KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
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2025
·
IF 3.1
Qing Su,Jia Chen
Steroid-induced osteonecrosis of the femoral head (SIONFH) is a debilitating orthopedic condition. This study investigated the mechanism of Tanshinone I (TsI) in SIONFH modulating apoptosis in SIONFH via the PI3K/AKT/mTOR pathway. A SIONFH rat model was treated with TsI and a PI3K activator. Bone mineral density (BMD), bone volume/total volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular separation (Tb.Sp) were determined by microCT. Empty lacunae count, Osteopontin, and apoptosis of the femoral head tissues were assessed. Levels of Bax, cleaved-caspase-3, Bcl-2, and AKT, PI3K, and mTOR phosphorylation in femoral head tissues were determined by Western blot. SIONFH rats exhibited decreased BMD, BV/TV, Tb.N, and Tb.Th, increased Tb.Sp, reduced Osteopontin-positive cells, increased empty lacunae rate, and TUNEL and Osteopontin co-positive cells, elevated Bax and cleaved-caspase-3 protein levels, and diminished Bcl-2 protein expression. TsI promoted osteogenesis, attenuated SIONFH, and reduced apoptosis in SIONFH rats. TsI inhibited AKT, PI3K, and mTOR phosphorylation levels in the femoral head tissues of SIONFH rats, thereby repressing the PI3K/AKT/mTOR pathway activation. Activating the PI3K/AKT/mTOR pathway partially reversed TsI's effect in rats. Collectively, TsI limited the PI3K/AKT/mTOR pathway activation to reduce osteocyte apoptosis in SIONFH rats, which provided potential therapeutic insights for SIONFH treatment.
研究领域:
骨科学
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分子药理学
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细胞生物学
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信号转导
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中医药学
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2023
·
IF 3.9
Huaxiang Wang,Minyong Chen,Chengkai Yang,Huanzhang Hu,Yi Jiang,Fang Yang,Lizhi Lv
Background Small nuclear ribonucleoprotein Sm D1 (SNRPD1) has been reported as an oncogene in some solid cancers. Our previous study suggested that SNRPD1 has diagnostic and prognostic value in hepatocellular carcinoma (HCC), but its role in tumor growth and biological behavior remains unknown. In this study, we aimed to unravel the role and mechanism of SNRPD1 in HCC. Methods We investigated the SNRPD1 mRNA level in adjacent normal liver tissues and HCC tissues with different tumor stages in the UALCAN database. The associations between SNRPD1 mRNA expression and HCC prognosis were investigated in TCGA database. Then, 52 pairs of frozen HCC tissues and corresponding adjacent normal liver tissues were collected to perform qPCR and immunohistochemistry assay. Next, we carried out a series of experiments in vitro and in vivo to investigate the effects of SNRPD1 expression on cell invasion, migration, proliferation, autophagy, and the PI3K/AKT/mTOR pathway. Results The bioinformatics analysis and qPCR in our patient cohort demonstrated that the SNRPD1 mRNA level in HCC tissues was higher than in adjacent normal tissues. In addition, the immunohistochemistry assay exhibited an increased SNRPD1 protein level with the tumor stage increase. Survival analysis suggested that higher expression of SNRPD1 was significantly associated with unfavorable prognosis of patients with HCC. The functional experiments in vitro indicated that SNRPD1 knockdown suppressed the cellular proliferation , migration, and invasion capacities. Furthermore, SNRPD1 inhibition induced cellular apoptosis and arrested the HCC cells at the G0/G1 phase of the cell cycle. Mechanistic analyses demonstrated that SNRPD1 knockdown induced the increase of autophagic vacuoles and the expression of autophagy-related genes (ATG5, ATG7 , and ATG12) and blocked the PI3K/AKT/mTOR/4EBP1 pathway in vitro. Moreover, SNRPD1 inhibition suppressed tumor growth and expression of the Ki67 protein in vivo. Conclusions SNRPD1 may serve as an oncogene in HCC and promote tumor proliferation via inhibiting autophagy induced through the PI3K/Akt/mTOR/4EBP1 pathway.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2022
·
IF 5.895
Xiaofei Zhou,Bowei Zhang,Xiuli Zhao,Yongxi Lin,Yuan Zhuang,Jingting Guo,Shuo Wang
Hyperuricemia is an independent hazard factor of renal injury and can induce renal fibrosis, promoting the development of chronic kidney disease (CKD). This study aimed to explore the probability of chlorogenic acid (CGA) as a potential substance for preventing hyperuricemia nephropathy (HN). Pretreatment with CGA downregulated SUA, BUN, and CR levels, relieved oxidative stress and inflammatory response, alleviated kidney fibrosis, and contributed to the prevention of HN. In the gut microbiota, Blautia, Enterococcus, and Faecalibaculum related to trimethylamine N-oxide (TMAO) synthesis were significantly increased in HN rats. In addition, it showed a significant increase in serum TMAO content in HN rats. However, CGA regulated the cascade response of the microbiota-TMAO signaling to reverse the increase of serum TMAO. CGA also decreased the protein expression of protein kinase B (AKT) phosphorylation, phosphatidylinositide 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) by reducing the production of TMAO. CGA delayed kidney fibrosis in HN rats as evidenced by regulating the cascade response of the microbiota-TMAO-PI3K/AKT/mTOR signaling pathway. In summary, CGA can be an excellent candidate for HN prevention.
