scholarly journals Identification of Vaccinia Virus Inhibitors and Cellular Functions Necessary for Efficient Viral Replication by Screening Bioactives and FDA-Approved Drugs

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 401
Author(s):  
Chen Peng ◽  
Yanan Zhou ◽  
Shuai Cao ◽  
Anil Pant ◽  
Marlene L. Campos Guerrero ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
High Throughput Screening ◽  
Janus Kinase ◽  
Cellular Functions ◽  
Cellular Targets ◽  
Stat3 Signaling ◽  
Assay Procedure ◽  
Stat3 Signaling Pathway ◽  
Cellular Pathways ◽  
Approved Drugs

Four decades after the eradication of smallpox, poxviruses continue to threaten the health of humans and other animals. Vaccinia virus (VACV) was used as the vaccine that successfully eradicated smallpox and is a prototypic member of the poxvirus family. Many cellular pathways play critical roles in productive poxvirus replication. These pathways provide opportunities to expand the arsenal of poxvirus antiviral development by targeting the cellular functions required for efficient poxvirus replication. In this study, we developed and optimized a secreted Gaussia luciferase-based, simplified assay procedure suitable for high throughput screening. Using this procedure, we screened a customized compound library that contained over 3200 bioactives and FDA (Food and Drug Administration)-approved chemicals, most having known cellular targets, for their inhibitory effects on VACV replication. We identified over 140 compounds that suppressed VACV replication. Many of these hits target cellular pathways previously reported to be required for efficient VACV replication, validating the effectiveness of our screening. Importantly, we also identified hits that target cellular functions with previously unknown roles in the VACV replication cycle. Among those in the latter category, we verified the antiviral role of several compounds targeting the janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3) signaling pathway by showing that STAT3 inhibitors reduced VACV replication. Our findings identify pathways that are candidates for use in the prevention and treatment of poxvirus infections and additionally provide a foundation to investigate diverse cellular pathways for their roles in poxvirus replications.

scholarly journals Computer-aided prediction of inhibitors against STAT3 for managing COVID-19 associate cytokine storm

2021 ◽  
Author(s):  
Anjali Dhall ◽  
Sumeet Patiyal ◽  
Neelam Sharma ◽  
Naorem Leimarembi Devi ◽  
Gajendra P. S. Raghava
Keyword(s):  
Prediction Models ◽  
Validation Dataset ◽  
Cytokine Storm ◽  
Hybrid Features ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Wide Range ◽  
Proinflammatory Responses ◽  
Highly Correlated ◽  
Approved Drugs

Abstract It has been shown in the past that levels of cytokines, including interleukin 6 (IL6), is highly correlated with the disease severity of COVID-19 patients. IL6 mediated activation of STAT3 is responsible to proliferate proinflammatory responses that leads to promotion of cytokine storm. Thus, STAT3 inhibitors may play a crucial role in managing pathogenesis of COVID-19. This paper describes a method developed for predicting inhibitors against the IL6-mediated STAT3 signaling pathway. The dataset used for training, testing, and evaluation of models contains small-molecule based 1564 STAT3 inhibitors and 1671 non-inhibitors. Analysis of data indicates that rings and aromatic groups are significantly abundant in STAT3 inhibitors compared to non-inhibitors. In order to build models, we generate a wide range of descriptors for each chemical compound. Firstly, we developed models using 2-D and 3-D descriptors and achieved maximum AUC 0.84 and 0.73, respectively. Secondly, fingerprints (FP) are used to build prediction models and achieved 0.86 AUC and accuracy of 78.70% on validation dataset. Finally, models were developed using hybrid features or descriptors, achieve a maximum of 0.87 AUC on the validation dataset. We used our best model to identify STAT3 inhibitors in FDA-approved drugs and found few drugs (e.g., Tamoxifen, and Perindopril) that can be used to manage COVID-19 associated cytokine storm. A webserver “STAT3In” (https://webs.iiitd.edu.in/raghava/stat3in/ ) has been developed to predict and design STAT3 inhibitors.

