ARCHIV DER PHARMAZIE
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2024
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IF 4.3
JiaHao Lu,XiuYang Yan,WuJi Lai,Li-He Jiang,Li-Qun Shen,Ai-Qun Wu,Chengguang Zhao
The phosphorylation of STAT3 plays a critical physiological role in the proliferation of rectal cancer. Hence, inhibiting STAT3 phosphorylation is an effective anticancer approach. In this work, we designed a novel 5-R'-1-naphthylmethylamide scaffold as a small molecule inhibitor of STAT3 phosphorylation. The results showed that 3D and 4D have exceptional inhibitory ability against three different colorectal cancer (CRC) cell lines, and can induce apoptosis of CRC cells by inhibiting STAT3 phosphorylation, while having no killing effect on normal human cells. 3D and 4D can inhibit STAT3 phosphorylation in a time- and concentration-dependent manner, and also inhibit the nuclear translocation of interleukin (IL)-6-induced STAT3. In the in vivo tumor model research, 4D significantly reduced the tumor volume of mice and had no drug toxicity on other organ tissues. Furthermore, molecular docking studies revealed that 3D and 4D had greater binding free energy when interacting with the STAT3 SH2 structural domain, and could establish H–π interaction modes. Dynamic simulation studies indicated that both compounds were able to bind tightly to STAT3.
研究领域:
癌症生物学
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药理学
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分子生物学
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化学生物学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
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2019
·Vol. 19
·期 6
·4579-4588
·
IF 1.851
Shiqi Wang,Fuwei He,Zhenwei Li,Yewen Hu,Ning Huangfu,Xiaomin Chen
Oxidative stress serves important roles in cardiac injury during the process of ischemia/reperfusion (I/R). Y‑box protein 1 (YB1), a member of the highly conserved Y‑box protein family, is closely associated with inflammation and stress responses by regulating gene transcription, RNA splicing and mRNA translation. However, the roles of YB1 in oxidative stress‑induced myocardial‑I/R (M‑I/R) injury are unknown. The aim of the present study was to examine the effects of YB1 on H2O2‑induced cardiomyocyte injury and its underlying mechanism. The results demonstrated that YB1 expression was upregulated during H2O2‑induced myocardial injury. YB1 knockdown through transfection of small interfering RNA significantly aggravated cardiac cell apoptosis. Furthermore, YB1 knockdown significantly reversed the H2O2‑mediated increase in phosphorylated signal transducer and activator of transcription (STAT)3, but did not affect the phosphorylation of P38, extracellular signal‑regulated kinases 1/2, c‑Jun N‑terminal kinases, P65, Janus kinase 1 and 2 or STAT1. Moreover, protein co‑immunoprecipitation and RNA‑binding protein immunoprecipitation assays revealed that YB1 interacted with protein inhibitor of activated STAT 3 (PIAS3) mRNA but not its translated protein. YB1 overexpression may have promoted PIAS3 mRNA decay, decreasing PIAS3 protein levels, and therefore increased the levels of phosphorylated STAT3. Finally, YB1 knockdown, mediated by a lentivirus carrying YB1 targeted short hairpin RNA, significantly decreased left ventricle percentage fractional shortening and ejection fraction values, while increasing the infarct sizes in a rat model of M‑I/R injury. These results demonstrated for the first time (to the best of our knowledge) that YB1 may protect cardiac myocytes against H2O2 or M‑I/R‑induced injury by binding to PIAS3 mRNA and resulting in the phosphorylation of STAT3.
