Multidisciplinary molecular consultation increases the diagnosis of pediatric epileptic encephalopathy and neurodevelopmental disorders.

BACKGROUND: Epilepsy (EP) is a common neurological disease in which 70-80% are thought to have a genetic cause. In patients with epilepsy, neurodevelopmental delay (NDD) was prevalent. Next generation of sequencing has been widely used in diagnosing EP/NDD. However, the diagnostic yield remains to be 40%-50%. Many reanalysis pipelines and software have been developed for automated reanalysis and decision making for the diseases. Nevertheless, it is a highly challenging task for smaller genetic centers or a routine pediatric practice. To address the clinical and genetic "diagnostic odyssey," we organized a Multidisciplinary Molecular Consultation (MMC) team for molecular consultation for 202 children with EP/NDD patients referred by lower level hospitals. METHODS: All the patients had undergone an aligned and sequential consultations and discussions by a "triple reanalysis" procedure by clinical, genetic specialists, and researchers. RESULTS: Among the 202 cases for MMC, we totally identified 47 cases (23%) harboring causative variants in 24 genes and 15 chromosomal regions after the MMC. In the 15 cases with positive CNVs, 3 cases harbor the deletions or duplications in 16p11.2, and 2 cases for 1p36. The bioinformatical reanalysis revealed 47 positive cases, in which 12 (26%) were reported to be negative, VUS or incorrectly positive in pre-MMC reports. Additionally, among 87 cases with negative cases, 4 (5%) were reported to be positive in pre-MMC reports. CONCLUSION: We established a workflow allowing for a "one-stop" collaborative assessments by experts of multiple fields and helps for correct the diagnosis of cases with falsenegative and -positive and VUS genetic reports and may have significant influences for intervention, prevention and genetic counseling of pediatric epilepsy and neurodevelopmental disorders.

SCN1A-Related Epilepsy: Novel Mutations and Rare Phenotypes.

Objectives: To expand the genotypes and phenotypes of sodium voltage-gated channel alpha subunit 1 (SCN1A)-related epilepsy. Methods: We retrospectively collected the clinical and genetic information of 22 epilepsy patients (10 males, 12 females; mean: 9.2 ± 3.9 years; 3.9-20.3 years) carrying 22 variants of SCN1A. SCN1A mutations were identified by next-generation sequencing. Results: Twenty-two variants were identified, among which 12 have not yet been reported. The median age at seizure onset was 6 months. Sixteen patients were diagnosed with Dravet syndrome (DS), two with genetic epilepsy with febrile seizures plus [one evolved into benign epilepsy with centrotemporal spikes (BECTS)], one with focal epilepsy, one with atypical childhood epilepsy with centrotemporal spikes (ABECTS) and two with unclassified epilepsy. Fourteen patients showed a global developmental delay/intellectual disability (GDD/ID). Slow background activities were observed in one patient and epileptiform discharges were observed in 11 patients during the interictal phase. Significance: This study enriches the genotypes and phenotypes of SCN1A-related epilepsy. The clinical characteristics of patients with 12 previously unreported variants were described.

Cytology, transcriptomics, and mass spectrometry imaging reveal changes in late-maturation elm (Ulmus pumila) seeds.

During seed maturation, the seed deposits storage compounds (starches, oils, and proteins), synthesizes defense compounds, produces a seed coat, initiates embryo dormancy, and becomes desiccated. During the late-maturation stage, seed storage compound contents and compositions change dramatically. Although maturation has been extensively studied in model species and crops, it remains less well characterized in woody perennial plants. In this study, we conducted morphological and cytological observations, transcriptome profiling, and chemical constituent analysis of elm (Ulmus pumila L.) seeds during the late-maturation stage. Light and electron microscopy revealed that closely packed yet discrete lipid bodies frequently surrounded the densely stained protein bodies, and the protein bodies became irregular or even partially disintegrated at the end of seed development. RNA-seq detected substantial transcriptome changes during the late-maturation stage, and pathway enrichment analysis showed that the differentially expressed genes were associated with phenylpropanoid biosynthesis, starch and sucrose metabolism, plant-pathogen interactions, and hormone signal transduction. Furthermore, we used mass spectrometry imaging to detect the relative intensity and spatial distribution of fatty acids, phospholipids, and waxes in elm seeds. Our findings provide a framework for understanding the changes in cytological features and chemical composition during the final stage of elm seed development, and a detailed reference for seed development in woody plants.

