It remains unclear how many hours of sleep are associated with the lowest risk of type 2 diabetes. This meta-analysis was performed to assess the dose-response relationship between sleep duration and ...risk of type 2 diabetes.
PubMed and Embase were searched up to 20 March 2014 for prospective observational studies that assessed the relationship of sleep duration and risk of type 2 diabetes. Both semiparametric and parametric methods were used.
Ten articles with 11 reports were eligible for inclusion in the meta-analysis. A total of 18,443 incident cases of type 2 diabetes were ascertained among 482,502 participants with follow-up periods ranging from 2.5 to 16 years. A U-shaped dose-response relationship was observed between sleep duration and risk of type 2 diabetes, with the lowest risk observed at a sleep duration category of 7-8 h per day. Compared with 7-h sleep duration per day, the pooled relative risks for type 2 diabetes were 1.09 (95% CI 1.04-1.15) for each 1-h shorter sleep duration among individuals who slept <7 h per day and 1.14 (1.03-1.26) for each 1-h increment of sleep duration among individuals with longer sleep duration.
Our dose-response meta-analysis of prospective studies shows a U-shaped relationship between sleep duration and risk of type 2 diabetes, with the lowest type 2 diabetes risk at 7-8 h per day of sleep duration. Both short and long sleep duration are associated with a significantly increased risk of type 2 diabetes, underscoring the importance of appropriate sleep duration in the delay or prevention of type 2 diabetes.
Gliosis is a histopathological characteristic of epilepsy that comprises activated microglia and astrocytes. It is unclear whether or how crosstalk occurs between microglia and astrocytes in the ...evolution of epilepsy. Here, we report in a mouse model of status epilepticus, induced by intracerebroventricular injection of kainic acid (KA), sequential activation of microglia and astrocytes and their close spatial interaction in the hippocampal CA3 region. Microglial ablation reduced astrocyte activation and their upregulation of complement C3. When compared to wild‐type mice, both C3−/− and C3aR−/− mice had significantly less microglia–astrocyte interaction in response to KA‐induced status epilepticus. Additionally, KA‐injected C3−/− mice had significantly less histochemical evidence of neurodegeneration. The results suggest that the C3‐C3aR pathway contributes to KA‐induced neurodegeneration by mediating microglia–astrocyte communication. The C3‐C3aR pathway may prove to be a potential therapeutic target for epilepsy treatment.
Main Points
Microglia are required for astrocytes activation in experimental status epilepticus.
C3 from astrocytes activates microglia via C3a receptors.
Microglia–astrocyte interaction promotes gliosis and neuronal injury after seizures.
Seizures are common in humans with various etiologies ranging from congenital aberrations to acute injuries that alter the normal balance of brain excitation and inhibition. A notable consequence of ...seizures is the induction of aberrant neurogenesis and increased immature neuronal projections. However, regulatory mechanisms governing these features during epilepsy development are not fully understood. Recent studies show that microglia, the brain's resident immune cell, contribute to normal neurogenesis and regulate seizure phenotypes. However, the role of microglia in aberrant neurogenic seizure contexts has not been adequately investigated. To address this question, we coupled the intracerebroventricular kainic acid model with current pharmacogenetic approaches to eliminate microglia in male mice. We show that microglia promote seizure-induced neurogenesis and subsequent seizure-induced immature neuronal projections above and below the pyramidal neurons between the DG and the CA3 regions. Furthermore, we identify microglial P2Y12 receptors (P2Y12R) as a participant in this neurogenic process. Together, our results implicate microglial P2Y12R signaling in epileptogenesis and provide further evidence for targeting microglia in general and microglial P2Y12R in specific to ameliorate proepileptogenic processes.
Epileptogenesis is a process by which the brain develops epilepsy. Several processes have been identified that confer the brain with such epileptic characteristics, including aberrant neurogenesis and increased immature neuronal projections. Understanding the mechanisms that promote such changes is critical in developing therapies to adequately restrain epileptogenesis. We investigated the role of purinergic P2Y12 receptors selectively expressed by microglia, the resident brain immune cells. We report, for the first time, that microglia in general and microglial P2Y12 receptors in specific promote both aberrant neurogenesis and increased immature neuronal projections. These results indicate that microglia enhance epileptogenesis by promoting these processes and suggest that targeting this immune axis could be a novel therapeutic strategy in the clinic.
