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Page 6 of 10 Watanabe. Vessel Plus 2020;4:4 I http://dx.doi.org/10.20517/2574-1209.2019.27
[61]
generation . The risk factors of Alzheimer’s disease are known to be inflammation, lipid metabolism
(Apoe), and atherosclerosis [61-63] . A clinical prospective study has shown that atherosclerosis in carotid
[64]
arteries leads to the progression of Alzheimer’s disease . Osmotin protects against amyloid-β deposition,
tau phosphorylation, and apoptotic neurodegeneration through AdipoR1 followed by the AMPK/
sirtuin 1/sterol regulatory element-binding protein 2 pathway in neuronal cells [25,65-67] . It also enhances
[68]
neurite outgrowth and synaptic complexity via AdipoR1/nogo-66 receptor NgR1 signaling . These
findings indicate that osmotin is a potential candidate for the treatment of neurological disorders such as
Alzheimer’s disease. A preclinical trial study recently reported the usefulness of intravenous administration
of osmotin-loaded magnetic nanoparticles in combination with electromagnetic guidance in the
[69]
treatment of Alzheimer’s disease . These effects of osmotin are compatible with neuroprotective effects of
adiponectin and AdipoRon in Alzheimer’s disease [70-73] .

ANTI-TUMORIGENESIS EFFECT
Cancer and atherosclerosis have been classified as non-communicable diseases by differing in target
[74]
cells . However, both diseases have principally identical mechanisms such as cell proliferation induced
[75]
by inflammation and reactive oxygen species . Adiponectin induces anti-angiogenesis and anti-tumor
[13]
activity through AdipoR1 via caspase-mediated EC apoptosis . Actually, adiponectin and AdipoRon
suppress the proliferation of a variety of human cancer cells [76-78] . Similarly, osmotin induces cell cycle
[10]
[33]
arrest in the G0/G1 phase and suppresses cell proliferation . These findings suggest the possibility that
osmotin may suppress tumor growth. However, further studies are needed to clarify this hypothesis.

THERAPEUTIC STRATEGY
[13]
Osmotin is a natural plant protein that is ubiquitous in fruits and vegetables . Osmotin is also known
[13]
to be a phytochemical that is resistant to heat treatment (cooking) . Furthermore, the osmotin protein
[13]
is relatively stable and may maintain activity even through contact with the human digestive system .
Therefore, this phytochemical could be administered by ingestion of fruits and vegetables containing a
great amount of osmotin or by oral administration of osmotin and/or its analogs that consist of the amino
[10]
acid residue including an active center . However, the best drug delivery system (DDS) for osmotin
administration is considered to be enveloped in nanocapsules in order to avoid digestive degradation [10,69] .
Moreover, continuing preclinical and clinical investigations with osmotin, in particular combined with a
[10]
nanocapsule system as carrier vehicles into atherosclerotic lesions, are essential for future studies . It is
very important for DDS establishment to design the size of the nanocapsule so that it can go through a
relatively wide gap between damaged vascular ECs, but not a normal gap between intact ECs in humans.
The magnetic nanocapsule-based DDS with external electromagnetic guidance may be more useful
[69]
to make osmotin cross endothelial gap junction . Future studies are needed to clarify whether oral
administration of osmotin-loaded nanocapsules can treat vascular lesions in patients with atherosclerosis.
Similarly, osmotin-like proteins derived from many vegetables and fruits are also regarded as adiponectin
peptidomimetics and gather attention as novel therapeutic drug candidates for atherosclerosis and related
[79]
diseases .

CONCLUSION
These findings indicate that the novel phytochemical osmotin might be an effective therapeutic agent for
atherosclerosis, inflammation, neurodegeneration, and their related diseases and that AdipoR1 might be
a crucial therapeutic target for these diseases. Osmotin may open up a new therapeutic window in the
treatment of atherosclerosis in cases with hypoadiponectinemia and/or resistance against adiponectin and
AdipoRon [10,30,80] . Osmotin also provides benefits to maintain vascular health and prevent vascular disease
in healthy individuals.