Polycyclic polyprenylated acylphloroglucinols from Garcinia xanthochymus fruits exhibit antitumor effects through inhibition of the STAT3 signaling pathway

2020 ◽  
Vol 11 (12) ◽  
pp. 10568-10579
Author(s):  
Jing Xu ◽  
Shan Jin ◽  
Fei Gan ◽  
Hui Xiong ◽  
Zhinan Mei ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Antitumor Effects ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Garcinia Xanthochymus

PPAPs from Garcinia xanthochymus fruits exhibit antitumor effects through STAT3 pathway.

Acute Monocytic Leukemia Associated Antigen MLAA-34 up-Regulates JAK2/STAT3 Expression and JAK2/STAT3 Enhances MLAA-34 Activation in a Positive Feedback Loop

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1393-1393
Author(s):  
Bo Lei ◽  
Ju Bai ◽  
Wanggang Zhang ◽  
Aili He ◽  
Yinxia Chen ◽  
...  
Keyword(s):  
Western Blot ◽  
Signaling Pathway ◽  
Expression Vectors ◽  
Acute Monocytic Leukemia ◽  
U937 Cells ◽  
Rt Pcr ◽  
Monocytic Leukemia ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Backgroud: The MLAA-34 gene (GenBank no. AY288977.2) was first discovered in acute monocytic leukemia (M5) in an effort to identify monocytic leukemia-associated antigens by serologic analysis of a recombinant cDNA expression library (SEREX). Previous study showed that high MLAA-34 levels were independently associated with a poorer relapse-free survival and overall survival in AML patients. The MLAA-34 is located on 13q14.2 and has been confirmed to be a novel splice variant of CAB39L (calcium binding protein 39-like). Both mRNA and protein levels of MLAA-34 were found to be higher in U937 cells and M5 patients. The study confirmed that MLAA-34 plays a role in the antiapoptosis of U937 cells, and has the function of oncogenes. Objective: This study is to explore the relationship of MLAA-34 and JAK2/STAT3 signaling pathway so as to further clarify antiapoptotic mechanisms of MLAA-34. Method: Potential binding sites for STAT3 was identified by computer-assisted analysis of the core promoter of MLAA-34 gene. We analyzed the role of STAT3 in the regulation of MLAA-34 gene expression in U937 cells by site-specific mutation, chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA). The expression of MLAA-34 was detected by RT-PCR and western blot after over-expressing and interfering STAT3. Through the different concentrations of AG490 (JAK2 inhibitors) and different concentrations of IL- 6 (JAK2 activator) study JAK2/STAT3 signaling pathway upregulated MLAA-34 expression. The gene chip and co-IP were applied to study the MLAA-34-induced JAK2/STAT3 activation. Peripheral blood mononuclear cells and bone marrow (BM) cells of M5 patients were obtained. In M5 patients, mRNA and protein expression of JAK-2, STAT3, p-STAT3 and MLAA-34 were determined by quantitative RT-PCR and western blot respectively to verify the forward feedback regulation pathway. Result: The reporter assay showed that the activity of reporter gene was downregulated after the mutation of STAT3 binding sites. ChIP assay and EMSA showed that STAT3 can directly bind to MLAA-34 gene promoter. The expression vectors of MLAA-34 as well as siRNA eukaryotic expression vectors respectively targeting STAT3 were successfully constructed. RT-PCR and western blot results showed that STAT3 can increase the level of MLAA-34. Research of administration of different concentrations of AG490 and different concentrations of IL-6 showed that JAK2/STAT3 signaling pathway could upregulate MLAA-34 expression. AML-M5 NOD / SCID mice leukemia model was successfully constructed,.Konckdown of MLAA-34 gene can promote apoptosis of leukemia cells, inhibit tumor growth and prolong survival time. Total RNA from shRNA-MLAA-34/U937 and Vec/U937 cells were analyzed by Human Genome U133 chip. Heat-map showed reduced expression of JAK2/STAT3 pathway genes. The result was verified by qPCR and western blot. CO-IP showed that MLAA-34 could form a complex with endogenous JAK2 under the enhanced role of IL-6. Thereby activating JAK2 may directly or indirectly dependent on the presence of MLAA-34. Furthermore, we detected JAK-2, STAT3, P-STAT3 and MLAA-34 gene and protein level in M5 patients, the results showed that they have a positive correlation. Conclusion: JAK2/STAT3 pathway up-regulates MLAA-34 transcription, and MLAA-34 enhances JAK2/STAT3 pathway activation. The forward feedback regulation may have profound therapeutic implications for M5 and could help invent novel approaches in treatment for acute monocytic leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Renoprotective Effect of the Recombinant Anti-IL-6R Fusion Proteins by Inhibiting JAK2/STAT3 Signaling Pathway in Diabetic Nephropathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Nanwen Zhang ◽  
Qingmei Zheng ◽  
Yaduan Wang ◽  
Juan Lin ◽  
He Wang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
Interleukin 6 ◽  
Fusion Proteins ◽  
Mesangial Cells ◽  
Glomerular Mesangial Cells ◽  
Stat3 Pathway ◽  
Renoprotective Effect ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Diabetic nephropathy the main reason for end stage renal disease is a common microvascular complication in patients with type 1 and type 2 diabetes. The interleukin-6 (IL-6), acting as a pleiotropic cytokine, play key roles in main autoimmune disorders. The recombinant anti-IL-6R fusion proteins (VHH-0031) constructed and obtained in our lab is a dual target-directed single domain-based fusion protein against the interleukin-6 receptor. This study aims to explore the renoprotective effect of VHH-0031 in diabetic nephropathy. VHH-0031 treatment alleviated renal inflammation, morphologic injury and renal insufficiency in both Goto-Kakizaki rats and STZ-induced Sprague Dawley rats. These renoprotective effects of VHH-0031 are associated with alleviating inflammation and suppression of the JAK2/STAT3 signaling pathway. The mesangial cells treated with VHH-0031 exhibited anti-proliferation, anti-inflammation and inactivation of JAK2/STAT3 pathway under high glucose condition. In conclusion, this study demonstrates that VHH-0031 exhibited a potent protective effect in kidney of diabetic rats and its mechanism may be concerned with the inhibition of the IL-6R/JAK2/STAT3 pathway of glomerular mesangial cells.