研究领域:
心脏病学
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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 BIOLOGY INTERNATIONAL
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2024
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IF 3.3
Guoqiang Xing,Hekai Chen,Zhiyue Guo,Yu Cui,Yongyuan Li,Jianwei Shen
Cholangiocarcinoma (CCA) is a hepatobiliary carcinoma with uncontrolled cell proliferation, poor prognosis, and high mortality. The ovarian tumor structural domain (OTU) containing protein 6B (OTUD6B) belongs to the OTU deubiquitin family and is vital in tumor development. However, its expression and biological function in CCA remain unknown. The expression of OTUD6B in CCA was analyzed using TIMER2.0, UALCAN, and GEO databases. MTT, clonal formation assay, immunofluorescence staining, immunohistochemistry staining, and flow cytometry examined the regulation of OTUD6B on cell proliferation, cycle, and apoptosis. The effects of OTUD6B on tumor volume and weight were assessed using the xenograft tumor model. The activities of PTK2 and STAT3 were detected by western blot and CO-IP. The biological database identified that OTUD6B was upregulated in CCA. In CCA cells, OTUD6B knockdown reduced CCA cell proliferation and promoted apoptosis. Cell cycle analysis indicated that the cycle stopped at the G0/G1 phase after OTU6B downregulation. Furthermore, OTUD6B knockdown resulted in a decrease in tumor volume and weight in xenograft tumor models. Mechanistically, OTUD6B is involved in the deubiquitination of PTK2. PTK2 further affected the phosphorylation of STAT3 thereby regulating the CCA process. Our study demonstrates that OTUD6B knockdown participates in the ubiquitination of PTK2 and phosphorylation of STAT3 to alleviate the process of CCA. These results suggest that OTUD6B may be a potential new strategy for CCA treatment.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Cell Metabolism
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2023
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IF 29
Qianmin Ou,Xinhua Qiao,Zhengshi Li,Luhan Niu,Fangcao Lei,Ruifeng Cheng,Ting Xie,Ning Yang,Yao Liu,Ling Fu,Jing Yang,Xueli Mao,Xiaoxing Kou,Chang Chen,Songtao Shi
Summary Over 50 billion cells undergo apoptosis each day in an adult human to maintain immune homeostasis. Hydrogen sulfide (H 2 S) is also required to safeguard the function of immune response. However, it is unknown whether apoptosis regulates H 2 S production. Here, we show that apoptosis-deficient MRL/ lpr (B6.MRL-Faslpr/J) and Bim −/− (B6.129S1-Bcl2l11tm1.1Ast/J) mice exhibit significantly reduced H 2 S levels along with aberrant differentiation of Th17 cells, which can be rescued by the additional H 2 S. Moreover, apoptotic cells and vesicles (apoVs) express key H 2 S-generating enzymes and generate a significant amount of H 2 S, indicating that apoptotic metabolism is an important source of H 2 S. Mechanistically, H 2 S sulfhydrates selenoprotein F (Sep15) to promote signal transducer and activator of transcription 1 (STAT1) phosphorylation and suppress STAT3 phosphorylation, leading to the inhibition of Th17 cell differentiation. Taken together, this study reveals a previously unknown role of apoptosis in maintaining H 2 S homeostasis and the unique role of H 2 S in regulating Th17 cell differentiation via sulfhydration of Sep15 C38 .
研究领域:
免疫学
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细胞生物学
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生物化学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2024
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IF 6.1
Taiping Li,Yougang Zhang,Rong Dong,Wenjie Bi,Songsong Wang,Kewu Zeng,Liwen Han
American ginseng (AG) has been reported to have anti-inflammatory effects in many diseases, but the key molecules and mechanisms are unclear. This study aims to evaluate the anti-inflammatory mechanism of AG and identify the key molecules by in vivo and in vitro models. Zebrafish was employed to assess the anti-inflammatory properties of AG and the compounds. Metabolomics was utilized to identify potential anti-inflammatory molecules in AG, while molecular dynamics simulations were conducted to forecast the interaction capabilities of these compounds with inflammatory targets. Additionally, macrophage cell was employed to investigate the anti-inflammatory mechanisms of the key molecules in AG by enzyme-linked immunosorbent assay and western blotting. Seven potential anti-inflammatory molecules were discovered in AG, with ginsenoside Rg1, ginsenoside Rs3 (G-Rs3), and oleanolic acid exhibiting the strongest affinity for signal transducer and activator of transcription 3. These compounds demonstrated inhibitory effects on macrophage migration in zebrafish models and the ability to regulate ROS levels in both zebrafish and macrophages. The cell experiments found that ginsenoside Rg1, ginsenoside Rs3, and oleanolic acid could promote macrophage M2/M1 polarization ratio and inhibit phosphorylation overexpression of signal transducer and activator of transcription 3. This study revealed the key anti-inflammatory molecules and mechanisms of AG, and provided new evidence of anti-inflammatory for the scientific use of AG.
研究领域:
药理学
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免疫学
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Journal of Translational Internal Medicine
·
2023
·Vol. 11
·期 2
·156-168
·
IF 4.9
Mengdi Guo,Qian Cao,Shengnan Xia,Xiang Cao,Jian Chen,Yi Qian,Xinyu Bao,Yun Xu
Background and Objectives
Overactivated glial cells, especially microglia, are core components in the progression of pathologic neuroinflammation, and the application of anti-inflammatory reagents has been regarded as a potential therapy in the management of infarction/reperfusion (I/R) brain injury. This research aims to clarify the anti-inflammatory efect of a novel lipophilic compound N-(2-[4-tert-butylphenyl]-2-[pyrrolidine-1-yl]ethyl)-7-methyl-4-oxo-4H-chromene-2-carboxamide (named CP-07 in this study) in LPS-stimulated BV2 cell line and primary mouse microglia, and its therapeutic effect on I/R brain injury.
