JOURNAL OF INORGANIC BIOCHEMISTRY
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2022
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IF 4.336
Ting Cui,Xueru Wang,Junyu Hu,Tianjin Lin,Zhisheng Hu,Huiling Guo,Gang Huang,Guoliang Hu,Caiying Zhang
Excessive molybdenum (Mo) and cadmium (Cd) are toxic environmental pollutants . Our previous research confirmed excessive Mo and Cd co-induced calcium homeostasis disorder and autophagy in duck kidneys, but how calcium ion (Ca 2+ ) regulates autophagy is unclear. The results revealed that the Mo- and/or Cd-induced cytosolic Ca 2+ concentration ([Ca 2+ ] c ) increase mainly came from intracellular calcium stores. Mo and/or Cd caused mitochondrial Ca 2+ content ([Ca 2+ ] mit ) and [Ca 2+ ] c increase with endoplasmic reticulum (ER) Ca 2+ content ([Ca 2+ ] ER ) decrease and upregulated calcium homeostasis-related factor expression levels, but 2-Aminoethoxydiphenyl borate (2-APB) reversed subcellular Ca 2+ redistribution. Increased Phospholipase C (PLC) and inositol 1,4,5-trisphosphate (IP 3 ) activities and inositol 1,4,5-trisphosphate receptor (IP 3 R) expression level were observed in Mo- and/or Cd-treated cells, which was reversed by the PLC inhibitor U-73122. 2-APB and 1,2-Bis (2-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid acetoxymethyl ester (BAPTA-AM) addition mitigated [Ca 2+ ] c and autophagy (variations in microtubule-associated protein light chain 3 (LC3), LC3B-II/LC3B-I, autophagy related 5 (ATG5), sequestosome-1(P62), programmed cell death-1 (Beclin-1) and Dynein expression levels, LC3 puncta, autophagosomes and acid vesicle organelles) under Mo and/or Cd treatment, respectively, while thapsigargin (TG) had the opposite impacts. Additionally, the calmodulin-dependent protein kinase kinase β (CaMKKβ) inhibitor STO-609 reversed the increased CaMKKβ, adenosine 5′-monophosphate-activated protein kinase (AMPK), Beclin-1, and LC3B-II/LC3B-I protein expression levels and reduced mammalian target of rapamycin (mTOR) and P62 protein expression levels in Mo- and/or Cd-exposed cells. Collectively, the results confirmed that [Ca 2+ ] c overload resulted from PLC/IP 3 /IP 3 R pathway-mediated ER Ca 2+ release, and then activated autophagy by the CaMKKβ/AMPK/mTOR pathway in Mo- and/or Cd-treated duck renal tubular epithelial cells.
研究领域:
毒理学
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细胞生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2019
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IF 3.17
Qi Wan,Hui Chen,Guirun Xiong,Rui Jiao,Yun Liu,Xiaolei Li,Yu Sun,Jingcheng Wang,Lianqi Yan
Intraarticular fibrosis following knee surgery is a troublesome complication and remains a challenging problem for clinicians. Artesunate (ART), a classical anti-malarial drug extracted from the Chinese medicinal herb Artemisia annua L, has been associated with some fibrosis-related diseases. However, its effect and underlying mechanism on knee arthrofibrosis are still obscure. In the present study, we found that ART induced cellular autophagy flux and inhibited cell proliferation in fibroblasts. Intriguingly, genetic depletion of Beclin-1 abolished ART-triggered cellular autophagy and further attenuated the inhibitory effect of ART on fibroblasts proliferation. Moreover, at molecular level, our results demonstrated that ART-induced autophagy activation was associated with the inhibition of mTOR signaling through PI3K/AKT/mTOR pathway and AMPK/mTOR pathway. In vivo, ART treatment triggered autophagy activation and alleviated the severity of surgery-induced knee arthrofibrosis. Taken together, we concluded that ART exhibited anti-proliferation efficacy in fibroblasts and alleviated the severity of knee arthrofibrosis in rabbits by inducing Beclin-1-mediated autophagy via inhibition of mTOR signaling. These findings indicated that ART might be a potential therapeutic agent for preventing the progression of surgery-induced intraarticular fibrosis of knee.
