The dopamine system has been characterized in motor function, goal-directed behaviors, and rewards. Recent studies recognize various dopamine system genes as being associated with autism spectrum ...disorder (ASD). However, how dopamine system dysfunction induces ASD pathophysiology remains unknown. In the present study, we demonstrated that mice with increased dopamine functions in the dorsal striatum via the suppression of dopamine transporter expression in substantia nigra neurons or the optogenetic stimulation of the nigro-striatal circuitry exhibited sociability deficits and repetitive behaviors relevant to ASD pathology in animal models, while these behavioral changes were blocked by a D1 receptor antagonist. Pharmacological activation of D1 dopamine receptors in normal mice or the genetic knockout (KO) of D2 dopamine receptors also produced typical autistic-like behaviors. Moreover, the siRNA-mediated inhibition of D2 dopamine receptors in the dorsal striatum was sufficient to replicate autistic-like phenotypes in D2 KO mice. Intervention of D1 dopamine receptor functions or the signaling pathways-related D1 receptors in D2 KO mice produced anti-autistic effects. Together, our results indicate that increased dopamine function in the dorsal striatum promotes autistic-like behaviors and that the dorsal striatum is the neural correlate of ASD core symptoms.
Understanding adipogenesis, the process of adipocyte development, may provide new ways to treat obesity and related metabolic diseases. Adipogenesis is controlled by coordinated actions of ...lineage-determining transcription factors and epigenomic regulators. Peroxisome proliferator-activated receptor gamma (PPARγ) and C/EBPα are master "adipogenic" transcription factors. In recent years, a growing number of studies have reported the identification of novel transcriptional and epigenomic regulators of adipogenesis. However, many of these novel regulators have not been validated in adipocyte development in vivo and their working mechanisms are often far from clear. In this minireview, we discuss recent advances in transcriptional and epigenomic regulation of adipogenesis, with a focus on factors and mechanisms shared by both white adipogenesis and brown adipogenesis. Studies on the transcriptional regulation of adipogenesis highlight the importance of investigating adipocyte differentiation in vivo rather than drawing conclusions based on knockdown experiments in cell culture. Advances in understanding of epigenomic regulation of adipogenesis have revealed critical roles of histone methylation/demethylation, histone acetylation/deacetylation, chromatin remodeling, DNA methylation, and microRNAs in adipocyte differentiation. We also discuss future research directions that may help identify novel factors and mechanisms regulating adipogenesis.
Metformin is used to treat type 2 diabetes. We sought to determine whether metformin reduces inflammation, by regulating p-signal transducer and activator of transcription 3 (STAT3) expression and ...T-helper 17 (Th17) cell proliferation, in a mouse model of inflammatory bowel disease (IBD).
IBD mice were administered metformin for 16 days and their tissues were analyzed. AMP-activated protein kinase (AMPK), the mammalian target of rapamycin (mTOR), p-STAT3 and p-STAT5 in the spleen and lymph nodes were detected using immunohistochemistry and confocal microscopy. Gene expression was determined using quantitative PCR assays, and protein expression levels were measured using western blotting and enzyme-linked immunosorbent assays. Human HT-29 cell proliferation was evaluated using MTT assays.
Metformin reduced disease activity index scores and inhibited weight loss. Metformin also decreased the colonic histological score and inflammatory mediators and increased colon lengths increased. Treatment with metformin inhibited the expression of interleukin (IL)-17, p-STAT3, and p-mTOR. In contrast, metformin treatment increased expression levels of p-AMPK and Foxp3. In addition, expression of inflammatory cytokines decreased in a dose-dependent manner in inflamed human HT-29 cells cultured with metformin at various concentrations.
Metformin attenuates IBD severity and reduces inflammation through the inhibition of p-STAT3 and IL-17 expression. Our results have increased our understanding of this chronic inflammatory disease, and support the strategy of using p-STAT3 inhibitors to treat IBD.
Objective
Olfactory function is altered in mild cognitive impairment (MCI) and Alzheimer's disease (AD); therefore, it may serve as a useful tool for the early detection of MCI before its advancement ...to AD. The aim of this meta‐analysis was to investigate olfactory deficits in patients with MCI and AD.
Study Design
Literature search.
Methods
A search was conducted of the electronic databases PubMed, Embase, and Web of Science from their inception until 2017. We included original articles with adequate data on the identification, threshold, and/or discrimination of olfactory function in MCI or AD. The standard mean difference and 95% confidence interval (CI) were calculated. The studies were weighted according to inverse variance estimates. The effect sizes were categorized as small Cohen's d = 0.2, medium (d = 0.5), or large (d ≥ 0.8) based on these methods. Subgroup analyses were performed based on mean age and sex differences between the groups.
Results
Twelve articles (reporting 21 effects) examining 563 patients with MCI and 788 patients with AD, were included in the meta‐analysis. Compared to MCI, AD had moderate to large heterogeneous effects on olfactory function (Cohen's d = 0.64, 95% CI: 0.50, 0.78). Olfactory identification tests demonstrated larger effects (d = 0.71, 95% CI: 0.51, 0.91) than did tests of other olfactory domains.