scholarly journals LINC00893 Inhibits The Progression of Prostate Cancer Through miR-3173-5p/SOCS3/JAK2/STAT3 Pathway

2021 ◽  
Author(s):  
Chuigong Yu ◽  
Yu Fan ◽  
Yu Zhang ◽  
Lupeng Liu ◽  
Gang Guo
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Janus Kinase ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Background: Prostate cancer (PCa) is one of the most common malignant tumors in the male urinary system. In recent years, the morbidity and mortality of PCa have been increasing due to the limited effects of existing treatment strategies. Long non-coding RNA (lncRNA) LINC00893 inhibits the proliferation and metastasis of papillary thyroid cancer (PTC) cells, but its role in PCa has not been reported. Our study aims to clarify the role and underlying mechanism of LINC00893 in regulating the progression of PCa.Methods: We analyzed LINC00893 expression through TCGA database. We also collected 66 paires of PCa tissues and matched para-cancerous tissues as well as cell lines and assessed LINC00893 expression. Subsequently, we conducted gain-of-function assays to confirm the role of LINC00893 in PCa. CCK-8, EdU, colony information and transwell assays were implemented to detect cell proliferation, colony formation and metastasis abilities, respectively. RT-qPCR and western blot assays were used to quantify the expression of mRNA and protein. Dual-luciferase reporter, RNA-binding protein immunoprecipitation (RIP) and RNA pull down assays were conducted to evaluate the interaction of molecules. Spearman correlation coefficient analysis was conducted to detect the correlation between molecules.Results: We found that the LINC00893 expression in PCa tissues and cell lines was upregulated compared with matched controls, and patients with low expression of LINC00893 suffered a low overall survival rate. Overexpression of LINC00893 hindered the proliferation, epithelial-mesenchymal transition (EMT) as well as metastasis of PCa cells in vitro and in vivo. In terms of mechanism, suppressor of cytokine signaling 3 (SOCS3)/Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway occupied a central position in the regulation of PCa progression by LINC00893. LINC00893 weakened the inhibition role of miR-3173-5p on SOCS3 expression through functioning as a miR-3173-5p sponge, which inhibited the JAK2/STAT3 signaling pathway. Conclusions: LINC00893 suppresses the progression of prostate cancer through miR-3173-5p/SOCS3/JAK2/STAT3 pathway. our data uncovers a novel mechanism by which LINC00893 hinders the progression of PCa, which enriches the molecular network of LINC00893 regulating the PCa progression and laies a theoretical foundation for PCa targeted therapy.

