International Journal of Biological Sciences
·
2022
·
IF 10.75
Ling Yang,Jing Yang,Hua Liu,Jingbin Lan,Ying Xu,Xiaobo Wu,Yushan Mao,Dongming Wu,Kejian Pan,Tao Zhang
Colorectal cancer (CRC) is one of the most common malignancies worldwide. Metastasis is a major cause of CRC recurrence and mortality. Several antibiotic drugs have been reported to exert potential anticancer activities, however, whether and how the tetracycline antibiotic minocycline exhibit tumor suppressive effect on CRC remains unknown. Here, we found that minocycline markedly inhibits the epithelial-mesenchymal transition (EMT) process and metastasis of CRC cells both in vitro and in vivo . Using chemical proteomics screening combined with docking analysis and site-directed mutagenesis, we identified LYN as a direct bind target of minocycline, and Ala255 of LYN is required for minocycline binding. Mechanistically, minocycline binding inactivates LYN, leading to STAT3 inactivation and EMT suppression, thereby inhibits CRC metastasis. Tissue microarray analysis further confirmed the clinical relevance of LYN-STAT3 axis in the EMT and progression of CRC. In addition to CRC, minocycline also significantly prevents EMT process and inhibits the metastasis of several other cancer types. Our findings elucidate the mechanism of action of minocycline for the inhibition of CRC metastasis by LYN binding, and suggest that repurposing minocycline may represent a promising strategy for the treatment of advanced CRC and other cancer types.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2021
·
IF 4.432
Guanghui Xu,Huiqi Wan,Litao Yi,Wei Chen,Youhua Luo,Yiqi Huang,Xiaojuan Liu
Accumulating evidence showed that berberine possessed the anti-inflammatory action in various diseases caused by inflammation. However, it was still unclear whether both inhalation and injection with berberine produced pulmonary protective role in acute respiratory distress syndrome (ARDS). This study was aimed to evaluate the effects of both administration routes including inhalation and injection with berberine in ARDS induced by lipopolysaccharide (LPS) inhalation. Histopathological examination and weight of lung were evaluated. Phosphorylation of NF-κB, JAK2 and STAT3 were measured to assess the activity of inflammation related signaling pathways. Proinflammatory cytokines including interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the bronchoalveolar lavage fluid (BALF) and serum were also detected. The results showed that LPS caused the lung injury, while both administration routes with berberine attenuated the injury and improved the pulmonary morphology. In addition, the primary TLR4/NF-κB and secondary JAK2/STAT3 signaling pathways which were activated by LPS in lung were totally inhibited by berberine administration. Moreover, proinflammatory cytokines in both BALF and serum were decreased by berberine. Considering that molecular docking simulation indicated that berberine could bind with TLR4, the present suggested that the inhibition of the inflammation related TLR4/NF-κB and JAK2/STAT3 signaling pathways might be involved in the pulmonary protective effect of berberine in LPS-induced ARDS.
研究领域:
药理学
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呼吸医学
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免疫学
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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 Traditional and Complementary Medicine
·
2024
·
IF 3.3
Jilang Li,Haixin Qiu,Siyuan Li,Shan Han,Yuming He,Jia He,Xiang Gao,Jingjing Li,Jianfang Feng,Shilin Yang,Renyikun Yuan,Hongwei Gao
Background and aim Pulsatilla saponin (Ps) was isolated from Pulsatilla chinensis (Bunge) Regel, a traditional Chinese medicine, that has anti-proliferation, anti-inflammation, anti-tumor and immunomodulation activities. However, the anti-psoriasis activity of Ps and its underlying mechanisms have not been fully elucidated. This study aims to investigate the effect and potential mechanisms of Ps on psoriasis. Experimental procedure Ps underwent quality control through HPLC and NMR analysis. Wound healing assay, MTT, clone assay, and EdU staining were used to detect HaCaT cells proliferation. Western blot and immunofluorescence were used to assess the expression of proteins. The th17 cells population was analyzed by flow cytometry. The levels of cytokines in the mice skin tissues were measured by RT-qPCR and ELISA. Results and conclusion In vitro, Ps has an inhibition effect on the proliferation of M5-induced HaCaT cells. Ps inhibited proliferation by regulating NF-κB and JAK1/STAT3 pathways. Additionally, Ps decreased TNF-α, IL-1β, and IL-6 mRNA levels in M5-induced HaCaT cells. In vivo, Ps improved the pathological damage of Imiquimod (IMQ)-induced psoriasis BALB/c mice skin and reduced the Ki67 level in mice skin tissue. Further results showed that Ps decreased Th17 cells differentiation and IL-22, IL-17A, IL-6, IFN-γ, TNF-α, and IL-1β secretion. Ps could ameliorate the psoriatic symptoms, decrease M5-induced HaCaT cell proliferation, and decrease the differentiation of Th17 cells in IMQ-induced psoriasis mice. Ps suppressed the release of inflammation cytokines by regulating NF-κB and JAK1/STAT3 pathways. Those results indicate that Ps has promising therapeutic potential for psoriasis treatment.
