scholarly journals Signal Transducer and Activator of Transcription-3 Modulation of Cardiac Pathology in Chronic Chagasic Cardiomyopathy

2021 ◽  
Vol 11 ◽  
Author(s):  
Kristyn A. Hoffman ◽  
Maria Jose Villar ◽  
Cristina Poveda ◽  
Maria Elena Bottazzi ◽  
Peter J. Hotez ◽  
...  
Keyword(s):  
Heart Function ◽  
Critical Role ◽  
Myocardial Strain ◽  
Clinical Manifestations ◽  
Type I ◽  
Signal Transducer ◽  
Cardiac Pathology ◽  
End Of Treatment ◽  
Chagasic Cardiomyopathy ◽  
Transcription 3

Chronic Chagasic cardiomyopathy (CCC) is a severe clinical manifestation that develops in 30%–40% of individuals chronically infected with the protozoal parasite Trypanosoma cruzi and is thus an important public health problem. Parasite persistence during chronic infection drives pathologic changes in the heart, including myocardial inflammation and progressive fibrosis, that contribute to clinical disease. Clinical manifestations of CCC span a range of symptoms, including cardiac arrhythmias, thromboembolic disease, dilated cardiomyopathy, and heart failure. This study aimed to investigate the role of signal transducer and activator of transcription-3 (STAT3) in cardiac pathology in a mouse model of CCC. STAT3 is a known cellular mediator of collagen deposition and fibrosis. Mice were infected with T. cruzi and then treated daily from 70 to 91 days post infection (DPI) with TTI-101, a small molecule inhibitor of STAT3; benznidazole; a combination of benznidazole and TTI-101; or vehicle alone. Cardiac function was evaluated at the beginning and end of treatment by echocardiography. By the end of treatment, STAT3 inhibition with TTI-101 eliminated cardiac fibrosis and fibrosis biomarkers but increased cardiac inflammation; serum levels of interleukin-6 (IL-6), and IFN−γ; cardiac gene expression of STAT1 and nuclear factor-κB (NF-κB); and upregulation of IL-6 and Type I and Type II IFN responses. Concurrently, decreased heart function was measured by echocardiography and myocardial strain. These results indicate that STAT3 plays a critical role in the cardiac inflammatory–fibrotic axis during CCC.

Expression of Activated and Latent Signal Transducer and Activator of Transcription 3 in 303 Non–Small Cell Lung Carcinomas and 44 Malignant Mesotheliomas: Possible Role for Chemotherapeutic Intervention

2007 ◽  
Vol 131 (9) ◽  
pp. 1350-1360 ◽  
Author(s):  
Rosanede Oliveira Duarte Achcar ◽  
Philip T. Cagle ◽  
Jaishree Jagirdar
Keyword(s):  
Therapeutic Target ◽  
Critical Role ◽  
Active Form ◽  
Small Cell ◽  
Tumor Type ◽  
Signal Transducer ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Transcription 3 ◽  
Mib 1

Abstract Context.—Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in diverse human cancers and plays a critical role in tumor cell survival, proliferation, migration, invasion, angiogenesis, and inhibition of apoptosis. The phosphorylated active form of STAT3 (pSTAT3) mediates its effects via nuclear transcriptional activity. However, it was recently observed that the nonphosphorylated, cytoplasmic, inactive form of STAT3 is involved in cell motility and consequently tumor invasion. It appears that, although STAT3 is not absolutely required for tumor formation, tumors that develop in the presence of STAT3 become dependent on its expression for their survival, making it a potential therapeutic target. Objective.—To investigate the possible utility of STAT3 as a future therapeutic target in non–small cell lung carcinoma (NSCLC) and malignant mesothelioma (MM). Design.—Immunohistochemical expression of MIB-1, STAT3, and pSTAT3 was assessed in 303 NSCLC and 44 MM archival cases. Results.—A more conspicuous expression of inactive STAT3 (91.44% in NSCLC and 79.5% in MM cases) was present compared with the nuclear activated form pSTAT3 (60.53% in NSCLC and 61.4% in MM cases). MIB-1 did not correlate with the expression of STAT3 or pSTAT3. Conclusions.—The strong expression of cytoplasmic inactive STAT3 in NSCLC and MM cases implies a major role for STAT3 in tumor motility, invasion, and metastasis via a nontranscriptional pathway. We conclude that STAT3 and pSTAT3 are up-regulated in a high percentage of NSCLCs and MMs, regardless of tumor type, age, sex, smoking status, stage and grade of tumor, or survival, providing a basis for therapeutic intervention.

