IN VIVO
·
2024
·Vol. 38
·期 3
·1133-1142
·
IF 1.8
LONGJIE XU,LILI HOU,CHUN CAO,XIAOHUA LI
Background/Aim: Cancer-induced bone pain (CIBP) is one of the most common symptoms of bone metastasis of tumor cells. The hypothalamus may play a pivotal role in the regulation of CIBP. However, little is known about the exact mechanisms. Materials and Methods: First, we established a CIBP model to explore the relationship among hypothalamic ghrelin, NPY and CIBP. Then, we exogenously administered NPY and NPY receptor antagonists to investigate whether hypothalamic NPY exerted an antinociceptive effect through binding to NPY receptors. Finally, we exogenously administered ghrelin to investigate whether ghrelin alleviated CIBP by inducing the production of hypothalamic NPY through the AMPK-mTOR pathway. Body weight, food intake and behavioral indicators of CIBP were measured every 3 days. Hypothalamic ghrelin, NPY and the AMPK-mTOR pathway were also measured. Results: The expression of hypothalamic ghrelin and NPY was simultaneously decreased in cancer-bearing rats, which was accompanied by CIBP. Intracerebroventricular (i.c.v.) administration of NPY significantly alleviated CIBP in the short term. The antinociceptive effect of NPY was reversed with the i.c.v. administration of the Y1R and Y2R antagonists. The administration of ghrelin activated the AMPK-mTOR pathway and induced hypothalamic NPY production to alleviate CIBP. This effect of ghrelin on NPY and antinociception was reversed with the administration of a GHS-R1α antagonist. Conclusion: Ghrelin could induce the production of hypothalamic NPY through the AMPK-mTOR pathway to alleviate CIBP, which can provide a novel therapeutic mechanism for CIBP.
研究领域:
神经科学
·
疼痛研究
·
肿瘤学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENT INTERNATIONAL
·
2024
·
IF 10.3
Bilin Zhao,Shuang Zheng,Gaoxiang Yang,Zhijun He,Jiewei Deng,Lijuan Luo,Xinyan Li,Tiangang Luan
Aryl organophosphorus flame retardants (aryl-OPFRs), commonly used product additives with close ties to daily life, have been regrettably characterized by multiple well-defined toxicity risks. Triphenyl phosphate (TPHP) and tri-o-cresyl phosphate (TOCP), two structurally similar aryl-OPFRs, were observed in our previous study to exhibit contrasting immunotoxic effects on THP-1 macrophages, yet the underlying mechanisms remain unclear. This study sought to address the knowledge gap by integrating transcriptomic and metabolomic analyses to elucidate the intricate mechanisms. During individual omics analyses, we unfortunately only obtained highly similar results for both TPHP and TOCP, failing to identify the key reasons for their differences. These results revealed comparable disturbances induced by both compounds, including disruptions in nucleic acid synthesis and energy metabolism, blocking ADP to ATP conversion by reducing TCA cycle intermediates, consequently leading to ATP depletion. However, through integrative analysis, specific pathways affected by each compound were successfully identified, shedding light on their unique effects. TPHP reduced GTP levels necessary for Rap1 activation, thereby inhibiting phagocytosis and adhesion of THP-1 macrophages. Conversely, TOCP stimulated the mTOR signaling pathway, enhancing phosphorylation of downstream proteins S6K, RHOA, and PKC, consequently promoting immune responses. This study not only clarified the distinct immunotoxic mechanisms of TPHP and TOCP but also provided critical insights into how structural variations in aryl-OPFRs can lead to markedly different immune responses, thereby informing future risk assessments and regulatory strategies for these compounds.
