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Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37 Page 13

increases oxidative stress, which has recently been linked to increased all-cause mortality by consumption of
non-fermented milk [162-165] . Galactose is a mitochondrial stressor experimentally used for the induction of
aging and neurodegeneration [401-404] . Disturbed oxidant/antioxidant balance has been implicated in the
[405]
pathophysiology of PCa, especially in high-risk PCa subjects . The ginsenoside Rg1 decreases oxidative
stress and downregulates AKT/mTORC1 signaling and attenuates cognitive impairment in mice and
[406]
senescence of neural stem cells induced by galactose . Accumulated evidence underlines that oxidative
stress is of critical importance in prostate carcinogenesis [407-414] . There is a close interaction between AMPK
and AKT on the ROS homeostasis via mTOR and FOXO regulation, which is of key importance for cancer
cells .
[415]

In a galactose-induced pseudo-aging mouse model, miR-21 significantly increased, whereas miR-21
knockout mice were resistant to galactose-induced alterations in aging-markers . Of note, treatment of rat
[416]
spinal cord neurons with hydrogen peroxide, a galactose-induced ROS, upregulates miR-21 expression .
[417]
Milk exosomal microRNAs
Pasteurized commercial cow milk transfers bioavailable extracellular vesicles (EVs) including MEX and
their gene-regulatory miRs [418-423] . There is recent evidence that vigorous heat‐treatment such as ultraheat-
treatment (UHT: 135 °C, > 1 s) and boiling (100 °C) of commercial cow milk destroys MEVs and MEX and
their miR cargo, including miR‐148a [421,424] , whereas pasteurization (72-78 °C, > 15 s) of commercial milk did
not affect total MEV numbers and preserved nearly 25%-40% of milk’s total small RNAs, including
[424]
miR‐148a . Bacterial fermentation of milk also attacks MEX and reduces their miR content, as
demonstrated for miR-21 and miR-29b in yogurt cultures . Translational evidence indicates that
[425]
pasteurized non-fermented cow milk is a stronger promoter of mTORC1 activity compared to fermented
milk products . Bovine and human MEX and their miRs resist degradative conditions in the
[426]
gastrointestinal tract, reach the systemic circulation, and distribute in various tissues [420,427-434] . In fact,
increasing evidence presented by studies in humans and animal models supports the view that MEX and
their miRs are bioavailable, reach the systemic circulation [420,422,434-437] , and modify gene expression of the milk
recipient [359,418,437-439] . It has been demonstrated that bovine MEX increased the expression of GRP94 ,
[253]
which is a key endoplasmic reticulum chaperone enhancing the synthesis of insulin, IGF-1, and
IGF-2 [254,255,440] . Of note, co-downregulation of GRP78 and GRP94 expression induced apoptosis and
[441]
inhibited migration in PC3 cells . MEX miR-mediated changes of epigenetic regulation appear to be
beneficial for growth and maturation of the infant [253,432,442-449] , but it may exert adverse health effects during
[450]
long-term exposure associated with persistent overactivation of mTORC1 .
MicroRNA-21
[451]
Bovine miR-21 is an abundant signature miR of cow milk . Bovine and human miR-21 exhibit nucleotide
sequence homology [452-454] . Plasma concentrations of Bos taurus (bta)-miR-21-5p was > 100% higher 6 h after
commercial cow milk consumption of healthy human volunteers than before milk consumption,
strengthening the bioavailability of milk-derived miRs in human milk consumers . Sadri et al. showed
[437]
[422]
that, after oral gavage of fluorophore-labeled bovine MEX to pregnant mice, miR-21-5p and miR-30d
accumulated in placenta and embryos. Experimental evidence provided in murine models demonstrates
that oral uptake of bovine MEX results in MEX distribution in various tissues and organs [420,437,455] . MEX
miR-21 most likely also affects the prostate gland, where it may target IGFBP3, PTEN, FoxO1, FoxO3,
PDCD4, etc., enhancing IGF-1-PI3K-AKT-mTORC1 signaling.

[456]
Marquez et al. established post-transcriptional regulation of SMAD7 by miR-21. miR-21 is a key negative
regulator of SMAD7 and directly interacts with the 3’UTR of SMAD7 mRNA [456,457] . Importantly,