scholarly journals Signal transducer and activator of transcription‐3 ( Stat3 ) plays a critical role in implantation via progesterone receptor in uterus

2013 ◽  
Vol 27 (7) ◽  
pp. 2553-2563 ◽  
Author(s):  
Jae Hee Lee ◽  
Tae Hoon Kim ◽  
Seo Jin Oh ◽  
Jung‐Yoon Yoo ◽  
Shizuo Akira ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
Critical Role ◽  
Signal Transducer ◽  
Transcription 3

scholarly journals The intragenic microRNA miR199A1 in the dynamin 2 gene contributes to the pathology of X-linked centronuclear myopathy

2020 ◽  
Vol 295 (26) ◽  
pp. 8656-8667 ◽  
Author(s):  
Xin Chen ◽  
Yun-Qian Gao ◽  
Yan-Yan Zheng ◽  
Wei Wang ◽  
Pei Wang ◽  
...  
Keyword(s):  
Critical Role ◽  
Disease Model ◽  
Underlying Mechanism ◽  
Centronuclear Myopathy ◽  
Signal Transducer ◽  
Double Knockout ◽  
Fatal Disease ◽  
Transcription 3 ◽  
Dynamin 2

Mutations in the myotubularin 1 (MTM1) gene can cause the fatal disease X-linked centronuclear myopathy (XLCNM), but the underlying mechanism is incompletely understood. In this report, using an Mtm1−/y disease model, we found that expression of the intragenic microRNA miR-199a-1 is up-regulated along with that of its host gene, dynamin 2 (Dnm2), in XLCNM skeletal muscle. To assess the role of miR-199a-1 in XLCNM, we crossed miR-199a-1−/− with Mtm1−/y mice and found that the resultant miR-199a-1-Mtm1 double-knockout mice display markers of improved health, as evidenced by lifespans prolonged by 30% and improved muscle strength and histology. Mechanistic analyses showed that miR-199a-1 directly targets nonmuscle myosin IIA (NM IIA) expression and, hence, inhibits muscle postnatal development as well as muscle maturation. Further analysis revealed that increased expression and phosphorylation of signal transducer and activator of transcription 3 (STAT3) up-regulates Dnm2/miR-199a-1 expression in XLCNM muscle. Our results suggest that miR-199a-1 has a critical role in XLCNM pathology and imply that this microRNA could be targeted in therapies to manage XLCNM.

scholarly journals Loss of Signal Transducer and Activator of Transcription 3 Impaired the Osteogenesis of Mesenchymal Progenitor Cells in Vivo and in Vitro

2021 ◽  
Author(s):  
ZIJING HUANG ◽  
Jingyi Feng ◽  
Xin Feng ◽  
Laiting Chan ◽  
Jiarui Lu ◽  
...  
Keyword(s):  
Critical Role ◽  
Micro Ct ◽  
Signal Transducer ◽  
Alizarin Red ◽  
Mesenchymal Progenitors ◽  
Osteogenic Markers ◽  
Osteogenic Induction ◽  
Transcription 3

