The NHE3 Inhibitor Tenapanor Prevents Intestinal Obstructions in CFTR-Deleted Mice.

Mutations in the CFTR chloride channel result in intestinal obstructive episodes in cystic fibrosis (CF) patients and in CF animal models. In this study, we explored the possibility of reducing the frequency of obstructive episodes in cftr-/- mice through the oral application of a gut-selective NHE3 inhibitor tenapanor and searched for the underlying mechanisms involved. Sex- and age-matched cftr+/+ and cftr-/- mice were orally gavaged twice daily with 30 mg kg-1 tenapanor or vehicle for a period of 21 days. Body weight and stool water content was assessed daily and gastrointestinal transit time (GTT) once weekly. The mice were sacrificed when an intestinal obstruction was suspected or after 21 days, and stool and tissues were collected for further analysis. Twenty-one day tenapanor application resulted in a significant increase in stool water content and stool alkalinity and a significant decrease in GTT in cftr+/+ and cftr-/- mice. Tenapanor significantly reduced obstructive episodes to 8% compared to 46% in vehicle-treated cftr-/- mice and prevented mucosal inflammation. A decrease in cryptal hyperproliferation, mucus accumulation, and mucosal mast cell number was also observed in tenapanor- compared to vehicle-treated, unobstructed cftr-/- mice. Overall, oral tenapanor application prevented obstructive episodes in CFTR-deficient mice and was safe in cftr+/+ and cftr-/- mice. These results suggest that tenapanor may be a safe and affordable adjunctive therapy in cystic fibrosis patients to alleviate constipation and prevent recurrent DIOS.

Depicting the composition of gut microbiota in children with tic disorders: an exploratory study.

BACKGROUND: Symptom improvement in children with tic disorder (TD) following fecal microbiota transplantation led us to investigate the gut microbiota in TD. This exploratory study aims to depict the gut microbial profile in patients with TD and explore the impact of dopamine receptor antagonist (DRA) drugs on the composition and metabolic function of the gut microbiota. METHODS: The gut microbiota were profiled in fecal samples of 49 children with TD and 50 matched healthy controls (HC) using shotgun metagenomic sequencing. A random forest (RF) model was constructed using the gut bacterial species to distinguish TD from HC. Associations between clinical metadata and microbial abundance or function were analyzed using MaAsLin2 and Spearman correlation. RESULTS: The gut microbiota in children with TD was featured by higher abundances of Bacteroides plebeius and Ruminococcus lactaris (a potential pro-inflammatory taxon) and lower abundances of Prevotella stercorea and Streptococcus lutetiensis compared to HC. The constructed RF model accurately distinguished TD from HC based on the gut microbiota profile, resulting in an AUC of 0.884. Significant correlations were observed between tic symptom severity and the abundances of multiple bacterial species and gut microbiota metabolic functions. Multivariate analysis identified an upregulation of 4-aminobutanoate (GABA) degradation in the gut microbiota associated with TD status. The gut microbiota of DRA-treated TD children showed a distinct gut microbiota compared to the treatment-naïve group, represented by an increase in some potential enteric pathogens such as Escherichia coli, a decline in several species including Akkermansia muciniphila, and alterations in various metabolic functions. CONCLUSIONS: Bacterial species promoting inflammatory responses and those modulating neurotransmitters such as GABA may be involved in the pathogenesis of TD. The use of DRA drugs is likely to induce overgrowth of some enteric pathogens and alter the gut microbiota metabolism.

Overexpression of zinc-α2-glycoprotein suppressed seizures and seizure-related neuroflammation in pentylenetetrazol-kindled rats.

BACKGROUND: Zinc-α2-glycoprotein (ZAG) is a 42-kDa protein reported as an anti-inflammatory adipocytokine. Evidences from clinical and experimental studies revealed that brain inflammation plays important roles in epileptogenesis and seizure. Interestingly, closely relationship between ZAG and many important inflammatory mediators has been proven. Our previous study identified ZAG in neurons and found that ZAG is decreased in epilepsy and interacts with TGFß and ERK. This study aimed to investigate the role of ZAG in seizure and explore its effect on seizure-related neuroinflammation. METHODS: We overexpressed AZGP1 in the hippocampus of rats via adeno-associated virus vector injection and observed their seizure behavior and EEG after pentylenetetrazol (PTZ) kindling. The level of typical inflammation mediators including TNFα, IL-6, TGFß, ERK, and ERK phosphorylation were determined. RESULTS: The overexpression of AZGP1 reduced the seizure severity, prolonged the latency of kindling, and alleviated epileptiform discharges in EEG changes induced by PTZ. Overexpression of AZGP1 also suppressed the expression of TNFα, IL-6, TGFß, and ERK phosphorylaton in PTZ-kindled rats. CONCLUSIONS: ZAG may inhibit TGFß-mediated ERK phosphorylation and inhibit neuroinflammation mediated by TNFα and IL-6, suggesting ZAG may suppress seizure via inhibiting neuroinflammation. ZAG may be a potential and novel therapeutic target for epilepsy.