研究领域:
药理学
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肾病学
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微生物学
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分子生物学
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病理生理学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2017
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IF 3.671
Jing-yi Zhang,Ying Guo,Jin-ping Si,Xiao-bo Sun,Gui-bo Sun,Jing-jing Liu
Dendrobium officinale is one valuable traditional Chinese medicine, which has skyscraping medicinal value. Polysaccharide is the main active ingredient in D. officinale ; its antioxidant activity is a hot research topic nowadays. Oxidative stress plays an important role in the pathological progress of a variety of cardiovascular disease, as one of key factors of cardiomyocyte apoptosis. This research adopts a model of H 2 O 2 induction-H9c2 cardiomyocytes apoptosis, aiming to study the effect of Dendrobium officinale Polysaccharide (DOP-GY) for cardiomyocyte apoptosis caused by oxidative stress and its possible mechanism. Our results showed that pretreatment of DOP-GY (low dose: 6.25 μg/mL, medium dose: 12.5 μg/mL, high dose: 25 μg/mL) followed by a 2 h incubation with 200 μM H 2 O 2 elevated the survival rate, cutted the LDH leakage, reduced lipid peroxidation damage, improved the activity of the endogenous antioxidant enzymes. In addition, the pretreatment of DOP-GY significantly inhibited the production of ROS, declined of the mitochondrial membrane potential, down-regulated pro-apoptosis protein and up-regulated anti-apoptosis protein. The protective effect was correlated with the PI3K/Akt and MAPK signal pathway. Collectively, these observations suggest that DOY-GY has the potential to exert cardioprotective effects against H 2 O 2 -induced H9c2 cardiomyocyte apoptosis.
研究领域:
药理学
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心脏病学
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分子生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2023
·
IF 5
Xueyu Han,Xin Liu,Xin Zhao,Xiukun Wang,Yazhou Sun,Chuan Qu,Jinjun Liang,Bo Yang
Background Sepsis-induced heart injury is one of the leading causes of circulation disorders worldwide. Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor mainly used for controlling blood glucose, has been shown to exert a protective effect on cardiomyocytes. However, the protective effect of dapagliflozin against sepsis-induced cardiac injury and the underlying mechanism needs to be studied. Aim This study aims to investigate the effect of dapagliflozin on sepsis-induced cardiomyopathy and the potential mechanisms involved. Methods The rat model of sepsis was constructed by intraperitoneal injection of lipopolysaccharide. Echocardiography and electrophysiological studies were performed to detect changes in cardiac function and electrical activity. Cardiac pathological alternation and cardiomyocyte apoptosis were measured by H&E staining, serological analysis, immunohistochemical, immunofluorescence, and TUNEL assays. Western blot and qRT-PCR were performed to elucidate the underlying mechanism of dapagliflozin. Additionally, corresponding experiments in H9c2 cells were performed to further validate the mechanisms in vitro . Results Dapagliflozin improved cardiac dysfunction and reduced the susceptibility to ventricular arrhythmias in sepsis rats by ameliorating cardiac inflammation, suppressing cardiomyocyte apoptosis, and alleviating ventricular electrical remodeling. The PI3K/Akt signaling pathway inhibitor inhibited the anti-apoptotic effect of dapagliflozin, indicating that the protective effect was related to the activation of the PI3K/Akt pathway. Conclusion Dapagliflozin ameliorated sepsis-induced cardiac injury by suppressing electrical remodeling and cardiomyocyte apoptosis, which could be attributed to the PI3K/Akt pathway.