Abstract Background: Signal transducer and activator of transcription 3 (Stat3) is a cytoplasmic transcription factor that participates in various biologic processes. Loss of Stat3 causes hyperimmunoglobulin E syndrome, presenting with skeletal disorders including osteoporosis, recurrent fractures, scoliosis, and craniosynostosis. The objective of this study is to explore the effect and mechanism of Stat3 on osteogenesis of mesenchymal progenitors.Methods: Stat3 was conditionally knockout (CKO) in mesenchymal progenitors by crossing the pair-related homeobox gene 1-cre (Prx1-Cre) with Stat3-floxed strain mice. Whole-mount-skeletal staining, histology, and Micro-CT were used to assess the differences between Stat3 CKO and control mice. Further, in vitro experiments were conducted to evaluate the osteogenesis potential of primary isolated bone marrow mesenchymal stem cells (BMSCs) from both control and Stat3 CKO mice. After osteogenic induction for 14d, alizarin red staining was used to show the calcium deposit, while the western blotting was applied to detect the expression of osteogenic markers.Results: Compared with the control, Stat3 CKO mice were present with shortened limbs, multiple fractures of long bone, and open calvarial fontanels. The abnormal growth plate structure and reduced collagen fiber were found in Stat3 CKO limbs. According to micro-CT analysis, the reduced cortical bone thickness and bone volume were found on Stat3 CKO mice. The in vitro osteogenic differentiation of BMSCs was inhibited in Stat3 CKO samples. After osteogenic induction for 14d, the significantly diminished calcium deposits were found in Stat3 CKO BMSCs. The decreased expression of osteogenic markers (OPN and COL1A1) was observed in Stat3 CKO BMSCs, compared with the control. Conclusions: Stat3 played a critical role in bone development and osteogenesis. Loss of Stat3 impaired the osteogenesis of mesenchymal progenitors in vivo and in vitro.

scholarly journals Uterine Epithelial Estrogen Receptor-α Controls Decidualization via a Paracrine Mechanism

2015 ◽  
Vol 29 (9) ◽  
pp. 1362-1374 ◽  
Author(s):  
S. Pawar ◽  
M. J. Laws ◽  
I. C. Bagchi ◽  
M. K. Bagchi
Keyword(s):  
Estrogen Receptor ◽  
Transcription Factor ◽  
Embryo Implantation ◽  
Critical Role ◽  
Estrogen Receptor Α ◽  
Signal Transducer ◽  
Factor Ii ◽  
Cell Type Specific ◽  
Transcription 3

Abstract Steroid hormone-regulated differentiation of uterine stromal cells, known as decidualization, is essential for embryo implantation. The role of the estrogen receptor-α (ESR1) during this differentiation process is unclear. Development of conditional Esr1-null mice showed that deletion of this gene in both epithelial and stromal compartments of the uterus leads to a complete blockade of decidualization, indicating a critical role of ESR1 during this process. To further elucidate the cell type-specific function of ESR1 in the uterus, we created WEd/d mice in which Esr1 is ablated in uterine luminal and glandular epithelia but is retained in the stroma. Uteri of WEd/d mice failed to undergo decidualization, indicating that epithelial ESR1 contributes to stromal differentiation via a paracrine mechanism. We noted markedly reduced production of the leukemia inhibitory factor (LIF) in WEd/d uteri. Supplementation with LIF restored decidualization in WEd/d mice. Our study indicated that LIF acts synergistically with progesterone to induce the expression of Indian hedgehog (IHH) in uterine epithelium and its receptor patched homolog 1 in the stroma. IHH then induces the expression of chicken ovalbumin upstream promoter-transcription factor II, a transcription factor that promotes stromal differentiation. To address the mechanism by which LIF induces IHH expression, we used mice lacking uterine epithelial signal transducer and activator of transcription 3, a well-known mediator of LIF signaling. Our study revealed that LIF-mediated induction of IHH occurs without the activation of epithelial signal transducer and activator of transcription 3 but uses an alternate pathway involving the activation of the ERK1/2 kinase. Collectively our results provide unique insights into the paracrine mechanisms by which ESR1 directs epithelial-stromal dialogue during pregnancy establishment.

scholarly journals Loss of signal transducer and activator of transcription 3 impaired the osteogenesis of mesenchymal progenitor cells in vivo and in vitro