Targeting estrogen receptor ß in microglia and T cells to treat experimental autoimmune encephalomyelitis.

A therapeutic goal in the treatment of certain CNS diseases, including multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson disease, is to down-regulate inflammatory pathways. Inflammatory molecules produced by microglia are responsible for removal of damaged neurons, but can cause collateral damage to normal neurons located close to defective neurons. Although estrogen can inactivate microglia and inhibit the recruitment of T cells and macrophages into the CNS, there is controversy regarding which of the two estrogen receptors (ERs), ERα or ERß, mediates the beneficial effects in microglia. In this study, we found that ERß, but not ERα, is expressed in microglia. Using the experimental autoimmune encephalomyelitis (EAE) model in SJL/J mice, we evaluated the benefit of an ERß agonist as a modulator of neuroinflammation. Treatment of EAE mice with LY3201, a selective ERß agonist provided by Eli Lilly, resulted in marked reduction of activated microglia in the spinal cord. LY3201 down-regulated the nuclear transcription factor NF-κB, as well as the NF-κB-induced gene inducible nitric oxide synthase in microglia and CD3(+) T cells. In addition, LY3201 inhibited T-cell reactivity through regulation of indoleamine-2,3-dioxygenase. In the EAE model, treatment with LY3201 decreased mortality in the first 2 wk after disease onset, and also reduced the severity of symptoms in mice surviving for 4 wk. Our data show that ERß-selective agonists, by modulating the immune system in both microglia and T cells, offer promise as a useful class of drugs for treating degenerative diseases of the CNS.

Liver X receptor ß protects dopaminergic neurons in a mouse model of Parkinson disease.

Parkinson disease (PD) is a progressive neurodegenerative disease whose progression may be slowed, but at present there is no pharmacological intervention that would stop or reverse the disease. Liver X receptor ß (LXRß) is a member of the nuclear receptor super gene family expressed in the central nervous system, where it is important for cortical layering during development and survival of dopaminergic neurons throughout life. In the present study we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of LXRß as a target for prevention or treatment of PD. The dopaminergic neurons of the substantia nigra of LXRß(-/-) mice were much more severely affected by MPTP than were those of their WT littermates. In addition, the number of activated microglia and GFAP-positive astrocytes was higher in the substantia nigra of LXRß(-/-) mice than in WT littermates. Administration of the LXR agonist GW3965 to MPTP-treated WT mice protected against loss of dopaminergic neurons and of dopaminergic fibers projecting to the striatum, and resulted in fewer activated microglia and astroglia. Surprisingly, LXRß was not expressed in the neurons of the substantia nigra but in the microglia and astroglia. We conclude that LXR agonists may have beneficial effects in treatment of PD by modulating the cytotoxic functions of microglia.

Anxiety in liver X receptor ß knockout female mice with loss of glutamic acid decarboxylase in ventromedial prefrontal cortex.

Anxiety disorders are the most prevalent mental disorders in adolescents in the United States. Female adolescents are more likely than males to be affected with anxiety disorders, but less likely to have behavioral and substance abuse disorders. The prefrontal cortex (PFC), amygdala, and dorsal raphe are known to be involved in anxiety disorders. Inhibitory input from the PFC to the amygdala controls fear and anxiety typically originating in the amygdala, and disruption of the inhibitory input from the PFC leads to anxiety, fear, and personality changes. Recent studies have implicated liver X receptor ß (LXRß) in key neurodevelopmental processes and neurodegenerative diseases. In the present study, we used elevated plus-maze, startle and prepulse inhibition, open field, and novel object recognition tests to evaluate behavior in female LXRß KO (LXRß(-/-)) mice. We found that the female LXRß(-/-) mice were anxious with impaired behavioral responses but normal locomotion and memory. Immunohistochemistry analysis revealed decreased expression of the enzyme responsible for GABA synthesis, glutamic acid decarboxylase (65+67), in the ventromedial PFC. Expression of tryptophan hydroxylase 2 in the dorsal raphe was normal. We conclude that the anxiogenic phenotype in female LXRß(-/-) mice is caused by reduced GABAergic input from the ventromedial PFC to the amygdala.

Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor ß ligand.

An estrogen receptor (ER) ß ligand (LY3201) with a preference for ERß over ERα was administered in s.c. pellets releasing 0.04 mg/d. The brains of these mice were examined 3 d after treatment had begun. Although estradiol-17ß is known to increase spine density and glutaminergic signaling, as measured by Golgi staining, a clear reduction in spines was evident on the dendritic branches in LY3201-treated mice but no morphological alteration and no difference in the number of dendritic spines on dendritic stems were observed. In the LY3201-treatment group, there was higher expression of glutamic acid decarboxylase (GAD) in layer V of cortex and in the CA1 of hippocampus, more GAD(+) terminals surrounding the pyramidal neurons and less glutamate receptor (NMDAR) on the neurons in layer V. There were no alterations in expression of Iba1 or in Olig2 or CNPase. However, GFAP(+) astrocytes were increased in the LY3201-treatment group. There were also more projections characteristic of activated astrocytes and increased expression of glutamine synthetase (GS). No expression of ERß was detectable in the nuclei of astrocytes. Clearly, LY3201 caused a shift in the balance between excitatory and inhibitory neurotransmission in favor of inhibition. This shift was due in part to increased synthesis of GABA and increased removal of glutamate from the synaptic cleft by astrocytes. The data reveal that treatment with a selective ERß agonist results in changes opposite to those reported in estradiol-17ß-treated mice and suggests that ERα and ERß play opposing roles in the brain.

Cloning and Expression Analysis of Key Enzyme Gene CoGPPS Involved in Iridoid Glycoside Synthesis in Cornus officinalis.

Cornus iridoid glycosides (CIGs), including loganin and morroniside, are the main active components of Cornus officinalis. As one of the key enzymes in the biosynthesis of CIGs, geranyl pyrophosphate synthase (GPPS) catalyzes the formation of geranyl pyrophosphate, which is the direct precursor of CIGs. In this study, the C. officinalis geranyl pyrophosphate synthase (CoGPPS) sequence was cloned from C. officinalis and analyzed. The cDNA sequence of the CoGPPS gene was 915 bp (GenBank No. OR725699). Phylogenetic analysis showed that CoGPPS was closely related to the GPPS sequence of Actinidia chinensis and Camellia sinensis, but relatively distantly related to Paeonia lactiflora and Tripterygium wilfordii. Results from the quantitative real-time PCR showed the spatiotemporal expression pattern of CoGPPS; that is, CoGPPS was specifically expressed in the fruits. Subcellular localization assay proved that CoGPPS was specifically found in chloroplasts. Loganin and morroniside contents in the tissues were detected by high-performance liquid chromatography, and both compounds were found to be at higher levels in the fruits than in leaves. Thus, this study laid the foundation for further studies on the synthetic pathway of CIGs.

Shewanella oneidensis MR-1 dissimilatory reduction of ferrihydrite to highly enhance mineral transformation and reactive oxygen species production in redox-fluctuating environments.

Diverse paths generated by reactive oxygen species (ROS) can mediate contaminant transformation and fate in the soil/aquatic environments. However, the pathways for ROS production upon the oxygenation of redox-active ferrous iron minerals are underappreciated. Ferrihydrite (Fh) can be reduced to produce Fe(II) by Shewanella oneidensis MR-1, a representative strain of dissimilatory iron-reducing bacteria (DIRB). The microbial reaction formed a spent Fh product named mr-Fh that contained Fe(II). Material properties of mr-Fh were characterized with X-ray diffraction (XRD), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS). Magnetite could be observed in all mr-Fh samples produced over 1-day incubation, which might greatly favor the Fe(II) oxygenation process to produce hydroxyl radical (•OH). The maximum amount of dissolved Fe(II) can reach 1.1 mM derived from added 1 g/L Fh together with glucose as a carbon source, much higher than the 0.5 mM generated in the case of the Luria-Bertani carbon source. This may confirm that MR-1 can effectively reduce Fh and produce biogenetic Fe(II). Furthermore, the oxygenation of Fe(II) on the mr-Fh surface can produce abundant ROS, wherein the maximum cumulative •OH content is raised to about 120 µM within 48 h at pH 5, but it is decreased to about 100 µM at pH 7 for the case of MR-1/Fh system after a 7-day incubation. Thus, MR-1-mediated Fh reduction is a critical link to enhance ROS production, and the •OH species is among them the predominant form. XPS analysis proves that a conservable amount of Fe(II) species is subject to adsorption onto mr-Fh. Here, MR-1-mediated ROS production is highly dependent on the redox activity of the form Fe(II), which should be the counterpart presented as the adsorbed Fe(II) on surfaces. Hence, our study provides new insights into understanding the mechanisms that can significantly govern ROS generation in the redox-oscillation environment.

