Journal of Functional Foods
·
2024
·
IF 3.8
Xi-you Li,Xiao-yuan Gu,Bai-ling Zhou,Bun Tsoi,Wei-xi Li
Eye deformity, a noteworthy embryopathy, is intricately linked with maternal diabetes, frequently resulting in embryonic malformation or even death. In this investigation, a hyperglycemic chick embryo model was established to delve into the protective potential of tamarind shell extract (TSE) on eye development. Chick embryos were administered with TSE (at dosages of 1, 2, and 4 µg/egg) through air sac injection on embryo development day 0 (EDD0) and later exposed to D-glucose (0.4 mmol/egg) on EDD1. To validate our findings, we replicated hyperglycemic environment using D-glucose in ARPE-19 cell model. Our research unveiled that TSE proficiently counters O-GlcNAcylation of proteins in the presence of D-glucose, thereby reinstating levels of key proteins involved in eye development, including Pax6, Daam1, mTOR, and Cdc42. Furthermore, TSE was pinpointed to curtail the D-glucose concentration within the embryo eye, considerably decreasing the accumulation of reactive oxygen species and malondialdehyde accumulation in both the ARPE-19 cells and chick embryos. Beyond its fundamental role in boosting the cellular antioxidative activity, the improved expression of apoptosis-related proteins like Caspase-3, BAX, BCL-2 and other like PI3K and AKT were observed. This suggests a probable activation of the PI3K-AKT-mTOR pathway on ARPE-19 cells by TSE, thereby downregulating apoptotic proteins in ARPE-19 cells during oxidative stress. TSE may become a potent natural countermeasure against D-glucose-induced eye malformation.
研究领域:
发育生物学
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药理学
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细胞生物学
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胚胎学
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DOI
高影响因子
JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
·
2022
·Vol. 78
·期 1
·213-227
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IF 5.08
Zhang Haihua,Lang Wuying,Liu Xin,Bai Jiangsong,Jia Qinghui,Shi Qiumei
Ulcerative colitis (UC) is a recurrent chronic inflammatory disease. The symptom of UC is mainly diarrhea including bloody stools. Increasing evidence has suggested that procyanidin A1 (PCA1) exerts an anti-inflammatory effect in several diseases. However, the role of PCA1 in UC is still a mystery. In our study, we explored the effect of PCA1 in dextran sulfate sodium (DSS)–induced UC mice and lipopolysaccharide (LPS)-stimulated HT-29 and IEC-6 cells. Then, cell proliferation, apoptosis, the production of proinflammatory cytokines, and autophagy-related markers were determined. Furthermore, the AMPK/mTOR/p70S6K signaling pathway was assayed by Western blot assay. In in vivo study, we found that PCA1 administration alleviated DSS-induced UC, as evidenced by reducing weight loss, clinical scores, colon weight/length ratio, histological damage, proinflammatory cytokines, and apoptosis. Moreover, we showed that the expression of Beclin-1 and LC3II/I ratio was increased, whereas the level of p62 was decreased after PCA1 treatment in vivo . Meanwhile, the reduced AMP/ATP ratio, enhanced expression of p-AMPK, and decreased p-p70S6K and p-mTOR levels indicate the activation of AMPK/mTOR/p70S6K signaling pathway. In in vitro study, PCA1 promoted cell proliferation and inhibited cell apoptosis in LPS-stimulated HT-29 and IEC-6 cells. Pro-inflammatory cytokines and autophagy-related factors exhibited the same trend as in in vivo results. Mechanically, PCA1 activated the AMPK/mTOR/p70S6K signaling pathway. The treatment with an AMPK inhibitor compound C significantly reversed the anti-inflammatory effect of PCA1 in LPS-stimulated cells. Taken together, these data indicated that PCA1 alleviated UC through induction of AMPK/mTOR/p70S6K-mediated autophagy.
