The liver is an exclusive organ with tremendous regenerative capacity. Liver metabolic functions exhibit spatial heterogeneity, reflecting liver zonation. The mechanisms controlling the proliferation ...of hepatocytes and the accompanying matrix reconstruction during regeneration have been well explored, but the recovery potential of differentiated metabolic functions and zonation after liver injury remains unclear. We employed a mouse model of carbon tetrachloride (CCl
) induced-acute liver injury with clodronate-induced macrophage depletion to clarify the impact of liver injury on liver metabolism and recovery dynamics of metabolic function and liver zonation during regeneration. Depleting macrophages suppressed tissue remodelling and partially delayed cell proliferation during regeneration after liver injury. In addition, recovery of metabolic functions was delayed by suppressing the tissue remodelling caused by the depleted macrophages. The model revealed that drug metabolic function was resilient against the dysfunction caused by liver injury, but glutamine synthesis was not. Metabolomic analysis revealed that liver branched-chain amino acid (BCAA) and carbohydrate metabolism were suppressed by injury. The plasma BCAA concentration reflected recovery of hepatic function during regeneration. Our study reveals one aspect of the regenerative machinery for hepatic metabolism following acute liver injury.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Apolipoprotein E (apoE) is a major apolipoprotein in the brain. The ϵ4 allele of apoE is a major risk factor for Alzheimer disease, and apoE deficiency in mice leads to blood-brain barrier (BBB) ...leakage. However, the effect of apoE isoforms on BBB properties are as yet unknown. Here, using an in vitro BBB model consisting of brain endothelial cells and pericytes prepared from wild-type (WT) mice, and primary astrocytes prepared from human apoE3- and apoE4-knock-in mice, we show that the barrier function of tight junctions (TJs) was impaired when the BBB was reconstituted with primary astrocytes from apoE4-knock-in mice (apoE4-BBB model). The phosphorylation of occludin at Thr residues and the activation of protein kinase C (PKC)η in mBECs were attenuated in the apoE4-BBB model compared with those in the apoE3-BBB model. The differential effects of apoE isoforms on the activation of PKCη, the phosphorylation of occludin at Thr residues, and TJ integrity were abolished following the treatment with an anti-low density lipoprotein receptor-related protein 1 (LRP1) antibody or a LRP1 antagonist receptor-associated protein. Consistent with the results of in vitro studies, BBB permeability was higher in apoE4-knock-in mice than in apoE3-knock-in mice. Our studies provide evidence that TJ integrity in BBB is regulated by apoE in an isoform-dependent manner.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
We previously demonstrated that cinnamon extract (CE) alleviates streptozotocin-induced type 1 diabetes in rats. The present study aimed to elucidate the detailed molecular target of ...cinnamon in cultured adipocytes and epididymal adipose tissue of type 2 diabetes model mice. Two-dimensional gel electrophoresis was employed to determine the molecular target of cinnamon in adipocytes. The function of Acyl-CoA synthetase long-chain family-1 (ACSL1), a molecular target of cinnamon that was identified in this study, was further investigated in 3T3-L1 adipocytes using specific inhibitors. Type 2 diabetes model mice (KK-Ay/TaJcl) were used to investigate the effect of CE on glucose tolerance, ACSL1 expression, and related signal molecules in vivo. CE decreased ACSL1 mRNA and protein expression in 3T3-L1 adipocytes but increased glucose uptake and AMPK signaling activation; moreover, a similar effect was observed with an ACSL1 inhibitor. CE improved glucose tolerance and downregulated ACSL1 in mice adipose tissue in vivo. ACSL1 was demonstrated as a molecular target of CE in type 2 diabetes both in a cell culture system and diabetic mouse model.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Adipose tissue fibrosis is a hallmark of malfunction that is linked to insulin resistance and type 2 diabetes; however, what regulates this process remains unclear. Here we show that the PRDM16 ...transcriptional complex, a dominant activator of brown/beige adipocyte development, potently represses adipose tissue fibrosis in an uncoupling protein 1 (UCP1)-independent manner. By purifying the PRDM16 complex, we identified GTF2IRD1, a member of the TFII-I family of DNA-binding proteins, as a cold-inducible transcription factor that mediates the repressive action of the PRDM16 complex on fibrosis. Adipocyte-selective expression of GTF2IRD1 represses adipose tissue fibrosis and improves systemic glucose homeostasis independent of body-weight loss, while deleting GTF2IRD1 promotes fibrosis in a cell-autonomous manner. GTF2IRD1 represses the transcription of transforming growth factor β-dependent pro-fibrosis genes by recruiting PRDM16 and EHMT1 onto their promoter/enhancer regions. These results suggest a mechanism by which repression of obesity-associated adipose tissue fibrosis through the PRDM16 complex leads to an improvement in systemic glucose homeostasis.