研究领域:
毒理学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2021
·
IF 4.24
Yonglu Li,Yiru Zhang,Yaxuan Wang,Xin Yu,Ting Yu,Xiaodong Zheng,Qiang Chu
With high morbidity and mortality, non-small cell lung cancer (NSCLC) has become a challenge for humans, because its clinic chemotherapies still remain unsatisfactory. In this study, the leaf part of a traditional Chinese plant, Tetrastigma hemsleyanum (TL), was studied, and its main flavones compounds were extracted and purified (TLF), which were composed of 5-caffeoylquinic acid, 3-caffeoylquinic acid, 4-caffeoylquinic acid, quercetin-3-O-rutinoside and kaempferol-3-O-rutinoside. To study the anti-NSCLC ability of TLF, in vitro and in vivo studies were done. TLF inhibited the proliferation and migration of A549 cells and caused mitochondrial dysfunction. TLF significantly suppressed the tumor weight and volume, and down-regulated Ki67, proliferation cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF) productions. To determine the intrinsic mechanism, proteins alternations were measured in solid tumors, and results showed that TLF blocked the Akt/mTOR pathway, and thereby induced autophagy, triggering Bcl and Caspase-dependent pathways, resulting in A549 cells’ apoptosis. This study indicated that TLF is a potential candidate to be an anti-NSCLC drug, or a supplementary resource for chemotherapy.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
中医药学
✓ 已验证
产品关联
DOI
高影响因子
Theranostics
·
2021
·
IF 11.556
Yiqun Xia,Jundixia Chen,Yun Yu,Fengjiao Wu,Xin Shen,Chenyu Qiu,Tingting Zhang,Lin Hong,Peisen Zheng,Rongrong Shao,Chenxin Xu,Fang Wu,Wei Chen,Congying Xie,Ri Cui,Peng Zou
Background: Cancer is a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that inhibit oncogenic signaling pathways. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of many cancers. Several mTOR inhibitors are approved for the treatment of cancers. However, the anticancer efficacies of mTOR inhibitor monotherapy are still limited. Methods: Western blot was used to detect the expression of indicated molecules. Thioredoxin reductase (TrxR) activity in cells was determined by the endpoint insulin reduction assay. Immunofluorescence staining was used to analyze precise location and expression of target proteins. Nude mice were used for xenograft tumor models. Results: We identified a synergistic lethal interaction of mTOR and TrxR inhibitors and elucidated the underlying molecular mechanisms of this synergism. We demonstrated that mTOR and TrxR inhibitors cooperated to induce cell death by triggering oxidative stress, which led to activation of autophagy, endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK) signaling pathway in cancer cells. Remarkably, we found that auranofin (AF) combined with everolimus significantly suppressed tumor growth in HCT116 and SGC-7901 xenograft models with no significant signs of toxicity. Conclusion: Our findings identify a promising therapeutic combination for cancer and has important implications for developing mTOR inhibitor-based combination treatments.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
HUMAN & EXPERIMENTAL TOXICOLOGY
·
2022
·
IF 3.247
Q Yang,Y Mao,J Wang,H Yu,X Zhang,X Pei,Z Duan,C Xiao,M Ma
Lipid metabolism is an important biochemical process in the body. Recent studies have found that environmental endocrine disruptors play an important role in the regulation of lipid metabolism. Bisphenol A (BPA), a common environmental endocrine disruptor, has adverse effects on lipid metabolism, but the mechanism is still unclear. This study aimed to investigate the effects of gestational BPA exposure on hepatic lipid metabolism and its possible mechanism in male offspring. The pregnant Sprague-Dawley rats were exposed to BPA (0, 0.05, 0.5, 5 mg/kg/day) from day 5 to day 19 of gestation to investigate the levels of triglyceride (TG) and total cholesterol (TC), and the expression of liver lipid metabolism-related genes in male offspring rats. The results showed that compared with the control group, the TG and TC levels in serum and liver in BPA-exposed groups was increased. And the expressions of liver fatty acid oxidation related genes, such as peroxisome proliferators-activated receptor α (PPARα) and carnitine palmitoyl transferase 1α (CPT1α), were down-regulated. However, the expressions of fatty acid synthesis related genes, such as sterol regulatory element binding proteins 1 (SREBP-1), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD-1), were up-regulated. The increased protein levels of mTOR and p-CRTC2 suggested that CREB-regulated transcription coactivator 2 (CRTC2) might be an important mediator in the mTOR/SREBP-1 pathway. In conclusion, these results demonstrated that mTOR/CRTC2/SREBP-1 could be affected by gestational BPA exposure, which may involve in the lipid metabolic disorders in later life.