研究领域:
药理学
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骨科
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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
Journal of Functional Foods
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2023
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IF 5.6
Lina Jian,Huixing Wu,Haiyan Zeng,Ting Quan,Fan Xia,Shijian Xiang,Benjie Zhou
The therapeutic and pharmacological potential of isoliquiritigenin has been reported in relieving inflammation and lipid metabolism disorders, particularly in the context of non-alcoholic fatty liver disease (NAFLD). The aim of this study is to investigate the effects of isoliquiritigenin on NAFLD, obesity-associated metabolic symptoms in vivo and in vitro , and explore new mechanisms underlying its effects. Our study revealed that isoliquiritigenin effectively reduced lipid accumulation and suppressed inflammation factors expression in hepatocytes and high fat diet (HFD) mice. Additionally, it prevented body weight gain and liver damage in HFD mice. Importantly, RNA-sequencing results revealed that isoliquiritigenin exerts its anti-NAFLD effect may through the mTOR pathway and autophagy. Rescue experiments further confirmed that it inhibits inflammation by suppressing the PI3K/AKT/mTOR pathway and reduces lipid accumulation by promoting autophagy. Therefore, it holds promise as a novel treatment for NAFLD.
研究领域:
药理学
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肝病学
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代谢学
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分子生物学
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产品关联
DOI
高影响因子
Journal of Orthopaedic Surgery and Research
·
2025
·Vol. 20
·期 1
·1-13
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IF 2.8
Lv Jianwei,Shan Duo,Jia Haobo,Wang Zengliang
Background Peripheral nerve injury (PNI) is currently an intractable disease for clinical therapeutics. Schwann cells (SCs) play pivotal roles in peripheral nerve regeneration. Naringin, a natural flavonoid, has potent beneficial effects on peripheral neuropathy. Researchers have rarely reported whether naringin attenuates SC apoptosis and the relevant mechanisms. Therefore, this study aimed to evaluate the antiapoptotic effects of naringin on SCs and probe the potential molecular mechanisms involved. Methods An in vitro SC apoptotic model was established by culturing RSC96 cells in foetal bovine serum (FBS)-free medium, namely, serum starvation. SC apoptosis was assessed by TUNEL staining and flow cytometry. The activities of the mitochondrial apoptotic pathway and autophagy in SCs were detected by western blotting and immunofluorescence staining. The autophagy inhibitor 3-methyladenine (3-MA) and the AMPK inhibitor Compound C were used to investigate whether autophagy mediated by AMPK/mTOR signalling is involved in the regulation of SC apoptosis by naringin. Results The results showed that starvation induced SC apoptosis and blocked autophagic flux. Naringin ameliorated SC apoptosis under starvation conditions by increasing the autophagy activity mediated by the AMPK/mTOR cascade, as Compound C inhibited its autophagy-activating effect, and 3-MA reversed its antiapoptotic efficacy. Conclusions Naringin mitigated starvation-induced SC apoptosis by increasing autophagy, which was attributed to the regulation of the AMPK/mTOR pathway. This study provides evidence that naringin could be an effective alternative drug for promoting peripheral nerve regeneration.
研究领域:
神经科学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE
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2025
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IF 1.6
Shaohao Luo,Yunfei Bai,Boqian Wang,Haixia Xu,Shu Zhang,Gang Guo,Xin Li,Hongyang Sun,Xiaobo Cui
Homeobox A1 (HOXA1) is implicated in the progression of various cancers, but its biological function in laryngeal cancer (LC) remains undefined, which is the foothold of our study. Bioinformatics analysis and survival analysis were performed to predict HOXA1 expression in LC tissues, and the prognostic relationship between high HOXA1 expression and LC. Whether high HOXA1 expression correlated with the clinical characteristics and prognosis of LC patients was analyzed. LC cell viability and sensitivity to cisplatin were determined by Methyl thiazolyl tetrazolium assay. The cell migration, invasion, and cell cycle after transfection were examined by Wound healing, Transwell, and flow cytometry assays, respectively. The corresponding mRNA and protein expressions were measured by quantitative real-time PCR or Western blot. A higher expression of HOXA1 was detected in LC tissues, which was found to be relevant to poor prognosis of LC patients. The association of high expression of HOXA1 with lymph node and clinical stage was also confirmed. Silencing of HOXA1 in LC cells enhanced the cell sensitivity to cisplatin, inhibited viability, migration, invasion and cell cycle, and reduced N-Cadherin, Vimentin, PCNA, p-AKT and p-mTOR expressions, while overexpression of HOXA1 had the opposite effects. Collectively, HOXA1 boosts migration, invasion and cell cycle, while suppressing cisplatin sensitivity of LC cells by mediating AKT/mTOR pathway, hinting that HOXA1 is a promising biomarker for diagnosis and prognosis of LC in clinical practice.