研究领域:
药理学
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免疫学
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皮肤病学
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分子生物学
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产品关联
DOI
高影响因子
MOLECULAR & CELLULAR PROTEOMICS
·
2018
·Vol. 17
·期 10
·2005-2017
·
IF 5.236
Weixuan Wang,Yadong Hu,Changmei Yang,Songbiao Zhu,Xiaofei Wang,Zhenyu Zhang,Haiteng Deng
Nicotinamide adenine dinucleotide (NAD) plays an essential role in all aspects of human life. NAD levels decrease as humans age, and supplementation with NAD precursors plays a protective role against aging and associated disease. Less is known about the effects of decreased NAD on cellular processes, which is the basis for understanding the relationship between cellular NAD levels and aging-associated disease. In the present study, cellular NAD levels were decreased by overexpression of CD38, a NAD hydrolase, or by treating cells with FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT). Quantitative proteomics revealed that declining NAD levels downregulated proteins associated with primary metabolism and suppressed cell growth in culture and nude mice. Decreased glutathione synthesis caused a 4-fold increase in cellular reactive oxygen species levels, and more importantly upregulated proteins related to movement and adhesion. In turn, this significantly changed cell morphology and caused cells to undergo epithelial to mesenchymal transition (EMT). Secretomic analysis also showed that decreased NAD triggered interleukin-6 and transforming growth factor beta (TGFβ) secretion, which activated integrin-β-catenin, TGFβ-MAPK, and inflammation signaling pathways to sustain the signaling required for EMT. We further revealed that decreased NAD inactivated sirtuin 1, resulting in increased signal transducer and activator of transcription 3 (STAT3) acetylation and phosphorylation, and STAT3 activation. Repletion of nicotinamide or nicotinic acid inactivated STAT3 and reversed EMT, as did STAT3 inhibition. Taken together, these results indicate that decreased NAD activates multiple signaling pathways to promote EMT and suggests that age-dependent decreases in NAD may contribute to tumor progression. Consequently, repletion of NAD precursors has potential benefits for inhibiting cancer progression.
研究领域:
细胞生物学
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分子生物学
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癌症研究
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衰老研究
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF HISTOCHEMISTRY
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2022
·
IF 1.966
Haixia Li,Ning Su,Yaqiao Zhu,Wei Wang,Meihong Cai,Xiaohuan Luo,Wei Xia,Song Quan
Recurrent implantation failure (RIF) is defined as failure to achieve clinical pregnancy after at least 3 transfers of good-quality embryos by natural or artificial means. RIF is often a complex problem with a wide variety of etiologies and mechanisms as well as treatment options. In this study, using immunohistochemistry and Western blot, we demonstrated that the expression of leukemia inhibitory factor (LIF), Janus kinase 1 (JAK1), and signal transducer and activator of transcription 3 (STAT3) was increased, while that of suppressor of cytokine signaling 1 (SOCS1) was decreased in RIF patients. Growth hormone (GH) administration proved to have positive effects on embryo implantation in RIF patients, but the action mechanism of GH has not been elucidated yet. To this aim, we studied the effects of GH on the proliferation in vitro of endometrial adenocarcinoma Ishikawa cells. GH stimulated the expression of LIF and SOCS1, and through SOCS1 inhibits the expression of phosphorylated STAT3, and finally inhibits the occurrence of RIF. Excessive phosphorylation of STAT can lead to decreased endometrial receptivity and abnormal embryo implantation. We also examined the effects of LIF overexpression and an LIF inhibitor (EC330) on the JAK/STAT pathway. LIF promoted cell proliferation, and the up-regulation of LIF increased the expression of SOCS1 and JAK1/STAT3 pathway-related genes in Ishikawa cells. As GH can inhibit the JAK1/STAT3 pathway through LIF, we hypothesize that upregulating SOCS1 may be a potential approach to treat RIF at the molecular level. GH can inhibit the JAK1/STAT3 pathway through LIF, up-regulating SOCS1 to treat RIF at the molecular level.