研究领域:
药理学
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心脏病学
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免疫学
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DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
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2020
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IF 6.793
Caiying Zhang,Tianjin Lin,Gaohui Nie,Ruiming Hu,Shaoxing Pi,Zejing Wei,Chang Wang,Chenghong Xing,Guoliang Hu
Cadmium (Cd) and excess molybdenum (Mo) are harmful to animals, but the combined nephrotoxic mechanism of Cd and Mo in duck remains poorly elucidated. To assess joint effects of Cd and Mo on pyroptosis via ROS/PTEN/PI3K/AKT axis in duck renal tubular epithelial cells, cells were cultured with 3CdSO 4 ·8H 2 O (4.0 μM), (NH 4 ) 6 Mo 7 O 24 ·4H 2 O (500.0 μM), MCC950 (10.0 μM), BHA (100.0 μM) and combination of Cd and Mo or Cd, Mo and MCC950 or Cd, Mo and BHA for 12 h, and the joint cytotoxicity was explored. The results manifested that toxicity of non-equitoxic binary mixtures of Mo and Cd exhibited synergic interaction. Mo or/and Cd elevated ROS level, PTEN mRNA and protein levels, and decreased PI3K, AKT and p-AKT expression levels. Simultaneously, Mo or/and Cd upregulated ASC, NLRP3, NEK7, Caspase-1, GSDMA, GSDME, IL-18 and IL-1β mRNA levels and Caspase-1 p20, NLRP3, ASC, GSDMD protein levels, increased the percentage of pyroptotic cells, LDH , NO , IL-18 and IL-1β releases as well as relative conductivity. Moreover, NLRP3 inhibitor MCC950 and ROS scavenger BHA could ameliorate the above changed factors induced by Mo and Cd co-exposure. Collectively, our results reveal that combination of Mo and Cd synergistically cause oxidative stress and trigger pyroptosis via ROS/PTEN/PI3K/AKT axis in duck tubular epithelial cells.
研究领域:
毒理学
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细胞生物学
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分子生物学
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动物科学
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DOI
PubMed
高影响因子
SURGICAL ONCOLOGY-OXFORD
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2020
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IF 2.521
Feng Xue,Yong Jia,Jian Zhao
Background Tyrosine-protein kinase Fyn (FYN) plays a crucial role in Src family, which participates in the signal transduction of brain nerves and the development and activation of T lymphocytes in physiological conditions. We probed into the roles and mechanisms of FYN in lung adenocarcinoma (LUAD). Methods Cell activity, apoptosis , invasion, and migration were detected by CCK-8, FCM , transwell, and wound-healing assays, respectively. The angiogenesis capacity was evaluated by in vitro angiogenesis test. Relative mRNA and protein expressions were determined by qRT-PCR, Western blot , and immunohistochemistry assays, respectively. Insulin-like growth factors-I (IGF-I) was used as an agonist of PI3K/AKT pathway. Results We demonstrated that FYN expression correlated with LUAD prognosis and was down-regulated in LUAD tissues and LUAD cells. Overexpression of FYN suppressed the cell viability , together with invasion and migration abilities of A549 cells. FYN overexpression accelerated the cell apoptosis and reduced the angiogenesis capacity of A549 cells. Overexpression of FYN suppressed E-cadherin, Vimentin , Snail , and PI3K/AKT expressions in A549 cells. High expression level of FYN reduced the migration and invasion capacities of A549 cells via down-regulating the PI3K/AKT pathway. Conclusion Collectively, our findings reveal that overexpression of FYN inhibits the epithelial-to-mesenchymal transition (EMT) through down-regulating the PI3K/AKT pathway in A549 cells.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
CELL AND TISSUE RESEARCH
·
2019
·Vol. 378
·期 1
·113-125
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IF 3.36
Zheng Rongzong,Huang Shuming,Zhu Junkun,Lin Wei,Xu Huan,Zheng Xiang
Rotator cuff tears (RCTs), the most common tendon injury, are always accompanied by muscle atrophy, which is characterized by excessive protein degradation. Autophagy–lysosome systems are the crucial proteolytic pathways and are activated in atrophying muscle. Thus, inhibition of the autophagy–lysosome pathway might be an alternative way to minimize skeletal muscle atrophy. In this present study, combined with a tendon transection-induced rat model of massive rotator cuff tears, HE staining and transmission electron microscopy methods, we found leucine supplementation effectively prevented muscle atrophy, muscle injury and autophagosome formation. Utilizing immunoblotting, we discovered that leucine supplementation is able to inhibit the rise in autophagy-related protein expression (including LC3, Atrogin-1, MuRF1, Bnip3 and FoxO3) driven by tendon transection. The PI3K/AKT/mTOR pathway that was essential in autophagosome formation and autophagy was blocked in atrophying muscle and reactivated in the presence of leucine. Once administrated with LY294002 (PI3K inhibitor) and Rapamycin (mTOR inhibitor), leucine mediated by the anti-atrophic effects was nearly blunted. These results suggest that leucine potentially attenuates tendon transection-induced muscle atrophy through autophagy inhibition via activating the PI3K/AKT/mTOR pathway.
