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Given that chronic hyperglycemia generates toxic methylglyoxal, the detoxifying effect of glyoxalase-1 (Glo1) on chronic hyperglycemia induced explant-derived cardiac stem cell (EDC) dysfunction was investigated. Wildtype (WT) and Glo1 over-expressing (Glo1TG) mice with or without streptozotocin treatment were studied. Hyperglycemia reduced overall culture yields while increasing the reactive dicarbonyl content within WT mice. These intrinsic cell changes reduced the angiogenic potential and nanoparticle production by hyperglycemic EDCs while promoting cell senescence. Compared to transplant of normoglycemic WT EDCs, hyperglycemic EDCs reduced myocardial function following infarction by inhibiting angiogenesis and endogenous repair mechanisms. In contrast, EDCs from hyperglycemic Glo1TG mice decreased reactive dicarbonyl content and restored culture yields. Intramyocardial injection of hyperglycemic Glo1TG EDCs also boosted myocardial function and reduced scarring. These findings demonstrate that, while chronic hyperglycemia decreases the regenerative performance of EDCs, over-expression of Glo1 reduces dicarbonyl stress and rescues the adverse effects of hyperglycemia on EDCs.

Myeloid precursor cell reprogramming into a myeloid-derived suppressor cell (MDSC) contributes to high mortality rates in mouse and human sepsis. S100A9 mRNA and intracellular protein levels increase during early sepsis and remain elevated in Gr1+CD11b+ MDSCs after pro-inflammatory sepsis transitions to the later chronic anti-inflammatory and immunosuppressive phenotype. The purpose of this study was to determine whether intracellular S100A9 protein might sustain Gr1+CD11b+ MDSC repressor cell reprogramming during sepsis. We used a chronic model of sepsis in mice to show that S100A9 release from MDSCs and circulating phagocytes decreases after early sepsis and that targeting the S100a9 gene improves survival. Surprisingly, we find that intracellular S100A9 protein translocates from the cytosol to nucleus in Gr1+CD11b+ MDSCs during late sepsis and promotes expression of miR-21 and miR-181b immune repressor mediators. We further provide support of this immunosuppression pathway in human sepsis. This study may inform a new therapeutic target for improving sepsis outcome.

Time-restricted eating is a fasting diet where the food intake is restricted to a short, typically eight-hour, window each day. It is associated with health benefits such as weight loss, improved sleep, protection against cognitive disorders, and improved cognitive function. The cognitive effects of time-restricted eating have primarily been explained by the production of ketogenesis – an alternative energy source produced when calories are restricted – and anti-inflammatory cytokines. The gut microbiota is the trillions of microorganisms inhabiting the intestinal tract and has also been associated with improved mental health through communication via the gut-brain axis. This review aims to investigate whether changes in the microbiota may mediate the effect of time-restricted eating on cognitive function. Studies investigating the effect of time-restricted eating on the microbiota were systematically reviewed. The results indicate that time-restricted eating may alter the microbiome composition and increase butyrate-producing bacteria. Butyrate is a short-chain fatty acid associated with the expression of genes involved in neural development and the reduction of neuroinflammation. Limited by the few studies reviewed, the results may indicate a possible link between time-restricted eating and cognitive function via the microbiota, although more research is needed.

The involvement of the endothelial cell in the vasoconstriction induced by angiotensin I and II (AI, AII), and norepinephrine (NE) was studied in microvessels of the hamster cheek pouch before and after the following procedures: endothelial impairment by light-dye treatment, inhibition of angiotensin-converting enzyme (ACE), blockade of endothelium-derived relaxing factor (EDRF) and inhibiting prostaglandin (PG) synthesis. The results showed that in large 2nd-order arterioles, endothelial impairment did not affect the vasoconstrictor activity of AII and NE, nor did it alter ACE activity. However, in small 4th-order arterioles, endothelial impairment significantly reduced angiotensin conversion without altering the vasoconstrictor responses to either AII or NE. Thus, the endothelium plays differential roles in the modulation of local angiotensin conversion in these distinct segments of serial-arranged arterioles. Furthermore, it is unlikely that the vasoconstrictor response to AII in these arterioles is modulated by the endothelium through a pathway involving the release of EDRF or PGs.

Oligodendrocytes are the predominant cell type in white matter and are highly vulnerable to ischemic injury. The role of oligodendrocyte dysfunction in ischemic brain injury is unknown. In this study, we used a 24-amino acid peptide S14G-Humanin (HNG) to examine oligodendrogenesis and neurological functional recovery in a hypoxic/ischemic (H/I) neonatal model. Intraperitoneal HNG pre-treatment decreased infarct volume following H/I injury. Delayed HNG treatment 24 h after H/I injury did not reduce infarct volume but did decrease neurological deficits and brain atrophy. Delayed HNG treatment did not attenuate axonal demyelination at 48 h after H/I injury. However, at 14 d after H/I injury, delayed HNG treatment increased axonal remyelination, the thickness of corpus callosum at the midline, the number of Olig2+/BrdU+ cells, and levels of brain-derived neurotrophic factor (BDNF). Our results suggest that targeting oligodendrogenesis via delayed HNG treatment may represent a promising approach for the treatment of stroke.

