Oxidative Stress and AKT-Associated Angiogenesis in a Zebrafish Model and Its Potential Application for Withanolides

Abstract

Oxidative stress and the AKT serine/threonine kinase (AKT) signaling pathway are essential regulators in cellular migration, metastasis, and angiogenesis. More than 300 withanolides were discovered from the plant family Solanaceae, exhibiting diverse functions. Notably, the relationship between oxidative stress, AKT signaling, and angiogenesis in withanolide treatments lacks comprehensive understanding. Here, we summarize connecting evidence related to oxidative stress, AKT signaling, and angiogenesis in the zebrafish model. A convenient vertebrate model monitored the in vivo effects of developmental and tumor xenograft angiogenesis using zebrafish embryos. The oxidative stress and AKT-signaling-modulating abilities of withanolides were highlighted in cancer treatments, which indicated that further assessments of their angiogenesis-modulating potential are necessary in the future. Moreover, targeting AKT for inhibiting AKT and its AKT signaling shows the potential for anti-migration and anti-angiogenesis purposes for future application to withanolides. This particularly holds for investigating the anti-angiogenetic effects mediated by the oxidative stress and AKT signaling pathways in withanolide-based cancer therapy in the future.

Keywords: AKT; angiogenesis; oxidative stress; withanolides; zebrafish.

Figure 1

Developmental angiogenesis stages and periods. (A) The embryos were subjected to analyses of intersegmental vessel (ISV) formation at 22–48 hpf, caudal vein plexus (CVP) at 25–48 hpf, subintestinal vessel (SIV) at 28–72 hpf, and hyaloid vessel (HV) at 2.5–30 dpf. (B) Representative images for different developmental stages. Tg (fli1: EGFP) zebrafish embryos were applied for observing the developmental angiogenesis for different stages. The red arrow indicates these structures.

Figure 2

AKT signaling network affects migration and angiogenesis. This flow chart summarizes Section 1, Section 2, Section 3, Section 4, Section 5, Section 6, Section 7 and Section 8.

Figure 3

Structures for the selected withanolides mentioned in this review.

Figure 4

Hypothesis: Withanolides affecting oxidative stress and AKT signaling may modulate angiogenesis, although this is rarely reported. Detailed investigation is warranted to examine the potential angiogenesis-modulating effects of withanolides in the future.