Effects of S-adenosylmethionine on AfsKRS regulation in pristinamycin biosynthesis in Streptomyces pristinaespiralis.

In Streptomyces pristinaespiralis, AfsKRS system has differential regulation for PI and PII component biosynthesis of pristinamycin, but it is unknown whether S-adenosylmethionine (SAM) plays an important role in the AfsK-AfsR-AfsS signal transduction cascade during pristinamycin production. The possible target of exogenous SAM in the AfsKRS system and the biological role of SAM during the production of PI and PII were investigated using three mutantsΔafsK,ΔafsR andΔafsS defective in signal cascade pathway of AfsKRS. It was found that external SAM had a significant activation of PI production (1.85-fold increase) but had no obvious effect on PII production in the original strain F618 with the normal response of AfsKRS regulation. Addition of SAM resulted in a similar increase in pristinamycin yield in the mutant with defective afsK or afsR, but induced more crucial activation of PI biosynthesis than PII biosynthesis both in ΔafsK (1.65-fold and 1.15-fold increase respectively) and ΔafsR (1.27-fold and 1.09-fold increase respectively). Exogenous SAM only significantly enhanced PII production in ΔafsS (1.1-fold increase). These results could provide valuable insights into the regulatory function of the AfsKRS system in S. pristinaespiralis.

MDGA2 Constrains Glutamatergic Inputs Selectively onto CA1 Pyramidal Neurons to Optimize Neural Circuits for Plasticity, Memory, and Social Behavior.

Synapse organizers are essential for the development, transmission, and plasticity of synapses. Acting as rare synapse suppressors, the MAM domain containing glycosylphosphatidylinositol anchor (MDGA) proteins contributes to synapse organization by inhibiting the formation of the synaptogenic neuroligin-neurexin complex. A previous analysis of MDGA2 mice lacking a single copy of Mdga2 revealed upregulated glutamatergic synapses and behaviors consistent with autism. However, MDGA2 is expressed in diverse cell types and is localized to both excitatory and inhibitory synapses. Differentiating the network versus cell-specific effects of MDGA2 loss-of-function requires a cell-type and brain region-selective strategy. To address this, we generated mice harboring a conditional knockout of Mdga2 restricted to CA1 pyramidal neurons. Here we report that MDGA2 suppresses the density and function of excitatory synapses selectively on pyramidal neurons in the mature hippocampus. Conditional deletion of Mdga2 in CA1 pyramidal neurons of adult mice upregulated miniature and spontaneous excitatory postsynaptic potentials, vesicular glutamate transporter 1 intensity, and neuronal excitability. These effects were limited to glutamatergic synapses as no changes were detected in miniature and spontaneous inhibitory postsynaptic potential properties or vesicular GABA transporter intensity. Functionally, evoked basal synaptic transmission and AMPAR receptor currents were enhanced at glutamatergic inputs. At a behavioral level, memory appeared to be compromised in Mdga2 cKO mice as both novel object recognition and contextual fear conditioning performance were impaired, consistent with deficits in long-term potentiation in the CA3-CA1 pathway. Social affiliation, a behavioral analog of social deficits in autism, was similarly compromised. These results demonstrate that MDGA2 confines the properties of excitatory synapses to CA1 neurons in mature hippocampal circuits, thereby optimizing this network for plasticity, cognition, and social behaviors.

Trpm2 deficiency in microglia attenuates neuroinflammation during epileptogenesis by upregulating autophagy via the AMPK/mTOR pathway.

Epilepsy is one of the most common neurological disorders. Neuroinflammation involving the activation of microglia and astrocytes constitutes an important and common mechanism in epileptogenesis. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that plays pathological roles in various inflammation-related diseases. Our previous study demonstrated that Trpm2 knockout exhibits therapeutic effects on pilocarpine-induced glial activation and neuroinflammation. However, whether TRPM2 in microglia and astrocytes plays a common pathogenic role in this process and the underlying molecular mechanisms remained undetermined. Here, we demonstrate a previously unknown role for microglial TRPM2 in epileptogenesis. Trpm2 knockout in microglia attenuated kainic acid (KA)-induced glial activation, inflammatory cytokines production and hippocampal paroxysmal discharges, whereas Trpm2 knockout in astrocytes exhibited no significant effects. Furthermore, we discovered that these therapeutic effects were mediated by upregulated autophagy via the adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in microglia. Thus, our findings highlight an important deleterious role of microglial TRPM2 in temporal lobe epilepsy.

