The interleukin (IL)-17 family, consisting of six members, promotes host defense but can in some context promote the development of autoimmune disease. Here, we examined the role of IL-17D, a poorly ...understood member in the IL-17 family. IL-17D was expressed primarily by colonic epithelial cells. Il17d−/− mice were more susceptible to acute colitis, bacterial infection and experimentally induced colon cancer than their wildtype counterparts. Il17d deficiency impaired IL-22 production by group 3 innate lymphoid cells (ILC3s) and reduced expression of IL-22-dependent antimicrobial peptides, RegIIIβ and RegIIIγ, in colon tissue at steady state and in colitis; this was associated with changes in microbial composition and dysbiosis. Protein purification studies revealed that IL-17D bound not canonical IL-17 receptors, but rather CD93, a glycoprotein expressed on mature ILC3s. Mice lacking Cd93 in ILC3s exhibited impaired IL-22 production and aggravated colonic inflammation in experimental colitis. Thus, an IL-17D-CD93 axis regulates ILC3 function to preserve intestinal homeostasis.
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•IL-17D is required for intestinal hemostasis•IL-17D deficiency results in defective IL-22 production by ILC3s•CD93 is a functional receptor of IL-17D expressed on mature ILC3s•CD93 deficiency decreases ILC3 development and IL-22 production in ILC3s
Among IL-17 cytokines, IL-17D is the least studied member. In this study, Dong et al. demonstrate that intestine epithelial cells-derived IL-17D serve as a critical factor in regulating ILC3s function and intestinal homeostasis by binding the receptor CD93.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recent evidence indicates that the composition of the gut microbiota contributes to the development of metabolic disorders by affecting the physiology and metabolism of the host. Metformin is one of ...the most widely prescribed type 2 diabetes (T2D) therapeutic agents.
To determine whether the antidiabetic effect of metformin is related to alterations of intestinal microbial composition.
C57BL/6 mice, fed either a normal-chow diet or a high-fat diet (HFD), were treated with metformin for 6 weeks. The effect of metformin on the composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing. Adipose tissue inflammation was examined by flow cytometric analysis of the immune cells present in visceral adipose tissue (VAT).
Metformin treatment significantly improved the glycaemic profile of HFD-fed mice. HFD-fed mice treated with metformin showed a higher abundance of the mucin-degrading bacterium Akkermansia than HFD-fed control mice. In addition, the number of mucin-producing goblet cells was significantly increased by metformin treatment (p<0.0001). Oral administration of Akkermansia muciniphila to HFD-fed mice without metformin significantly enhanced glucose tolerance and attenuated adipose tissue inflammation by inducing Foxp3 regulatory T cells (Tregs) in the VAT.
Modulation of the gut microbiota (by an increase in the Akkermansia spp. population) may contribute to the antidiabetic effects of metformin, thereby providing a new mechanism for the therapeutic effect of metformin in patients with T2D. This suggests that pharmacological manipulation of the gut microbiota in favour of Akkermansia may be a potential treatment for T2D.
Consumption of a typical Western diet is a risk factor for several disorders. Metabolic syndrome is the most common disease associated with intake of excess fat. However, the incidence of ...inflammatory bowel disease is also greater in subjects consuming a Western diet, although the mechanism of this phenomenon is not clearly understood. We examined the morphological and functional changes of the intestine, the first site contacting dietary fat, in mice fed a high-fat diet (HFD) inducing obesity. Paneth cell area and production of antimicrobial peptides by Paneth cells were decreased in HFD-fed mice. Goblet cell number and secretion of mucin by goblet cells were also decreased, while intestinal permeability was increased in HFD-fed mice. HFD-fed mice were more susceptible to experimental colitis, and exhibited severe colonic inflammation, accompanied by the expansion of selected pathobionts such as Atopobium sp. and Proteobacteria. Fecal microbiota transplantation transferred the susceptibility to DSS-colitis, and antibiotic treatment abrogated colitis progression. These data suggest that an experimental HFD-induced Paneth cell dysfunction and subsequent intestinal dysbiosis characterized by pathobiont expansion can be predisposing factors to the development of inflammatory bowel disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite growing interest in the relationship between autophagy and systemic metabolism, how global changes in autophagy affect metabolism remains unclear. Here we show that mice with global ...haploinsufficiency of an essential autophagy gene (Atg7(+/-) mice) do not show metabolic abnormalities but develop diabetes when crossed with ob/ob mice. Atg7(+/-)-ob/ob mice show aggravated insulin resistance with increased lipid content and inflammatory changes, suggesting that autophagy haploinsufficiency impairs the adaptive response to metabolic stress. We further demonstrate that intracellular lipid content and insulin resistance after lipid loading are increased as a result of autophagy insufficiency, and provide evidence for increased inflammasome activation in Atg7(+/-)-ob/ob mice. Imatinib or trehalose improves metabolic parameters of Atg7(+/-)-ob/ob mice and enhances autophagic flux. These results suggest that systemic autophagy insufficiency could be a factor in the progression from obesity to diabetes, and autophagy modulators have therapeutic potential against diabetes associated with obesity and inflammation.