研究领域:
胃肠病学
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药理学
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免疫学
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细胞生物学
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DOI
PubMed
高影响因子
CHEMICAL & PHARMACEUTICAL BULLETIN
·
2021
·
IF 1.645
Bai-ling Sun,En-bo Cai,Yan Zhao,Yu Wang,Li-min Yang,Jing-Yao Wang
Arctigenin(ARG) , a natural lignans compound isolated from Arctium lappa L. In this study, the anti-tumor effect of ARG on prostate cancer cell PC-3M and the mechanism of apoptosis and autophagy induced by PI3K/Akt/mTOR signaling pathway were discussed, and further confirmed by the joint treatment of ARG and PI3K inhibitor LY294002. Here, the effect of ARG on cell viability was evaluated in PC-3M cells by CCK-8 assay. After the treatment of ARG, colony formation assay was used to detect the anti-proliferation effect. Annexin V-FITC/PI kit and DAPI staining were used to detect the apoptosis level, and cell cycle changes were analyzed by flow cytometry. The expression of autophagy was detected by acridine orange staining. In addition, the expression levels of apoptosis and autophagy-related proteins were analyzed by western blot. The result showed that different concentrations of ARG inhibited the proliferation of PC-3M cells. DAPI staining and flow cytometry showed that ARG induced PC-3M cell apoptosis and arrested cell in G0/G1 phase. Acridine orange staining showed that ARG induced autophagy in PC-3M cells. Western blot experiments showed that ARG inhibited the expression of Bcl-2 , promoted the expression of Bax and cleaved caspase-3. At the same time, the expression of autophagy-related proteins LC3B-II and Beclin-1 increased after ARG treatment, but P62 decreased. In addition, further studies have shown that treatment with LY294002 enhanced the effects of ARG on the expression of proteins associated with apoptosis and autophagy , indicating that ARG may induce apoptosis and autophagy through PI3K/Akt/mTOR pathway.
研究领域:
肿瘤学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
LIFE SCIENCES
·
2018
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IF 3.234
Han Zhang,Fenfen Qin,Anlong Liu,Qinmei Sun,Qisheng Wang,Shuwu Xie,Shengfeng Lu,Dong Zhang,Zhigang Lu
Aims Electro-acupuncture (EA) is frequently recommended as a complementary therapy for premature ovarian failure (POF) in the clinical. However, little information exists about its potential treatment mechanisms. The study was designed to observe the effect of EA to ovarian function and fertility in POF mice model, and investigated its potential mechanisms on PI3K/AKT/mTOR signaling pathway. Materials and methods Forty-five female C57/BL6 mice were divided into the Control, the Model and the EA group. The ovaries morphology of mice was observed by hematoxylin and eosin (HE) staining, and all follicles were counted under microscope. The protein expression of PI3K, phospho-PI3K, AKT, phospho-AKT, mTOR, phospho-mTOR, S6, phospho-S6, 4E-BP1 and phospho-4E-BP1 were detected by western blotting. The data was presented as the ratio of phosphorylation protein to total protein. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E 2 ) and anti-Mullerian hormone (AMH) levels were measured by enzyme-linked immunosorbent assay (ELISA). The fertility was observed by giving treated mice 8 weeks for breeding. Key findings We found that primordial follicle counts were increased in EA group compared to Model group. The phosphorylation of PI3K, AKT, mTOR, 4E-BP1 and S6K in EA group significantly reduced compared to Model group. Serum FSH and LH levels in EA group were decreased compared to Model group, while, serum E 2 and AMH levels in EA group were increased compared with Model group. The litter size in EA group was improved compared to Model group. Significance The effects of EA on the PI3K/AKT/mTOR signaling pathway may represent one of the mechanisms involved in attenuating the mice POF.
研究领域:
生殖生物学
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针灸疗法
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信号转导
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2018
·Vol. 9
·期 6
·1-14
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IF 5.638
Le Yunchen,Zhang Sulin,Ni Jiahui,You Yan,Luo Kejing,Yu Yunqiu,Shen Xiaoyan
Amino-acid metabolism plays a vital role in mammalian target of rapamycin (mTOR) signaling, which is the pivot in colorectal cancer (CRC). Upregulated chaperone-mediated autophagy (CMA) activity contributes to the regulation of metabolism in cancer cells. Previously, we found that sorting nexin 10 (SNX10) is a critical regulator in CMA activation. Here we investigated the role of SNX10 in regulating amino-acid metabolism and mTOR signaling pathway activation, as well as the impact on the tumor progression of mouse CRC. Our results showed that SNX10 deficiency promoted colorectal tumorigenesis in male FVB mice and CRC cell proliferation and survival. Metabolic pathway analysis of gas chromatography–mass spectrometry (GC-MS) data revealed unique changes of amino-acid metabolism by SNX10 deficiency. In HCT116 cells, SNX10 knockout resulted in the increase of CMA and mTOR activation, which could be abolished by chloroquine treatment or reversed by SNX10 overexpression. By small RNA interference (siRNA), we found that the activation of mTOR was dependent on lysosomal-associated membrane protein type-2A (LAMP-2A), which is a limiting factor of CMA. Similar results were also found in Caco-2 and SW480 cells. Ultra-high-performance liquid chromatography–quadrupole time of flight (UHPLC-QTOF) and GC-MS-based untargeted metabolomics revealed that 10 amino-acid metabolism in SNX10-deficient cells were significantly upregulated, which could be restored by LAMP-2A siRNA. All of these amino acids were previously reported to be involved in mTOR activation. In conclusion, this work revealed that SNX10 controls mTOR activation through regulating CMA-dependent amino-acid metabolism, which provides potential target and strategy for treating CRC.