Classification and prediction of spinal disease based on the SMOTE-RFE-XGBoost model.

Spinal diseases are killers that cause long-term disturbance to people with complex and diverse symptoms and may cause other conditions. At present, the diagnosis and treatment of the main diseases mainly depend on the professional level and clinical experience of doctors, which is a breakthrough problem in the field of medicine. This article proposes the SMOTE-RFE-XGBoost model, which takes the physical angle of human bone as the research index for feature selection and classification model construction to predict spinal diseases. The research process is as follows: two groups of people with normal and abnormal spine conditions are taken as the research objects of this article, and the synthetic minority oversampling technique (SMOTE) algorithm is used to address category imbalance. Three methods, least absolute shrinkage and selection operator (LASSO), tree-based feature selection, and recursive feature elimination (RFE), are used for feature selection. Logistic regression (LR), support vector machine (SVM), parsimonious Bayes, decision tree (DT), random forest (RF), gradient boosting tree (GBT), extreme gradient boosting (XGBoost), and ridge regression models are used to classify the samples, construct single classification models and combine classification models and rank the feature importance. According to the accuracy and mean square error (MSE) values, the SMOTE-RFE-XGBoost combined model has the best classification, with accuracy, MSE and F1 values of 97.56%, 0.1111 and 0.8696, respectively. The importance of four indicators, lumbar slippage, cervical tilt, pelvic radius and pelvic tilt, was higher.

Preferential pruning of inhibitory synapses by microglia contributes to alteration of the balance between excitatory and inhibitory synapses in the hippocampus in temporal lobe epilepsy.

BACKGROUND: A consensus has formed that neural circuits in the brain underlie the pathogenesis of temporal lobe epilepsy (TLE). In particular, the synaptic excitation/inhibition balance (E/I balance) has been implicated in shifting towards elevated excitation during the development of TLE. METHODS: Sprague Dawley (SD) rats were intraperitoneally subjected to kainic acid (KA) to generate a model of TLE. Next, electroencephalography (EEG) recording was applied to verify the stability and detectability of spontaneous recurrent seizures (SRS) in rats. Moreover, hippocampal slices from rats and patients with mesial temporal lobe epilepsy (mTLE) were assessed using immunofluorescence to determine the alterations of excitatory and inhibitory synapses and microglial phagocytosis. RESULTS: We found that KA induced stable SRSs 14 days after status epilepticus (SE) onset. Furthermore, we discovered a continuous increase in excitatory synapses during epileptogenesis, where the total area of vesicular glutamate transporter 1 (vGluT1) rose considerably in the stratum radiatum (SR) of cornu ammonis 1 (CA1), the stratum lucidum (SL) of CA3, and the polymorphic layer (PML) of the dentate gyrus (DG). In contrast, inhibitory synapses decreased significantly, with the total area of glutamate decarboxylase 65 (GAD65) in the SL and PML diminishing enormously. Moreover, microglia conducted active synaptic phagocytosis after the formation of SRSs, especially in the SL and PML. Finally, microglia preferentially pruned inhibitory synapses during recurrent seizures in both rat and human hippocampal slices, which contributed to the synaptic alteration in hippocampal subregions. CONCLUSIONS: Our findings elaborately characterize the alteration of neural circuits and demonstrate the selectivity of synaptic phagocytosis mediated by microglia in TLE, which could strengthen the comprehension of the pathogenesis of TLE and inspire potential therapeutic targets for epilepsy treatment.

Single-cell transcriptomic characterization reveals the landscape of airway remodeling and inflammation in a cynomolgus monkey model of asthma.