Conclusions
Meta‐analysis results revealed that olfactory identification was more profoundly impaired in patients with AD than in those with MCI. These findings suggest that a simple test of odor identification is valuable in differentiating individuals at a risk of AD.
Level of Evidence
NA Laryngoscope, 129:362–369, 2019
Objective
Increased protein phosphatase magnesium‐dependent 1A (PPM1A) levels in patients with ankylosing spondylitis regulate osteoblast differentiation in bony ankylosis; however, the potential ...mechanisms that regulate osteoclast differentiation in relation to abnormal bone formation remain unclear. This study was undertaken to investigate the relationship of PPM1A to osteoclast differentiation by generating conditional gene‐knockout (PPM1Afl/fl;LysM‐Cre) mice and evaluating their bone phenotype.
Methods
The bone phenotypes of LysM‐Cre mice (n = 6) and PPM1Afl/fl;LysM‐Cre mice (n = 6) were assessed by micro–computed tomography. Osteoclast differentiation was induced by culturing bone marrow–derived macrophages in the presence of RANKL and macrophage colony‐stimulating factor (M‐CSF), and was evaluated by counting tartrate‐resistant acid phosphatase–positive multinucleated cells. Levels of messenger RNA for PPM1A, RANK, and osteoclast‐specific genes were examined by real‐time quantitative polymerase chain reaction, and protein levels were determined by Western blotting. Surface RANK expression was analyzed by fluorescence flow cytometry.
Results
The PPM1Afl/fl;LysM‐Cre mice displayed reduced bone mass (P < 0.001) and increased osteoclast differentiation (P < 0.001) and osteoclast‐specific gene expression (P < 0.05) compared with their LysM‐Cre littermates. Mechanistically, reduced PPM1A function in osteoclast precursors in PPM1Afl/fl;LysM‐Cre mice induced osteoclast lineage commitment by up‐regulating RANK expression (P < 0.01) via p38 MAPK activation in response to M‐CSF. PPM1A expression in macrophages was decreased by Toll‐like receptor 4 activation (P < 0.05). The Ankylosing Spondylitis Disease Activity Score was negatively correlated with the expression of PPM1A in peripheral blood mononuclear cells from patients with axial spondyloarthritis (SpA) (γ = −0.7072, P < 0.0001).
Conclusion
The loss of PPM1A function in osteoclast precursors driven by inflammatory signals contributes to osteoclast lineage commitment and differentiation by elevating RANK expression, reflecting a potential role of PPM1A in dynamic bone metabolism in axial SpA.
Abstract
Background
Toll-like receptor 4 (TLR4) conducts a highly regulated inflammatory process by limiting the extent of inflammation to avoid toxicity and tissue damage, even in bone tissues. ...Thus, it is plausible that strategies for the maintenance of normal bone-immunity to prevent undesirable bone damage by TLR4 activation can exist, but direct evidence is still lacking.
Methods
Osteoclast precursors (OCPs) obtained from
WT
or
Slit3
-deficient mice were differentiated into osteoclast (OC) with macrophage colony-stimulating factor (M-CSF), RANK ligand (RANKL) and lipopolysaccharide (LPS) by determining the number of TRAP-positive multinuclear cells (TRAP
+
MNCs). To determine the alteration of OCPs population, fluorescence-activated cell sorting (FACS) was conducted in bone marrow cells in mice after LPS injection. The severity of bone loss in LPS injected
WT
or
Slit3
-deficient mice was evaluated by micro-CT analysis.
Result
We demonstrate that TLR4 activation by LPS inhibits OC commitment by inducing the concomitant expression of
miR-218–2-3p
and its host gene,
Slit3
, in mouse OCPs. TLR4 activation by LPS induced SLIT3 and its receptor ROBO1 in BMMs, and this SLIT3-ROBO1 axis hinders RANKL-induced OC differentiation by switching the protein levels of C/EBP-β isoforms. A deficiency of SLIT3 resulted in increased RANKL-induced OC differentiation, and the elevated expression of OC marker genes including
Pu.1
,
Nfatc1
, and
Ctsk
. Notably,
Slit3
-deficient mice showed expanded OCP populations in the bone marrow. We also found that miR-218–2 was concomitantly induced with SLIT3 expression after LPS treatment, and that this miRNA directly suppressed
Tnfrsf11a
(RANK) expression at both gene and protein levels, linking it to a decrease in OC differentiation. An endogenous
miR-218–2
block rescued the expression of RANK and subsequent OC formation in LPS-stimulated OCPs. Aligned with these results,
SLIT3
-deficient mice displayed increased OC formation and reduced bone density after LPS challenge.
Conclusion
Our findings suggest that the TLR4-dependent concomitant induction of
Slit3
and
miR-218–2
targets RANK in OCPs to restrain OC commitment, thereby avoiding an uncoordinated loss of bone through inflammatory processes. These observations provide a mechanistic explanation for the role of TLR4 in controlling the commitment phase of OC differentiation.