δ-Secretase, an age-dependent asparagine protease, cleaves both amyloid precursor protein (APP) and Tau and is required for amyloid plaque and neurofibrillary tangle pathologies in Alzheimer's ...disease (AD). However, whether δ-secretase activation is sufficient to trigger AD pathogenesis remains unknown. Here we show that the fragments of δ-secretase-cleavage, APP (586-695) and Tau(1-368), additively drive AD pathogenesis and cognitive dysfunctions. Tau(1-368) strongly augments BACE1 expression and Aβ generation in the presence of APP. The Tau(1-368) fragment is more robust than full-length Tau in binding active STAT1, a BACE1 transcription factor, and promotes its nuclear translocation, upregulating BACE1 and Aβ production. Notably, Aβ-activated SGK1 or JAK2 kinase phosphorylates STAT1 and induces its association with Tau(1-368). Inhibition of these kinases diminishes stimulatory effect of Tau(1-368). Knockout of STAT1 abolishes AD pathologies induced by δ-secretase-generated APP and Tau fragments. Thus, we show that Tau may not only be a downstream effector of Aβ in the amyloid hypothesis, but also act as a driving force for Aβ, when cleaved by δ-secretase.
Triggering receptor expressed on myeloid cell 2 (TREM2) is linked to risk of neurodegenerative disease. However, the function of TREM2 in neurodegeneration is still not fully understood. Here, we ...investigated the role of microglial TREM2 in TAR DNA-binding protein 43 (TDP-43)-related neurodegeneration using virus-mediated and transgenic mouse models. We found that TREM2 deficiency impaired phagocytic clearance of pathological TDP-43 by microglia and enhanced neuronal damage and motor impairments. Mass cytometry analysis revealed that human TDP-43 (hTDP-43) induced a TREM2-dependent subpopulation of microglia with high CD11c expression and phagocytic ability. Using mass spectrometry (MS) and surface plasmon resonance (SPR) analysis, we further demonstrated an interaction between TDP-43 and TREM2 in vitro and in vivo as well as in human tissues from individuals with amyotrophic lateral sclerosis (ALS). We computationally identified regions within hTDP-43 that interact with TREM2. Our data highlight that TDP-43 is a possible ligand for microglial TREM2 and that this interaction mediates neuroprotection of microglia in TDP-43-related neurodegeneration.
The P2Y12 receptor (P2Y12R) is a purinoceptor that is selectively expressed in microglia in the central nervous system. As a signature receptor, microglial P2Y12R mediates process chemotaxis towards ...ADP/ATP gradients and is engaged in several neurological diseases including chronic pain, stroke and seizures. However, the role of microglial P2Y12R in regulating neuronal excitability and innate behaviors is not fully understood. Here, we generated P2Y12-floxed mice to delete microglial P2Y12R beginning in development (CX
CR1
:P2Y12
; "constitutive knockout"), or after normal development in adult mice (CX
CR1
:P2Y12
; "induced knockout"). Using a battery of behavioral tests, we found that both constitutive and induced P2Y12R knockout mice exhibited innate fear but not learned fear behaviors. After mice were exposed to the elevated plus maze, the c-fos expression in ventral hippocampus CA1 neurons was robustly increased in P2Y12R knockout mice compared with wild-type mice. Consistently, using whole cell patch clamp recording, we found the excitability of ventral hippocampus CA1 neurons was increased in the P2Y12R knockout mice. The results suggest that microglial P2Y12R regulates neuronal excitability and innate fear behaviors in developing and adult mice.
Purpose of Review
Environmental endocrine disruptors, such as polybrominated diphenyl ethers (PBDEs), have been suggested to be a possible risk factor for thyroid disease, but the association is ...still inconclusive. This study performed a meta-analysis of epidemiological studies to investigate the relationship between PBDE exposure and the risk of thyroid disease.
Recent Findings
A total of nine epidemiological studies (published by January 20, 2023) reporting the association of PBDEs with thyroid disease were included. These studies investigated the effects of eight PBDE congeners and the sum of all PBDE congeners (∑PBDEs) and reported effect sizes and confidence intervals.
Summary
The results showed that high levels of BDE-183 exposure were associated with an increased risk of thyroid disease (OR = 3.26; 95% CI = 2.14–4.98). The relationship between other PBDE congeners and thyroid disease was not statistically significant. Subgroup analysis by region found that BDE-047 (OR = 2.62, 95% CI = 1.34–3.91), BDE-183 (OR = 2.92, 95% CI = 1.56–4.28), and ∑PBDEs (OR = 2.42, 95% CI = 1.31–3.53) were only associated with thyroid disease in Asian populations. No publication bias was detected by Egger’s test, and sensitivity analysis indicated the stability of the results. The present study suggests that exposure levels of certain PBDE congeners are associated with an increased risk of thyroid disease, only in Asian populations. Further large-scale and high-quality studies are needed to confirm these findings.
