subtype. The naturally occurring sesquiterpene lactone, arnicolide D (AD), has proven effective against a variety of tumors, however, the inhibitory effects of AD against TNBC and the underlying mechanisms remain unclear. In the present study, two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and an MDA-MB-231 xenograft mouse model were employed to investigate the anti-TNBC effects of AD in vitro and in vivo . Cell viability was assessed by MTT assay. Cell cycle arrest and apoptosis were analyzed by flow cytometry. Protein levels were determined by immunoblotting. In vitro studies demonstrated that AD significantly decreased cell viability, and induced G2/M cell cycle arrest and apoptosis. In vivo assays showed that oral administration of 25 or 50 mg/kg AD for 22 days led to a reduction of tumor weights by 24.7% or 41.0%, without appreciable side effects. Mechanistically, AD inhibited the activation of Akt/mTOR and STAT3 signaling pathways. Based on our findings, AD is a promising candidate for development as an adjunctive therapeutic drug for TNBC.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
American Journal of Translational Research
·
2021
·
IF 4.06
Zhen Zhang,Dongming Zhu,Xiaobo Zhang,Yun Liu,Jingcheng Wang,Lianqi Yan
Post-surgery arthrofibrosis is one of the most restrictive factors in the development of intra-articular surgery and has presented tremendous obstacles for most orthopaedic surgeons. Tanshinone IIA (Tan IIA), a key active ingredient of Den-shen, has been used to treat fibrosis-related diseases, such as pulmonary, hepatic and myocardial fibrosis. In the present study, we aimed to investigate the effects of Tan IIA on post-surgery arthrofibrosis in vivo and in vitro . Histological analysis indicated that topical application of Tan IIA (10 mg/mL) could significantly alleviate postsurgery arthrofibrosis in rabbits. Immunohistochemistry results showed that proliferating cell nuclear antigen (PCNA) and tubulin protein expression was inhibited, whereas LC3 was activated in vivo . In vitro , EdU and flow cytometry assays demonstrated that Tan IIA could inhibit fibroblast proliferation by arresting cells in G2 phase. Scratch, Transwell and cytoskeleton protein immunofluorescence assays revealed that fibroblast migration was attenuated. Interestingly, LC3 immunofluorescence staining and transmission electron microscopy indicated that autophagy flux could be induced in fibroblasts by Tan IIA. However, the inhibitory effects of Tan IIA against fibroblast proliferation and migration were partially restored when fibroblast autophagy was suppressed after combined treatment with the autophagy inhibitor 3-methyladenine (3-MA). Finally, the expression of p-mTOR was suppressed in a dose-dependent manner after Tan IIA treatment but partially restored when Tan IIA treatment was combined with 3-MA intervention. The inhibitory effect of Tan IIA against fibroblast proliferation and migration may be related to autophagy induction mediated by the PI3K and AMPK-mTOR signaling pathway.
研究领域:
骨科
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
·
2018
·Vol. 78
·期 2
·157-171
·
IF 3.49
Yan Bing Chun,Wang Jie,Rui Yanggang,Cao Jianwen,Xu Pei,Jiang Dan,Zhu Xiaolu,Won Moo-Ho,Bo Ping,Su Peiqing
Gabapentin (GBP), an analgesic, adjunct antiepileptic, and migraine prophylactic drug, reduces neuronal injury induced by cerebral ischemia reperfusion (IR). However, the underlying biological molecular mechanism of GBP neuroprotection is not clear. In this study, we confirmed that dose-dependent (75 and 150 mg/kg) GBP treatment could significantly reduce IR-induced neuronal death. IR-induced neuronal death was inhibited by pretreatment with 150 mg/kg GBP in a middle cerebral artery occlusion rat model. In addition, 150 mg/kg GBP treatment remarkably promoted the levels of antioxidants and reduced the autophagy of neurons in the infarct penumbra. Moreover, the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway was activated by pretreatment with 150 mg/kg GBP, as detected by Western blot analyses. In vitro, pretreatment of PC12 cells with 450 µM GBP significantly reduced cell death induced by oxygen-glucose deprivation, increased antioxidant function, and reduced the levels of autophagy and reactive oxygen species via activation of the PI3K/Akt/mTOR pathway. This neuroprotection by GBP was inhibited significantly by 10 µM LY294002. In summary, dose-dependent pretreatment with GBP protected against cerebral IR injury via activation of the PI3K/Akt/mTOR pathway, which provided a neuroprotective function to inhibit oxidative stress-related neuronal autophagy.
研究领域:
神经科学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2023
·
IF 5.1
Ren-Fen Ma,Hu Liu,Xue-Chun Zhao,Peipei Shan,Ping Sun,Jun-Juan Xue,Guodong Wei,Hua Zhang
Phytochemical investigation into the leaves and branches of Daphne genkwa afforded 25 meroterpenoids ( 1 – 16 ) including nine pairs of enantiomers ( 1a / 1b − 8a / 8b and 12a / 12b ), among which 20 compounds have been reported in the present work for the first time. The structures with absolute configurations of the new molecules (excluding 10 – 13 ) were established via comprehensive spectroscopic analyses especially electronic circular dichroism (ECD) and Mosher’s methods. A preliminary in vitro cell viability assay revealed remarkable cytotoxicities of selective compounds against A549 (lung), Hela (cervical), MDA-MB231 (breast) and MCF-7 (breast) cancer cells, and compound 8a showed the best inhibitory activity with IC 50 values in the range of 3.12–4.67 μM toward the four cell lines. Subsequent in vitro antitumor evaluation of 8a disclosed that it could inhibit the proliferation and metastasis, as well as induce significant apoptosis and cycle arrest, of A549 cells. Further mechanistic investigations revealed that 8a could exert its antitumor activity via inhibiting the PI3K/Akt/mTOR signaling pathway.