In this study, we evaluated accumulation and adverse effects of ingestion of microplastics in the monogonont rotifer (Brachionus koreanus). The dependence of microplastic toxicity on particle size ...was investigated by measuring several in vivo end points and studying the ingestion and egestion using 0.05-, 0.5-, and 6-μm nonfunctionalized polystyrene microbeads. To identify the defense mechanisms activated in response to microplastic exposure, the activities of several antioxidant-related enzymes and the phosphorylation status of mitogen-activated protein kinases (MAPKs) were determined. Exposure to polystyrene microbeads of all sizes led to significant size-dependent effects, including reduced growth rate, reduced fecundity, decreased lifespan and longer reproduction time. Rotifers exposed to 6-μm fluorescently labeled microbeads exhibited almost no fluorescence after 24 h, while rotifers exposed to 0.05- and 0.5-μm fluorescently labeled microbeads displayed fluorescence until 48 h, suggesting that 6-μm microbeads are more effectively egested from B. koreanus than 0.05- or 0.5-μm microbeads. This observation provides a potential explanation for our findings that microbead toxicity was size-dependent and smaller microbeads were more toxic. In vitro tests revealed that antioxidant-related enzymes and MAPK signaling pathways were significantly activated in response to microplastic exposure in a size-dependent manner.
Adolescent pregnancy causes serious problems not only for girls, but also for their family, and society. This study aimed to understand factors related to adolescent pregnancy in low- and ...middle-income countries using a multilevel approach adopted by Bronfenbrenner's ecological model.
A total of 11,933 studies published in between 2000 and 2015 were identified in 4 databases. Based on inclusion criteria and risk of bias assessment, a total of 67 articles were retrieved for analysis.
Thematic analysis revealed that early marriage, sexual risk behaviors, substance use, family experience of adolescent birth, peer pressure, and lack of sex education and health service increased the hazards of adolescent pregnancy. Communication with parents, school activities, community meetings, laws, and government policies protected adolescents from pregnancy.
Results of this study suggests that the background of adolescents and complex interactions among various factors should be considered for pregnancy. In future research, mixed-method that supplements the methodological weaknesses of previous studies is also recommended.
To evaluate the influence of myoma characteristics on cesarean myomectomy and to demonstrate its additional advantages.
Retrospective data were collected from 292 women with myomas who had undergone ...cesarean section at Kangnam Sacred Heart Hospital between 2007 and 2019. We performed subgroup analysis according to the type, weight, number, and size of myomas. Preoperative and postoperative hemoglobin levels, operative time, estimated blood loss, length of hospital stay, incidence of transfusion, uterine artery embolization, ligation, hysterectomy, and postoperative complications were compared among subgroups.
There were 119 patients who had cesarean myomectomy and 173 who had cesarean section only. An increase in postoperative hospitalization and operation time was observed in the cesarean myomectomy group compared to that in the caesarean section only group (mean difference, 0.7 days, p = 0.01, 13.5 minutes, p <0.001). Estimated blood loss, hemoglobin differences, and transfusion rates were higher in the cesarean myomectomy than in the cesarean section only group. There were no differences in postoperative complications (fever, bladder injury, and ileus) between the two groups. No hysterectomy cases were reported in the cesarean myomectomy group. In subgroup analysis, the larger and heavier the myoma, the higher the risk of bleeding that led to transfusion. Estimated blood loss, differences in hemoglobin, and transfusion rate increased depending on myoma size and weight. A significant increase in postoperative hospitalization was observed in women with larger and heavier myomas. However, there was no statistical difference among the three types of myomas.
In cesarean myomectomy, larger (≥ 10 cm), and heavier myomas (≥ 500 g), were associated with postoperative outcomes, but not the number or type of myoma. The safety of cesarean myomectomy is not inferior to that of caesarean section only, considering its positive effects such as gynecological symptom relief and avoidance of the next surgery.
Probiotics are the most useful tools for balancing the gut microbiota and thereby influencing human health and disease. Probiotics have a range of effects, from those on nutritional status to medical ...conditions throughout the body from the gut to non-intestinal body sites such as the brain and skin. Research interest in probiotics with nutritive claims (categorized as nutribiotics) has evolved into interest in therapeutic and pharmacological probiotics with health claims (pharmabiotics). The concept of pharmabiotics emerged only two decades ago, and the new categorization of probiotics to nutribiotics and pharmabiotics was recently suggested, which are under the different regulation depending on that they are food or drug. Information of the gut microbiome has been continuously accumulating, which will make possible the gut microbiome-based healthcare in the future, when nutribiotics show potential for maintaining health while pharmabiotics are effective therapeutic tools for human diseases. This review describes the current understanding in the conceptualization and classification of probiotics. Here, we reviewed probiotics as nutribiotics with nutritional functions and pharmabiotics with pharmaceutic functions in different diseases.
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