Advancements in the treatment of non-alcoholic fatty liver disease (NAFLD).

Non-alcoholic fatty liver disease (NAFLD) is a series of diseases, involving excessive lipid deposition in the liver and is often accompanied by obesity, diabetes, dyslipidemia, abnormal blood pressure, and other metabolic disorders. In order to more accurately reflect its pathogenesis, an international consensus renamed NAFLD in 2020 as metabolic (dysfunction) associated with fatty liver disease (MAFLD). The changes in diet and lifestyle are recognized the non-drug treatment strategies; however, due to the complex pathogenesis of NAFLD, the current drug therapies are mainly focused on its pathogenic factors, key links of pathogenesis, and related metabolic disorders as targets. There is still a lack of specific drugs. In clinical studies, the common NAFLD treatments include the regulation of glucose and lipid metabolism to protect the liver and anti-inflammation. The NAFLD treatments based on the enterohepatic axis, targeting gut microbiota, are gradually emerging, and various new metabolism-regulating drugs are also under clinical development. Therefore, this review article has comprehensively discussed the research advancements in NAFLD treatment in recent years.

The Correlation of ELP4-PAX6 With Rolandic Spike Sources in Idiopathic Rolandic Epilepsy Syndromes.

Objective: To study the single nucleotide polymorphism rs662702 of ELP4-PAX6 in patients with idiopathic rolandic epilepsy syndromes (IRES) in China and explore the relationship between the distribution of rolandic spike sources and the single nucleotide polymorphism rs662702 in ELP4-PAX6. Methods: First, clinical information was obtained from patients diagnosed with IRES. Next, the single nucleotide polymorphism rs662702 of ELP4 was analyzed by using the Sanger method. Resting-state magnetoencephalography data were collected from 17 patients. We analyzed the epileptic spike sources using the single equivalent current dipole (SECD) model and determined the spike distributions across the whole brain. Finally, Fisher's test was performed to assess the correlation between the single nucleotide polymorphism rs662702 of ELP4-PAX6 and rolandic spike sources. Results: ELP4 rs662702 T alleles were found in 10.7% of IRES patients and occurred four times more frequently in these patients than in the healthy controls. TT homozygosity was found in one IRES patient (1.3%), while no TT homozygosity was found in the healthy control group. The IRES rolandic spike sources were unilateral in sixteen patients (94.1%) and were mainly located in the anterior central gyrus (58.8%). The spike source of patients without the ELP4 rs662702 T allele was correlated with the central region (p < 0.05). The rolandic spikes sources were significant correlated with the non-central gyrus (frontal and temporal lobes) in patients with the ELP4 rs662702 T allele (p < 0.05). Conclusion: The rolandic spike sources of the IRES patients with the ELP4 rs662702 T allele were significantly associated with the non-central gyrus, including the frontal and temporal lobes. Our study confirmed for the first time in vivo that ELP4 rs662702 T allele overexpression is correlated with the rolandic spike distribution in patients with IRES and provides important insights into how genetic abnormalities can lead to brain dysfunction and into the precise targeting of abnormal discharge sources in the brain.

Longitudinal change and prognostic value of anxiety and depression in coronary heart disease patients.

