Browsing by Subject "Signaling pathway"

Now showing 1 - 3 of 3
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    Editorial: Novel signaling pathways and therapy in breast cancer
    (Frontiers Media, 2023-05-16) Katsuta, Eriko; Opyrchal, Mateusz; Medicine, School of Medicine
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    Neuroprotection and its molecular mechanism following spinal cord injury
    (Wanfang Med Online, 2012-09-15) Liu, Nai-Kui; Xu, Xiao-Ming; Department of Neurological Surgery, IU School of Medicine
    Acute spinal cord injury initiates a complex cascade of molecular events termed 'secondary injury', which leads to progressive degeneration ranging from early neuronal apoptosis at the lesion site to delayed degeneration of intact white matter tracts, and, ultimately, expansion of the initial injury. These secondary injury processes include, but are not limited to, inflammation, free radical-induced cell death, glutamate excitotoxicity, phospholipase A2 activation, and induction of extrinsic and intrinsic apoptotic pathways, which are important targets in developing neuroprotective strategies for treatment of spinal cord injury. Recently, a number of studies have shown promising results on neuroprotection and recovery of function in rodent models of spinal cord injury using treatments that target secondary injury processes including inflammation, phospholipase A2 activation, and manipulation of the PTEN-Akt/mTOR signaling pathway. The present review outlines our ongoing research on the molecular mechanisms of neuroprotection in experimental spinal cord injury and briefly summarizes our earlier findings on the therapeutic potential of pharmacological treatments in spinal cord injury.
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    Small molecule compounds targeting DNA binding domain of STAT3 for inhibition of tumor growth and metastasis
    (2014) Huang, Wei; Zhang, Jian-Ting; Jerde, Travis J.; Pollok, Karen E.; Safa, Ahmad R.; Zhang, Zhong-Yin
    Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors, and its activation is associated with high histological grade and advanced cancer stage. STAT3 has been shown to play important roles in multiple aspects of cancer aggressiveness including proliferation, survival, self-renewal, migration, invasion, angiogenesis and immune response by regulating the expression of diverse downstream target genes. Thus, inhibiting STAT3 promises to be an attractive strategy for treatment of advanced tumors with metastatic potential. We firstly identified a STAT3 inhibitor, inS3-54, by targeting the DNA-binding site of STAT3 using an in-silico screening approach; however, inS3-54 was finally found not to be appropriate for further studies because of low specificity on STAT3 and poor absorption in mice. To develop an effective and specific STAT3 inhibitor, we identified 89 analogues for the structure-activity relationship analysis. By using hematopoietic progenitor cells isolated from wild-type and STAT3 conditional knockout mice, further studies showed that three analogues (A18, A26 and A69) only inhibited STAT3-dependent colony formation of hematopoietic progenitor cells, indicating a higher selectivity for STAT3 than their parental compound, inS3-54. These compounds were found to (1) inhibit STAT3-specific DNA binding activity; (2) bind to STAT3 protein; (3) suppress proliferation of cancer cells harboring aberrant STAT3 signaling; (4) inhibit migration and invasion of cancer cells and (5) inhibit STAT3-dependent expression of downstream targets by blocking the binding of STAT3 to the promoter regions of responsive genes in cells. In addition, A18 can reduce tumor growth in a mouse xenograft model of lung cancer with little effect on body weight. Taken together, we conclude that it is feasible to inhibit STAT3 by targeting its DNA-binding domain for discovery of anticancer therapeutics.