研究领域:
骨骼肌生物学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2016
·Vol. 36
·期 4
·2160-2168
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IF 2.486
Ming Liu,Jiwei Wang,Qichao Qi,Bin Huang,Anjing Chen,Xingang Li,Jian Wang
Recent studies have demonstrated that nitidine chloride (NC), a natural bioactive alkaloid, displays potent antitumor activity in various types of cancer. In the present study, NC was examined for efficacy in the treatment of human glioblastoma multiforme (GBM) as well as the molecular basis for its more general inhibitory effects in cancer. U251 and U87 GBM cell lines were exposed to three concentrations of NC (5, 25 and 50 µM) in vitro, and tumor cell growth was assessed on the basis of proliferation, migration and energy metabolism. Decreases in viability and proliferation reached ~50% for both cell lines with 50 µM NC at 24 h as assessed by cell viability Cell Counting Kit-8 (CCK-8) and EdU assays. In wound closure and Transwell assays, migration and invasion were inhibited at 50 µM after 24 h (~20 and 80%, respectively; P<0.05). ATP and L-lactate levels were also decreased after treatment with NC (50 µM, 24 h; P<0.05 and P<0.01, respectively). Finally, in western blot analysis, phosphorylation of Akt and mTOR was suppressed by NC, but partially restored when cells were treated simultaneously with a novel Akt activator, SC79. Partial restoration was also observed in viability/proliferation (U251 and U87, ~15 vs. 40%; NC vs. NC + SC79; P<0.05) and invasion (U251 and U87, ~30 vs. 60%; NC vs. NC + SC79; P<0.05). Our results demonstrated that NC inhibits development of GBM by targeting the PI3K/Akt/mTOR signaling pathway and provides a potential therapeutic agent for the treatment of GBM.
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
Quantitative Imaging in Medicine and Surgery
·
2025
·Vol. 16
·期 1
·18
·
IF 2.3
Xi Weizhe,Liu Fenfang,Zhong Guangen,Chen Fen,Xie Yin,Lai Meilian,He Qiting,Lu Yiqing,Zhang Jiping,Chen Ying,Meng Luo,Yang Lu
Background Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that leads to cartilage degradation and bone destruction, significantly impacting daily life. Melittin acupoint injection (MAI) is a promising traditional Chinese medicine treatment, but its molecular mechanisms are not fully understood. This study aimed to investigate the therapeutic effects of MAI on RA and elucidate its underlying mechanisms. Methods A collagen-induced arthritis (CIA) mouse model was established using bovine type II collagen, administered every other day for 28 days. The mice were randomly divided into a CIA model group (MO group), melittin acupoint subcutaneous injection group (ST group), melittin acupoint intramuscular injection group (IT group), and methotrexate group (MTX group), with an additional normal control group (NC group) established. Each group contained 8 mice, all of which were treated for 28 days. Therapeutic outcomes were assessed by measuring body weight, swollen joint count (SJC), arthritis index (AI), ankle circumference, and plantar thickness. Radiological and histological changes were analyzed with micro-computed tomography (CT) imaging and pathological staining. Cytokine levels were measured via enzyme-linked immunosorbent assay (ELISA), and autophagy levels were assessed using immunofluorescence staining. The phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway and autophagy status were examined through western blot (WB) and immunofluorescence techniques. Results MAI significantly improved clinical symptoms in CIA mice by reducing plantar thickness, AI scores, and swollen joints (P<0.05). Histopathological analysis showed decreased inflammatory cell infiltration, synovial proliferation, and cartilage damage (P<0.01). Micro-CT and immunohistochemistry revealed reduced inflammation, bone destruction, and cartilage erosion, along with decreased tumor necrosis factor-α (TNF-α) expression (P<0.05). MAI also lowered serum levels of interleukin (IL)-1β (P<0.05), IL-17A, and TNF-α (P<0.01), while increasing IL-10 levels (P<0.05). Immunofluorescence indicated increased microtubule-associated protein 1 light chain 3 beta (LC3B) fluorescence intensity (P<0.05). WB analysis showed elevated levels of Unc-51-like autophagy activating kinase 1 (ULK1), beclin-1 (P<0.01), and microtubule-associated protein 1 light chain 3 II (LC3II) (P<0.05), and reduced phosphorylation of PI3K, AKT, and mTOR (P<0.05). Conclusions MAI alleviates RA symptoms by inhibiting the PI3K/AKT/mTOR pathway and promoting autophagy.