BACKGROUND: This study aimed to investigate the longitudinal changes and risk factors of anxiety and depression, as well as their values in predicting major adverse cardiovascular events (MACE) occurrence in coronary heart disease (CHD) patients. METHODS: Every 3 months until 36 months (M36), 190 newly diagnosed CHD patients were consecutively recruited and followed up. Anxiety and depression were assessed using hospital anxiety and depression scale (HADS) at each follow-up timepoint. Meanwhile, MACE occurrence was recorded. RESULTS: Anxiety occurrence sustainably increased from 42.6% at baseline to 51.1% at M36; meanwhile, depression occurrence also sustainably elevated from 33.3% at baseline to 43.7% at M36. Then, independent risk factors for anxiety and depression at baseline/1 year/2 years/3 years were assessed, which revealed that female, diabetes, and higher Gensini score independently predicted anxiety occurrence at each time point, while single/divorced/widowed status independently predicted anxiety occurrence at some specific time points; regarding depression, female, single/divorced/widowed status, diabetes and higher Gensini score independently predicted depression occurrence at each time point, whereas higher education duration, family history of CHD and age > 60 years only predicted depression at some individual time points. Interestingly, baseline/1-year depression were correlated with increased accumulating MACE occurrence, while no correlation of baseline/1-year /2-year/3-year anxiety or 2-year/3-year depression with accumulating MACE occurrence was found. CONCLUSION: Anxiety and depression are common and progress sustainably with female, diabetes, and higher Gensini score as their independent risk factors; meanwhile, depression but not anxiety may predict increased accumulating MACE occurrence in CHD patients.

Frequency-specific changes in the default mode network in patients with cingulate gyrus epilepsy.

To identify abnormal functional connectivity of the default mode network in cingulate gyrus epilepsy, which may yield new information about the default mode network and suggest a new cingulate gyrus epilepsy biomarker. Fifteen patients with cingulate gyrus epilepsy (mean age = 21 years) and 15 healthy controls (mean age = 24 years) were studied in the resting state using magnetoencephalography. Twelve brain areas of interest in the default mode network were extracted and investigated with multifrequency signals that included alpha (α, 8-13 Hz), beta (ß, 14-30 Hz), and gamma (γ, 31-80 Hz) band oscillations. Patients with cingulate gyrus epilepsy had significantly greater connectivity in all three frequency bands (α, ß, γ). A frequency-specific elevation of functional connectivity was found in patients compared to controls. The greater functional connectivity in the γ band was significantly more prominent than that of the α and ß bands. Patients with cingulate gyrus epilepsy and controls differed significantly in functional connectivity between the left angular gyrus and left posterior cingulate cortex in the α, ß, and γ bands. The results of the node degree analysis were similar to those of the functional connectivity analysis. Our findings reveal for the first time that brain activity in the γ band may play a key role in the default mode network in cingulate gyrus epilepsy. Altered functional connectivity of the left angular gyrus and left posterior cingulate cortex may be a new biomarker for cingulate gyrus epilepsy.

Trihexyphenidyl for treatment of dystonia in ataxia telangiectasia: a case report.

Ataxia telangiectasia (AT) is an autosomal recessive multisystem disorder caused by mutations of ATM gene. And dystonia may develop as a late manifestation in typical AT. Here we report a novel homozygous frameshift ATM mutation (c.1402_1403delAA; p. K468Efs*18) in a 10-year-old male. The patient was diagnosed as typical AT according to clinical presentations which included progressive cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, and cerebellar atrophy. The genetic finding confirmed the diagnosis. Severe dystonia was presented in late stage of this disease. After 3 months of trihexyphenidyl treatment, the frequency of dystonia was reduced significantly. Although dystonia is not uncommon in phenotype spectrum of AT, compared with other symptoms of this syndrome, such as cerebellar ataxia and dysarthria, dystonia can be treated.

The effects of climate warming on the migratory status of early summer populations of Mythimna separata (Walker) moths: A case-study of enhanced corn damage in central-northern China, 1980-2016.