Method
Cell Counting Kit-8 assay was used to determine the maximal nontoxic dose of CP-07. The mRNA levels of representative proinflammatory cytokines were determined by quantitative real-time polymerase chain reaction both in vitro and in vivo . TTC staining was performed to calculate infarct volumes while behavioral tests were used to assess the neurological deficits at 24 h after middle cerebral artery occlusion (MCAO). Flow cytometry analysis and immunofluorescence staining were performed to calculate the percentage of pro-inflammatory microglia in vivo .A selective JAK2/STAT3 pathway inhibitor, AG490 was used to block STAT3 phosphorylation before the CP-07 anti-inflammation tests in vitro .
Results
CP-07 could effectively suppress the mRNA levels of IL-6, IL-1β, iNOS and TNF-α induced by lipopolysaccharide (LPS) in vitro , and markedly block the evaluation of the fluorescence intensity of Iba-1 in primary mouse microglia. In middle cerebral arteryocclusion models, intraperitoneal injection with 1 mg/kg CP-07 significantly reduced cerebral infarct volumes at 24 h after surgery compared with vehicle treatment group, and promoted the recovery of neurological functions in MCAO mice. Further studies validated that CP-07 administration reduced the percentage of CD86 positive microglia after I/R injury, and the expression level of p-STAT3 was also markedly reduced in both microglial cells and the penumbra tissues. Blocking STAT3 phosphorylation with AG490 could completely eliminate the anti-inflammatory effects of CP-07, at least in vitro .
Conclusion
We showed that a newly synthesized compound, CP-07, could effectively reduce the inflammatory responses in LPS-stimulated BV2 cells and primary mouse microglia, and overproduction of cytokines in middle cerebral artery occlusion mouse models by inhibiting STAT3 phosphorylation, leading to a neuroprotective effect on I/R brain injury.
研究领域:
神经科学
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药理学
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炎症
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神经保护
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产品关联
DOI
PubMed
高影响因子
Nature Communications
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2024
·Vol. 15
·期 1
·1-18
·
IF 14.7
Qiu Sheng,Wu Qinan,Wang Hao,Liu Dongfang,Chen Chen,Zhu Zhiming,Zheng Hongting,Yang Gangyi,Li Ling,Yang Mengliu
Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.
研究领域:
神经科学
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代谢研究
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分子生物学
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内分泌学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2021
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IF 5.858
Mingming Sun,Hao Sheng,Tingfeng Wu,Jiaqi Song,Huanran Sun,Yingzhi Wang,Jiyan Wang,Zhen Li,Huifang Zhao,Junzhen Tan,Yanping Li,Guo Chen,Qingrong Huang,Yuan Zhang,Bei Lan,Shuangping Liu,Changliang Shan,Shuai Zhang
Reprogramming of energy metabolism is a hallmark of cancer, and the pentose phosphate pathway (PPP) is a major glucose metabolic pathway important for meeting the cellular demands of biosynthesis and anti-oxidant defense. Our previous study showed that phosphoinositide 3-kinase enhancer-activating Akt (PIKE-A) plays an important role in glioblastoma cell survival and growth under cellular energy stress condition. However, the crucial functions of PIKE-A in cancer energy metabolism are poorly understood. In the present study, we show that PIKE-A promotes DNA biosynthesis, NADPH production and inhibits reactive oxygen species (ROS) production, leading to increasing proliferation and growth of glioblastoma cell and suppressing cellular senescence. Mechanistically, PIKE-A binds to STAT3 and stimulates its phosphorylation mediated by tyrosine kinase Fyn , which enhances transcription of the rate-limitting enzyme glucose-6-phosphate dehydrogenase (G6PD) in the PPP. Finally, targeting PIKE-A-G6PD axis sensitizes glioblastoma to temozolomide (TMZ) treatment. This study reveals that STAT3 is a novel binding partner of PIKE-A which recruits Fyn to phosphorylate STAT3, contributing to the expression of G6PD, leading to promoting tumor growth and suppressing cellular senescence. Thus, the PIKE-A/STAT3/G6PD axis strongly links the PPP to carcinogenesis and may become a promising cancer therapeutic target.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Stem Cell Research & Therapy
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2024
·Vol. 15
·期 1
·1-21
·
IF 7.1
Liu Hua,Liu Huina,Yang Qiubo,Fan Zhipeng