A natural product phillygenin suppresses osteosarcoma growth and metastasis by regulating the SHP-1/JAK2/STAT3 signaling

2021 ◽  
Vol 85 (2) ◽  
pp. 307-314
Author(s):  
Xiaomin Ding ◽  
Danqing Lu ◽  
Jianbo Fan
Keyword(s):  
Cell Growth ◽  
Signaling Pathway ◽  
Janus Kinase ◽  
Potential Candidate ◽  
Osteosarcoma Cell ◽  
Cancer Cell Growth ◽  
Functional Roles ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

ABSTRACT Osteosarcoma represents one of the most devastating cancers due to its high metastatic potency and fatality. Osteosarcoma is insensitive to traditional chemotherapy. Identification of a small molecule that blocks osteosarcoma progression has been a challenge in drug development. Phillygenin, a plant-derived tetrahydrofurofuran lignin, has shown to suppress cancer cell growth and inflammatory response. However, how phillygenin plays functional roles in osteosarcoma has remained unveiled. In this study, we showed that phillygenin inhibited osteosarcoma cell growth and motility in vitro. Further mechanistic studies indicated that phillygenin blocked STAT3 signaling pathway. Phillygenin led to significant downregulation of Janus kinase 2 and upregulation of Src homology region 2 domain-containing phosphatase 1. Gene products of STAT3 regulating cell survival and invasion were also inhibited by phillygenin. Therefore, our studies provided the first evidence that phillygenin repressed osteosarcoma progression by interfering STAT3 signaling pathway. Phillygenin is a potential candidate in osteosarcoma therapy.

scholarly journals JANEX-1 improves acute pulmonary embolism through VEGF and FAK in pulmonary artery smooth muscle cells

2020 ◽  
Vol 245 (15) ◽  
pp. 1395-1403
Author(s):  
Longfei Pan ◽  
Zhuo Peng ◽  
Ruipeng Zhang ◽  
Rui Zhang ◽  
Dean Liang ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Acute Pulmonary Embolism ◽  
Janus Kinase ◽  
Vegf Expression ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Janus Kinase 3

Although clinical treatment has significant progress, acute pulmonary embolism is still a common disease with high morbidity and mortality. Janus Kinase 3, a member of JAK family, has been demonstrated to promote smooth muscle cell proliferation through STAT3. In this work, we explored the effect of JANEX-1 (a specific Janus Kinase 3 inhibitor) on platelet-derived growth factor (PDGF)-induced proliferation-related molecules in pulmonary artery smooth muscle cells (PVSMCs) in vitro and assessed the therapeutic potential of Janus Kinase 3 for vascular remodeling in acute pulmonary embolism mice. The results revealed that Janus Kinase 3 was overexpressed and active in PDGF-induced PVSMCs and acute pulmonary embolism mice, compared to a low expression in normal conditions. JANEX-1, blocking Janus Kinase 3 expression or activity, reduced Janus Kinase 3/STAT3 signaling pathway, VEGF expression, FAK activation, and PDGF-induced proliferation of PVSMCs, while overexpression of VEGF or FAK induced PVSMCs proliferation and resisted the negative effects of JANEX-1. Moreover, JANEX-1 improved right ventricular systolic pressure, survival and lung damage in acute pulmonary embolism-mice, and inhibited the thrombus-induced intimal hyperplasia and the expression of α-SMA, VEGF, and FAK activation under neointimal smooth muscle cells of acute pulmonary embolism mice. In conclusion, the data suggest that JANEX-1 exerts protective effects by inhibiting PVSMCs proliferation and vascular remodeling post-acute pulmonary embolism, in part through Janus Kinase 3/STAT3 signaling pathway-mediated VEGF expression and FAK activation. The data are helpful to elucidate the pharmacological mechanism and potential therapeutic effect of JANEX-1 in APE. Impact statement Accumulating evidence suggests that vascular remodeling due to immoderate proliferation and migration of SMCs is a common process occurring in APE. In this work, we tried to find a breakthrough in the pathological mechanism to alleviate the prognosis of APE by improving SMCs proliferation and explored the effect of JANEX-1 on PDGF-induced proliferation-related molecules in PVSMCs and assessed the therapeutic potential of JAK3 for vascular remodeling in APE mice. We demonstrated that JANEX-1, blocking JAK3 expression or activity, reduced JAK3/STAT3 signaling pathway, VEGF expression and FAK activation, and PDGF-induced proliferation of PVSMCs. Moreover, JANEX-1 inhibited the thrombus-induced intimal hyperplasia and the expression of VEGF and FAK activation in neointimal SMCs of APE mice. The data are helpful to elucidate the pharmacological mechanism and potential therapeutic effect of JANEX-1 in APE.