研究领域:
肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
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2025
·Vol. 66
·期 3
·44-44
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IF 4.7
Boda Li,Junpeng Liu,Di Zhang,Yiran Chu,Zeying Chen,Jiaruei Tsao,Taige Chen,Jiaxuan Jiang,Kai Hu
Purpose:This study aims to explore the therapeutic efficacy of evodiamine (EVO) in the treatment of dry eye disease (DED).Methods:Mouse models of DED was developed using benzalkonium chloride eye drops and subcutaneous atropine injections. Corneal epithelial defects were assessed by fluorescein sodium staining, and tear secretion was measured with the phenol red thread test. For the in vitro model, human corneal epithelial cells were cultured in a sodium chloride–enriched medium. Phenotypic and mechanistic analyses were conducted using real-time quantitative PCR, Western blotting, flow cytometry, and immunofluorescence staining.Results:The administration of EVO eye drops significantly enhanced tear secretion in mice, ameliorated ocular surface damage, decreased the expression of corneal inflammatory factors, and increased the density of conjunctival goblet cells. Furthermore, EVO reduced oxidative stress by promoting autophagy. Mechanistically, EVO-induced autophagy was mediated via the p53/mammalian target of rapamycin pathway.Conclusions:These findings suggest that EVO is a potential therapeutic agent for the treatment of DED, with its beneficial effects attributed to the activation of autophagy through the p53/mammalian target of rapamycin pathway.
研究领域:
眼科
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药理学
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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
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
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2025
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IF 4.9
Jiayin Zhang,Rong Zhang,Lemei Sun,Bingqi Chen,Xiaohan Li,Jing Duan
Urolithin A (UA), a gut microbiota-derived metabolite of ellagic acid, exhibits diverse biological activities. Emerging evidence suggests its anti-tumor potential, possibly mediated through gut microbiota modulation, yet its role in lung cancer remains unclear. In this study, UA dose- and time-dependently suppressed lung cancer cell proliferation. Mechanistically, UA triggered autophagy, as evidenced by increased LC3-II protein levels, and transcriptome analysis revealed this effect was mediated through inhibition of the PI3K/AKT/mTOR pathway. In vivo , UA supplementation markedly inhibited tumor growth in H1975 xenograft models, concomitant with enhanced autophagy and downregulation of associated proteins. Notably, 16S rRNA sequencing demonstrated that UA modulated gut microbiota composition, increasing Lactobacillus while decreasing Desulfovibrio abundance. Spearman’s correlation analysis further linked these microbial shifts to altered expression of autophagy-related genes. Collectively, our findings highlight UA as a promising gut microbial metabolite for lung cancer intervention via coordinated autophagy induction and microbiota remodeling.
研究领域:
癌症生物学
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微生物学
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药理学
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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 IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Tianjiao Ma,Lei Yang,Binmei Zhang,Xin Lv,Feifei Gong,Wei Yang
Aims Doxorubicin is a drug widely used in clinical cancer treatment, but severe cardiotoxicity limits its clinical application. Autophagy disorder is an important factor in the mechanism of doxorubicin-induced cardiac injury. As the smallest molecule in nature, hydrogen has various biological effects such as anti-oxidation, anti-apoptosis and regulation of autophagy. Hydrogen therapy is currently considered to be an emerging therapeutic method, but the effect and mechanism of hydrogen on doxorubicin-induced myocardial injury have not been determined. The purpose of this study was to investigate the protective effect of hydrogen inhalation on doxorubicin-induced chronic myocardial injury and its effect and mechanism on autophagy. Methods In this study, we established a chronic heart injury model by intraperitoneal injection of doxorubicin in rats for 30 days, accumulating 20 mg/kg. The effect of hydrogen inhalation on the cardiac function in rats was explored by echocardiography, Elisa, and H&E staining. To clarify the influence of autophagy, we detected the expression of LC3 and related autophagy proteins in vivo and in vitro by immunofluorescence and western blot.In order to further explore the mechanism of autophagy, we added pathway inhibitors and used western blot to preliminarily investigate the protective effect of hydrogen inhalation on myocardial injury caused by doxorubicin. Results Hydrogen inhalation can improve doxorubicin-induced cardiac function decline and pathological structural abnormalities in rats. It was confirmed by immunofluorescence that hydrogen treatment could restore the expression of autophagy marker protein LC3 (microtubule-associated protein 1 light chain 3) in cardiomyocytes reduced by doxorubicin, while reducing cardiomyocyte apoptosis. Mechanistically, Western blot results consistently showed that hydrogen treatment up-regulated the ratio of p-AMPK (phosphorylated AMP-dependent protein kinase) to AMPK and down-regulated p-mTOR (phosphorylated mammalian target of rapamycin) and mTOR ratio. Conclusions These results suggest that hydrogen inhalation can activate autophagy through the AMPK/mTOR pathway and protect against myocardial injury induced by doxorubicin. Hydrogen inhalation therapy may be a potential treatment for doxorubicin-induced myocardial injury.