scholarly journals Da Cheng Qi Decoction Alleviates Cerulein-Stimulated AR42J Pancreatic Acinar Cell Injury via the JAK2/STAT3 Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Zehua Zhou ◽  
Ying Chen ◽  
Wenmin Dong ◽  
Rui An ◽  
Kun Liang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Signaling Pathway ◽  
Acinar Cell ◽  
Biochemical Markers ◽  
Cell Injury ◽  
Pancreatic Acinar Cell ◽  
Stat3 Pathway ◽  
Jak2 Inhibitor ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Background. Acute pancreatitis (AP) is a common acute abdomen inflammation, characterized by the dysregulation of digestive enzyme production and secretion. Many studies have shown that Da Cheng Qi Decoction (DCQD) is a secure, effective prescription on AP. In this study, cerulein-stimulated AR42J cells damage model was established to further explore the feasibility and underlying mechanism of DCQD as a potential inhibitor of JAK2/STAT3 pathway for the treatment of AP. Methods. Cell viability of DCQD was measured using a cell counting Kit-8 assay. Pancreatic biochemical markers such as amylase, lipase, and C-reactive protein production were measured by assay kits, respectively. Cytokines (TNF-α, IL-6, IL-10, and IL-1β) were assayed by ELISA. Protein location and protein expression were detected by immunofluorescence staining and Western blotting, respectively. Gene expression was assessed by real-time PCR. For mechanistic analysis of the effect of DCQD on JAK2/STAT3 signaling pathway, selective JAK2 inhibitor (Fedratinib) and STAT3 inhibitor (Stattic) as well as STAT3 activator (Garcinone D) were used. Results. DCQD protected cells by regulating cerulein-induced inflammation and reducing the secretion of pancreatic biochemical markers. Moreover, DCQD could not only inhibit the nuclear translocation of p-STAT3, but also decrease the mRNA expression of JAK2 and STAT3 as well as the ratio of p-JAK2/JAK2 and p-STAT3/STAT3 in protein level. Additionally, DCQD could regulate the mRNA and protein expression of JAK2/STAT3 downstream effectors, Bax and Bcl-XL. The activated effect of cerulein on JAK2/STAT3 pathway was also reversed by JAK2 inhibitor Fedratinib or STAT3 inhibitor Stattic. And the overexpression of JAK2/STAT3 pathway, via STAT3 activator Garcinone D, did exert damage on cells, which bore a resemblance to cerulein. Conclusion. The activation of JAK2/STAT3 pathway may play a key role in the pathogenesis of cerulein-stimulated AR42J pancreatic acinar cell injury. DCQD could improve inflammatory cytokines and cell injury, which might be mediated by suppressing the activation of JAK2/STAT3 signaling pathway.

scholarly journals Da Cheng Qi Decoction Alleviates Cerulein-Stimulated AR42J Pancreatic Acinar Cell Injury via the JAK2/STAT3 Signalling Pathway

2020 ◽  
Author(s):  
Zehua Zhou ◽  
Ying Chen ◽  
Wenmin Dong ◽  
Rui An ◽  
Kun Liang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Acinar Cell ◽  
Biochemical Markers ◽  
Cell Injury ◽  
Pancreatic Acinar Cell ◽  
Cell Counting ◽  
Stat3 Pathway ◽  
Jak2 Inhibitor ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Background: Acute pancreatitis (AP) is a common acute abdomen, characterized by the dysregulation of digestive enzyme production and secretion. Many studies have shown that Da Cheng Qi Decoction (DCQD) is a secure, effective prescription on AP. In this study, cerulein-stimulated AR42J cells damage model was established to further explore the feasibility and underlying mechanism of DCQD as a potential JAK2/STAT3 pathway inhibitor for the treatment of AP. Methods: Cell viability of DCQD was measured using a Cell Counting Kit-8 assay. Pancreatic biochemical markers such as amylase, lipase and C-reactive protein production were measured by assay kits respectively. Cytokines (TNF-α, IL-6, IL-10 and IL-1β) were assayed by ELISA. Protein location was detected by immunofluorescence staining. Proteins expression was quantified by Western blotting, and gene expression was assessed by real‑time PCR. For mechanistic analysis of the effect of DCQD on JAK2/STAT3 signaling pathway, selective JAK2 inhibitor (Fedratinib) and STAT3 inhibitor (Stattic) as well as STAT3 activator (Garcinone D) were used.Results: DCQD protected cells by regulating cerulein-induced inflammation and reducing the secretion of pancreatic biochemical markers. The mechanisms mediating these effects may be related to the suppression of the JAK2/STAT3 pathway. Additionally, DCQD significantly attenuated cell injury and regulated the expression of downstream targets Bax and Bcl-XL. Moreover, treatment with JAK2 inhibitor Fedratinib or STAT3 inhibitor Stattic reversed the activated effect of cerulein on JAK2/STAT3 pathway. And the activation of JAK2/STAT3 pathway, via STAT3 activator Garcinone D, did exert damage on cells, which bore a resemblance to cerulein.Conclusion: The activation of JAK2/STAT3 pathway may play a key role in the pathogenesis of cerulein-stimulated AR42J pancreatic acinar cell injury. DCQD could improve inflammatory cytokines and cell injury, which might be mediated by suppressing the activation of JAK2/STAT3 signaling pathway.

