BackgroundMicroglia of the central nervous system act as sentinels and rapidly react to infection or inflammation. The pathophysiological role of bone marrow-derived microglia is of particular interest because they affect neurodegenerative disorders and neuropathic pain. The hypothesis of the current study is that chronic psychological stress (chronic PS) induces the infiltration of bone marrow-derived microglia into hypothalamus by means of chemokine axes in brain and bone marrow.Methods and FindingsHere we show that bone marrow-derived microglia specifically infiltrate the paraventricular nucleus (PVN) of mice that received chronic PS. Bone marrow derived-microglia are CX3CR1lowCCR2+CXCR4high, as distinct from CX3CR1highCCR2-CXCR4low resident microglia, and express higher levels of interleukin-1β (IL-1β) but lower levels of tumor necrosis factor-α (TNF-α). Chronic PS stimulates the expression of monocyte chemotactic protein-1 (MCP-1) in PVN neurons, reduces stromal cell-derived factor-1 (SDF-1) in the bone marrow and increases the frequency of CXCR4+ monocytes in peripheral circulation. And then a chemokine (C-C motif) receptor 2 (CCR2) or a β3-adrenoceptor blockade prevents infiltration of bone marrow-derived microglia in the PVN.ConclusionChronic PS induces the infiltration of bone marrow-derived microglia into PVN, and it is conceivable that the MCP-1/CCR2 axis in PVN and the SDF-1/CXCR4 axis in bone marrow are involved in this mechanism.

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Obestatin is a novel peptide encoded by the ghrelin precursor gene; however, its effects on gastrointestinal motility remain controversial. Here we have examined the effects of obestatin on fed and fasted motor activities in the stomach and duodenum of freely moving conscious rats. We examined the effects of intravenous (IV) injection of obestatin on the percentage motor index (%MI) and phase III-like contractions in the antrum and duodenum. The brain mechanism mediating the action of obestatin on gastroduodenal motility and the involvement of vagal afferent pathway were also examined. Between 30 and 90 min after IV injection, obestatin decreased the %MI in the antrum and prolonged the time taken to return to fasted motility in the duodenum in fed rats given 3 g of chow after 18 h of fasting. Immunohistochemical analysis demonstrated that corticotropin-releasing factor- and urocortin-2-containing neurons in the paraventricular nucleus in the hypothalamus were activated by IV injection of obestatin. Intracerebroventricular injection of CRF type 1 and type 2 receptor antagonists prevented the effects of obestatin on gastroduodenal motility. Capsaicin treatment blocked the effects of obestatin on duodenal motility but not on antral motility. Obestatin failed to antagonize ghrelin-induced stimulation of gastroduodenal motility. These results suggest that, in the fed state, obestatin inhibits motor activity in the antrum and duodenum and that CRF type 1 and type 2 receptors in the brain might be involved in these effects of obestatin on gastroduodenal motility.

Nesfatin-1 was recently identified as a peptide with anorexigenic effects that is localized in the hypothalamus and adipocytes. Not much is known about the effect of nesfatin-1 on gut motility. Food intake was measured after intracerebroventricular administration of nesfatin-1 in food-deprived mice. Antral and duodenal motility was assessed by using a manometric method in conscious fed mice. We found that centrally administered nesfatin-1 decreased food intake and inhibited gastroduodenal motility in mice. These results suggest that nesfatin-1 influences gut motility and feeding behaviour.

Although mesenchymal stem cells (MSCs) have been implicated in hepatic injury, the mechanism through which they contribute to diabetic liver disease has not been clarified. In this study, we investigated the effects of MSC therapy on diabetic liver damage with a focus on the role of bone-marrow-derived cells (BMDCs), which infiltrate the liver, and elucidated the mechanism mediating this process. Rat bone-marrow (BM)-derived MSCs were administered to high-fat diet (HFD)-induced type 2 diabetic mice and streptozotocin (STZ)-induced insulin-deficient diabetic mice. MSC-conditioned medium (MSC-CM) was also administered to examine the trophic effects of MSCs on liver damage. Therapeutic effects of MSCs were analyzed by assessing serum liver enzyme levels and histological findings. Kinetic and molecular profiles of BMDCs in the liver were evaluated using BM-chimeric mice. Curative effects of MSC and MSC-CM therapies were similar because both ameliorated the aggravation of aspartate aminotransferase and alanine aminotransferase at 8 weeks of treatment, despite persistent hyperlipidemia and hyperinsulinemia in HFD-diabetic mice and persistent hyperglycemia in STZ-diabetic mice. Furthermore, both therapies suppressed the abnormal infiltration of BMDCs into the liver, reversed excessive expression of proinflammatory cytokines in parenchymal cells, and regulated proliferation and survival signaling in the liver in both HFD-and STZ-diabetic mice. In addition to inducing hepatocyte regeneration in STZ-diabetic mice, both therapies also prevented excessive lipid accumulation and apoptosis of hepatocytes and reversed insulin resistance (IR) in HFD-diabetic mice. Conclusion: MSC therapy is a powerful tool for repairing diabetic hepatocyte damage by inhibiting inflammatory reactions induced by BMDCs and IR. These effects are likely the result of humoral factors derived from