Mythimna separata (Walker) moths captured in light traps were monitored in Luohe, central-northern China, from 1980 to 2016. Annual average temperature recorded an increase of 0.298°C/10 years in this region in the period. Our results indicate that a rising April and May average temperature and earlier occurrences of days recording the highest day temperature (30°C) caused an advanced peak and increasing proportion of high ovarian development levels of first-generation females in earlier summers. Results using Johnson's formulation of "oogenesis-flight syndrome" indicate that increasing sexual maturity proportion has resulted in more emigrant individuals in the local first-generation moth becoming residents, and then increased individuals rapidly in the local second-generation moth since 2006. Consequences of this action have a boom in corn damage since 2007 in this region. Advanced peak dates of the first and second-generation moth revealed the same response to increasing average monthly temperatures in the monitoring period. Increasing temperatures, the average May temperature exceeds or equal to 22°C, during the early 2000's may represent a physiological threshold for M. separata development. Our results suggest that climate warming may impact M. separata migratory status and cause a problem of crop production in this region.

Curcumin attenuates migration of vascular smooth muscle cells via inhibiting NFκB-mediated NLRP3 expression in spontaneously hypertensive rats.

Migration of vascular smooth muscle cell (VSMC) plays a critical role in the pathophysiology of hypertension and several other vascular diseases. Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a bioactive constituent from Curcuma longa, is commonly used as a spice, food additive or dietary pigment. It has several health benefits including antioxidant, anti-inflammatory and anticancer properties. This study examined the roles of curcumin in VSMC migration in hypertension and underlying mechanism. VSMC was isolated and prepared from thoracic aorta of Wistar-Kyoto rats and spontaneously hypertensive rats (SHR). VSMC migration was evaluated with Boyden chamber assay and wound-healing assay. Curcumin attenuated VSMC migration, inhibited nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression and reduced interleukin (IL)-1ß concentration in VSMC of SHR, which were similar to the effects of NLRP3 knockdown on IL-1ß concentration and VSMC migration. Curcumin inhibited NFκB activation in VSMC of SHR, which was similar to the effects of NFκB inhibitor BAY11-7082 on NFκB activation. In another in vitro model of rat VSMC migration, curcumin also inhibited angiotensin II-induced VSMC migration, NFκB activation, NLRP3 expression and IL-1ß production. Intragastric administration of curcumin in SHR attenuated hypertension and reduced NFκB activation, NLRP3 and matrix metalloproteinase-9 expressions and aortic media thickness. These results indicate that curcumin inhibits VSMC migration via inhibiting NFκB-mediated NLRP3 expression in VSMC of SHR or in angiotensin II-treated VSMC. Curcumin attenuates hypertension, vascular inflammation and vascular remodeling in SHR.

Loquat leaf polysaccharides improve glomerular injury in rats with anti-Thy 1 nephritis via peroxisome proliferator-activated receptor alpha pathway.

Chronic glomerulonephritis frequently develops into renal failure that cannot be completely cured. Based on the success of anti-inflammatory Chinese herbs in treating chronic nephritis, our goal was to investigate the therapeutic effects and mechanism of action of loquat leaf polysaccharides (LLPS) on chronic anti-Thy-1 nephritis. A rat model of glomerulonephritis was used to study the effects of 8 weeks of enalapril or LLPS treatment. Twenty-four-hour rat urinary protein excretions were measured every week for 8 weeks. Then, all animals were sacrificed, renal-related biochemical parameters were analyzed, and histology and electron microscopy examinations of renal tissue samples were conducted. Renal cortex tissue was used to detect markers of renal fibrosis. RNA sequencing (RNA-seq) and in vitro experiments explored the signaling pathway involved in LLPS treatment effects. Compared with the disease control group, LLPS treatment significantly decreased the levels of serum creatinine and blood urea nitrogen, reduced urinary protein excretion, glomerular mesangial cell proliferation, and extracellular matrix hyperplasia, and attenuated the expression of proteins associated with podocyte injury and renal fibrosis. RNA-seq results showed that peroxisome proliferator-activated receptor (PPAR) is a potential signaling pathway involved in LLPS treatment of chronic glomerulonephritis. Increases in PPARα and plasminogen activator inhibitor-1 (PAI-1) caused by glomerulonephritis were inhibited by LLPS in vitro. Furthermore, when an agonist of PPARα (BMS-687453) was used to stimulate PPARα activity, LLPS treatment suppressed the expression of fibrosis factor PAI-1 partially via PPARα inhibition. These findings demonstrate that LLPS improved glomerular injury in rats with anti-Thy 1 nephritis via the PPARα pathway.