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•GTF2IRD1 is a transcription factor that forms a complex with PRDM16 and EHMT1•A PRDM16-GTF2IRD1 complex cell-autonomously represses adipose tissue fibrosis•Repression of adipose tissue fibrosis improves systemic glucose homeostasis•GTF2IRD1 expression inversely correlates with subcutaneous WAT fibrosis in humans
Hasegawa et al. identify GTF2IRD1 as a cold-inducible transcription factor that represses adipose tissue fibrosis through a PRDM16-EHMT1 complex. Repression of adipose tissue fibrosis by the complex improves systemic glucose homeostasis independent of UCP1-mediated thermogenesis and body weight. In humans, GTF2IRD1 expression inversely correlates with subcutaneous WAT fibrosis and visceral adiposity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Periodic myometrial contraction is one of the important uterine functions to achieve embryo implantation and parturition. Although it is well-known that the mammalian myometrium is composed of ...longitudinal (outer) and circular (inner) layers, the precise mechanisms that coordinate both muscular contractions to produce peristaltic movements remain unclear. Recently, by treatment with our modified Clear Unobstructed Brain Imaging Cocktails and Computational analysis (CUBIC) tissue-clearing method, we obtained well-contrasted three-dimensional images of the transparent murine ovary using enhanced green fluorescent protein (EGFP) transgenic mice and light-sheet microscopy. Consequently, to investigate accurate anatomical connections between outer and inner myometrial fibers, we observed whole structures of the myometrium using a transparent murine uterus. By this method, we identified a novel muscle layer, a middle layer of the myometrium, which anatomically connects the conventional outer longitudinal and inner circular muscles. This new layer was visualized as a mesh-like structure and this structure was observed throughout the whole uterus from proximal to distal sites. In this area, CD31-positive vessels were abundantly localized around the mesh-like muscle fibers. In addition, CD34-positive uterine telocytes and tubulin β-3-positive nerve fibers were closely located in this middle layer. These findings indicate the presence of a novel mesh-like stratum that connects longitudinal and circular muscle layers, and suggest its coordinating role in myometrial contractions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cycloclypeus carpenteri
is the largest extant benthic foraminifer, dwelling in the deep euphotic zone (a water depth between 60 and 130 m) of the warm oligotrophic Indo-West Pacific. This foraminifer ...harbors diatom endosymbionts and the foraminifer-microalgal association acts like a holobiont. To verify that light is an important limiting factor controlling the vertical (depth) distribution of living
Cycloclypeus
holobionts, their physiological responses to light intensity were examined by short-term metabolic measurements and long-term incubations. Net oxygen production (OP) rates measured under different light levels using an oxygen microelectrode indicate that
Cycloclypeus
holobionts are daily net primary producers adapted to low light levels, with slight photoinhibition (reduced net OP rates relative to a light-saturated rate) over 100 µmol photons m
−2
s
−1
. Long-term growth increments of asexually reproduced juveniles incubated for two months at different light levels ranging from 0 to 100 µmol photons m
−2
s
−1
show that
Cycloclypeus
holobionts are adapted to a low light level (∼5 µmol photons m
−2
s
−1
), but can be acclimatized to a certain low light ranges (<50 µmol photons m
−2
s
−1
). These experimental results confirm that light is an important environmental gradient affecting the vertical distribution of
Cycloclypeus
holobionts.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aim
The aim of the present study was to assess the efficacy of endoscopic repair for secondary infertility caused by post‐cesarean scar defect (PCSD). Our investigation focused on the validity of new ...diagnostic criteria and selection methods.
Material and Methods
The subjects were 22 women with secondary infertility due to PCSD with retention of bloody fluid in the uterine cavity. Women with a residual myometrial thickness of ≥2.5 mm and an anteflexed or straight uterus underwent hysteroscopic surgery, while all others underwent laparoscopic repair. Hysteroscopic surgery involved resection and coagulation of scarred areas, whereas laparoscopic surgery involved removal of scarred areas combined with hysteroscopy, followed by resuturing.