研究领域:
肿瘤学
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细胞生物学
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代谢
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PubMed
高影响因子
FASEB JOURNAL
·
2020
·Vol. 34
·期 10
·14006-14023
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IF 4.966
Chang-Sheng Zhan,Jia Chen,Jing Chen,Li-Gang Zhang,Yi Liu,He-Xi Du,Hui Wang,Mei-Juan Zheng,Zi-Qiang Yu,Xian-Guo Chen,Li Zhang,Chao-Zhao Liang
Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is a complicated syndrome characterized by genitourinary pain in the absence of bacterial infection. Th17 cell-driven autoimmunity has been proposed as a cause of CP/CPPS. However, the factors that promote Th17-driven autoimmunity in experimental autoimmune prostatitis (EAP) and the molecular mechanisms are still largely unknown. Here, we showed that Th17 cells were excessively activated, and blockade of IL-17A could effectively ameliorate various symptoms in EAP. Furthermore, we revealed that calcium/calmodulin-dependent kinase Ⅳ (CaMK4), especially Thr 196 p-CaMK4 was increased in the Th17 cells of the EAP group, which were activated by intracellular cytosolic Ca 2+ . Pharmacologic and genetic inhibition of CaMK4 decreased the proportion of Th17 cells, and the protein and mRNA level of IL-17A, IL-22, and RORγt. The phosphorylation of CaMK4 was dependent on the increase in intracellular cytosolic Ca 2+ concentration in Th17 cells. A mechanistic study demonstrated that inhibition of CaMK4 reduced IL-17A production by decreasing the phosphorylation of Akt-mTOR, which was well accepted to positively regulate Th17 differentiation. Collectively, our results demonstrated that Ca 2+ -CaMK4-Akt/mTOR-IL-17A axis inhibition may serve as a promising therapeutic strategy for CP/CPPS.
研究领域:
免疫学
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分子生物学
·
泌尿科
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Zhouchun Chen,Qingshan Yang,Mengyu Fan,Tianran Chai,Yang Liu,Xue Xia,Muhammad Ismail,Meng Zheng
Targeting mitochondrial-mediated energy metabolism has emerged as a promising therapeutic strategy for glioblastoma multiforme (GBM), given its crucial role in sustaining the rapid growth and survival of tumor cells. In this study, we developed a combinatory, non-cationic siRNA-conjugated self-assembled micelle system core-encapsulated with Gboxin (siRNA-micelle@Gboxin) designed to induce severe mitochondrial dysfunction in GBM cells. The mTOR-siRNA component in the micelle silences mTOR expression, downregulates mTORC1 activity, and reduces 4EBP1 phosphorylation, leading to inhibition of mRNA translation and disruption of cellular energy metabolism, ultimately resulting in decreased ATP production. Concurrently, the GBM-specific drug Gboxin inhibits oxidative phosphorylation (OXPHOS), directly inducing mitochondrial dysfunction and exacerbating the energy crisis within glioma cells, synergistically accelerating apoptosis through mitochondrial damage. Notably, this dual-target inhibition of mTORC1 and OXPHOS by siRNA-micelle@Gboxin resulted in a more potent, synergistic anti-tumor effect than targeting either pathway alone. These findings highlighted that the Gboxin-loaded siRNA micelle offers a promising and innovative nanotherapeutic approach for GBM treatment, harnessing the synergistic effects of gene silencing and chemotherapy-based mitochondrial disruption to achieve a powerful therapeutic efficacy.