研究领域:
生殖生物学
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分子生物学
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内分泌学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
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IF 4.7
Zhifeng Geng,Guoyi Deng,Ziyu Wang,Xin Xu,Xiaojiao Yin,Sen Zhang,Jiale Shao,Jiyue Wen
Astrocytes may fail to perform their neuroprotective roles against cerebral ischemia/reperfusion (I/R) injury due to phenotypic transformation. We aimed to demonstrate the distinct roles of A1 astrocytes and A2 astrocytes on the blood-brain barrier (BBB) injury following cerebral I/R, and explore whether H 2 S-mediated A2 astrocytes polarization protects against BBB injury via inhibiting ROCK/NF-κB pathway. The mice cerebral I/R model and the oxygen-glucose deprivation/re‑oxygenation (OGD/R) model of astrocytes were used in present study. Cerebral I/R-induced BBB injury is evidenced by increased EB dye leakage and reduced expressions of ZO-1 and occludin in mice hippocampal tissues. We found that H 2 S-mediated A2 polarization and lipopolysaccharide (LPS)-induced polarization of A1 astrocytes respectively display beneficial and harmful role in BBB injury. Besides, harmful roles of A1 astrocytes in BBB injury can be reduced by H 2 S. Additionally, A1 astrocytes exhibit excessive activation of NF-κB and enhanced expressions of MMP9 and AQP4, which can be inhibited by H 2 S. Moreover, H 2 S-mediated polarization of A2 astrocyte displays enhanced phosphorylation and nuclear translocation of STAT3 and reduced expressions of MMP9 and AQP4. Importantly, ROCK inhibitor Fasudil likewise inhibits the activation of NF-κB and promotes STAT3 activation in OGD/R astrocytes, and NF-κB inhibitor BAY11–7082 reduces the expressions of MMP9 and AQP4 in OGD/R astrocytes. In conclusion, H 2 S-mediated polarization of A2 astrocyte protects against BBB injury following cerebral I/R, the mechanisms may be related to inhibition of ROCK/NF-κB pathway, and activation of STAT3.
研究领域:
神经科学
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Ying Li,Zhi-Hao Ma,Xiao Liu,Wenting Zhu,Long Chen,Wanyi Xu,Lei Wang,Jingquan Dong,Zi-Bo Dong
Higenamine Hydrochloride (HGN) is an alkaloid derived from the traditional Chinese medicinal herb Aconite, possesses pharmacological activities such as anti-inflammatory and antioxidant properties. Its specific role in diabetic nephropathy (DN) remains unknown. The purpose of this work was to investigate the protective impact of HGN against streptozotocin (STZ)-induced renal inflammation and fibrosis in DN mice, as well as to investigate its probable mechanism of action in vitro using high glucose (HG)-treated HK-2 cells. We constructed a mouse model of DN by intraperitoneal injection of STZ and a HK-2 cell model using HG treatment, followed by administration of HGN. Tissue distribution experiments, biochemical analysis, real-time PCR, immunoblotting, and histopathological examination were used to assess the effects of HGN on renal histopathology, inflammation, and fibrosis in DN mice and its molecular mechanisms. The results demonstrated that in the renal tissues of DN mice, HGN had the highest concentration. HGN treatment led to body weight increase, and blood glucose levels fell as well as the improvement in metabolic abnormalities. It further proved that HGN alleviated renal function damage by lowering serum creatinine (SCr), blood urea nitrogen (BUN), cystatin C (Cys-C), and renal index values. Moreover, HGN improved kidney histopathology, reduced renal tubular damage, and decreased interstitial inflammation. The kidneys had less collagen accumulation. At the same time, HGN decreased the expression of markers associated with inflammation (iNOS, IL-1β, IL-6, MCP-1) and fibrosis (Collagen-I, MMP9, α-SMA, CTGF). Mechanistic studies have shown that, in vitro, HGN inhibits STAT3 phosphorylation, thereby inhibiting the expression of inflammatory (iNOS, IL-1β, IL-6, and MCP-1) and fibrosis-related cytokines (Collagen-I, MMP9, α-SMA, and CTGF) in HK-2 cells under HG conditions. To summarize, HGN inhibits renal inflammation and fibrosis in DN mice by inhibiting the STAT3 pathway, and this discovery offers a new possible target for DN treatment.