Organophosphate esters (OPEs) may interfere with thyroid function, but the relationship between OPEs and thyroid disease remains unclear. This study aims to elucidate the relationship between OPEs ...exposure and thyroid disease risk in the general population in the United States.
Data were obtained from the 2011-2014 National Health and Nutrition Examination Survey cycle. All participants were tested for seven OPE metabolites in their urine and answered questions about whether they had thyroid disease through questionnaires. Logistic regression was employed to analyze the association between exposure to individual OPE metabolites and thyroid disease. Weighted Quantile Sum (WQS) regression modeling was utilized to assess exposure to mixed OPE metabolites and risk of thyroid disease. Bayesian kernel machine regression(BKMR) models to analyze the overall mixed effect of OPE metabolites.
A total of 2,449 participants were included in the study, 228 of whom had a history of thyroid disease. Bis(1,3-dichloro-2-propyl) phos (BDCPP), Diphenyl phosphate (DPHP) and Bis(2-chloroethyl) phosphate (BCEP) were the top three metabolites with the highest detection rates of 91.75%, 90.77% and 86.57%, respectively. In multivariate logistic regression models, after adjustment for confounding variables, individuals with the highest tertile level of BCEP were significantly and positively associated with increased risk of thyroid disease (OR=1.57, 95% CI=1.04-2.36), using the lowest tertile level as reference. In the positive WQS regression model, after correcting for confounding variables, mixed exposure to OPE metabolites was significantly positively associated with increased risk of thyroid disease (OR=1.03, 95% CI=1.01-1.06), with BCEP and DPHP having high weights. In the BKMR model, the overall effect of mixed exposure to OPE metabolites was not statistically significant, but univariate exposure response trends showed that the risk of thyroid disease decreased and then increased as BCEP exposure levels increased.
The study revealed a significant association between exposure to OPE metabolites and an increased risk of thyroid disease, with BCEP emerging as the primary contributor. The risk of thyroid disease exhibits a J-shaped pattern, whereby the risk initially decreases and subsequently increases with rising levels of BCEP exposure. Additional studies are required to validate the association between OPEs and thyroid diseases.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, and ...eventually death. Motor cortical hyperexcitability is a common phenomenon observed at the presymptomatic stage of ALS. Both cell-autonomous (the intrinsic properties of motor neurons) and non-cell-autonomous mechanisms (cells other than motor neurons) are believed to contribute to cortical hyperexcitability. Decoding the pathological relevance of these dynamic changes in motor neurons and glial cells has remained a major challenge. This review summarizes the evidence of cortical hyperexcitability from both clinical and preclinical research, as well as the underlying mechanisms. We discuss the potential role of glial cells, particularly microglia, in regulating abnormal neuronal activity during the disease progression. Identifying early changes such as neuronal hyperexcitability in the motor system may provide new insights for earlier diagnosis of ALS and reveal novel targets to halt the disease progression.
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•Conjugated linoleic acid (CLA) improves dyslipidemia caused by high fat diet.•CLA alters fecal metabolites via arachidonic acid metabolism pathway.•High-precision biomarkers of CLA ...for lowering blood lipids were screened in serum.•CLA alters oxylipin profile in serum by regulating Cox/Lox-PGE2-Pparγ pathway.
This study aimed to investigate the metabolites of conjugated linoleic acid (CLA) in vivo from the perspective of metabolomics, so as to reveal the potential mechanism of CLA in lowing blood lipids. 30 male non-adult SD rats were divided into: normal diet group, high-fat diet group, and CLA group (intragastric administration of 0.5 g/kg·BW CLA). Results indicate improvements in body weight and visceral fat deposition in obese rats treated with CLA. Metabolomic analysis reveals significant changes in the arachidonic acid (ARA) pathway and its intestinal metabolite oxylipins. Key biomarkers (PGE1, PGE2, TXB2, PGF2α, and 12S-HHTrE) catalyzed by Cox and Lox are identified, influencing blood lipid reduction. Network analysis links these biomarkers to Pparγ. PCR and western blot confirm Pparγ changes in rat liver and intestine, impacting downstream lipid metabolism. This study reveals a potential mechanism: CLA mitigates obesity through the ARA-Cox/Lox-PGE2-Pparγ pathway, offering insights for treating obesity and dyslipidemia.
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