MiR-375 Mediates Chondrocyte Metabolism and Oxidative Stress in Osteoarthritis Mouse Models through the JAK2/STAT3 Signaling Pathway

2019 ◽  
Vol 208 (1-2) ◽  
pp. 13-24
Author(s):  
Li-xue Zou ◽  
Ling Yu ◽  
Xun-ming Zhao ◽  
Jun Liu ◽  
Hou-gen Lu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Mouse Models ◽  
Control Group ◽  
Tunel Staining ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Chondrocyte Metabolism ◽  
And Oxidative Stress

Objective: The aim of this work was to determine the effect of miR-375 on chondrocyte metabolism and oxidative stress in osteoarthritis (OA) mouse models through the JAK2/STAT3 signaling pathway. Methods: Chondrocytes were divided into control, IL-1β, IL-1β + miR-375 mimic, IL-1β + miR-375 inhibitor, IL-1β + miR-NC (negative control), and IL-1β + miR-375 inhibitor + siJAK2 groups. The chondrocyte proliferation was determined by MTT assay, the superoxide dismutase (SOD) and malondialdehyde (MDA) levels by corresponding kits, and the chondrocyte apoptosis by TUNEL staining. Furthermore, OA mouse models were divided into Sham, OA + miR-NC, and OA + miRNA-375 antagomir groups. The pathological changes were observed, and the expressions of miR-375 and the JAK2/STAT3 pathway were determined by qRT-PCR and Western blotting, respectively. Results: IL-1β-induced chondrocytes had significant increases in miR-375 and MDA, with decreased proliferation and SOD levels, as compared to the control group. Meanwhile, they also exhibited elevated apoptosis, with upregulations of ADAMTS-5 and MMP-13 and downregulations of COL2A1 and ACAN, as well as decreased p-JAK2/JAK2, p-STAT3/STAT3, and Bcl-2/Bax. However, these changes were significantly improved after transfection with miR-375 inhibitor, but transfection with miR-375 mimic resulted in severer exacerbation. Notably, the improvement of miR-375 inhibitor could be abolished by transfection with siJAK2. Furthermore, miR-375 antagomir significantly alleviated OA progression in OA mice in vivo. Conclusion: MiR-375 suppression enhanced the ability of chondrocyte to antagonize the oxidative stress and maintained the homeostasis of extracellular matrix metabolism to protect chondrocytes from OA via activation of the JAK2/STAT3 pathway, indicating that miR-375 is a potential molecular target for OA treatment.

Panobinostat Inhibits JAK2/STAT3 Pathway in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2849-2849
Author(s):  
Giulia Perrone ◽  
Elisabetta Calabrese ◽  
Teru Hideshima ◽  
Gullu Gorgun ◽  
Ikeda Hiroshi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Research Funding ◽  
Histone Deacetylase Inhibitors ◽  
Nuclear Translocation ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Stat3 Phosphorylation

