Nonalcoholic fatty liver disease (NAFLD) includes simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The gut-derived endotoxin plays an essential role in the pathophysiological development and progression of NAFLD. By using rat models of choline-deficient/L-amino acid-defined (CDAA)-diet-induced NAFLD, we examined whether MIYAIRI 588–a butyrate-producing probiotic – prevents the progression of pathophysiological changes from steatosis to hepatocarcinogenesis. In vivo experiments showed that treatment with MIYAIRI 588 reduced CDAA-diet-induced hepatic lipid deposition and significantly improved the triglyceride content, insulin resistance, serum endotoxin levels, and hepatic inflammatory indexes. We also found that MIYAIRI 588 substantially increased the activation of hepatic adenosine 5′-monophosphate-activated protein kinase (AMPK) and AKT and the expression of lipogenesis- or lipolysis-related proteins. MIYAIRI 588 also improved CDAA-diet-induced delocalization and substantially decreased the expression of the tight-junction proteins intestinal zonula occluden-1 and occludin in CDAA-diet-fed rats. Further, the MIYAIRI 588-treated rats also showed remarkable induction of nuclear factor erythoid 2-related factor 2 (Nrf2) and its targeted antioxidative enzymes, which suppressed hepatic oxidative stress. In vitro studies revealed that treatment with sodium butyrate (NaB) also activated AMPK and AKT and enhanced Nrf2 expression by precluding ubiquitination, thereby increasing the half-life of the Nrf2 protein. Pharmacological studies and siRNA knockdown experiments showed that NaB-mediated AMPK activation induced the phosphorylation and nuclear translocation of Sirtuin 1, leading to the increased assembly of mammalian TOR complex 2 and phosphorylation of AKT at Ser473 and subsequent induction of Nrf2 expression and activation. These favorable changes caused an obvious decrease in hepatic fibrous deposition, GST-P-positive foci development, and hepatocarcinogenesis. Our data clearly established that the probiotic MIYAIRI 588 has beneficial effects in the prevention of NAFLD progression.

Key Words: cardiomyogenesis Ⅲ human mesenchymal stem cell Ⅲ immunologic tolerance Ⅲ myocardial infarction Ⅲ cell-based therapy A lthough embryonic stem cells 1 and induced pluripotent stem (iPS) cells 2 can be differentiated into cells of various organs, including cardiomyocytes, there are many underlining problems to overcome before clinical applications can be used, eg, tumorigenicity. 3 Autografts of iPS cells may not cause immunologic rejection; ironically, however, possible neoplasm formation would cause a serious problem because the neoplasm would not be rejected by the withdrawal of immunosuppressive agents. On the other hand, mesenchymal stem cells (MSCs) have recently been used for clinical application, and their safety and feasibility in cardiac stem cell-based therapy have been demonstrated. 4 Thus, MSCs are a more important cellular source for stem cell-based therapy from a practical point of view.The efficacy of human bone marrow-derived MSCs (BMMSCs) was still limited, 5 however, because of low efficiency for cardiomyogenic transdifferentiation. 6 We previously reported that non-marrow-derived mesenchymal cells had higher cardiomyogenic transdifferentiation efficiency, eg, menstrual blood-derived mesenchymal cells (MMCs), 7 umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs), 8 and placental chorionic plate-derived mesenchymal cells (PCPCs). 9 These cells are thought to be used by an allograft; therefore, problems of immunologic rejection arise. However, an allograft may be superior to an autograft in several ways. Taking into account the background condition of the patient (eg, metabolic disease or age), Original received July 16, 2009; revision received April 14, 2010; accepted April 22, 2010 16 reported significant recovery of cardiac function by the rat amnion-derived cell transplantation in rat myocardial infarction (MI) model, however, they failed to show clear evidence of cardiomyogenic differentiation in vivo. Therefore, in the present study, we attempted to show: (1) the powerful cardiomyogenic transdifferentiation potential of our isolated hAMCs, and the beneficial effect of transplantation of hAMCs on cardiac function in vivo; (2) the induction of immunologic tolerance so that hAMCs can be a powerful allograftable stem cell source without either the administration of immunosuppressive agents or matching of MHC typing; (3) the mechanism of induction of tolerance; and (4) the close relationship between the cardiomyogenic transdifferentiation of mesenchymal cells and the process of immunologic tolerance. MethodsAn expanded Methods section is available in the Online Data Supplement at http://circres.ahajournals.org. Isolation and Culture of Human Amniotic Membrane-Derived Mesenchymal CellsHuman amniotic membrane was collected, with informed consent from individual patients, after delivery of a male neonate. The study was approved by the ethics committee of Keio University School of Medicine. The precise methods for culture have been described previously. 9,17 Detail is shown in...

Clostridium butyricum MIYAIRI is effective for both the treatment and the prophylaxis of AAD in children, as it normalizes the intestinal flora disturbed by antibiotics.

Reproductive capacity in women starts to decline beyond their mid-30s and pregnancies in older women result in higher rates of miscarriage with aneuploidy. Age-related decline in fertility is strongly attributed to ovarian aging, diminished ovarian reserves, and decreased developmental competence of oocytes. In this review, we discuss the underlying mechanisms of age-related decline in oocyte quality, focusing on oxidative stress (OS) in oocytes. The primary cause is the accumulation of spontaneous damage to the mitochondria arising from increased reactive oxygen species (ROS) in oocytes, generated by the mitochondria themselves during daily biological metabolism. Mitochondrial dysfunction reduces ATP synthesis and influences the meiotic spindle assembly responsible for chromosomal segregation. Moreover, reproductively aged oocytes produce a decline in the fidelity of the protective mechanisms against ROS, namely the ROS-scavenging metabolism, repair of ROS-damaged DNA, and the proteasome and autophagy system for ROS-damaged proteins. Accordingly, increased ROS and increased vulnerability of oocytes to ROS lead to spindle instability, chromosomal abnormalities, telomere shortening, and reduced developmental competence of aged oocytes.

The most distinctive feature of oocyte-specific linker histones is the specific timing of their expression during embryonic development. In Xenopus nuclear transfer, somatic linker histones in the donor nucleus are replaced with oocyte-specific linker histone B4, leading to the involvement of oocyte-specific linker histones in nuclear reprogramming. We recently have discovered a mouse oocyte-specific linker histone, named H1foo, and demonstrated its expression pattern in normal preimplantation embryos. The present study was undertaken to determine whether the replacement of somatic linker histones with H1foo occurs during the process of mouse nuclear transfer. H1foo was detected in the donor nucleus soon after transplantation. Thereafter, H1foo was restricted to the chromatin in up to two-cell stage embryos. After fusion of an oocyte with a cell expressing GFP (green fluorescent protein)-tagged somatic linker histone H1c, immediate release of H1c in the donor nucleus was observed. In addition, we used fluorescence recovery after photobleaching (FRAP), and found that H1foo is more mobile than H1c in living cells. The greater mobility of H1foo may contribute to its rapid replacement and decreased stability of the embryonic chromatin structure. These results suggest that rapid replacement of H1c with H1foo may play an important role in nuclear remodeling.