Research Topic Areas
- Targeting HSF1 to mitigate pro-fibrotic gene expression in pulmonary fibrosis.
- Bioactive properties of secondary metabolites from kava (Piper methysticum)
Lab Location: Interim Facility C (COP-C), Room 102
- Rachel Gristock, UH Hilo student
- San Ly, Pharm.D. student
Detailed Research Description
- Idiopathic pulmonary fibrosis (IPF) is a rapidly progressing disease of the lung that has a median survival of less than three years after patient diagnosis. The pathology of IPF is characterized by death of the alveolar epithelium and its progressive replacement by a collagenous extracellular matrix, which is deposited by a differentiated cell type termed myofibroblasts. These changes in tissue composition cause impaired gas exchange and reduced compliance that result in significant morbidity and the eventual death of the patient. Despite recent advances in our knowledge of IPF disease processes, none of the targeted interventions have had a significant clinical benefit. Therefore, better understanding of the processes that mediate disease progression is critical to finding new approaches for IPF therapy. Our work is focused on the contribution of heat shock transcription factor 1 (HSF1) in pulmonary gene expression, and understanding how it controls the expression of pro-fibrotic genes in myofibroblasts. Using cell culture models of TGF-beta differentiated pulmonary fibroblasts, gene silencing, microarray, and analysis of patient samples, we are interested in finding whether HSF1 activation is a feasible approach to limiting the rate and severity of IPF progression.
- Kava (Piper methysticum Forst. f., Piperaceae) is a plant that has been utilised for centuries in Pacific Island communities for medicinal, social and ceremonial purposes. Among its many actions, kava has been demonstrated to possess anxiolytic, sedative-hypnotic and anticonvulsant properties. We are interested in the bioactive properties of kava at a cellular level, analyzing the effects of pure secondary metabolites on cell signaling processes and gene expression. Among our findings is that a class of chalcone compounds termed flavokawains activate cytoprotective responses in human hepatocyte cell culture, mediated by the transcription factors Nrf2 and HSF1. This leads to the induction of antioxidant genes and protein chaperones that protect liver cells from subsequent oxidative stress. We are currently examining the effects of flavokawains on metabolic pathways in hepatocytes, including the expression of sterol biosynthetic genes and cytochromes P450.
- P20GM103466 (Nichols, R.) INBRE-III
- Pinner, K.D., Wales, C.T., Gristock, R.A., Vo, H.T., So, N. and Jacobs, A.T. Flavokawains A and B from kava (Piper methysticum) activate heat shock and antioxidant responses and protect against hydrogen peroxide‐induced cell death in HepG2 hepatocytes. Pharmaceutical Biology (2016) 54(9):1503-1512. PMID: 26789234; PMCID: PMC5040346
- Konkle, M.E., Blobaum, A.L., Moth, C.W., Prusakiewicz, J.J., Xu, S., Ghebreselasie, K., Akingbade, D., Jacobs, A.T., Rouzer, C.A., Lybrand, T.P. and Marnett, L.J. Conservative secondary shell substitution in cyclooxygenase-2 reduces inhibition by indomethacin amides and esters via altered enzyme dynamics. Biochemistry (2016) 55(2):348-359. PMID: 26704937; PMCID: PMC4721528
- Wales, C.T., Taylor, F.R., Higa, A.T., McAllister, H.A. and Jacobs, A.T. ERK‐dependent phosphorylation of HSF1 mediates chemotherapeutic resistance to benzimidazole carbamates in colorectal cancer cells. Anticancer Drugs (2015) 26(6): 657‐666. PMID: 25811962
- DeGuire, S.M., Earl, D.C., Du, Y., Crews, B.C., Jacobs, A.T., Ustione, A., Daniel, C., Chong, K., Marnett, L.J., Piston, D.W., Bachmann, B.O. and Sulikowski, G.A. Fluorescent probes of the apoptolidins and their utility in cellular localization studies. Angewandte Chemie, International Edition (2015) 54(3):961‐964. PMID: 25430909; PMCID: PMC4293314
- Samarasinghe, B., Wales, C.T., Taylor, F.R. and Jacobs, A.T. Heat shock factor 1 confers resistance to Hsp90 inhibitors through p62/SQSTM1 expression and promotion of autophagic flux. Biochemical Pharmacology (2014) 87(3):445‐455. PMID: 24291777; PMCID: PMC3934577
- Cusick J.K., Mustiand A, Jacobs A.T. and Reyland M.E. Identification of PLSCR1 as a protein that interacts with RELT family members. Molecular and Cellular Biochemistry (2012) 362: 55‐63. PMID: 22052202
- Jacobs, A.T. and Marnett, L.J. Systems Analysis of Protein Modification and Cellular Responses Induced by Electrophile Stress. Accounts of Chemical Research (2010) 43(5):673‐683. PMID: 20218676
- Ghidu V.P., Ntai I., Wang J., Jacobs A.T., Marnett L.J., Bachmann B.O. and Sulikowski, G. Combined chemical and biosynthetic route to access a new apoptolidin congener. Organic Letters (2009) 11(14):3032‐3034. PMID: 19552384; PMCID: PMC2720611
- Jacobs, A.T. and Marnett, L.J. HSF1‐mediated BAG3 expression attenuates apoptosis in 4‐hydroxynonenal‐treated colon cancer cells via stabilization of anti‐apoptotic Bcl‐2 proteins. The Journal of Biological Chemistry (2009) 284(14):9176‐9183. PMID: 19179333; PMCID: PMC2666569