Abstract Abstract 2849 Poster Board II-825 Histone deacetylase inhibitors (HDACi) are emerging as a potential therapy for Multiple Myeloma (MM). Their antineoplastic activity depends not only on nucleosomal histone acetylation, but also on direct modulation of non-histone proteins, including p53 or HSP90. Previous studies suggest that histone deacetylases inhibitors modulate Jak2/Stat3 signaling pathway, a cascade mediating tumor cell survival. Here we examine how Panobinostat, a class I-HDAC inhibitor currently in phase I/II clinical trial, can modulate the function of the Jak2/ Stat3 pathway in MM. We first observed that Panobinostat inhibited IL6-induced Stat3 phosphorylation (Tyr705) and Jak2 phosphorylation (Tyr 1007/1008) in MM cell lines ( MM1S and INA6) in a dose- and time- depend fashion, associated with induction of Stat3 acetylation (Lys 685). Since acetylation of Stat3 alters the distribution rather than the functional status of Stat3, we next examined whether Panobinostat altered the nuclear versus cytoplasmic localization of Stat3 in MM cell lines. Although total STAT3 protein level did not change, Panobinostat treatment did trigger decreased nuclear Stat3 phosphorylation, suggesting that Panobinostat blocks Stat3 transcriptional activity. We showed by western blot analysis that the down stream pathway induced by Stat3 (Survivin, Bcl XL, c-Myc) was also down regulated after Panobinostat treatment, further confirming inhibition of STAT3 activity. Take together, our results suggest that Panobinostat inhibits the Jak2/Stat3 pathway by inhibiting STAT3 binding to DNA consensus region, rather than modulating nuclear translocation. To establish the molecular mechanism whereby Panobinostat regulates this pathway, we examined IL6/gp130 receptor, which is upstream in the Jak2 /Stat3 pathway. Panobinostat decreased both cell surface and intracellular gp130 protein expression. Interestingly, Panobinostat also inhibited IL6-induced phosphorylation of gp130, suggesting that it can directly inhibit gp130 activation. Our study therefore suggests a dual mechanism of inhibition of the JAK2/Stat3 pathway induced by Panobinostat via modulation of STAT 3 transcriptional function and gp130 -induced STAT3 activation. Finally, we observed upregulation of the MEK/ERK signaling pathway associated with HDAC inhibition, suggesting that combined blockade of these cascades may be useful. Indeed our preliminary data demonstrate enhanced cytotoxicity in MM cell lines (MM1S and INA6) induced by treatment with combined Panobinostat and MEK inhibitors, even in the presence of bone marrow stromal cells or survival cytokines ( IL6 or IGF). Our study therefore suggests a novel mechanism of action of HDAC inhibitors that provides the rationale for clinical evaluation of novel combinations based upon targeting STAT3 signaling pathway. Disclosures: Anderson: Celgene : Research Funding; Novartis: Research Funding; Millennium: Research Funding.

scholarly journals New bitongling (NBTL) ameliorates rheumatoid arthritis in rats through inhibiting JAK2/STAT3 signaling pathway

2021 ◽  
Vol 65 (1) ◽  
Author(s):  
Xiang Li ◽  
Yu Xie ◽  
An Kang ◽  
Yue Wang
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Proliferation ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Rheumatoid arthritis (RA) is featured by a variety of physical symptoms and fibroblast-like synoviocytes (FLSs) abnormal proliferation. Increasing evidence has demonstrated that traditional Chinese medicine exerts an important role in RA treatment. New bitongling (NBTL) as one of the traditional Chinese medicine has been reported to be involved in the progression of RA, but the exact mechanism is unclear. In our study, we intended to investigate the effect of NBTL on RA to identify the mechanisms related to JAK2/STAT3 signaling pathway. Extracts of Tripterygium wilfordii (TW), a traditional Chinese herbal medicine, have been widely used for treating RA in China for several decades, so, TW was used as a positive control drug for TBNL. RA rats were constructed by immunization with collagen type II to evaluate the action of NBTL in vivo. Body weight and arthritic index were evaluated. Hematoxylin and Eosin staining was performed to analysis the morphological changes of ankle joints tissue. TUNEL and flow cytometry were performed to examine cell apoptosis, while CCK8 and Ethynyl-2′-deoxyuridine (EdU) were performed to examine cell proliferation. In addition, the markers of inflammation were detected by Western blot, ELISA, and RT-qPCR. Firstly, we find that rats treated with NBTL or TW not only reduced swelling degree and bone destruction, but also repressed IL-1 β and IL-6 levels. In addition, NBTL and TW could increase the weight of rats, and promote the level of IL-10 and IL-4 in vivo. Furthermore, NBTL inhibited inflammation of FLS, induced cell apoptosis and hindered cell proliferation, which was reversed by dipeptidyl peptidase (DPP), a JAK2/STAT3 pathway activator. Taken together, NBTL potentially retarded RA via JAK2/STAT3 pathway, highlighting novel mechanisms associated with RA.

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