Impact of exercise on brain-bone marrow interactions in chronic stress: potential mechanisms preventing stress-induced hypertension.

We examined the effect of chronic restraint stress and the counteractive effects of daily exercise on the molecular basis of the brain-bone marrow (BM) interactions, by especially focusing on the paraventricular nucleus (PVN) of the hypothalamus. Male Wistar rats were assigned into control, restraint stress, and stress + daily spontaneous exercise (SE) groups. BM and hypothalamic gene expression profiles were examined through the undertaking of RT-PCR and microarrays, respectively. The inflammatory blood cell population was investigated through flow cytometry. Through the use of immunohistochemistry, we examined the presence of BM-derived C-C chemokine receptor type 2 (CCR2)-expressing microglial cells in the rat PVN. The gene expression levels of BM inflammatory factors such as those of interleukin 1 beta and CCR2, and the inflammatory blood cell population were found to be significantly higher in both restrained groups compared with control group. Interestingly, chronic restraint stress alone activated the recruitment of BM-derived CCR2-expressing microglial cells into the PVN, whereas daily spontaneous exercise prevented it. A notable finding was that restraint stress upregulated relative gene expression of hypothalamic matrix metalloproteinase 3 (MMP3), which increases the permeability of the blood-brain barrier (BBB), and that exercise managed to normalize it. Moreover, relative expression of some hypothalamic genes directly involved in the facilitation of cell migration was downregulated by daily exercise. Our findings suggest that daily spontaneous exercise can reduce the numbers of BM-derived CCR2-expressing microglial cells into the PVN through the prevention of stress-induced changes in the hypothalamic gene expression.NEW & NOTEWORTHY Chronic restraint stress can upregulate MMP3 gene expression in the rat hypothalamus, whereas daily spontaneous exercise can prevent this stress-induced effect. Stress-induced BM-derived inflammatory cell recruitment into the rat PVN can be prevented by daily spontaneous exercise. Stress-induced increase of hypothalamic MMP3 gene expression may be responsible for BBB injury, thereby allowing for BM-derived inflammatory cells to be recruited and to accumulate in the rat PVN, and to be subsequently involved in the onset of stress-induced hypertension.

Estradiol-dependent gene expression profile in the amygdala of young ovariectomized spontaneously hypertensive rats.

Estrogen plays a role in cardiovascular functions, emotional health, and energy homeostasis via estrogen receptors expressed in the brain. The comorbid relationship between rising blood pressure, a decline in mood and motivation, and body weight gain after menopause, when estrogen levels drop, suggests that the same brain area(s) contributes to protection from all of these postmenopausal disorders. The amygdala, a major limbic system nuclear complex known to express high estrogen receptor levels, is involved in the regulation of such physiological and psychological responses. We hypothesized that elevated estrogen levels contribute to premenopausal characteristics by activating specific genes and pathways in the amygdala. We examined the effect of 1 mo of estradiol treatment on the gene expression profile in the amygdala of ovariectomized young adult female spontaneously hypertensive rats. Estradiol substitution significantly decreased blood pressure, prevented body weight gain, and enhanced the voluntary physical activity of ovariectomized rats. In the amygdala of ovariectomized rats, estradiol treatment downregulated the expression of genes associated with estrogen signaling, cholinergic synapse, dopaminergic synapse, and long-term depression pathways. These findings indicate that the transcriptomic characteristics of the amygdala may be involved in estrogen-dependent regulation of blood pressure, physical activity motivation, and body weight control in young adult female spontaneously hypertensive rats.

Lectin ZG16p inhibits proliferation of human colorectal cancer cells via its carbohydrate-binding sites.

Zymogen granule protein 16 (ZG16p) is a soluble lectin that binds to both mannose and heparin/heparan sulfate. It is highly expressed in the human digestive tract and is secreted into the mucus. In this study, we investigated the effect of ZG16p on the proliferation of human colorectal cancer cells. Overexpression of ZG16p in Caco-2 cells decreased cell growth. Recombinant ZG16p markedly inhibited proliferation of Caco-2, LS174T, HCT116 and HCT15 cells. Caco-2 cell growth was not inhibited by two mutated ZG16p proteins, D151A and M5 (K36A, R37A, R53A, R55A and R79A) lacking mannose- and heparin-binding activities, respectively. Immunofluorescent cell staining revealed that ZG16p-D151A maintained its binding to the Caco-2 cell surface, whereas ZG16p-M5 failed to bind to the cells. These results suggest that ZG16p interacts with the cell surface via basic amino acids substituted in ZG16p-M5 and inhibits Caco-2 cell proliferation via Asp151. In addition, growth of patient-derived colorectal tumor organoids in a 3D intestinal stem cell system was suppressed by ZG16p but not by ZG16p-M5. Taken together, our findings indicate that ZG16p inhibits the growth of colorectal cancer cells via its carbohydrate-binding sites in vitro and ex vivo. In this study, a novel pathway in cancer cell growth regulation through cell surface carbohydrate chains is suggested.