Lycium barbarum polysaccharides attenuate rat anti-Thy-1 glomerulonephritis through mediating pyruvate dehydrogenase.

Glomerulonephritis is the major cause of chronic kidney disease characterized by mesangial cell proliferation and extracellular matrix deposition. The aim of this study was to investigate the effects of Lycium barbarum polysaccharides (LBPs) on anti-Thy 1 nephritis rats and explore the protective mechanism of LBPs. After the model of glomerulonephritis created by injecting anti-thymocyte serum (ATS), rats were treated with enalapril or LBPs for 8 weeks. The therapeutic effect was evaluated by detection of renal-related biochemical parameters, histological observation and markers of renal fibrosis. Moreover, RNA-seq analysis and experiments in vitro were employed to explore the signaling pathway involved in LBPs treatment. The results found that LBPs treatment significantly suppressed ATS-caused increment at levels of blood urea nitrogen, creatinine, proteinuria, PAI-1 protein expression, glomerular mesangial cell proliferation and extracellular matrix hyperplasia, along with reduction of creatinine clearance. RNA sequencing showed pyruvate metabolism acting as a potential signaling pathway, which was evidenced by the inhibitory effect on up-regulation of pyruvate dehydrogenase and PAI-1 levels via treatment with LBPs in vitro. LBPs are the promising agents for the management of glomerulonephritis through pyruvate metabolism signaling pathway.

Fibronectin Type III Domain-Containing 5 Attenuates Liver Fibrosis Via Inhibition of Hepatic Stellate Cell Activation.

BACKGROUND/AIMS: Fibronectin type III domain-containing 5 (FNDC5) protein is involved in the beneficial effects of exercise on metabolism. FNDC5 attenuates hepatic steatosis induced by high fat diet (HFD). Here, we examined the effects of FNDC5 on liver fibrosis and underline mechanisms. METHODS: Experiments were carried out on wild-type and FNDC5-/- mice, primary mouse hepatic stellate cells (HSCs) and human hepatic stellate cell line (LX-2). The mice were fed with HFD for 6 months to induce liver fibrosis. Oxidized low density lipoprotein (oxLDL) were used to induce the activation of hepatic stellate cells and fibrosis in mouse HSCs and human LX-2 cells. H&E, Masson's trichrome staining and Sirius red staining were used for liver sections. Protein and mRNA expressions were evaluated with Western blot and RT-PCR, respectively. RESULTS: FNDC5 deficiency aggravated the HFD-induced liver fibrosis and HSCs activation in mice. It exacerbated the HFD-induced inhibition of AMPK phosphorylation, upregulation of connective tissue growth factor (CTGF) and transforming growth factor-ß (TGF-ß), and deposition of extracellular matrix (ECM) in liver of mice. Administration of FNDC5 attenuated oxLDL-induced AMPK deactivation, HSCs activation, CTGF and TGF-ß upregulation and ECM deposition in mouse HSCs. The beneficial effects of FNDC5 on oxLDL-induced AMPK dephosphorylation, HSCs activation and ECM deposition were prevented by the inhibition of AMPK with compound C in human LX-2 cells. However, the effects of FNDC5 on hepatic fibrosis in vivo in this study cannot be distinguished from its effects on adiposity and hepatic steatosis. CONCLUSIONS: FNDC5 deficiency aggravates HFD-induced liver fibrosis in mice. FNDC5 plays beneficial roles in attenuating liver fibrosis via AMPK phosphorylation-mediated inhibition of HSCs activation.

Fibronectin type III domain containing 5 attenuates NLRP3 inflammasome activation and phenotypic transformation of adventitial fibroblasts in spontaneously hypertensive rats.