研究领域:
环境健康
·
内分泌学
·
代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
·
2025
·
IF 4.3
Yujia Wang,Hongbo Zhang,Jie Yu,Jin Jing,Zhaojiang Fu,Yuanping Hao,Qihang Huang,Ruibin Ma,Yingjie Xu,Yingtao Wu
Background Chronic periodontitis is a prevalent inflammatory and destructive oral disease, and its primary treatment is to control the development of inflammation and promote the regeneration of periodontal tissue. Psoralen (Pso) has been shown to promote the osteogenic differentiation of periodontal ligament stem cells (PDLSCs), suggesting its potential as a therapeutic agent for osteogenic regeneration. Methods Network pharmacology and transcriptomic sequencing were exploited to screen target genes of Pso in PDLSCs, lentiviruses were employed to interfere with the target gene, and RT-qPCR was conducted to assess the expression levels of osteogenesis-related factors. Pso-loaded mesoporous polydopamine (MPDA-Pso) nanoparticles were constructed and evaluated in vitro , and in vivo osteogenesis was assessed in rats with alveolar bone defects. Results Network pharmacology analysis revealed that the mammalian target of rapamycin (mTOR) was a potential target of Pso, and Pso significantly modulated the expression levels of mTOR in PDLSCs and markedly enhanced osteogenic differentiation. However, Pso did not significantly alter osteogenesis-related genes in PDLSCs after mTOR-inhibitor treatment. We also confirmed that MPDA-Pso nanoparticles promoted the expression of osteogenesis-related genes in PDLSCs; and compared with the control group, observed that the mass of new bone was augmented in the MPDA-Pso group. Conclusion Pso was shown to promote the osteogenic differentiation of PDLSCs, and we postulate that this differentiation was facilitated in the LPS-induced inflammatory microenvironment via inhibition of the autophagy-related mTOR-signaling pathway. Additionally, the MPDA-Pso nanoparticles we developed promoted osteogenesis.
研究领域:
干细胞生物学
·
牙周病学
·
药理学
·
再生医学
·
信号转导
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2022
·Vol. 59
·期 11
·6903-6917
·
IF 5.682
Zhao Maofang,Cheng Yuan,Wang Xiaoxuan,Cui Xiaoying,Cheng Xiaojing,Fu Qian,Song Yilin,Yu Peiquan,Liu Yi,Yu Yinghua
Obesity has become a public health epidemic worldwide and is associated with many diseases with high mortality including hypertension, diabetes, and heart disease. High-fat diet (HFD)-induced energy imbalance is one of the primary causes of obesity, but the underlying mechanisms are not fully elucidated. Our study showed that HFD reduced the level of hydrogen sulfide (H 2 S) and its catalytic enzyme cystathionine β-synthase (CBS) in mouse hypothalamus and plasma. We found that HFD activated mTOR, IKK/NF-κB, the main pathway regulating inflammation. Activation of inflammatory pathway promoted the production of pro-inflammatory cytokines including IL-6, IL-1β, and TNF-α, which caused cell damage and loss in the hypothalamus. The disturbance of the hypothalamic neuron circuits resulted in body weight gain in HFD-induced mice. Importantly, we also showed that restoration of H 2 S level with NaHS or activation of CBS with SAMe attenuated HFD-induced activation of mTOR, IKK/NF-κB signaling, which reduced the inflammation and the neuronal cell loss in the hypothalamus, and also inhibited body weight gain in mice. The same effects were obtained by inhibiting mTOR or NF-κB, which suggested that mTOR and NF-κB were the critical molecular factors involved in hypothalamic inflammation. Taken together, this study identified that HFD-induced hypothalamus inflammation plays a critical role in the development of obesity. Moreover, the inhibition of hypothalamic inflammation by regaining H 2 S level could be a potential therapeutic to prevent the development of obesity. Graphical abstract
研究领域:
营养学
·
内分泌学
·
免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Ginseng Research
·
2025
·
IF 5.6
Risheng Zhao,Zhuoqun Wang,Chang Liu,Linxin Zhang,Min Zhang,Huizhu Du,Gege Yang,Haiming Sun,Wei Liu,Shuang Yan,Mengyang Wang
Background (20S)-Protopanaxatriol (PPT), a bioactive triterpenoid from Panax ginseng , has been used in Traditional Chinese Medicine (TCM) to tonify kidney yang and regulate blood pressure. The research aimed to elucidate PPT's protective effects against angiotensin II (Ang II)-induced renal injury. Methods A C57BL/6 mouse model of kidney injury was established by continuous infusion of Ang II for 4 weeks using an osmotic minipump. Treatment with PPT was initiated two weeks after Ang II infusion and administered daily for 14 days. Molecular docking, drug affinity response target stability (DARTS), and cellular thermal shift assay (CETSA) were employed to identify and validate potential targets of PPT in alleviating Ang II-induced renal injury. Additionally, biochemical assays, histopathological analysis, and Western blotting were performed to assess renal function, tissue damage, and signaling pathway modulation. Results Our findings demonstrated that PPT exerted protective effects against Ang II-induced renal dysfunction in mice by significantly attenuating renal fibrosis and inflammation. Mechanistically, PPT targeted PTPN1 and inhibited the AMPK/mTOR signaling pathway, thereby effectively alleviating autophagy dysregulation in both renal tissues of mice and Ang II-stimulated NRK-52E cells in vitro. Molecular docking, DARTS, and CETSA experiments confirmed PTPN1 as a direct target of PPT, providing a molecular basis for its renoprotective effects. Conclusion These findings validate ginseng's traditional use in kidney disorders and demonstrate PPT's potential as a therapeutic agent for hypertensive nephropathy by targeting PTPN1/AMPK/mTOR signaling. Further clinical exploration is needed to translate these results into practice.