研究领域:
医学
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药理学
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心血管科学
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产品关联
DOI
PubMed
高影响因子
npj Breast Cancer
·
2024
·Vol. 10
·期 1
·1-15
·
IF 6.5
Rossetti Stefano,Broege Aaron,Sen Adrish,Khan Salmaan,MacNeil Ian,Molden Jhomary,Kopher Ross,Schulz Stephen,Laing Lance
The PI3K, AKT, and mTOR (PAM) pathway is frequently dysregulated in breast cancer (BC) to accommodate high catabolic and anabolic activities driving tumor growth. Current therapeutic options for patients with hormone receptor (HR) + / HER2- advanced BC (ABC) include PAM inhibitors that selectively inhibit only one PAM pathway node, which can lead to drug resistance as cells rapidly adapt to maintain viability. We hypothesized that gedatolisib, which potently inhibits all Class I PI3K isoforms, as well as mTORC1 and mTORC2, may be more effective in BC cells than single-node PAM inhibitors by limiting adaptive resistances. By using multiple functional assays, a panel of BC cell lines was evaluated for their sensitivity to four different PAM inhibitors: gedatolisib (pan-PI3K/mTOR inhibitor), alpelisib (PI3Kα inhibitor), capivasertib (AKT inhibitor), and everolimus (mTORC1 inhibitor). Gedatolisib exhibited more potent and efficacious anti-proliferative and cytotoxic effects regardless of the PAM pathway mutational status of the cell lines compared to the single-node PAM inhibitors. The higher efficacy of gedatolisib was confirmed in three-dimensional culture and in BC PDX models. Mechanistically, gedatolisib decreased cell survival, DNA replication, cell migration and invasion, protein synthesis, glucose consumption, lactate production, and oxygen consumption more effectively than the other PAM inhibitors tested. These results indicate that inhibition of multiple PAM pathway nodes by a pan-PI3K/mTOR inhibitor like gedatolisib may be more effective at inducing anti-tumor activity than single-node PAM inhibitors. A global Phase 3 study is currently evaluating gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2− ABC.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
DOI
高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·1-15
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IF 3.9
Xia Hong,Tai Xue-jiao,Cheng Wang,Wu Yi,He Dan,Wang Li-feng,Liu Hao,Zhang Shen-yi,Sun Yu-ting,Liu Hang-zhi,Liu Dan-dan,Zhao Hu-zi,Ji Fu-yun,Li Xi-hua
Small cell lung cancer (SCLC) is a therapeutically challenging disease. Metformin, an effective agent for the treatment of type 2 diabetes, has been shown to have antitumour effects on many cancers, including non-small cell lung cancer (NSCLC) and breast cancer. Currently, the antitumour effects of metformin on SCLC and the underlying molecular mechanisms remain unclear. CCK-8, EdU, colony formation, flow cytometry, immunofluorescence, molecular docking, western blotting, nude mouse transplanted tumour model, and immunohistochemistry experiments were conducted to analyse gene functions and the underlying mechanism involved. In vitro experiments demonstrated that metformin inhibited the growth of SCLC cells (H446, H526, H446/DDP and H526/DDP), which was confirmed in xenograft mouse models in vivo. Additionally, metformin induced cell cycle arrest, apoptosis, and autophagy in these SCLC cells. The molecular docking results indicated that metformin has a certain binding affinity for EGFR. The western blotting results revealed that metformin decreased the expression of EGFR, p-EGFR, AKT, and p-AKT, which could be reversed by EGF and SC79. Moreover, metformin activated AMPK and inactivated mTOR, and compound C and SC79 increased the levels of p-mTOR. Metformin can not only enhance the antitumour effect of cisplatin but also alleviate the toxic effects of cisplatin on the organs of xenograft model animals. In summary, the current study revealed that metformin inhibits the growth of SCLC by inducing autophagy and apoptosis via suppression of the EGFR/AKT/AMPK/mTOR pathway. Metformin might be a promising candidate drug for combination therapy of SCLC.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Shiyi Yao,Hui Yuan,Luqi Yang,Yin Zhang,Hanyu Wang,Renxuan Li,Tingjun Ye,Wenguo Cui,Lei Wang