OBJECTIVE: Phenotypic transformation of adventitial fibroblasts is important in the pathogenesis of hypertension. This study was designed to determine whether fibronectin type III domain containing 5 (FNDC5) alleviates the phenotypic transformation of adventitial fibroblasts in hypertension and the underlying mechanisms. METHODS AND RESULTS: Experiments were carried out in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and primary aortic adventitial fibroblasts. FNDC5 was downregulated and NLRP3 inflammasome was activated in aortic adventitia of SHR. FNDC5 overexpression attenuated adventitial fibroblasts phenotypic transformation, excessive synthesis and secretion of matrix components, NLRP3 inflammasome activation and inflammation in adventitial fibroblasts from SHR. Moreover, FNDC5 overexpression reduced NADPH oxidase 2 (NOX2) expression and reactive oxygen species (ROS) production in adventitial fibroblasts from SHR. Similarly, exogenous FNDC5 inhibited adventitial fibroblasts phenotypic transformation, expression of matrix components, NLRP3 inflammasome activation and NOX2 expression in adventitial fibroblasts from SHR. FNDC5 overexpression in rats attenuated phenotypic transformation, inflammation and reactive oxygen species (ROS) production in the aortic adventitia of SHR. Furthermore, FNDC5 overexpression reduced blood pressure and alleviated vascular remodeling in SHR. CONCLUSION: FNDC5 reduces NOX2-derived ROS production, NLRP3 inflammasome activation and phenotypic transformation in adventitial fibroblasts of SHR. FNDC5 plays a beneficial role in attenuating vascular inflammation, vascular remodeling and hypertension in SHR.

NLRP3 Gene Deletion Attenuates Angiotensin II-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells and Vascular Remodeling.

BACKGROUND/AIMS: Angiotensin (Ang) II plays vital roles in vascular inflammation and remodeling in hypertension. Phenotypic transformation of vascular smooth muscle cells (VSMCs) is a major initiating factor for vascular remodeling. The present study was designed to determine the roles of NLRP3 inflammasome activation in Ang II-induced VSMC phenotypic transformation and vascular remodeling in hypertension. METHODS: Primary VSMCs from the aorta of NLRP3 knockout (NLRP3-/-) mice and wild-type (WT) mice were treated with Ang II for 24 h. Subcutaneous infusion of Ang II via osmotic minipump for 2 weeks was used to induce vascular remodeling and hypertension in WT and NLRP3-/- mice. RESULTS: NLRP3 gene deletion attenuates Ang II-induced NLRP3 inflammasome activation, phenotypic transformation from a contractile phenotype to a synthetic phenotype and proliferation in primary mice VSMCs. Ang II-induced hypertension and vascular remodeling in WT mice were attenuated in NLRP3-/- mice. Furthermore, Ang II-induced NLRP3 inflammasome activation, phenotypic transformation and proliferating cell nuclear antigen (PCNA) upregulation were inhibited in the media of aorta of NLRP3-/- mice. CONCLUSIONS: NLRP3 inflammasome activation contributes to Ang II-induced VSMC phenotypic transformation and proliferation as well as vascular remodeling and hypertension.

Gain-of-function mutation p.Arg225Cys in SCN11A causes familial episodic pain and contributes to essential tremor.

Familial episodic pain is a rare autosomal-dominant disorder characterized by recurrent attacks of pain. The pathogenesis of familial episodic pain is not very clear so far. Essential tremor is the most common movement disorder, but the identification of essential tremor genes has remained elusive. We studied a four-generation Chinese family with early-onset familial episodic pain and adult onset familial essential tremor. All essential tremor diagnoses were confirmed based on a review of the questionnaires, videotaped neurological examinations and was then reconfirmed by a senior neurologist specializing in movement disorders using published criteria. SCN11A analysis was performed by whole-exome sequencing or Sanger sequencing. We confirmed the presence of the SCN11A (c.673C>T) mutation in family members with episodic pain and essential tremor. We identified a missense mutation of p.Arg225Cys in SCN11A in a four-generation Chinese family with early-onset familial episodic pain and adult onset familial essential tremor syndrome. This may belong to a rare hereditary syndrome that has not been reported up to now. For the first time, we associated the genetic variability of SCN11A with the development of essential tremor, and further confirmed essential tremor is one of the neurological channelopathies.