Monkey disease models, which are comparable to humans in terms of genetic, anatomical, and physiological characteristics, are important for understanding disease mechanisms and evaluating the efficiency of biological treatments. Here, we established an A.suum-induced model of asthma in cynomolgus monkeys to profile airway inflammation and remodeling in the lungs by single-cell RNA sequencing (scRNA-seq). The asthma model results in airway hyperresponsiveness and remodeling, demonstrated by pulmonary function test and histological characterization. scRNA-seq reveals that the model elevates the numbers of stromal, epithelial and mesenchymal cells (MCs). Particularly, the model increases the numbers of endothelial cells (ECs), fibroblasts (Fibs) and smooth muscle cells (SMCs) in the lungs, with upregulated gene expression associated with cell functions enriched in cell migration and angiogenesis in ECs and Fibs, and VEGF-driven cell proliferation, apoptotic process and complement activation in SMCs. Interestingly, we discover a novel Fib subtype that mediates type I inflammation in the asthmatic lungs. Moreover, MCs in the asthmatic lungs are found to regulate airway remodeling and immunological responses, with elevated gene expression enriched in cell migration, proliferation, angiogenesis and innate immunological responses. Not only the numbers of epithelial cells in the asthmatic lungs change at the time of lung tissue collection, but also their gene expressions are significantly altered, with an enrichment in the biological processes of IL-17 signaling pathway and apoptosis in the majority of subtypes of epithelial cells. Moreover, the ubiquitin process and DNA repair are more prevalent in ciliated epithelial cells. Last, cell-to-cell interaction analysis reveals a complex network among stromal cells, MCs and macrophages that contribute to the development of asthma and airway remodeling. Our findings provide a critical resource for understanding the principle underlying airway remodeling and inflammation in a monkey model of asthma, as well as valuable hints for the future treatment of asthma, especially the airway remodeling-characterized refractory asthma.

Captopril alleviates epilepsy and cognitive impairment by attenuation of C3-mediated inflammation and synaptic phagocytosis.

Evidence from experimental and clinical studies implicates immuno-inflammatory responses as playing an important role in epilepsy-induced brain injury. Captopril, an angiotensin-converting enzyme inhibitor (ACEi), has previously been shown to suppress immuno-inflammatory responses in a variety of neurological diseases. However, the therapeutic potential of captopril on epilepsy remains unclear. In the present study, Sprague Dawley (SD) rats were intraperitoneally subjected to kainic acid (KA) to establish a status epilepticus. Captopril (50 mg/kg, i.p.) was administered daily following the KA administration from day 3 to 49. We found that captopril efficiently suppressed the KA-induced epilepsy, as measured by electroencephalography. Moreover, captopril ameliorated the epilepsy-induced cognitive deficits, with improved performance in the Morris water maze, Y-maze and novel objective test. RNA sequencing (RNA-seq) analysis indicated that captopril reversed a wide range of epilepsy-related biological processes, particularly the glial activation, complement system-mediated phagocytosis and the production of inflammatory factors. Interestingly, captopril suppressed the epilepsy-induced activation and abnormal contact between astrocytes and microglia. Immunohistochemical experiments demonstrated that captopril attenuated microglia-dependent synaptic remodeling presumably through C3-C3ar-mediated phagocytosis in the hippocampus. Finally, the above effects of captopril were partially blocked by an intranasal application of recombinant C3a (1.3 µg/kg/day). Our findings demonstrated that captopril reduced the occurrence of epilepsy and cognitive impairment by attenuation of inflammation and C3-mediated synaptic phagocytosis. This approach can easily be adapted to long-term efficacy and safety in clinical practice.

Miconazole exerts disease-modifying effects during epilepsy by suppressing neuroinflammation via NF-κB pathway and iNOS production.