Cognitive training can potentially prevent cognitive decline. However, the results of recent studies using semi-immersive virtual reality (VR)-assisted cognitive training are inconsistent.
We aimed ...to examine the hypothesis that cognitive training using fully immersive VR, which may facilitate visuospatial processes, could improve visuospatial functioning, comprehensive neuropsychological functioning, psychiatric symptoms, and functional connectivity in the visual brain network in predementia.
Participants over 60 years old with subjective cognitive decline or mild cognitive impairment from a memory clinic were randomly allocated to the VR (n=23) or the control (n=18) group. The VR group participants received multidomain and neuropsychologist-assisted cognitive training in a fully immersive VR environment twice a week for 1 month. The control group participants did not undergo any additional intervention except for their usual therapy such as pharmacotherapy. Participants of both groups were evaluated for cognitive function using face-to-face comprehensive neuropsychological tests, including the Rey-Osterrieth Complex Figure Test (RCFT) copy task; for psychiatric symptoms such as depression, apathy, affect, and quality of life; as well as resting-state functional magnetic resonance imaging (rsfMRI) at baseline and after training. Repeated-measures analysis of variance was used to compare the effect of cognitive training between groups. Seed-to-voxel-based analyses were used to identify the cognitive improvement-related functional connectivity in the visual network of the brain.
After VR cognitive training, significant improvement was found in the total score (F
=14.69, P=.001) and basic components score of the RCFT copy task (F
=9.27, P=.005) compared with those of the control group. The VR group also showed improvements, albeit not significant, in naming ability (F
=3.55, P=.07), verbal memory delayed recall (F
=3.03, P=.09), and phonemic fluency (F
=3.08, P=.09). Improvements in psychiatric symptoms such as apathy (F
=7.02, P=.01), affect (F
=14.40, P=.001 for positive affect; F
=4.23, P=.047 for negative affect), and quality of life (F
=4.49, P=.04) were found in the VR group compared to the control group. Improvement in the RCFT copy task was associated with a frontal-occipital functional connectivity increase revealed by rsfMRI in the VR group compared to the control group.
Fully immersive VR cognitive training had positive effects on the visuospatial function, apathy, affect, quality of life, and increased frontal-occipital functional connectivity in older people in a predementia state. Future trials using VR cognitive training with larger sample sizes and more sophisticated designs over a longer duration may reveal greater improvements in cognition, psychiatric symptoms, and brain functional connectivity.
Clinical Research Information Service KCT0005243; https://tinyurl.com/2a4kfasa.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
•Metformin induces FGF21 expression in an AMPK independent manner.•Metformin enhances FGF21 expression by inhibiting mitochondrial complex I activity.•The PERK-eIF2α-ATF4 axis is required for ...metformin-induced FGF21 expression.•Metformin activates the ATF4-FGF21 axis in the liver of mouse.•Metformin increases serum FGF21 level in diabetic human subjects.
Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-obesity and anti-diabetes effects. Because metformin is widely used as a glucose-lowering agent in patients with type 2 diabetes (T2D), we investigated whether metformin modulates FGF21 expression in cell lines, and in mice or human subjects. We found that metformin increased the expression and release of FGF21 in a diverse set of cell types, including rat hepatoma FaO, primary mouse hepatocytes, and mouse embryonic fibroblasts (MEFs). Intriguingly, AMP-activated protein kinase (AMPK) was dispensable for the induction of FGF21 by metformin. Mammalian target of rapamycin complex 1 (mTORC1) and peroxisome proliferator-activated receptor α (PPARα), which are additional targets of metformin, were not involved in metformin-induced FGF21 expression. Importantly, inhibition of mitochondrial complex I activity by metformin resulted in FGF21 induction through PKR-like ER kinase (PERK)-eukaryotic translation factor 2α (eIF2α)-activating transcription factor 4 (ATF4). We showed that metformin activated ATF4 and increased FGF21 expression in the livers of mice, which led to increased serum levels of FGF21. We also found that serum FGF21 level was increased in human subjects with T2D after metformin therapy for 6months. In conclusion, our results indicate that metformin induced expression of FGF21 through an ATF4-dependent mechanism by inhibiting mitochondrial respiration independently of AMPK. Therefore, FGF21 induction by metformin might explain a portion of the beneficial metabolic effects of metformin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Echiura is one of the most intriguing major subgroups of phylum Annelida because, unlike most other annelids, echiuran adults lack metameric body segmentation.