研究领域:
药理学
·
肿瘤学
·
植物化学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Materials Today Bio
·
2024
·
IF 8.7
Linquan Zhou,Chengcheng Zhang,Tengbin Shi,Dingwei Wu,Huina Chen,Jiaxin Han,Dehui Chen,Jinxin Lin,Wenge Liu
The migration and differentiation of bone marrow mesenchymal stem cells (BMSCs) play crucial roles in bone repair processes. However, conventional scaffolds often lack of effectively inducing and recruiting BMSCs. In our study, we present a novel approach by introducing a 3D-bioprinted scaffold composed of hydrogels, with the addition of laponite to the GelMA solution, aimed at enhancing scaffold performance. Both in vivo and in vitro experiments have confirmed the outstanding biocompatibility of the scaffold. Furthermore, for the first time, Apt19s has been chemically modified onto the surface of the hydrogel scaffold, resulting in a remarkable enhancement in the migration and adhesion of BMSCs. Moreover, the scaffold has demonstrated robust osteogenic differentiation capability in both in vivo and in vitro environments. Additionally, the hydrogel scaffold has shown the ability to induce the polarization of macrophages from M1 to M2, thereby facilitating the osteogenic differentiation of BMSCs via the bone immune pathway. Through RNA-seq analysis, it has been revealed that macrophages regulate the osteogenic differentiation of BMSCs through the AMPK/mTOR signaling pathway. In summary, the functionalized GelMA/Laponite scaffold offers a cost-effective approach for tailored in situ bone regeneration.
研究领域:
组织工程
·
生物材料
·
再生医学
·
骨免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2020
·
IF 3.263
Ying Liu,ShiJi Deng,Zhi Zhang,Yue Gu,ShengNan Xia,XinYu Bao,Xiang Cao,Yun Xu
Neuroinflammation is critical for the pathogenesis of ischemia brain damage . Over-activated microglia-mediated inflammation plays a very important role in ischemia cerebral injuries. 6-Gingerol, obtained from edible ginger (Zingiber Officinale) exhibits protective effects against inflammation. In this study, we found that 6-Gingerol could reduce the size of infarction (P = 0.0184) and improve neurological functions (P = 0.04) at the third day after ischemic brain injury in vivo. Since 6-Gingerol has the anti-inflammatory effects, we further investigated its impacts on neuroinflammation mediated by microglia both in vivo and in vitro. We found that the levels of pro-inflammatory cytokines Interleukin-1 beta (IL-1β, P = 0.0213), Interleukin-6 (IL-6, P = 0.0316), and inducible NO synthase (iNOS, P = 0.0229) in the infarct penumbra were lower in 6-Gingerol treated groups. Furthermore, microglia induced pro-inflammatory cytokines, such as IL-6, IL-1β, incremental intercellular nitric oxide (NO), as well as iNOS were blocked by the treatment of 6-Gingerol in lipopolysaccharide (LPS) stimulated microglia. In terms of mechanism, 6-Gingerol potently suppressed phosphorylation of serine-threonine protein kinase (Akt) - mammalian target of rapamycin (mTOR) - signal transducer and activator of transcription 3 (STAT3) in LPS-treated microglia. Taken together, the present study suggested that 6-Gingerol improved cerebral ischemia injury by suppressing microglia-mediated neuroinflammation by down-regulating Akt-mTOR-STAT3 pathway.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR MEDICINE
·
2021
·Vol. 27
·期 1
·1-16
·
IF 6.354
Cui Jing,Guo Yao,Wu Heshui,Xiong Jiongxin,Peng Tao
Background Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer. Methods The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEM sen ) and GEM-resistant (GEM res ) pancreatic cancer cells. Results We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEM sen and GEM res cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEM res cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEM res cells than that in GEM sen cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEM res tumors, Evr significantly decreased the volume of GEM res tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM. Conclusions Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2022
·
IF 10.761
Lili Liu,Xianjing Li,Wenhuan Bu,Nianqiang Jin,Yuan Meng,Yi Wang,Duan Wang,Xiaowei Xu,Ding Zhou,Hongchen Sun
Pulp injury is one of the most common clinical diseases, and severe cases are usually associated with the functional loss of the tooth, while the current clinical treatment modality is only a cavity filling procedure without the regeneration of the dentin-pulp complex, thus leading to a devitalized and brittle tooth. In this study, carbon dots (CDots) with excellent biocompatibility are prepared from ascorbic acid and polyethyleneimine via a hydrothermal method. The as-prepared CDots can enhance extracellular matrix (ECM) secretion of human dental pulp stem cells (DPSCs), giving rise to increased cell adhesion on ECM and a stronger osteogenic/odontogenic differentiation capacity of DPSCs. Further, the mechanism underlying CDots-enhanced ECM secretion is revealed by the transcriptome analysis, Western blot assay and molecular dynamics simulation, identifying that the pharmacological activities of CDots are originated from a reasonable activation of the autophagy, which is mediated by regulating phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Based on the abundant CDots-induced ECM and thereby the reinforcement of the cell-ECM adhesion, an intact dental pulp stem cell sheet can be achieved, which in return promote in vivo the efficient regeneration of dentin-pulp complex as well as blood vessels.
研究领域:
材料科学
·
生物材料
·
组织工程
·
干细胞生物学
·
牙科研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）