Neuroinflammation contributes to the generation of epilepsy and has been proposed as an effective therapeutic target. Recent studies have uncovered the potential effects of the anti-fungal drug miconazole for treating various brain diseases by suppressing neuroinflammation but have not yet been studied in epilepsy. Here, we investigated the effects of different doses of miconazole (5, 20, 80 mg/kg) on seizure threshold, inflammatory cytokines release, and glial cells activation in the pilocarpine (PILO) pentylenetetrazole (PTZ), and intrahippocampal kainic acid (IHKA) models. We demonstrated that 5 and 20 mg/kg miconazole increased seizure threshold, but only 20 mg/kg miconazole reduced inflammatory cytokines release, glial cells activation, and morphological alteration during the early post-induction period (24 h, 3 days). We further investigated the effects of 20 mg/kg miconazole on epilepsy (4 weeks after KA injection). We found that miconazole significantly attenuated cytokines production, glial cells activation, microglial morphological changes, frequency and duration of recurrent hippocampal paroxysmal discharges (HPDs), and neuronal and synaptic damage in the hippocampus during epilepsy. In addition, miconazole suppressed the KA-induced activation of the NF-κB pathway and iNOS production. Our results indicated miconazole to be an effective drug for disease-modifying effects during epilepsy, which may act by attenuating neuroinflammation through the suppression of NF-κB activation and iNOS production. At appropriate doses, miconazole may be a safe and effective approved drug that can easily be repositioned for clinical practice.

Polymer-Modified Liposomes for Drug Delivery: From Fundamentals to Applications.

Liposomes are highly advantageous platforms for drug delivery. To improve the colloidal stability and avoid rapid uptake by the mononuclear phagocytic system of conventional liposomes while controlling the release of encapsulated agents, modification of liposomes with well-designed polymers to modulate the physiological, particularly the interfacial properties of the drug carriers, has been intensively investigated. Briefly, polymers are incorporated into liposomes mainly using "grafting" or "coating", defined according to the configuration of polymers at the surface. Polymer-modified liposomes preserve the advantages of liposomes as drug-delivery carriers and possess specific functionality from the polymers, such as long circulation, precise targeting, and stimulus-responsiveness, thereby resulting in improved pharmacokinetics, biodistribution, toxicity, and therapeutic efficacy. In this review, we summarize the progress in polymer-modified liposomes for drug delivery, focusing on the change in physiological properties of liposomes and factors influencing the overall therapeutic efficacy.

[Protective Effects of Akkermansia muciniphila and Amuc_1100 Protein on Rats on High-Fat Diet Combined with Streptozotocin Injection].

OBJECTIVE: To explore the protective effects of live or pasteurized Akkermansia muciniphila and Amuc_1100 protein on a rat model of diabetes mellitus induced by high-fat diet (HFD) combined with streptozotocin (STZ). METHODS: A total of 96 Sprague-Dawley (SD) rats were randomly assigned to 8 groups, including 6 experimental groups and 2 control groups, with 12 rats in each group. HFD combined with STZ injection was given to the rats to create a simulated model of the progression of diabetes mellitus type 2. In addition, the rats were treated with different doses of live or pasteurized Akkermansia muciniphila or Amuc_1100 protein by way of gavage for 8 weeks simultaneously. Plasma samples were collected to determine the level of parameters related to lipid and glucose metabolism, and inflammation mediators. Colon tissue specimens were collected for HE staining. Stool samples of the rats were collected for 16S rRNA gene sequencing. RESULTS: Compared with the HFD control group, rats in the group treated with Akkermansia muciniphila exhibited significantly lower body mass gain ( P<0.01) and lower plasma TNF-α level ( P<0.05). Administration of Akkermansia muciniphila or Amuc_1100 protein increased the number of goblet cells and mucin secretion. The ß diversity analysis of the samples showed no overall difference in the intervention groups. CONCLUSION: Oral administration of Akkermansia muciniphila can effectively ameliorate HFD-induced metabolic disorders, including body mass gain and systemic inflammation. Akkermansia muciniphila and Amuc_1100, to a certain degree, improved the gut barrier function. After eight weeks of intervention, there was no significant impact on the structure of the gut microbiota.

TRPM2 contributes to neuroinflammation and cognitive deficits in a cuprizone-induced multiple sclerosis model via NLRP3 inflammasome.

Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that is characterized by demyelination, axonal injury and neurological deterioration. Few medications are available for progressive MS, which is associated with neuroinflammation confined to the CNS compartment. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that plays pathological roles in a wide range of neuroinflammatory diseases; however, the underlying molecular mechanisms of TRPM2 remain elusive. Here, we established a cuprizone model that presents hallmark MS pathologies to investigate the role of TRPM2 in progressive MS. We demonstrated that genetic deletion of TRPM2 yields protection from the cuprizone-induced demyelination, synapse loss, microglial activation, NLRP3 inflammasome activation and proinflammatory cytokines production and ultimately leads to an improvement in cognitive decline. Furthermore, we showed that the pharmacological inhibition of NLRP3 ameliorated the demyelination, neuroinflammation and cognitive impairment in the model with no additive effects on the TRPM2 KO mice. Taken together, these results indicated that TRPM2 plays important roles in regulating neuroinflammation in progressive MS via NLRP3 inflammasome, and the results shed light on TRPM2's potential role as a therapeutic target for MS.

A paper-based ELISA for rapid sensitive determination of anaphylaxis-related MRGPRX2 in human peripheral blood.

Mas-related G-protein-coupled receptor X2 (MRGPRX2) has recently been reported to be associated with anaphylaxis. Detection of MRGPRX2 levels in human peripheral blood might serve as a powerful tool for predicting the predisposition of patients to anaphylactic reactions. For rapid measurement of MRGPRX2, we established a paper-based double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) using mouse monoclonal antibody and horseradish peroxidase (HRP)-labelled rabbit polyclonal antibody as capture antibody and detection antibody, respectively. We avoided chemical functionalization of the cellulose paper by introducing bovine serum albumin (BSA) to provide COOH and NH2 groups for covalent immobilization of the capture antibody. Through amide condensation, a two-layer immobilization strategy was applied with BSA-BSA and BSA-capture antibody networks as the first and second layers, respectively. This strategy improved the quantity, activity and stability of the immobilized antibody. We then established a paper-based ELISA to detect MRGPRX2 in human peripheral blood. Our method is less laborious, easier to implement, and more cost-effective than conventional ELISA, while offering similar sensitivity, specificity, and accuracy. Therefore, it could serve as an innovative clinical point-of-care diagnostic tool, especially in areas that lack advanced clinical equipment.

Gas adsorption and separation in metal-organic frameworks by PC-SAFT based density functional theory.

In this work, we examine the theoretical performance of perturbed-chain statistical associating fluid theory based density functional theory (DFT) in predicting gas adsorption and separation in metal-organic frameworks by using simulation and experimental data as the benchmark. Adsorption isotherms of methane and ethane in pure gas and mixtures and selectivities for ethane/methane mixtures are calculated. The predicted isotherms by DFT are in excellent agreement with simulation and experimental data for pure methane and ethane, whereas for the mixture, DFT is in semi-quantitative accordance with simulation results. For fast and high-throughput screening of material purpose, three algorithms including Picard iteration with line search, Anderson mixing, and Picard-Anderson-hybrid algorithm are proposed to calculate the three dimensional density distribution of confined gases. The advantages and limitations of the three algorithms under various conditions are discussed.

Intrauterine hyperglycemia induces liver inflammation in mouse male offspring.

Gestational diabetes mellitus (GDM) is a common complication of pregnancy characterized by intrauterine hyperglycemia, which is often associated with a high risk of obesity and diabetes in the offspring. In this study, we established a GDM mouse model by intraperitoneal injection of streptozotocin to investigate the immuno-inflammatory responses in the liver of adult offspring. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were employed to evaluate the glucose tolerance status. Hematoxylin-eosin staining was used to examine the histological changes in the liver. Quantitative real-timePCR (qRT-PCR) was applied to examine the mRNA expression of immune factors. Western blot and immunofluorescence analyses were used to examine the expression of target protein. Additionally, cell experiments were performed to validate the in vivo results. Compared to the control group, the area of fat vacuoles and the number of lymphocyte cells were significantly higher in the 20 weeks-old offspring of GDM mice. The elevated mRNA level of the pro-inflammatory cytokines IL-1ß, IL-6, IL-33 and immune receptors CD3 and CD36 were found in the liver of F1-GDM. The protein level of IL-6r and the phosphorylation of JAK2 and STAT3 were significantly up-regulated. Moreover, the mRNA level of IL-6, IL-1ß and IL-33 and the phosphorylation of JAK2 and STAT3 were also up-regulated in the hepatocyte treated with high concentration of glucose. Our results suggest that intrauterine hyperglycemia is associated with increased inflammation in the liver of adult male offspring.