OBJECTIVE. To determine if the levels of circulating myeloid-derived suppressor cells increase with progression of prostate cancer (PCa); to determine if such cells could contribute to the relative inefficiency of PCa immunotherapy. MATERIALS AND METHODS. We analyzed peripheral blood mononuclear cells isolated from untreated PCa patients (uPCa; N=18; mean age±SD: 72.1± 6.9 years), tPCa (N = 22; 72.8 ± 9.8 years) and age matched controls (AMC; N = 12; 68.8 ± 7.5 years). We quantified surface marker phenotype, differentiation potential, effects on T cell proliferation and intracellular cytokines. RESULTS. We observed an unexpectedly high percentage of a type of myeloid-derived suppressor cells, CD14+HLA-DR low/- monocytes, in tPCa (30.7±15.0% of CD14+ cells) relative to AMC (4.1+6.5%, P<0.0001) and uPCa (10.6 ± 14.3%, P = 0.0001). The levels of CD14+ HLA-DR low/- cells were significantly correlated with circulating PSA levels and treatment with LHRH-agonist leuprolide in combination with either an antiandrogen or dexamethasone. Monocytes from tPCa inhibited autologous T cell proliferation statistically significantly more effectively than AMC monocytes and were defective in their ability to differentiate into phenotypically mature dendritic cells. Isolated CD14+HLA-DRlow/- cells expressed higher levels of intracellular interleukin-10 and suppressed T cell proliferation more effectively than isolated CD14+HLA-DR+ cells. CONCLUSIONS. This is the first report of CD14+ cells exhibiting reduced expression of HLADRmolecules in PCa patients. These cells suppress immune cell function in vitro and, plausibly, in vivo, a finding that must be factored into the design of immunotherapy protocols for PCa patients.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23601号 / 医博第4788号 / 新制||医||1055(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 羽賀 博典, 教授 戸井 雅和, 教授 伊藤 貴浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

RUNX1 overlapping RNA (RUNXOR) is a long noncoding RNA and a key regulator of myeloid-derived suppressor cells (MDSCs) via targeting runt-related transcription factor 1 (RUNX1). We and others have previously reported MDSC expansion and inhibition of host immune responses during viral infections; however, the mechanisms regulating MDSC differentiation and suppressive functions, especially the role of RUNXOR-RUNX1 in the regulation of MDSCs in people living with HIV (PLHIV), remain unknown. In this study, we demonstrate that RUNXOR and RUNX1 expressions are upregulated in MDSCs that expand and accumulate in human PBMCs derived from PLHIV. We found that the upregulation of RUNXOR and RUNX1 is associated with the expressions of several key immunosuppressive molecules, including arginase 1, inducible NO synthase, STAT3, IL-6, and reactive oxygen species. RUNXOR and RUNX1 could positively regulate each other's expression and control the expressions of these suppressive mediators. Specifically, silencing RUNXOR or RUNX1 expression in MDSCs from PLHIV attenuated MDSC expansion and immunosuppressive mediator expressions, whereas overexpressing RUNXOR in CD33+ myeloid precursors from healthy subjects promoted their differentiation into MDSCs and enhanced the expression of these mediators. Moreover, loss of RUNXOR-RUNX1 function in MDSCs improved IFN-γ production from cocultured autologous CD4 T cells derived from PLHIV. These results suggest that the RUNXOR-RUNX1 axis promotes the differentiation and suppressive functions of MDSCs via regulating multiple immunosuppressive signaling molecules and may represent a potential target for immunotherapy in conjunction with antiviral therapy in PLHIV.

Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. C1q/TNF-related protein 3 (CTRP3) is a relatively novel adipose tissue-derived cytokine (adipokine) which has been linked to improved glucose regulation and insulin sensitivity. However, the relationship between circulating CTRP3 levels and diabetes is controversial. CTRP3 can circulate in different oligomeric complexes: trimeric, hexameric, and high molecular weight (HMW) oligomeric complexes. However, the concentration of the different oligomeric complexes in human disease states has not been previously investigated. Therefore, the purpose of this study was to compare the levels of different oligomeric complexes of CTRP3 between type 2 diabetic and nondiabetic individuals. Additionally, the association between the oligomeric complexes and other serum factors was examined. CTRP3 primarily circulates in the HMW complex (>50%) and the hexametric multimer, with no CTRP3 detected in the trimeric complex or as a monomer. Further, no differences were observed in total, hexameric, or HMW CTRP3 levels regardless of diabetic status. Surprisingly, HMW CTRP3 was found to be positively correlated with circulating triglyceride levels. Combined, these data suggest that CTRP3 is associated with triglyceride regulation, not diabetic status. These data may explain some of the discrepancies in the literature as elevated triglyceride levels are often detected in patients with obesity and type 2 diabetes.