Electronic Theses and Dissertations

Date of Award

1-1-2019

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

Ziaeddin Shariat-Madar

Second Advisor

Asok K. Dasmahapatra

School

University of Mississippi

Relational Format

dissertation/thesis

Abstract

An additional goal of this project was to characterize the Wnt/β-catenin signaling pathway to unravel the adverse potential of MH on the cardiovascular system (CVS). Our study suggested that MH-mediated cardiovascular injury may be caused due to upregulation of some major components of the Wnt/β-catenin pathway through expression of excessive pro-inflammatory mediators. Moreover MH decreased expression of ErbB3 and NRG-2 suggesting impaired cardiac structure. MH exposure caused a slow heartbeat blood occlusion absence of blood circulation decreased hatching efficiency and increased mortality in medaka embryos in a concentration- and time-dependent manner. MH might cause blood vessel occlusion by increasing the expression of FVII FX FXI of the blood coagulation pathway and decreasing the fold differences between the tissue plasminogen activator (tPA) and the plasminogen activator inhibitor-1 (PAI-1) of the thrombolytic system. MH might also damage the blood vessels through production of excessive pro-inflammatory mediators or reactive oxygen species which resulted in blood vessel occlusion. Another objective of this study was to evaluate the effect of MH on locomotion in 2 days post hatch (dph) larvae. Exposed larvae shoan overall decline in the duration of movement after the first dark cycle relative to the untreated controls however the change was not significant. The overall goal of this project is to characterize the teratogenic potential of 4-O-Methylhonokiol (MH) and to identify the underlying mechanisms of teratogenesis. Although Magnolia extracts have been reported previously for their cardioprotective effects including anti-obesity anti-atherosclerosis and vascular relaxation toxicity data are lacking. Effects of Magnolia compounds on embryonic development are not known yet. Therefore the potential toxic effects of MH a major bioactive constituent of Magnolia grandiflora seeds or Magnolia officinalis bark on Japanese medaka embryogenesis and on locomotion during larval stage were studied. This project established the concentration-and time-dependent teratogenic potential of MH on the cardiovascular system during medaka embryogenesis. Moreover it revealed potential mechanisms for producing these toxicities.

Available for download on Wednesday, February 16, 2022

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