[Prokaryotic expression of Amuc_1100 protein and its effects on high-fat diet rats combined streptozotocin injection].

OBJECTIVE: Establish the prokaryotic expression system of Amuc_1100 protein from Akkermansia muciniphila, and analyze the effects of this protein on the body weight, blood glucose, intestinal barrier function and Akkermansia muciniphila abundance in rats fed with high-fat diet combined streptozotocin(STZ)injection. METHODS: PCR product of Amuc_1100 Gene(Gene ID: 34174504) was linked to the double enzyme-digested pET-26 b plasmid vector. The recombinant expression plasmid pET-26 b-Amuc_1100 then transformed into E. Coli BL21. The verified clones through sequence analysis were induced by the addition of IPTG. High-fat diet rats were interfered with the purified protein at high and low doses. The changes of body weight, blood glucose, intestinal barrier function and Akkermansia muciniphila abundance were analyzed. RESULTS: The recombinant expression plasmid pET-26 b-Amuc_1100 was successfully constructed. The sequencing result showed 100% similarity to the Amuc_1100 gene in GenBank. The molecular weight of the protein obtained was 42 kDa. The intervention of Amuc_1100 protein can reduce the weight of rats fed with high-fat diet combined STZ injection to some extent, improve barrier function and increase the abundance of Akkermansia muciniphila in intestine. CONCLUSION: The prokaryotic expression system of Amuc_1100 protein was successfully constructed, which has a certain regulatory effect on rats fed with high-fat diet combined STZ injection.

RNA sequencing analysis of cortex and hippocampus in a kainic acid rat model of temporal lobe epilepsy to identify mechanisms and therapeutic targets related to inflammation, immunity and cognition.

Temporal lobe epilepsy (TLE) is the most common type of refractory epilepsy, in which inflammation is suggested to cause abnormal neuronal connections and neural networks. However, the expression of inflammatory genes in epilepsy remains incomplete, particularly in the context of the cortex, which is a hub of epileptic transmission but also is essential for mediating sensory, motor and cognitive function. Here, a rat model of epilepsy was established by kainic acid (KA) administration Gene transcriptome was explored in 4 signature phases in the hippocampus and cortex: acute damage (3 h), onset of epileptogenesis (3 d), spontaneous epilepsy (2 w) and cognitive impairment (9 w). Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis was applied to unravel the significantly altered pathways. We found, in both the hippocampus and cortex, the inflammatory gene was up-regulated in the acute phase, followed by a gradual decline; the phagocytosis and glial activation were remarkably increased since day 3; persistently down-regulated synaptic transmission and neuronal development started from the 3 h phase and lasted through the 9 w phase. While, the changed gene expression in the cortex fall into the same categories but were relatively lagging behind that in the hippocampus, also showing less number and distinct genes. Collectively, this study demonstrated the changes of gene transcriptome in the cortex and hippocampus in the signature phases after the KA administration, illustrating the association between epileptogenesis, inflammation genes and cognitive dysfunction, and may benefit identifying novel therapeutic targets for treating TLE and its comorbidities.

[Effects of Akkermansia muciniphila on the Proliferation, Apoptosis and Insulin Secretion of Rat Islet Cell Tumor Cells].