研究领域:
药理学
·
肾脏病学
·
中医中药
·
分子生物学
·
信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2021
·Vol. 37
·期 3
·549-563
·
IF 4.119
Yanan Zhao,Ankang Mao,Ranran Zhang,Shuang Guan,Jing Lu
Lead (Pb) is a common and toxic metal pollutant in the ecological environment and has drawn significant attention due to its presence in various channels, including the use of lead-based paint, mineral extraction and smelting, exhaust gas from gasoline combustion. Autophagy is an essential catabolic pathway and blocked autophagy may result in abnormal lipid metabolism in liver. A body of evidence demonstrates that Pb exposure causes abnormal lipid droplet (LDs) accumulation in the liver, but the mechanism remains unknown. Here, we investigated whether Pb induced lipid accumulation by regulating autophagy in HepG2 cells. In this study, we found that Pb (50 μM) blocked the autophagy flux mainly by transcription factor EB (TFEB)-mediated impairment of lysosome formation and activity. Then we demonstrated that the dense lipid accumulation was observed upon Pb exposure, and induction of autophagy by the autophagy activator rapamycin (Rap) alleviated Pb-induced lipid accumulation, while suppression of autophagy by chloroquine (CQ) exacerbated Pb-induced lipid accumulation, suggested that Pb-induced autophagy blockage might be responsible for lipid accumulation. Moreover, we demonstrated that the SIRT1/mTOR pathway participated in Pb-induced autophagy dysregulation, leading to Pb-induced hepatic lipid accumulation. In summary, these results revealed a new insight into the relationship between Pb-caused autophagy dysregulation and lipid accumulation for the first time and highlight autophagy as a novel therapeutic target against Pb-induced hepatic lipid accumulation which supplying the theoretical basis and potential strategies for the intervention and treatment of Pb-related disease.
研究领域:
毒理学
·
细胞生物学
·
分子生物学
·
环境健康
✓ 已验证
DOI
PubMed
高影响因子
PeerJ
·
2025
·
IF 2.4
Jia Song,Jinyu Qiao,Mingxue Chen,Jiahui Li,Jixia Wang,Dayong Yu,Huachuan Zheng,Liying Shi
Chaetoglobosin A (ChA) is an antitumor compound produced by Chaetomium globosum . However, the mechanism of its antitumor effect has been rarely reported. In this study, we evaluated the anti-proliferative effect of ChA on T-24 human bladder cancer cells and explored its mechanism of action. ChA was found to have a good inhibitory effect on T-24 cells by MTT assay with an IC50 value of 48.14 ± 10.25 μΜ. Moreover, it was found to have a migration inhibitory ability and a sustained proliferation inhibitory effect on tumor cells by cell aggregation assay and cell migration assay. The cells morphological changes were determined by Hoechst33342 assay. While Annexin V-FITC/PI double-staining assay also demonstrated that the number of apoptotic cells increased with the increase of drug concentration. Flow cytometry results showed that ChA treatment increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential (MMP) in T-24 cells and inhibited cell mitosis, resulting in an increase in the number of sub-G1 phase cells. Further western blot experiments demonstrated that MAPK and PI3K-AKT-mTOR pathways were activated after drug treatment in addition to endogenous and exogenous apoptotic pathways. The addition of the ROS inhibitor N-acetylcysteine (NAC) upregulated the expression level of Bcl-2 protein, decreased p38 phosphorylation, increased ERK phosphorylation and restored the levels of PI3K and p-mTOR after ChA treatment. These suggest that ChA induces apoptosis by regulating oxidative stress, MAPK, and PI3K-AKT-mTOR signaling pathways in T-24 cells.