scholarly journals Jak1/Stat3 Activation Alters Phosphate Metabolism Independently of Sex and Extracellular Phosphate Levels

2021 ◽  
pp. 1-9
Author(s):  
Nicole Gehring ◽  
Carla Bettoni ◽  
Carsten A. Wagner ◽  
Isabel Rubio-Aliaga
Keyword(s):  
Signaling Pathway ◽  
Mineral Metabolism ◽  
Janus Kinase ◽  
Phosphate Metabolism ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
The Impact

<b><i>Introduction:</i></b> Phosphate homeostasis is regulated by a complex network involving the parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and calcitriol acting on several organs including the kidney, intestine, bone, and parathyroid gland. Previously, we showed that activation of the Janus kinase 1 (Jak1)-signal transducer and activator of transcription 3 (Stat3) signaling pathway leads to altered mineral metabolism with higher FGF23 levels, lower PTH, and higher calcitriol levels. Here, we investigated if there are sex differences in the role of Jak1/Stat3 signaling pathway on phosphate metabolism and if this pathway is sensitive to extracellular phosphate alterations. <b><i>Methods:</i></b> We used a mouse model (<i>Jak1</i><sup>S645P+/−</sup>) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans and analyzed the impact of sex on mineral metabolism parameters. Furthermore, we challenged <i>Jak1</i><sup>S645P+/−</sup> male and female mice with a high (1.2% w/w) and low (0.1% w/w) phosphate diet and a diet with phosphate with organic origin with lower bioavailability. <b><i>Results:</i></b> Female mice, as male mice, showed higher intact FGF23 levels but no phosphaturia, and higher calcitriol and lower PTH levels in plasma. A phosphate challenge did not alter the effect of Jak1/Stat3 activation on phosphate metabolism for both genders. However, under a low phosphate diet or a diet with lower phosphate availability, the animals showed a tendency to develop hypophosphatemia. Moreover, male and female mice showed similar phosphate metabolism parameters. The only exception was higher PTH levels in male mice than those in females. <b><i>Discussion/Conclusion:</i></b> Sex and extracellular phosphate levels do not affect the impact of Jak1/Stat3 activation on phosphate metabolism.

scholarly journals Tofacitinib Ameliorates Lipopolysaccharide-Induced Acute Kidney Injury by Blocking the JAK-STAT1/STAT3 Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Yang Yun ◽  
Jingyu Chen ◽  
Xuejiao Wang ◽  
Yingzhuo Li ◽  
Zhifan Hu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Inhibitory Effect ◽  
Janus Kinase ◽  
Protective Effects ◽  
Lps Challenge ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Septic Acute Kidney Injury ◽  
Underlying Mechanisms

Septic acute kidney injury (AKI) is the most common AKI syndrome in the intensive care unit (ICU), and it accounts for approximately half of AKI cases. Tofacitinib (TOFA) is a pan-Janus kinase (JAK) inhibitor that exhibits potent anti-inflammatory activity in rheumatoid arthritis. However, no study has examined the functional role of TOFA in septic AKI. In the present study, we investigated the protective effects of TOFA on septic AKI and the underlying mechanisms. A lipopolysaccharide- (LPS-) induced AKI model was established in C57BL/6 mice via an intraperitoneal injection of LPS (10 mg/kg). One hour after LPS challenge, the mice were orally administered TOFA (5, 10, or 15 mg/kg) every 6 h until sacrifice at 24 h. We found that TOFA significantly ameliorated LPS-induced renal histopathological changes and dysfunction. TOFA also suppressed the expression levels of proinflammatory cytokines (TNF-α, IL-1β, IL-6, and IFN-γ) and the parameters of oxidative stress (MDA, GSH, SOD, and CAT) in kidney tissues. These results may be associated with the inhibitory effect of TOFA on the JAK-STAT1/STAT3 pathway, which was significantly activated by LPS challenge. TOFA treatment also inhibited LPS-induced activation of the TLR4/NF-κB pathway. In conclusion, we revealed that TOFA had a protective effect on LPS-induced AKI, and it may be a promising therapeutic agent for septic AKI.