研究领域:
药理学
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传统中医药
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分子生物学
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病理学
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生物化学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Nan Hu,Meng Sun,Nan Lv,Yangyang Gao,Xiaohong Fu,Dayi Xing,Xiang Guo,Shaodong Zhai,Ruiping Zhang
Myocardial infarction (MI) is the leading cause of death worldwide. The most effective way to treat myocardial infarction is to rescue ischemic cardiomyocytes. After an ischemic event, the overproduction of reactive oxygen species (ROS) is a key driver of myocardial injury. The produced ROS affects mitochondrial function and induces apoptosis in cardiomyocytes. This was accomplished by constructing platelet-membrane-encapsulated ROS-responsive drug-releasing nanoparticles (PMN@NIC-MalNPs) to deliver malonate and niclosamide (NIC). The results revealed that PMN@NIC-MalNPs degraded and released malonate and niclosamide in a high-level ROS microenvironment, effectively reducing the oxidative stress and apoptosis rate. By enhancing basal mitochondrial oxygen consumption rate (OCR), adenosine triphosphate (ATP) production, and spare respiratory capacity (SRC) in vitro, reduced the oxidative stress levels and restored mitochondrial function. In vivo studies revealed that the PMN@NIC-MalNPs improved cardiac dysfunction, inhibited succinate dehydrogenase (SDH) activity, increased ATP production, and reduced the myocardial infarct size in myocardial infarction model mice. Further, transcriptome analysis and Western blot revealed that PMN@NIC-MalNPs prevented apoptosis by activating the expressions of the signal transducer and activator of transcription 3 (STAT3) and Bcl-2, and inhibiting the expression of Bax. Thus, this study provides a novel therapeutic solution for treating myocardial infarction and predicting the viability of an antioxidant and antiapoptotic therapeutic solution in the treatment of myocardial injury.
研究领域:
心脏病学
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药学
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纳米技术
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分子生物学
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治疗学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2022
·Vol. 477
·期 5
·1439-1451
·
IF 3.842
Li Jie,Chen Rongchang,Lu Yongzhen,Zeng Yuwei
This study investigated the regulatory effects of microRNA-1278 (miR-1278) on airway inflammation, airway reconstruction, and the proliferation and apoptosis of airway smooth muscle cells (ASMCs) induced by transforming growth factor β1 (TGF-β1). The results showed that miR-1278 was upregulated in the blood and lung tissues (LTs) of patients with asthma compared with that in healthy volunteers; miR-1278 expression was also upregulated in asthmatic mice, and miR-1278 inhibition improved the LTs of asthmatic mice. Moreover, miR-1278 inhibited inflammation in asthmatic mice and counteracted the effect of TGF-β1 of induced proliferation and reduced apoptosis in ASMCs. DLRA indicated that miR-1278 targeted the 3′-UTR of Src-homology 2-containing phosphatase 1 (SHP-1). Furthermore, miR-1278 promoted ASMC proliferation, in which TGF-β1 played an important role by regulating the SHP-1/STAT3 signaling pathway. In conclusion, this study showed that miR-1278 played a critical role in the processes of airway remodeling and reduction of apoptosis by targeting SHP-1.
研究领域:
呼吸医学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2021
·Vol. 22
·期 4
·1-10
·
IF 2.447
Jing Yang,Xiaoli Xie
The present study aimed to investigate the role and potential mechanism of action of tofacitinib (Tofa) in intestinal ischemia/reperfusion (I/R) injury. The normal rat small intestine epithelial cell line, IEC‑6, was used to establish an I/R injury model by inducing oxygen‑glucose deprivation/reoxygenation (OGD/R). Cells were divided into the following five groups: Control, OGD/R, OGD/R with 50, 100 and 200 nM Tofa. Following Tofa administration, cell viability was measured using Cell Counting Kit‑8 assay and a lactate dehydrogenase detection kit. The expression levels of cell apoptosis‑related proteins, Bcl‑2, cleaved‑caspase‑3 and cleaved‑caspase‑9 were detected using western blot analysis. Additionally, the levels of oxidative stress‑related markers, such as reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD), and inflammatory cytokines, TNF‑α, IL‑6 and IL‑1β were assessed using the colorimetric method. Western blot analysis was also used to measure the expression levels of the Janus kinase (JAK)/STAT3 signaling pathway‑related proteins, including phosphorylated (p)‑JAK1, p‑JAK3 and p‑STAT3. Subsequently, colivelin, an agonist of the JAK/STAT3 pathway, was used to investigate whether the effects of Tofa on intestinal I/R injury were mediated by this signaling pathway. The results showed that Tofa dose‑dependently elevated cell viability compared with that in the OGD/R group. By contrast, Tofa attenuated cell apoptosis, which was coupled with upregulated Bcl‑2 expression, downregulated cleaved‑caspase‑3 and downregulated cleaved‑caspase‑9 levels, in OGD/R‑induced IEC‑6 cells. Furthermore, the contents of ROS and MDA were significantly increased following exposure to OGD/R, which were accompanied by the decreased activity of SOD. These effects were reversed following cell treatment with Tofa. Consistently, Tofa intervention reduced the secretion levels of TNF‑α, IL‑6 and IL‑1β in a dose‑dependent manner. Additionally, Tofa markedly downregulated the phosphorylation levels of JAK1, JAK3 and STAT3 in OGD/R‑induced IEC‑6 cells. However, treatment with colivelin markedly reversed the inhibitory effects of Tofa on cell viability, cell apoptosis, oxidative stress and inflammation. Overall, the findings of the present study suggested that Tofa could protect against intestinal I/R injury by inhibiting the JAK/STAT3 signaling pathway, which may hold promise as a therapeutic agent for intestinal I/R injury.