研究领域:
肿瘤学
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纳米医学
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分子生物学
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癌症代谢
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基因治疗
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Shangheng Fan,Youbo Yu,Yunqin Wei,Jing An,Qi Wang,Yan Yang
Sarcopenic obesity (SO) manifests as intramuscular lipid deposition and regenerative impairment triggered by dysregulation of the mitophagy-associated axis. Mitochondria-associated membranes (MAMs) are critical for lipid metabolism and mitochondrial function regulation. The mechanistic target of rapamycin (mTOR) is a functional protein at the MAMs and a central metabolic regulator; however, the underlying mechanisms by which mTOR dysregulation affects SO remain unclear. Calcitriol possesses the potential to improve mitochondrial function and fatty acid oxidation. This study investigated the mechanism of Calcitriol in SO using an in vivo SO mice model and an in vitro lipotoxicity-induced myoblast atrophy model. Calcitriol significantly ameliorated muscle atrophy in SO mice, as evidenced by increased grip strength, enhanced behavioral activity, and improved histopathological lesions. Untargeted metabolomic analysis revealed that Calcitriol intervention significantly ameliorated lipid metabolic disorders in SO mice, manifested by a marked reversal of aberrant changes in key lipid metabolites and the restoration of β-oxidation and mitochondrial function-related metabolites to physiological levels. Calcitriol treatment reduced pro-inflammatory cytokines while increasing anti-inflammatory cytokines, restored the contact distance between mitochondria and endoplasmic reticulum at MAMs, and enhanced mitophagy. RNA-Seq, molecular docking, and molecular dynamics simulations collectively demonstrated that these effects were attributable to mTOR downregulation. Furthermore, in vitro mTOR knockdown confirmed that Calcitriol ameliorates lipotoxicity-induced myoblast atrophy through an mTOR-dependent pathway, maintaining MAMs, stabilizing calcium homeostasis, mitigating mitochondrial dysfunction, and reducing ROS generation. In summary, this study demonstrates a novel mechanism whereby Calcitriol effectively inhibits mTOR, which is associated with the restoration of structural integrity of MAMs and the amelioration of disordered lipid metabolism, thereby attenuating SO.
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Yudi Yao,Yang Chen,Huijian Chen,Xin Pan,Xiaojun Li,Wenqi Liu,Yerlan Bahetjan,Binan Lu,Kejian Pang,Xinzhou Yang,Zongran Pang
Ethnopharmacological relevance Black mulberry ( Morus nigra L.) is an ancient dual-use plant resource for medicine and food. It is widely used in Uyghur folklore for hypoglycemic treatment and is a folkloric plant medicine with regional characteristics. However, the mechanism of Morus nigra L. treatment in diabetes mellitus has not been fully understood, especially from the perspective of hepatic lipid accumulation is less reported. Objective of this study This study was to explore the potential of Morus nigra L. fruit ethyl acetate extract (MNF-EA) to reduce blood sugar levels by preventing the production of hepatic lipogenesis and to provide more evidence for the use of MNF-EA as an adjuvant therapy for type 2 diabetes mellitus (T2DM). Materials and methods In this study, the chemical composition of MNF-EA was first analyzed and characterized using UPLC-Q-TOF-MS technique. A series of in vitro studies were performed with HepG2-IR cells and oleic acid (OA)-induced HepG2 cells, including MTT assay, glucose uptake assay, oil red O staining and Western blot analysis . The STZ-HFD co-induced T2DM mice were employed for in vivo research, including physical indices, biochemical analysis, histopathological examination, and Western blot analysis. Results The 19 compounds in MNF-EA were identified by UPLC-Q-TOF-MS technique. Insulin resistance (IR) and lipid droplet accumulation in HepG2 cells were greatly improved by MNF-EA treatment, which had no appreciable side effects at the dosage used. In T2DM mice, MNF-EA decreased fasting blood glucose (FBG), saved body weight, and significantly improved oral glucose tolerance (OGTT) and IR status. In addition, MNF-EA treatment also improved lipid metabolism disorders and liver function in T2DM mice. Histopathological sections showed that MNF-EA treatment reduced hepatic steatosis . Mechanistic studies suggest that MNF-EA acted through the AMPK/mTOR pathway. Conclusions These results suggest that MNF-EA has great potential to reverse the metabolic abnormalities associated with T2DM by regulating the AMPK/mTOR signaling pathway. Therefore, we believe that MNF is a promising medicinal and food-homologous agent to improve T2DM.
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PubMed
高影响因子
Journal of Orthopaedic Surgery and Research
·
2023
·Vol. 18
·期 1
·1-13
·
IF 2.6
Zhang Yang,Liu Wenguang,Liu Zhonghao,Liu Yi
Background Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degeneration and intra-articular inflammation. Daurisoline (DAS) is an isoquinoline alkaloid isolated from Rhizoma Menispermi, whose antitumor and anti-inflammatory pharmacological effects have been demonstrated, but the effects of DAS on OA have rarely been researched. In this study, we aimed to explore the potential role of DAS in OA and its partial mechanism.