Liver X receptor beta and thyroid hormone receptor alpha in brain cortical layering.

In the past year, two members of the nuclear receptor family, liver X receptor beta (LXRbeta) and thyroid hormone receptor alpha (TRalpha), have been found to be essential for correct migration of neurons in the developing cortex in mouse embryos. TRalpha and LXRbeta bind to identical response elements on DNA and sometimes regulate the same genes. The reason for the migration defect in the LXRbeta(-/-) mouse and the possibility that TRalpha may be involved are the subjects of the present study. At E15.5, expression of reelin and VLDLR was similar but expression of apolipoprotein E receptor 2 (ApoER2) (the reelin receptor) was much lower in LXRbeta(-/-) than in WT mice. Knockout of ApoER2 is known to lead to abnormal cortical lamination. Surprisingly, by postnatal day 14 (P14), no morphological abnormalities were detectable in the cortex of LXRbeta(-/-) mice and ApoER2 expression was much stronger than in WT controls. Thus, a postnatal mechanism leads to increase in ApoER2 expression by P14. TRalpha also regulates ApoER2. In both WT and LXRbeta(-/-) mice, expression of TRalpha was high at postnatal day 2. By P14 it was reduced to low levels in WT mice but was still abundantly expressed in the cortex of LXRbeta(-/-) mice. Based on the present data we hypothesize that reduction in the level of ApoER2 is the reason for the retarded migration of later-born neurons in LXRbeta(-/-) mice but that as thyroid hormone (TH) increases after birth the neurons do find their correct place in the cortex.

Gene Expression and Interaction Analysis of FsWRKY4 and FsMAPK3 in Forsythia suspensa.

Forsythia suspensa is a deciduous shrub that belongs to the family Myrtaceae, and its dried fruits are used as medicine. F. suspensa contains several secondary metabolites, which exert pharmacological effects. One of the main active components is forsythin, which exhibits free radical scavenging, antioxidant, anti-inflammatory, and anti-cancer effects. Mitogen-activated protein kinase (MAPKs) can increase the activity of WRKY family transcription factors in a phosphorylated manner, thereby increasing the content of secondary metabolites. However, the mechanism of interaction between MAPKs and WRKYs in F. suspensa remains unclear. In this study, we cloned the genes of FsWRKY4 and FsMAPK3, and performed a bioinformatics analysis. The expression patterns of FsWRKY4 and FsMAPK3 were analyzed in the different developmental stages of leaf and fruit from F. suspensa using real-time fluorescence quantitative PCR (qRT-PCR). Subcellular localization analysis of FsWRKY4 and FsMAPK3 proteins was performed using a laser scanning confocal microscope. The existence of interactions between FsWRKY4 and FsMPAK3 in vitro was verified by yeast two-hybridization. Results showed that the cDNA of FsWRKY4 (GenBank number: OR566682) and FsMAPK3 (GenBank number: OR566683) were 1587 and 522 bp, respectively. The expression of FsWRKY4 was higher in the leaves than in fruits, and the expression of FsMAPK3 was higher in fruits but lower in leaves. The subcellular localization results indicated that FsWRKY4 was localized in the nucleus and FsMAPK3 in the cytoplasm and nucleus. The prey vector pGADT7-FsWRKY4 and bait vector pGBKT7-FsMAPK3 were constructed and co-transferred into Y2H Glod yeast receptor cells. The results indicated that FsWRKY4 and FsMAPK3 proteins interact with each other in vitro. The preliminary study may provide a basis for more precise elucidation of the synthesis of secondary metabolites in F. suspensa.

Direct Atomic-Scale Insight into the Precipitation Formation at the Lanthanum Hydroxide Nanoparticle/Solution Interface.