研究领域:
药理学
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细胞生物学
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分子生物学
·
胃肠病学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2017
·
IF 2.759
Yang Liu,Lei Wang,Yang Du,Zhiyuan Chen,Jia Guo,Xiaodong Weng,Xiao Wang,Min Wang,Danyang Chen,Xiuheng Liu
The aim of our study is to investigate the protective effect of apigenin and the role of the JAK2/STAT3 signaling pathway in renal ischemia/reperfusion injury (IRI) in rats. For in vivo experiments, rat kidneys were subjected to 45 min of ischemia , followed by 24 h of reperfusion. The kidneys were pretreated for 24 h with apigenin (4 mg/kg) intraperitoneally in the absence or presence of the JAK2 kinase-specific inhibitor AZD1480 (30 mg/kg). The serum creatinine and urea nitrogen levels were analyzed. Histologic examinations were evaluated. Expression of p-JAK2, p-STAT3, Bcl-2, Bax and Caspase-3 was detected by immunohistochemistry or western blot . For In vitro experiments, NRK-52E cells were exposed to I/R in the absence or presence of apigenin and JAK2 siRNA was used to explore JAK2/STAT3 activity. Cell viability , cell apoptosis and expression of p-JAK2, p-STAT3, Bcl-2, Bax and Caspase-3 were examined in NRK-52E culture after I/R. Consequently, apigenin conferred a renoprotective effect on the kidneys against IRI, as evidenced by decreased serum creatinine and urea nitrogen, mitigated renal histologic damage, improved NRK-52E cell viability and a decreased apoptotic index, including up-regulation of the anti-apoptotic protein Bcl-2 and down-regulation of the pro-apoptotic proteins Bax and Caspase3. However, AZD1480 and JAK2 siRNA blocked the apigenin-mediated renoprotective effects by attenuating the JAK2/STAT3 signaling pathway as well as abolished the effect of anti-oxidative stress and anti-apoptosis of apigenin. Our study demonstrates that apigenin pretreatment can protect against renal IRI via the activation of the JAK2/STAT3 signaling pathway.
研究领域:
药理学
·
肾病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
·
2019
·
IF 2.086
Rui-Li Zhu,Ying-Kun Zhi,Lang Yi,Jin-Fang Luo,Jing Li,Sha-Sha Bai,Liang Liu,Pei-Xun Wang,Hua Zhou,Yan Dong
Objective: To investigate the cellular mechanism that sinomenine (SIN) inhibits inflammation in macrophages induced by LPS through α7 nicotinic acetylcholine receptor (α7nAChR).Materials and methods: RAW264.7 cells were stimulated with LPS and treated by SIN or nicotine (Nic). A selective antagonist of α7nAChR, α-bungarotoxin (BTX) was used to block α7nAChR. AG490 was used to inhibit JAK2 activation. ELISA was performed to detect the levels of TNF-α and MCP-1. Western blotting was used to analyze the expression of MIF, MMP-9, CD14, TLR4, STAT3 and p-STAT3. Intracellular-free calcium level was measured by Fluorescent probe fluo-3/AMResults: SIN inhibited the production of TNF-α, MCP-1, MIF, and MMP-9, decreased the expression of CD14 and TLR4, and inhibited the release of intracellular-free calcium from intracellular stores in RAW 264.7 cells stimulated by LPS. JAK-specific inhibitor AG490 attenuated the inhibitory effect of SIN on TNF-α. SIN increased the phosphorylation of STAT3. And the above effects of SIN were attenuated by antagonist of α7nAChR.Conclusions: SIN can decrease the expression of CD14/TLR4 and intracellular free calcium level, activate JAK2/STAT3 pathway to inhibit inflammatory response through α7nAChR in macrophages.
研究领域:
免疫学
·
药理学
·
细胞生物学
·
炎症研究
✓ 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）