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zijing Huang ◽  
Jingyi Feng ◽  
Xin Feng ◽  
Laiting Chan ◽  
Jiarui Lu ◽  
...  
Keyword(s):  
Critical Role ◽  
Micro Ct ◽  
Signal Transducer ◽  
Alizarin Red ◽  
Mesenchymal Progenitors ◽  
Osteogenic Markers ◽  
Osteogenic Induction ◽  
Transcription 3

Abstract Background Signal transducer and activator of transcription 3 (Stat3) is a cytoplasmic transcription factor that participates in various biologic processes. Loss of Stat3 causes hyperimmunoglobulin E syndrome, presenting with skeletal disorders including osteoporosis, recurrent fractures, scoliosis, and craniosynostosis. The objective of this study is to explore the effect and mechanism of Stat3 on osteogenesis of mesenchymal progenitors. Methods Stat3 was conditionally knockout (CKO) in mesenchymal progenitors by crossing the pair-related homeobox gene 1-cre (Prx1-Cre) with Stat3-floxed strain mice. Whole-mount-skeletal staining, histology, and micro-CT were used to assess the differences between Stat3 CKO and control mice. Further, in vitro experiments were conducted to evaluate the osteogenesis potential of primary isolated bone marrow mesenchymal stem cells (BMSCs) from both control and Stat3 CKO mice. After osteogenic induction for 14d, alizarin red staining was used to show the calcium deposit, while the western blotting was applied to detect the expression of osteogenic markers. Results Compared with the control, Stat3 CKO mice were present with shortened limbs, multiple fractures of long bone, and open calvarial fontanels. The abnormal growth plate structure and reduced collagen fiber were found in Stat3 CKO limbs. According to micro-CT analysis, the reduced cortical bone thickness and bone volume were found on Stat3 CKO mice. The in vitro osteogenic differentiation of BMSCs was inhibited in Stat3 CKO samples. After osteogenic induction for 14d, the significantly diminished calcium deposits were found in Stat3 CKO BMSCs. The decreased expression of osteogenic markers (OPN and COL1A1) was observed in Stat3 CKO BMSCs, compared with the control. Conclusions Stat3 played a critical role in bone development and osteogenesis. Loss of Stat3 impaired the osteogenesis of mesenchymal progenitors in vivo and in vitro.

scholarly journals Acacetin Inhibits the Growth of STAT3-Activated DU145 Prostate Cancer Cells by Directly Binding to Signal Transducer and Activator of Transcription 3 (STAT3)

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6204
Author(s):  
Sun Yun ◽  
Yu-Jin Lee ◽  
Jiyeon Choi ◽  
Nam Doo Kim ◽  
Dong Cho Han ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Cancer Drug ◽  
Dependent Manner ◽  
Signal Transducer ◽  
Prostate Cancer Cells ◽  
Stat3 Phosphorylation ◽  
Transcription 3

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in the formation and growth of human cancer. Therefore, STAT3 is a therapeutic target for cancer drug discovery. Acacetin, a flavone present in various plants, inhibits constitutive and inducible STAT3 activation in STAT3-activated DU145 prostate cancer cells. Acacetin inhibits STAT3 activity by directly binding to STAT3, which we confirmed by a pull-down assay with a biotinylated compound and two level-free methods, namely, a drug affinity responsive target stability (DARTS) experiment and a cellular thermal shift assay (CETSA). Acacetin inhibits STAT3 phosphorylation at the tyrosine 705 residue and nuclear translocation in DU145 cells, which leads to the downregulation of STAT3 target genes. Acacetin then induces apoptosis in a time-dependent manner. Interestingly, acacetin induces the production of reactive oxygen species (ROS) that are not involved in the acacetin-induced inhibition of STAT3 activation because the suppressed p-STAT3 level is not rescued by treatment with GSH or NAC, which are general ROS inhibitors. We also found that acacetin inhibits tumor growth in xenografted nude mice. These results suggest that acacetin, as a STAT3 inhibitor, could be a possible drug candidate for targeting STAT3 for the treatment of cancer in humans.