Understanding precipitation formation at lanthanum hydroxide (La(OH)3) nanoparticle-solution interfaces plays a crucial role in catalysis, adsorption, and electrochemical energy storage applications. Liquid-phase transmission electron microscopy enables powerful visualization with high resolution. However, direct atomic-scale imaging of the interfacial metal (hydro)oxide nanostructure in solutions has been a major challenge due to their beam-driven dissolution. Combining focused ion beam and aberration-corrected high-angle annular dark-field scanning transmission electron microscopy, we present an atomic-scale study of precipitation formation at La(OH)3 nanoparticle interfaces after reaction with phosphate. The structure transformation is observed to occur at high- and low-crystalline La(OH)3 nanoparticle surfaces. Low-crystalline La(OH)3 mostly transformed and high-crystalline ones partly converted to LaPO4 precipitations on the outer surface. The long-term structure evolution shows the low transformation of high-crystalline La(OH)3 nanoparticles to LaPO4 precipitation. Because precipitation at solid-solution interfaces is common in nature and industry, these results could provide valuable references for their atomic-scale observation.

A review on pathology, mechanism, and therapy for cerebellum and tremor in Parkinson's disease.

Tremor is one of the core symptoms of Parkinson's disease (PD), but its mechanism is poorly understood. The cerebellum is a growing focus in PD-related researches and is reported to play an important role in tremor in PD. The cerebellum may participate in the modulation of tremor amplitude via cerebello-thalamo-cortical circuits. The cerebellar excitatory projections to the ventral intermediate nucleus of the thalamus may be enhanced due to PD-related changes, including dopaminergic/non-dopaminergic system abnormality, white matter damage, and deep nuclei impairment, which may contribute to dysregulation and resistance to levodopa of tremor. This review summarized the pathological, structural, and functional changes of the cerebellum in PD and discussed the role of the cerebellum in PD-related tremor, aiming to provide an overview of the cerebellum-related mechanism of tremor in PD.

Integrative Analysis Reveals Potentially Functional N6-Methylandenosine-Related Long Noncoding RNAs in Colon Adenocarcinoma.

N6-methyladenosine (m6A) is one of the most prevalent RNA modifications in mRNA and non-coding RNA. In this study, we identified 10 upregulated m6A regulators at both mRNA and protein levels, and 2,479 m6A-related lncRNAs. Moreover, the m6A-related long noncoding RNAs (lncRNAs) could clearly stratify the colon adenocarcinoma (COAD) samples into three subtypes. The subtype 2 had nearly 40% of samples with microsatellite instability (MSI), significantly higher than the two other subtypes. In accordance with this finding, the inflammatory response-related pathways were highly activated in this subtype. The subtype-3 had a shorter overall survival and a higher proportion of patients with advanced stage than subtypes 1 and 2 (p-value < 0.05). Pathway analysis suggested that the energy metabolism-related pathways might be aberrantly activated in subtype 3. In addition, we observed that most of the m6A readers and m6A-related lncRNAs were upregulated in subtype 3, suggesting that the m6A readers and the m6A-related lncRNAs might be associated with metabolic reprogramming and unfavorable outcome in COAD. Among the m6A-related lncRNAs in subtype 3, four were predicted as prognostically relevant. Functional inference suggested that CTD-3184A7.4, RP11-458F8.4, and RP11-108L7.15 were positively correlated with the energy metabolism-related pathways, further suggesting that these lncRNAs might be involved in energy metabolism-related pathways. In summary, we conducted a systematic data analysis to identify the key m6A regulators and m6A-related lncRNAs, and evaluated their clinical and functional importance in COAD, which may provide important evidences for further m6A-related researches.

Inhibition of Na+ /H+ exchanger isoform 3 improves gut fluidity and alkalinity in cystic fibrosis transmembrane conductance regulator-deficient and F508del mutant mice.