OBJECTIVE: To investigate the effects of Akkermansia muciniphila ( A. muciniphila) on the proliferation, apoptosis and insulin secretion of rat pancreatic islet cell tumor cells (INS-1). METHODS: INS-1 cells were divided into three groups, normal, repair, and protect groups, and subsequently every group was subjected with A. muciniphila metabolites, live A. muciniphilaorpasteurized A. muciniphila for 48 h. A group that did not treat with anything was set as blank control. After intervention, the cell viability was determined by MTT method, the insulin secretion level stimulated by glucose was determined by ELISA, the expressions of the genes involved in insulin secretion and apoptosis were tested by qRT-PCR, and the expression of apoptosis related protein Bax was evaluated by Western blot. RESULTS: There was no significant change in INS-1 cell morphology after co-incubation with 3 types of A. Muciniphila interventions for 48 h. The proliferative activity of INS-1 cells was decreased in the repair group that treated with live A. muciniphila than that of control ( P<0.005). A. muciniphila intervention had no effect on insulin secretion in INS-1 cells in normal, repair or protection group ( P>0.05). A. muciniphila secretions promoted the expression of glucose transporter 2 ( Glut2) in 3 groups and the expression of glucokinase ( GCK) in repair group ( P<0.05). The expression of Baxof the INS-1 cell in the normal group was decreased after intervented with 3 kinds of A. muciniphila intervention materials ( P<0.001).The expression of Bax gene of the INS-1 cell in the repair group that treated with dead A. muciniphilawas decreased ( P<0.05). The expression of Bax protein of INS-1 cells that treated with A. muciniphila interventions was decreased. CONCLUSION: A. muciniphila can promote the expression of insulin secretion-related genes in INS-1 cells, inhibit the expression of apoptotic genes and apoptosis protein Bax.This research provides a new direction for applying A. muciniphila in improving type 2 diabetes.

A negative regulator of synaptic development: MDGA and its links to neurodevelopmental disorders.

BACKGROUND: Formation of protein complexes across synapses is a critical process in neurodevelopment, having direct implications on brain function and animal behavior. Here, we present the understanding, importance, and potential impact of a newly found regulator of such a key interaction. DATA SOURCES: A systematic search of the literature was conducted on PubMed (Medline), Embase, and Central-Cochrane Database. RESULTS: Membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins (MDGAs) were recently discovered to regulate synaptic development and transmission via suppression of neurexins-neuroligins trans-synaptic complex formation. MDGAs also regulate axonal migration and outgrowth. In the context of their physiological role, we begin to consider the potential links to the etiology of certain neurodevelopmental disorders. We present the gene expression and protein structure of MDGAs and discuss recent progress in our understanding of the neurobiological role of MDGAs to explore its potential as a therapeutic target. CONCLUSION: MDGAs play a key role in neuron migration, axon guidance and synapse development, as well as in regulating brain excitation and inhibition balance.

Intrauterine hyperglycemia exposure results in intergenerational inheritance via DNA methylation reprogramming on F1 PGCs.

BACKGROUND: The existing reports about intergenerational or transgenerational effects of intrauterine hyperglycemia have included both intrauterine and postnatal metabolic exposure factors, while the impact of intrauterine hyperglycemia per se has not been assessed alone. A number of studies suggest DNA methylation reprogramming of gametes plays a crucial role in the metabolic inheritance, but it is unclear when and how DNA methylation patterns are altered when exposed to intrauterine hyperglycemia. In this study, we selected nondiabetic F1- and F2-gestational diabetes mellitus (GDM) male mice as founders to examine metabolic changes in the next generation and performed methylome sequencing of day 13.5 primordial germ cells (PGCs) from F1-GDM to explore the underlying epigenetic mechanism. RESULTS: We found that intrauterine hyperglycemia exposure resulted in obesity, insulin resistance, and/or glucose intolerance in F2 male mice, but no metabolic changes in F3 male mice at 8 weeks. Using reduced representation bisulfite sequencing, we found DNA methylome of day 13.5 PGCs from F1-GDM fetuses revealed differently methylated genes enriched in obesity and diabetes. Methylation validation of the insulin resistance and fat accumulation gene Fyn showed a consistent hypomethylation status in F1 PGCs, F1 fetal testes, sperm from F1/C-GDM mice, and somatic cells from F2-GDM male mice. In contrast, no methylation alteration was observed in F2-GDM male germ cells and F3-GDM somatic cells. CONCLUSION: We provide evidence that intrauterine hyperglycemia exposure per se contributes to intergenerational metabolic changes in the F2 but not F3 generation. And the aberrant DNA methylation reprogramming occurs as early as day 13.5 in PGCs of the F1 generation. Our findings suggest that intrauterine exposure alone is sufficient to cause the epigenetic inheritance in F2 offspring, and the epigenetic memory carried by DNA methylation pattern could be erased by the second wave of methylation reprogramming in F2 PGCs during fetal development.