scholarly journals Diet-Induced Obesity Increases Tumor Growth and Promotes Anaplastic Change in Thyroid Cancer in a Mouse Model

Endocrinology ◽  
2013 ◽  
Vol 154 (8) ◽  
pp. 2936-2947 ◽  
Author(s):  
Won Gu Kim ◽  
Jeong Won Park ◽  
Mark C. Willingham ◽  
Sheue-yann Cheng
Keyword(s):  
Thyroid Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Thyroid Tumor ◽  
Janus Kinase ◽  
Histopathological Analysis ◽  
Diet Induced Obesity ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Recent epidemiological studies provide strong evidence suggesting obesity is a risk factor in several cancers, including thyroid cancer. However, the molecular mechanisms by which obesity increases the risk of thyroid cancer are poorly understood. In this study, we evaluated the effect of diet-induced obesity on thyroid carcinogenesis in a mouse model that spontaneously develops thyroid cancer (ThrbPV/PVPten+/− mice). These mice harbor a mutated thyroid hormone receptor-β (denoted as PV) and haplodeficiency of the Pten gene. A high-fat diet (HFD) efficiently induced the obese phenotype in ThrbPV/PVPten+/− mice after 15 weeks. Thyroid tumor growth was markedly greater and survival was significantly lower in ThrbPV/PVPten+/− mice fed an HFD than in controls fed a low-fat diet (LFD). The HFD increased thyroid tumor cell proliferation by increasing the protein levels of cyclin D1 and phosphorylated retinoblastoma protein to propel cell cycle progression. Histopathological analysis showed that the frequency of anaplasia of thyroid cancer was significantly greater (2.6-fold) in the HFD group than the LFD group. The HFD treatment led to an increase in parametrial/epididymal fat pad and elevated serum leptin levels in ThrbPV/PVPten+/− mice. Further molecular analyses indicated that the HFD induced more aggressive pathological changes that were mediated by increased activation of the Janus kinase 2-signaling transducer and activator of transcription 3 (STAT3) signaling pathway and induction of STAT3 target gene expression. Our findings demonstrate that diet-induced obesity exacerbates thyroid cancer progression in ThrbPV/PVPten+/− mice and suggest that the STAT3 signaling pathway could be tested as a potential target for the treatment of thyroid cancer.

scholarly journals Da-Cheng-Qi Decoction Alleviates Intestinal Injury in Rats with Severe Acute Pancreatitis by Inhibiting the JAK2-STAT3 Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Wenyin Jin ◽  
Yinfeng Shen
Keyword(s):  
Acute Pancreatitis ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Severe Acute Pancreatitis ◽  
Terminal Ileum ◽  
Intestinal Injury ◽  
Janus Kinase ◽  
Jak2 Inhibitor ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Objective. To investigate the effect of Da-Cheng-Qi decoction (DCQD) on treating intestinal injury in rats with severe acute pancreatitis (SAP), based on the Janus kinase 2 (JAK2)/signal transducers and transcription 3 (STAT3) signaling pathway. Methods. Rats were randomly divided into the SAP group, SAP + ruxolitinib (JAK2 inhibitor) group, SAP + Stattic (STAT3 inhibitor) group, SAP + DCQD group, and sham operation group. They were further divided into 3-hour, 6-hour, 12-hour, and 18-hour subgroups. Levels of amylase and the inflammatory cytokines tumor necrosis factor-α, interleukin 6, interleukin 10, and interleukin 4 in plasma were tested. The messenger ribonucleic acid (mRNA) expression of JAK2 and STAT3 and the protein expression of phosphorylated JAK2 (p-JAK2) and phosphorylated STAT3 (p-STAT3) in the pancreas and terminal ileum tissues were examined. Results. Rats with SAP had severe changes in plasma levels of amylase and inflammatory cytokines and showed an overexpression of JAK2 mRNA, STAT3 mRNA, p-JAK2 protein, and p-STAT3 protein in the pancreas and terminal ileum. The events could be downregulated by treatment with DCQD, JAK2 inhibitor, and STAT3 inhibitor. Conclusions. In rats with SAP, DCQD ameliorated inflammatory cytokines and intestinal injury, which may be closely associated with the inhibition of the JAK2/STAT3 signaling pathway.

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.

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