BACKGROUND AND PURPOSE: Constipation and intestinal obstructive episodes are major health problems in cystic fibrosis (CF) patients. Three FDA-approved drugs against constipation-prone irritable bowel syndrome were tested for their ability to increase luminal fluidity and alkalinity in cystic fibrosis transmembrane conductance regulator (CFTR) null (cftr-/- ) and F508del mutant (F508delmut/mut ) murine intestine. EXPERIMENTAL APPROACH: Guanylate cyclase C agonist linaclotide, PGE1 analogue lubiprostone and intestine-specific NHE3 inhibitor tenapanor were perfused through a ~3 cm jejunal, proximal or mid-distal colonic segment in anaesthetized cftr-/- , F508delmut/mut and WT mice. Net fluid balance was determined gravimetrically and alkaline output by pH-stat back titration. KEY RESULTS: Basal jejunal fluid absorptive rates were significantly higher and basal HCO3- output was significantly lower in cftr-/- and F508delmut/mut compared to WT mice. In cftr-/- and F508delmut/mut mice, all three drugs significantly inhibited the fluid absorptive rate and increased alkaline output in the jejunum and tenapanor and lubiprostone, but not linaclotide, in the colon. After tenapanor pre-incubation, linaclotide elicited a robust fluid secretory response in WT jejunum, while no further change in absorptive rates was observed in cftr-/- and F508delmut/mut jejunum, suggesting that the increase in gut fluidity and alkalinity by linaclotide in CF gut is mediated via NHE3 inhibition. Lubiprostone also inhibited fluid absorption in cftr-/- and F508delmut/mut jejunum via NHE3 inhibition but had a residual NHE3-independent effect. CONCLUSION AND IMPLICATIONS: Linaclotide, lubiprostone and tenapanor reduced fluid absorption and increased alkaline output in the CF gut. Their application may ameliorate constipation and reduce obstructive episodes in CF patients.

Preparation of Nanocomposite Polymer Electrolyte via In Situ Synthesis of SiO2 Nanoparticles in PEO.

Composite polymer electrolytes provide an emerging solution for new battery development by replacing liquid electrolytes, which are commonly complexes of polyethylene oxide (PEO) with ceramic fillers. However, the agglomeration of fillers and weak interaction restrict their conductivities. By contrast with the prevailing methods of blending preformed ceramic fillers within the polymer matrix, here we proposed an in situ synthesis method of SiO2 nanoparticles in the PEO matrix. In this case, robust chemical interactions between SiO2 nanoparticles, lithium salt and PEO chains were induced by the in situ non-hydrolytic sol gel process. The in situ synthesized nanocomposite polymer electrolyte delivered an impressive ionic conductivity of ~1.1 × 10-4 S cm-1 at 30 °C, which is two orders of magnitude higher than that of the preformed synthesized composite polymer electrolyte. In addition, an extended electrochemical window of up to 5 V vs. Li/Li+ was achieved. The Li/nanocomposite polymer electrolyte/Li symmetric cell demonstrated a stable long-term cycling performance of over 700 h at 0.01-0.1 mA cm-2 without short circuiting. The all-solid-state battery consisting of the nanocomposite polymer electrolyte, Li metal and LiFePO4 provides a discharge capacity of 123.5 mAh g-1, a Coulombic efficiency above 99% and a good capacity retention of 70% after 100 cycles.

Slc26a3 deletion alters pH-microclimate, mucin biosynthesis, microbiome composition and increases the TNFα expression in murine colon.

AIM: SLC26A3 (DRA) mediates the absorption of luminal Cl- in exchange for HCO3- in the distal intestine. Its expression is lost in congenital chloride diarrhoea (CLD) and strongly decreased in the presence of intestinal inflammation. To characterize the consequences of a loss of Slc26a3 beyond disturbed electrolyte transport, colonic mucus synthesis, surface accumulation and composition, pH microclimate, microbiome composition and development of inflammation was studied in slc26a3-/- mice. METHODS: The epithelial surface pH microclimate and the surface mucus accumulation in vivo was assessed by two photon microscopy in exteriorized mid colon of anaesthetized slc26a3-/- and wt littermates. Mucus synthesis, composition and inflammatory markers were studied by qPCR and immunohistochemistry and microbiome composition by 16S rRNA sequencing. RESULTS: Colonic pH microclimate was significantly more acidic in slc26a3-/- and to a lesser extent in cftr-/- than in wt mice. Goblet cell thecae per crypt were decreased in slc26a3-/- and increased in cftr-/- colon. Mucus accumulation in vivo was reduced, but much less so than in cftr-/- colon, which is possibly related to the different colonic fluid balance. Slc26a3-/- colonic luminal microbiome displayed strong decrease in diversity. These alterations preceded and maybe causally related to increased mucosal TNFα mRNA expression levels and leucocyte infiltration in the mid-distal colon of slc26a3-/- but not of cftr-/- mice. CONCLUSIONS: These findings may explain the strong increase in the susceptibility of slc26a3-/- mice to DSS damage, and offer insight into the mechanisms leading to an increased incidence of intestinal inflammation in CLD patients.