Results
Fourteen of the 22 women (63.6%) who were followed up for ≥1 year after surgery achieved pregnancy. Pregnancies occurred in all four women (100%) who underwent hysteroscopic surgery and in 10 of the 18 women (55.6%) who underwent laparoscopic surgery. Three out of four women who underwent hysteroscopic surgery had term deliveries. Among the women who underwent laparoscopic surgery, five had term deliveries. No cases of uterine rupture were experienced, and the delivery method was cesarean section in all cases.
Conclusion
We propose that infertility associated with PCSD, cesarean scar syndrome, is caused by the retention of bloody fluid in the uterine cavity and scarring. Endoscopic treatment, such as hysteroscopy or laparoscopy, was effective for cesarean scar syndrome.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Diallyl trisulfide (DATS) is a secondary metabolite of allicin, a volatile organosulfur flavoring compound generated by the crushing of garlic. These compounds have various medicinal effects such as ...antiplatelet activity. In this study, we demonstrated for the first time the cellular mechanism involved in the inhibition of platelet aggregation by DATS and dipropyl trisulfide (DPTS), which is a saturated analogue of DATS. Washed murine platelets were incubated with these sulfides, and platelet aggregation was evaluated by light transmission aggregometry. The amount of reaction products produced by DATS, DPTS, and glutathione (GSH) was measured using liquid chromatography–mass spectrometry. Compared with DPTS, DATS potently inhibited platelet aggregation induced by thrombin, U46619, and collagen. N-Ethylmaleimide (NEM), which is commonly used to modify sulfhydryl groups, also suppressed platelet aggregation. The reactivity of DATS with GSH was higher than that of DPTS. These data suggested that DATS inhibited platelet aggregation through the reaction of sulfhydryl groups.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
We previously demonstrated that cinnamon extract (CE) ameliorates type 1 diabetes induced by streptozotocin in rats through the up-regulation of glucose transporter 4 (GLUT4) translocation in both ...muscle and adipose tissues. This present study was aimed at clarifying the detailed mechanism(s) with which CE increases the glucose uptake in vivo and in cell culture systems using 3T3-L1 adipocytes and C2C12 myotubes in vitro. Specific inhibitors of key enzymes in insulin signaling and AMP-activated protein kinase (AMPK) signaling pathways, as well as small interference RNA, were used to examine the role of these kinases in the CE-induced glucose uptake. The results showed that CE stimulated the phosphorylation of AMPK and acetyl-CoA carboxylase. An AMPK inhibitor and LKB1 siRNA blocked the CE-induced glucose uptake. We also found for the first time that insulin suppressed AMPK activation in the adipocyte. To investigate the effect of CE on type 2 diabetes in vivo, we further performed oral glucose tolerance tests and insulin tolerance tests in type 2 diabetes model rats administered with CE. The CE improved glucose tolerance in oral glucose tolerance tests, but not insulin sensitivity in insulin tolerance test. In summary, these results indicate that CE ameliorates type 2 diabetes by inducing GLUT4 translocation via the AMPK signaling pathway. We also found insulin antagonistically regulates the activation of AMPK.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The circadian rhythm, which is necessary for reproduction, is controlled by clock genes. In the mouse uterus, the oscillation of the circadian clock gene has been observed. The transcription of the ...core clock gene period (
) and cryptochrome (
) is activated by the heterodimer of the transcription factor circadian locomotor output cycles kaput (
) and brain and muscle Arnt-like protein-1 (
). By binding to E-box sequences in the promoters of
and
genes, the CLOCK-BMAL1 heterodimer promotes the transcription of these genes. Per1/2 and Cry1/2 form a complex with the Clock/Bmal1 heterodimer and inactivate its transcriptional activities. Endometrial BMAL1 expression levels are lower in human recurrent-miscarriage sufferers. Additionally, it was shown that the presence of BMAL1-depleted decidual cells prevents trophoblast invasion, highlighting the importance of the endometrial clock throughout pregnancy. It is widely known that hormone synthesis is disturbed and sterility develops in Bmal1-deficient mice. Recently, we discovered that animals with uterus-specific Bmal1 loss also had poor placental development, and these mice also had intrauterine fetal death. Furthermore, it was shown that time-restricted feeding controlled the uterine clock's circadian rhythm. The uterine clock system may be a possibility for pregnancy complications, according to these results. We summarize the most recent research on the close connection between the circadian clock and reproduction in this review.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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