lives in U-shape burrows of soft ...sediments. Little is known about the molecular mechanisms underlying the development of
. Herein, we overviewed the developmental process from zygote to juvenile
using immunohistochemistry and F-actin staining for the nervous and muscular systems, respectively. Through F-actin staining, we found that muscle fibers began to form in the trochophore phase and that muscles for feeding were produced first. Subsequently, in the segmentation larval stage, the transversal muscle was formed in the shape of a ring in an anterior-to-posterior direction with segment formation, as well as a ventromedian muscle for the formation of a ventral nerve cord. After that, many muscle fibers were produced along the entire body and formed the worm-shaped larva. Finally, we investigated the spatiotemporal expression of
,
,
, and
genes found in
. During embryonic development, the striated and smooth muscle genes were co-expressed in the same region. However, the adult body wall muscles showed differential gene expression of each muscle layer. The results of this study will provide the basis for the understanding of muscle differentiation in Echiura.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Objective This study evaluated whether Quantitative Light-induced Fluorescence-Digital (QLF-D) can detect the levels of cariogenicity of dental microcosm biofilms by assessing the red ...fluorescence intensity. Methods Dental microcosm biofilms were initiated from human saliva on bovine enamel discs. Biofilms with various levels of cariogenicity were then grown in artificial saliva supplemented with sucrose at different concentrations (0.05%, 0.1%, 0.2%, and 0.5%) in 24-well microplates. After 10 days, fluorescence images of the biofilms were captured by the QLF-D to analyse the red fluorescence intensity, which was quantified as the red/green ratio ( R / G value). The supernatant pH was also measured, as well as the total and aciduric bacteria counts of the collected biofilms. Mineral loss in enamel was also evaluated by calculating the percentage of surface microhardness changes (%SHC). Results The R / G values of the biofilms differed significantly with the sucrose concentration ( p < 0.0001), increasing consistently as the sucrose concentration increased from 0.05% (=0.91) to 0.5% (=2.56). Strong correlation was identified between the R/G value and the number of aciduric bacteria ( r = 0.83, p < 0.0001), supernatant pH ( r = −0.95, p < 0.0001), and %SHC ( r = 0.90, p < 0.0001). Conclusions The red fluorescence as observed by the QLF-D was correlated with the cariogenic properties of dental microcosm biofilms in vitro , which indicates that this device can be used to detect the levels of cariogenicity of a dental biofilm. Clinical significance The QLF-D is able to assess the cariogenic levels of dental plaque based on the intensity of red fluorescence.
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Montreal Cognitive Assessment (MoCA) is a brief cognitive screening tool with high sensitivity for screening patients with mild cognitive impairment (MCI). The authors examined the validity and ...reliability of the Korean version of the MoCA (MoCA-K) in elderly outpatients. The MoCA-K, a Korean version of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR) scale, and neuropsychological batteries were administered to 196 elderly persons (mild Alzheimer's disease AD = 44, MCI = 37, normal controls NC = 115). MoCA-K scores were highly correlated with those of MMSE and CDR. Using a cutoff score of 22/23, the MoCA-K had an excellent sensitivity of 89% and a good specificity of 84% for screening MCI. Internal consistency and test−retest reliability were good. The results obtained show that the MoCA-K is brief, reliable, and suitable for use as a screening tool to screen MCI patients in elderly outpatient clinic settings.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Autophagy, which is critical for the proper turnover of organelles such as endoplasmic reticulum and mitochondria, affects diverse aspects of metabolism, and its dysregulation has been incriminated ...in various metabolic disorders. However, the role of autophagy of myeloid cells in adipose tissue inflammation and type 2 diabetes has not been addressed. We produced mice with myeloid cell-specific deletion of Atg7 (autophagy-related 7), an essential autophagy gene (Atg7 conditional knockout cKO mice). While Atg7 cKO mice were metabolically indistinguishable from control mice, they developed diabetes when bred to ob/w mice (Atg7 cKO-ob/ob mice), accompanied by increases in the crown-like structure, inflammatory cytokine expression and inflammasome activation in adipose tissue. Mφs (macrophages) from Atg7 cKO mice showed significantly higher interleukin 1 β release and inflammasome activation in response to a palmitic acid plus lipopolysaccharide combination. Moreover, a decrease in the NAD
+
:NADH ratio and increase in intracellular ROS content after treatment with palmitic acid in combination with lipopolysaccharide were more pronounced in Mφs from Atg7 cKO mice, suggesting that mitochondrial dysfunction in autophagy-deficient Mφs leads to an increase in lipid-induced inflammasome and metabolic deterioration in Atg7 cKO-ob/ob mice. Atg7 cKO mice were more susceptible to experimental colitis, accompanied by increased colonic cytokine expression, T helper 1 skewing and systemic bacterial invasion. These results suggest that autophagy of Mφs is important for the control of inflammasome activation in response to metabolic or extrinsic stress, and autophagy deficiency in Mφs may contribute to the progression of metabolic syndrome associated with lipid injury and colitis.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
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