ERß-selective agonist alleviates inflammation in a multiple sclerosis model via regulation of MHC II in microglia.

Multiple sclerosis (MS) is an autoimmune, demyelinating, and neurodegenerative disease of the central nervous system (CNS) that affects 2-2.5 million people worldwide. Although the etiology of MS is not well known, MS is widely considered to be an autoimmune disease. Currently approved MS drugs reduce relapse rates but fail to reverse or prevent neurodegeneration and disability progression. Increasing evidence indicates that microglia and major histocompatibility complex class II (MHC II) expression in these cells play important roles in the pathophysiology of MS. For a T cell to contribute to CNS pathogenesis, it must be reactivated by antigen-presenting cells within the CNS parenchyma. Susceptibility to MS is associated with MHC II genes, suggesting that presentation of antigens on MHC II plays an important role in CD4+ T-cell reactivation and disease initiation. An ERß-selective agonist was previously reported to suppress reactivation of T cells invading the spinal cord, thereby reducing the severity of symptoms and decreasing mortality in the first 2 weeks after disease onset. However, the mechanism by which the expression of MHC II in microglia is regulated by ERß-selective agonists is still unclear. Therefore, we hypothesize that ERß-selective agonists inhibit MHC II expression in microglia via inhibition of class II trans-activator (CIITA) expression by a mechanism involving inhibition of the translocation of IFNγ regulatory factor (IRF-1) to the nucleus, thereby inhibiting the inflammatory response and symptoms in the MS model.

Resumption of antiplatelet therapy in patients with primary intracranial hemorrhage-benefits and risks: A meta-analysis of cohort studies.

BACKGROUND: Clinical disagreement over antiplatelet (AP) resumption in patients with primary intracranial hemorrhage (ICH) has long existed. This meta-analysis aimed to evaluate the benefits of AP resumption on preventing ischemic or thromboembolic events against its risks of promoting ICH recurrence or hematoma expansion. METHODS: All relevant articles published in Pubmed, EMBASE, the Cochrane Library, and Science Direct from January 1950 to March 2017 were sourced, and the combined relative risk (RR) was calculated. RESULTS: A total of 3648 articles were found, and after screening, 6 cohort studies including 1916 patients were included in this meta-analysis. AP resumption was associated with a decreased risk of ischemic or thromboembolic events (RR, 0.61; 95% confidence interval (CI), 0.48-0.79; P<0.01). There was no significant difference in the risk of ICH recurrence or hematoma expansion between patients with or without AP resumption (RR, 0.84; 95% CI, 0.47-1.51; P=0.56). CONCLUSION: AP resumption in patients with primary ICH reduced the risk of ischemic or thromboembolic events, without significant increase of risk of ICH recurrence or hematoma expansion.

Adherence to Antihypertensive Medications and Stroke Risk: A Dose-Response Meta-Analysis.

BACKGROUND: Inconsistent findings have been obtained for previous studies evaluating the association between antihypertensive medication (AHM) adherence and the risk of stroke. This dose-response meta-analysis was designed to investigate the association between AHM adherence and stroke risk. METHODS AND RESULTS: MEDLINE and Embase databases were systematically searched to identify relevant studies. The quantification of adherence to AHM was calculated as the percentage of the sum of days with AHM actually taken divided by the total number of days in a specific period. Summary relative risks (RR) and 95% CIs were estimated using a random-effects model. Stratified and dose-response analyses were also performed. A total of 18 studies with 1 356 188 participants were included. The summary RR of stroke for the highest compared with the lowest AHM adherence level was 0.73 (95% CI, 0.67-0.79). Stratified by stroke subtype, a higher AHM adherence was associated with lower risks of ischemic stroke (RR, 0.74; 95% CI, 0.69-0.79) and hemorrhagic stroke (RR, 0.55; 95% CI, 0.42-0.72). Moreover, both fatal (RR, 0.51; 95% CI, 0.36-0.73) and nonfatal stroke (RR, 0.52; 95% CI, 0.28-0.94) were lower in participants with higher AHM adherence. The results of a dose-response analysis indicated that a 20% increment in AHM adherence level was associated with a 9% lower risk of stroke (RR, 0.91; 95% CI, 0.86-0.96). CONCLUSIONS: Higher AHM adherence is dose-dependently associated with a lower risk of stroke in patients with hypertension.