Background Cartilage is a kind of avascular tissue, and it is difficult to repair itself when it is damaged. In this study, we investigated the regulation of chondrogenic differentiation and vascular formation in human jaw bone marrow mesenchymal stem cells (h-JBMMSCs) by the long-chain noncoding RNA small nucleolar RNA host gene 1 (SNHG1) during cartilage tissue regeneration. Methods JBMMSCs were isolated from the jaws via the adherent method. The effects of lncRNA SNHG1 on the chondrogenic differentiation of JBMMSCs in vitro were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), Pellet experiment, Alcian blue staining, Masson’s trichrome staining, and modified Sirius red staining. RT-qPCR, matrix gel tube formation, and coculture experiments were used to determine the effect of lncRNA SNHG1 on the angiogenesis in JBMMSCs in vitro. A model of knee cartilage defects in New Zealand rabbits and a model of subcutaneous matrix rubber suppositories in nude mice were constructed for in vivo experiments. Changes in mitochondrial function were detected via RT-qPCR, dihydroethidium (DHE) staining, MitoSOX staining, tetramethyl rhodamine methyl ester (TMRM) staining, and adenosine triphosphate (ATP) detection. Western blotting was used to detect the phosphorylation level of signal transducer and activator of transcription 3 (STAT3). Results Alcian blue staining, Masson’s trichrome staining, and modified Sirius Red staining showed that lncRNA SNHG1 promoted chondrogenic differentiation. The lncRNA SNHG1 promoted angiogenesis in vitro and the formation of microvessels in vivo. The lncRNA SNHG1 promoted the repair and regeneration of rabbit knee cartilage tissue. Western blot and alcian blue staining showed that the JAK inhibitor reduced the increase of STAT3 phosphorylation level and staining deepening caused by SNHG1. Mitochondrial correlation analysis revealed that the lncRNA SNHG1 led to a decrease in reactive oxygen species (ROS) levels, an increase in mitochondrial membrane potential and an increase in ATP levels. Alcian blue staining showed that the ROS inhibitor significantly alleviated the decrease in blue fluorescence caused by SNHG1 knockdown. Conclusions The lncRNA SNHG1 promotes chondrogenic differentiation and angiogenesis of JBMMSCs. The lncRNA SNHG1 regulates the phosphorylation of STAT3, reduces the level of ROS, regulates mitochondrial energy metabolism, and ultimately promotes cartilage regeneration.
研究领域:
干细胞生物学
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再生医学
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分子生物学
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骨科
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产品关联
DOI
PubMed
高影响因子
Science Signaling
·
2020
·Vol. 13
·期 646
·
IF 6.467
Xiao-Wei Gu,Zi-Cong Chen,Zhen-Shan Yang,Yan Yang,Ya-Ping Yan,Yue-Fang Liu,Ji-Min Pan,Ren-Wei Su,Zeng-Ming Yang
Embryo implantation involves a sterile inflammatory reaction that is required for the invasion of the blastocyst into the decidua. Adenosine triphosphate (ATP) released from stressed or injured cells acts as an important signaling molecule to regulate many key physiological events, including sterile inflammation. We found that the amount of ATP in the uterine luminal fluid of mice increased during the peri-implantation period, and this depended on the presence of an embryo. We further showed that the release of ATP from receptive epithelial cells was likely stimulated by lactate released from the blastocyst through connexin hemichannels. The ATP receptor P2y2 was present on uterine epithelial cells during the preimplantation period and increased in the stromal cells during the time at which decidualization began. Pharmacological inhibition of P2y2 compromised decidualization and implantation. ATP-P2y2 signaling stimulated the phosphorylation of Stat3 in uterine luminal epithelial cells and the expression of early growth response 1 ( Egr1 ) and prostaglandin-endoperoxide synthase 2 ( Ptgs2, also known as Cox-2 ), all of which are required for decidualization and/or implantation, in stromal cells. Short exposure to high concentrations of ATP promoted decidualization of primary stromal cells, but longer exposures or lower ATP concentrations did not. The expression of genes encoding ATP-degrading ectonucleotidases increased in the decidua during the peri-implantation period, suggesting that they may limit the duration of the ATP signal. Together, our results indicate that the blastocyst-induced release of ATP from uterine epithelial cells during the peri-implantation period may be important for the initiation of stromal cell decidualization.
研究领域:
生殖生物学
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发育生物学
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细胞信号转导
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分子胚胎学
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免疫学（无菌性炎症）
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）