Interface friction impedes tissue healing and stimulates interface cells to produce matrix metalloproteinases (MMPs); however, the precise mechanisms underlying matrix degradation, and the formation of fibrous scars remain unclear. This research involved the development of interface lubricating microspheres that inhibit the PI3K/AKT/mTOR signaling pathway in tenocytes. This inhibition significantly decreased MMP-13 expression and increased COL-1 production, thereby facilitating interface repair and regeneration. In vitro experiments demonstrated that interface friction activates the PI3K/AKT/mTOR/MMP-13 signaling pathway, while the use of interface lubricating microspheres reduced friction by 78 %, resulting in a threefold decrease in MMP-13 expression through pathway inhibition. Animal studies showed that the application of interface lubricating microspheres reduced friction at the tendon-bone interface, mitigating MMP-13-mediated matrix degradation and effectively reducing fibrous scar formation (as evidenced by decreased α-SMA expression), thus promoting interface healing following ACLR surgery in rats. Consequently, this study suggests that interface friction can trigger the PI3K/AKT/mTOR signaling pathway in tenocytes, leading to increased MMP-13 expression, matrix degradation, and fibrous scar formation. The use of interface lubricating microspheres can enhance interface healing by inhibiting this pathway, offering strategies for improving interface healing and minimizing fibrous scar formation. Statement of significance Interface healing plays a crucial role following tendon-bone surgeries, yet it is often hindered by challenges such as interface friction and scar formation. In this study, we propose a combined approach in which lubricating microspheres and an anti-matrix degradation drug are used to enhance interface healing. We fabricated novel lubricating microspheres that exhibit outstanding biocompatibility and degradability; these microspheres serve as lubricants for the tendon-bone interface and facilitate the delivery of doxycycline to reduce excessive matrix metalloproteinase (MMP) secretion. The experimental results demonstrated that this method could enhance tendon-bone interface healing in rats, resulting in increased bone formation and higher histological scores than those of the control group. This study represents a preliminary effort to integrate lubrication and anti-matrix degradation in interface healing, potentially offering new insights into the mechanism between interface friction and fibrous scar healing, while promoting interface healing by reducing interfacial friction.
研究领域:
生物医学工程
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分子生物学
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再生医学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-20
·
IF 15.7
Zhang Zehong,Wan Qianyi,Zhu Yuedan,Ye Jinbao,Fu Fang,Fan Xinxin,Chen Haiou,Ren Gang,Jiang Wei,Guo Xiaoxin,Zhou Juanyu,Yan La,Yan Jinhua,Liu Xingzhu,Yuan Yu,Chen Yi,Chen Haiyang
Intestinal stem cell (ISC) aging diminishes the regenerative capacity of the intestinal epithelia, but effective therapeutic strategies to counteract human ISC aging remain elusive. Here, we find that the synthesis of α-lipoic acid (ALA) is reduced in old human small intestine. Notably, ALA supplementation inhibits ISC aging and decreases the number of atypical Paneth cells in old human intestinal organoids and in old mouse small intestines. Importantly, we discern that the effect of ALA on mitigating ISC aging is contingent upon the presence of Paneth cells. Inhibiting the mTOR pathway in Paneth cells with ALA or rapamycin significantly increases cyclic ADP ribose (cADPR) secretion and decreases Notum secretion, which, in turn, enhances ISC functions. In this work, our findings substantiate the role of ALA in inhibiting human ISC aging and present a potential therapeutic approach for managing age-related human intestinal diseases.
研究领域:
发育生物学
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再生医学
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营养学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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