研究领域:
肿瘤学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2025
·Vol. 15
·期 10
·4734
·
IF 13.3
Zi-Yue Xi,Chuan-Yong Fan,Ying-Ying Jiang,Xin-Ran Xi,Gan-Yu Nie,Shuang Zhu,Jun-Jie Zhang,Lu Xu
Background: Traditional programmed cell death, including ferroptosis, cuproptosis, and apoptosis, has demonstrated excellent anti-tumor effects and declared their complete mechanisms, however, the zinc ion-mediated tumor inhibiting mechanisms remain insufficiently explored. In this study, a self-generated oxygen nanocatalytic system (ZnO@COF@EM, ZCE) was developed to stimulate cascade amplified effect (CAE) of reactive oxygen species (ROS) generation leading to Znproptosis. The underlying Znproptosis mechanism to disrupt mitochondrial (Mito) metabolism was also investigated. Methods: Specifically, the principle of Znproptosis caused by accumulated zinc and ROS, which served as key factors, was declared through western blot analysis and genetic testing. The mechanism of generated ROS (·OH and 1 O 2 ) under NIR irradiation by ZCE was detected by UV scanning curves, confocal laser scanning microscopy (CLSM) images, and density functional analysis. The injury condition of Fe-S protein of mitochondria metabolism, which triggered Znproptosis with FDX2/LIAS pathway by zinc and ROS, was examined by PCR test and MTT assay. Notably, a Mito-targeting strategy for ZCE was proposed by using molecular docking technology, wherein Zn 2+ was recognized by zinc finger proteins (ZFPs) with the Mito. Results: ZCE, along with CAE, produced abundant ROS (2.42-time more than control group). At the quantum chemical level, the CAE mechanism was associated with a narrower highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gap and increased electronic energy motion within ZCE, which prolonged the excited triplet state (ETS). At the gene level, Znproptosis was achieved by regulating FDX2 and ZIP7 proteins to damage Fe-S protein. The cell cycle was interrupted by Chk2/Cdc25C/Cdc2 and Chk2/p21/Cyclin B1 pathways, leading to the arrest of G1/S and G2/M phases of the cell cycle and inhibition of the Akt/mTOR signaling pathway. Moreover, Znproptosis induced by overloading zinc ions and ROS resulted in a significant antitumor effect (up to 83.81%). Conclusion: Hence, the research reveals a detailed Znproptosis mechanism in nanocatalytic system. Through regulating FDX2/LIAS pathway, Znproptosis could improve the death rate of mitochondria by decreasing the production of Fe-S protein, contributing to advancements in the field of antitumor therapy.
研究领域:
肿瘤学
·
细胞生物学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2021
·
IF 6.244
Heng Yongqing,Liang Yupei,Zhang Junqian,Li Lihui,Zhang Wenjuan,Jiang Yanyu,Wang Shiwen,Jia Lijun
The neddylation pathway is overactivated in esophageal cancer. Our previous studies indicated that inactivation of neddylation by the NAE inhibitor induced apoptosis and autophagy in cancer cells. Camptothecin (CPT), a well-known anticancer agent, could induce apoptosis and autophagy in cancer cells. However, whether CPT could affect the neddylation pathway and the molecular mechanisms of CPT-induced autophagy in esophageal cancer remains elusive. We found that CPT induced apoptosis and autophagy in esophageal cancer. Mechanistically, CPT inhibited the activity of neddylation and induced the accumulation of p-IkBa to block NF-κB pathway. Furthermore, CPT induced the generation of ROS to modulate the AMPK/mTOR/ULK1 axis to finally promote protective autophagy. In our study, we elucidate a novel mechanism of the NF-κB/AMPK/mTOR/ULK1 pathway in CPT-induced protective autophagy in esophageal cancer cells, which provides a sound rationale for combinational anti-ESCC therapy with CPT and inhibition AMPK/ULK1 pathway.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）