Materials and methods The cytotoxicity of H 2 O 2 and DAS toward chondrocytes was detected by the Cell Counting Kit-8 assay. Safranin O staining was used to detect chondrocyte phenotype changes. Cell apoptosis was measured by both flow cytometry and quantitative analysis of the protein levels of the apoptosis-related factors Bax, Bcl-2 and cleaved caspase-3 by western blot. Western blotting and immunofluorescence were used to assess the expression of the autophagy-related proteins LC3, Beclin-1 and p62. In addition, key signal pathway targets and matrix-degrading indicators were measured by western blot. Results Our results indicated that H 2 O 2 induced human chondrocyte apoptosis and activated autophagy in a dose-dependent manner. DAS treatment dose-dependently reversed the expression of apoptosis-related proteins (Bax, Bcl-2 and cleaved caspase3) and the apoptosis rate induced by H 2 O 2 . Western blot and immunofluorescence analyses showed that DAS decreased the H 2 O 2 -induced upregulation of the autophagy marker Beclin-1 and the LC3 II/LC3 I ratio and upregulated the p62 protein level. Mechanistically, DAS inhibited autophagy through the activation of the classical PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis. In addition, DAS alleviated the H 2 O 2 -induced degradation of type II collagen and the high expression of matrix metalloproteinase 3 (MMP3) and MMP13. Conclusion Our research demonstrated that DAS alleviated chondrocyte autophagy caused by H 2 O 2 through activation of the PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis and matrix degradation. In conclusion, these findings suggest that DAS may serve as a promising therapeutic strategy for OA.
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PubMed
高影响因子
PLoS One
·
2023
·Vol. 18
·期 2
·e0281845
·
IF 3.7
Hao Tang,Shida Zhu,Kai Chen,Shujie Yuan,Junzu Hu,Hongkai Wang
Bone is a frequent target of tumor metastasis, with high incidence rate and poor prognosis. Osteoclasts play a key role in the process of tumor bone metastasis. Interleukin-17A (IL-17A) is an inflammatory cytokine, highly expressed in a variety of tumor cells, that can alter the autophagic activity of other cells, thereby causing corresponding lesions. Previous studies have shown that low concentration IL-17A can promote osteoclastogenesis. The aim of this study was to clarify the mechanism of low concentration IL-17A promoting osteoclastogenesis by regulating autophagic activity. The results of our study showed that IL-17A could promote the differentiation of osteoclast precursors (OCPs) into osteoclasts in the presence of RANKL, and increase the mRNA levels of osteoclast-specific genes. Moreover, IL-17A increased the expression of Beclin1 by inhibiting the phosphorylation of ERK and mTOR, leading to enhanced autophagy of OCPs, accompanied by decreased OCP apoptosis. Furthermore, knockdown of Beclin1 and suppression of autophagy by 3-methyladenine (3-MA) significantly attenuated the enhanced osteoclastogenesis induced by IL-17A. In summary, these results indicate that low concentration IL-17A enhances the autophagic activity of OCPs through the ERK/mTOR/Beclin1 pathway during osteoclastogenesis, and further promotes osteoclast differentiation, suggesting that IL-17A may serve as a potential therapeutic target for cancer-related bone resorption in cancer patients.
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2023
·
IF 5
Changsheng Zhong,Yilin Xie,Huifang Wang,Wenxian Chen,Zhenbo Yang,Lei Zhang,Qin Deng,Ting Cheng,Mengyang Li,Jin Ju,Yanyan Liu,Haihai Liang
Diabetes cardiomyopathy (DCM) refers to myocardial dysfunction and disorganization resulting from diabetes. In this study, we investigated the effects of berberine on cardiac function in male db/db mice with metformin as a positive control. After treatment for 8 weeks, significant improvements in cardiac function and a reduction in collagen deposition were observed in db/db mice. Furthermore, inflammation and pyroptosis were seen to decrease in these mice, as evidenced by decreased expressions of p-mTOR, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), IL-1β, IL-18, caspase-1, and gasdermin D (GSDMD). In vitro experiments on H9C2 cells showed that glucose exposure at 33 mmol/L induced pyroptosis, whereas berberine treatment reduced the expression of p-mTOR and NLRP3 inflammasome components. Moreover, berberine treatment was seen to inhibit the generation of mitochondrial reactive oxygen species (mtROS) and effectively improve cell damage in high glucose-induced H9C2 cells. The mTOR inhibitor, Torin-1, showed a therapeutic effect similar to that of berberine, by reducing the expression of NLRP3 inflammasome components and inhibiting mtROS generation. However, the activation of mTOR by MHY1485 partially nullified berberine's protective effects during high glucose stress. Collectively, our study reveals the mechanism that berberine regulates the mTOR/mtROS axis to inhibit pyroptosis induced by NLRP3 inflammasome activation, thereby alleviating DCM.
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PubMed
高影响因子
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