Bryostatin‐1 ameliorated experimental colitis in Il‐10^−/− Mice by protecting the intestinal barrier and limiting immune dysfunction

Abstract

Bryostatin‐1 (Bry‐1) has been proven to be effective and safe in clinical trials of a variety of immune‐related diseases. However, little is known about its effect on Crohn's disease (CD). We aimed to investigate the impact of Bry‐1 on CD‐like colitis and determine the mechanism underlying this effect. In the present study, 15‐week‐old male Il‐10 −/− mice with spontaneous colitis were divided into positive control and Bry‐1‐treated (Bry‐1, 30 μg/kg every other day, injected intraperitoneally for 4 weeks) groups. Age‐matched, male wild‐type (WT) mice were used as a negative control. The effects of Bry‐1 on colitis, intestinal barrier function and T cell responses as well as the potential regulatory mechanisms were evaluated. We found that the systemic delivery of Bry‐1 significantly ameliorated colitis in Il‐10 −/− mice, as demonstrated by decreases in the disease activity index (DAI), inflammatory score and proinflammatory mediator levels. The protective effects of Bry‐1 on CD‐like colitis included the maintenance of intestinal barrier integrity and the helper T cell (Th)/regulatory T cell (Treg) balance. These effects of Bry‐1 may act in part through nuclear factor erythroid 2‐related factor 2 (Nrf2) signalling activation and STAT3/4 signalling inhibition. The protective effect of Bry‐1 on CD‐like colitis suggests Bry‐1 has therapeutic potential in human CD, particularly given the established clinical safety of Bry‐1.

Encapsulation of bryostatin-1 by targeted exosomes enhances remyelination and neuroprotection effects in the cuprizone-induced demyelinating animal model of multiple sclerosis

“…Here, the natural compound bryostatin, derived from macrocyclic lactone, 25 was shown to be a potent PKC modulator that exhibited great neuroprotective and immune modulate effects in various animal disease models. 5,24,26,27 As a lipid-activated enzyme, PKC is widely regarded as a critical participant in the pathophysiology of complex diseases such as cancer, Alzheimer's disease and AIDS. 6 At present, a large number of natural PKC activators have been discovered, such as phorbol esters, 28 ingenol ester 29 and 12- O -tetradecanoylphorbol 13-acetate (TPA), 30 that owing to their severe side effects are banned for use in clinical research.…”

Epac‐2 ameliorates spontaneous colitis in Il‐10−/− mice by protecting the intestinal barrier and suppressing NF‐κB/MAPK signalling

“…After completion of the therapeutic schedule, the mice were fasted under water restriction for 4 h then administered oral FITC‐dextran (Sigma, Cat #: F‐7250) as previously reported 27 (Appendix S1 ).…”

“…qRT‐PCR was performed as previously reported to measure the mRNA levels 27 of TNF‐α, IL‐1β, IL‐17A and β‐actin in tissues. The sequence information for mouse gene‐specific primers is provided in the Appendix S1 .…”

Targeting ADAM10 in Cancer and Autoimmunity

“…Etazolate activates ADAM10 secondary to activation of the GABAA receptor and therefore displays significant tropism to cells of the central nervous system (124). Bryostatin activates ADAM10 via protein kinase C and can therefore induce ADAM10 activity in a variety of cell types (125,126). EGCG, a natural occurring compound derived from green tea, has also been described to induce ADAM10 activity (127).…”