scholarly journals Targeting STAT3 in Cancer with Nucleotide Therapeutics

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1681 ◽  
Author(s):  
Yue-Ting K. Lau ◽  
Malini Ramaiyer ◽  
Daniel E. Johnson ◽  
Jennifer R. Grandis
Keyword(s):  
Nucleic Acid ◽  
Tumor Cells ◽  
Target Genes ◽  
Critical Role ◽  
Signal Transducer ◽  
Clinical Testing ◽  
Antisense Molecule ◽  
Novel Approaches ◽  
Transcription 3 ◽  
Stat3 Decoy

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting the proliferation and survival of tumor cells. As a ubiquitously-expressed transcription factor, STAT3 has commonly been considered an “undruggable” target for therapy; thus, much research has focused on targeting upstream pathways to reduce the expression or phosphorylation/activation of STAT3 in tumor cells. Recently, however, novel approaches have been developed to directly inhibit STAT3 in human cancers, in the hope of reducing the survival and proliferation of tumor cells. Several of these agents are nucleic acid-based, including the antisense molecule AZD9150, CpG-coupled STAT3 siRNA, G-quartet oligodeoxynucleotides (GQ-ODNs), and STAT3 decoys. While the AZD9150 and CpG-STAT3 siRNA interfere with STAT3 expression, STAT3 decoys and GQ-ODNs target constitutively activated STAT3 and modulate its ability to bind to target genes. Both STAT3 decoy and AZD9150 have advanced to clinical testing in humans. Here we will review the current understanding of the structures, mechanisms, and potential clinical utilities of the nucleic acid-based STAT3 inhibitors.

scholarly journals Loss of signal transducer and activator of transcription 3 impaired the osteogenesis of mesenchymal progenitor cells in vivo and in vitro

2021 ◽  
Author(s):  
ZIJING HUANG ◽  
Jingyi Feng ◽  
Xin Feng ◽  
Laiting Chan ◽  
Jiarui Lu ◽  
...  
Keyword(s):  
Critical Role ◽  
Micro Ct ◽  
Signal Transducer ◽  
Alizarin Red ◽  
Mesenchymal Progenitors ◽  
Osteogenic Markers ◽  
Osteogenic Induction ◽  
Transcription 3

Abstract Background Signal transducer and activator of transcription 3 (Stat3) is a cytoplasmic transcription factor that participates in various biologic processes. Loss of Stat3 causes hyperimmunoglobulin E syndrome, presenting with skeletal disorders including osteoporosis, recurrent fractures, scoliosis, and craniosynostosis. The objective of this study is to explore the effect and mechanism of Stat3 on osteogenesis of mesenchymal progenitors. Methods Stat3 was conditionally knockout (CKO) in mesenchymal progenitors by crossing the pair-related homeobox gene 1-cre (Prx1-Cre) with Stat3-floxed strain mice. Whole-mount-skeletal staining, histology, and Micro-CT were used to assess the differences between Stat3 CKO and control mice. Further, in vitro experiments were conducted to evaluate the osteogenesis potential of primary isolated bone marrow mesenchymal stem cells (BMSCs) from both control and Stat3 CKO mice. After osteogenic induction for 14d, alizarin red staining was used to show the calcium deposit, while the western blotting was applied to detect the expression of osteogenic markers. Results Compared with the control, Stat3 CKO mice were present with shortened limbs, multiple fractures of long bone, and open calvarial fontanels. The abnormal growth plate structure and reduced collagen fiber were found in Stat3 CKO limbs. According to micro-CT analysis, the reduced cortical bone thickness and bone volume were found on Stat3 CKO mice. The in vitro osteogenic differentiation of BMSCs was inhibited in Stat3 CKO samples. After osteogenic induction for 14d, the significantly diminished calcium deposits were found in Stat3 CKO BMSCs. The decreased expression of osteogenic markers (OPN and COL1A1) was observed in Stat3 CKO BMSCs, compared with the control. Conclusions Stat3 played a critical role in bone development and osteogenesis. Loss of Stat3 impaired the osteogenesis of mesenchymal progenitors in vivo and in vitro.

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