研究领域:
风湿病学
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分子医学
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中医中药
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免疫学
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信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Inflammation Research
·
2026
·
IF 4.6
Jianglong Chen,Yunfei Cui,Rujie Zhou,Yu Zhu,Meijia Chen,Jinhua Su,Jinhui Wang,Guang Li
Objective To explore the therapeutic effect and molecular mechanism of Arundina graminifolia (D.Don) Hochr (BYJ) on renal fibrosis in chronic kidney disease (CKD) mice.Methods Phytochemical profiles of the methanol extract BYJ were analyzed using ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS), while network pharmacology and molecular docking were employed to predict the core active components and therapeutic targets. For experimental validation, a CKD mouse model was established via adenine induction. Mice were randomly assigned to normal control, model, and three BYJ treatment groups (low-dose: 2 g/kg·d, middle-dose: 4 g/kg·d, and high-dose: 8 g/kg·d, crude drug equivalent). Assessments included renal function parameters, histopathological changes, inflammatory markers, and oxidative stress indicators. The associated molecular mechanisms were analyzed using immunohistochemistry staining and Western blot.Results In silico analysis identified five core targets—PIK3R1, AKT1, SRC, MTOR, and EGFR—and suggested esculetin as a key active component with strong binding affinity to these targets. Experimentally, BYJ administration significantly reduced in serum creatinine (SCr), blood urea nitrogen (BUN), and the kidney index, and ameliorated glomerular atrophy and tubular dilation. Furthermore, BYJ treatment downregulated pro-inflammatory factors (eg, IL-1β), elevated superoxide dismutase (SOD) activity, and decreased malondialdehyde (MDA) content. The intervention suppressed the epithelial-mesenchymal transition (EMT) process, as evidenced by the upregulation of E-cadherin and downregulation of α-SMA expression. Mechanistic verification indicated that BYJ treatment was associated with attenuated the overactivated of TGF-β/PI3K-AKT/mTOR pathway in renal tissues.Conclusion The methanolic extract of BYJ effectively attenuates CKD progression in mice, which is associated with by modulated the overactivation of the TGF-β/PI3K-AKT/mTOR pathway, inhibited the EMT process, and ameliorated inflammatory response and oxidative stress. These findings provide a preliminary theoretical basis for the development of BYJ as a potential candidate agent for CKD treatment.
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2026
·Vol. 17
·期 1
·750
·
IF 12.2
Luomeng Qian,Ping Chen,Bo Wang,Qing Zhang,Yuan Guo,Jie Cui,Ran Ding,Hongkai Zhang,Sihe Zhang
Sorafenib is a widely used targeting drug for hepatocellular carcinoma (HCC) patients; however, sorafenib resistance poses a significant clinical challenge. Hypoxia and extracellular vesicles (EVs) induce vasculogenic mimicry (VM) which is linked to sorafenib resistance in HCC. Migrasomes (Migs), the newly discovered large EVs, foster HCC malignant phenotypes by facilitating the intercellular transfer of functional molecules. Despite these advancements, the precise mechanism by which Migs cause sorafenib resistance is still unknown. In this study, we found that hypoxia upregulates the Migs release and CD147 expression on Migs surface, which is related to sorafenib resistance in HCC. Further investigations revealed that hypoxia-induced migrasomes (hypo-Migs) induce VM formation, thereby promoting sorafenib resistance in HCC. Notably, hypo-Migs are internalized into HCC cells through macropinocytosis, which depends on the expression of lysophosphatidic acid receptor 6 (LPAR6). Mechanistically, CD147-positive (CD147 + ) hypo-Migs activate the PI3K/AKT/TWIST1 signaling pathway, subsequently inducing VM formation and promoting sorafenib resistance. Importantly, dual blockade of CD147 + -hypo-Migs macropinocytosis and VM formation enhances the sorafenib-killing efficacy to HCC. Conclusively, our findings uncover a novel sorafenib resistance mechanism induced by CD147 + -hypo-Migs, and highlight dual-targeting of macropinocytosis and VM as a promising strategy to overcome the sorafenib resistance in HCC.
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DOI
PubMed
高影响因子
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