MKL1 defines the H3K4Me3 landscape for NF-κB dependent inflammatory response.

Macrophage-dependent inflammatory response is considered a pivotal biological process that contributes to a host of diseases when aberrantly activated. The underlying epigenetic mechanism is not completely understood. We report here that MKL1 was both sufficient and necessary for p65-dependent pro-inflammatory transcriptional program in immortalized macrophages, in primary human and mouse macrophages, and in an animal model of systemic inflammation (endotoxic shock). Extensive chromatin immunoprecipitation (ChIP) profiling and ChIP-seq analyses revealed that MKL1 deficiency erased key histone modifications synonymous with transactivation on p65 target promoters. Specifically, MKL1 defined histone H3K4 trimethylation landscape for NF-κB dependent transcription. MKL1 recruited an H3K4 trimethyltransferase SET1 to the promoter regions of p65 target genes. There, our work has identified a novel modifier of p65-dependent pro-inflammatory transcription, which may serve as potential therapeutic targets in treating inflammation related diseases.

Hydrogen sulfide protects against amyloid beta-peptide induced neuronal injury via attenuating inflammatory responses in a rat model.

Neuroinflammation has been recognized to play a critical role in the pathogenesis of Alzheimer's disease (AD), which is pathologically characterized by the accumulation of senile plaques containing activated microglia and amyloid ß-peptides (Aß). In the present study, we examined the neuroprotective effects of hydrogen sulfide (H2S) on neuroinflammation in rats with Aß1-40 hippocampal injection. We found that Aß-induced rats exhibited a disorder of pyramidal cell layer arrangement, and a decrease of mean pyramidal cell number in the CA1 hippocampal region compared with those in sham operated rats. NaHS (a donor of H2S, 5.6 mg/kg/d, i.p.) treatment for 3 weeks rescued neuronal cell death significantly. Moreover, we found that H2S dramatically suppressed the release of TNF-α, IL-1ß and IL-6 in the hippocampus. Consistently, both immunohistochemistry and Western blotting assays showed that H2S inhibited the upregulation of COX-2 and the activation of NF-κB in the hippocampus. In conclusion, our data indicate that H2S suppresses neuroinflammation via inhibition of the NF-κB activation pathway in the Aß-induced rat model and has potential value for AD therapy.

Losartan supports liver regrowth via distinct boost of portal vein pressure in rodents with 90 % portal branch ligation.

OBJECTIVES: The study used a model of 90 % portal branch ligation (PBL) in rats to study the effect of losartan on portal vein pressure (PVP) and liver regeneration in rats after PBL. METHODS: A total of 144 male Sprague-Dawley rats were arbitrarily designated into three treatment method groups: a sham operation group (Sham), a PBL treatment group (PBL), and a PBL plus losartan treatment group (PBL + L). Losartan (2 mg/day) was intragastrically gavaged 3 days before the PBL or sham operation to time points of study. RESULTS: Both the PBL and PBL + L groups showed an intense surge in PVP after PBL treatment, peaking at 12 h postsurgery, then lessening progressively afterwards. PVP was substantially greater in these two groups compared with the Sham group at 6-72 h postsurgery (p < 0.01). Compared with the PBL group, the PBL + L group showed a noticeable reduction in PVP 6-48 h postsurgery (p < 0.05); the PBL group showed considerably raised levels of plasma ALT and AST 6-72 h postsurgery (p < 0.01). Compared to the PBL group, the PBL + L group showed drastically reduced plasma ALT and AST levels 12-72 h postsurgery (p < 0.05). CONCLUSIONS: Losartan supports liver regeneration in 90 % of rats that underwent PBL. The mechanism may be related to losartan's ability to regulate PVP and increase serum hepatocyte growth factor levels.

Effect of LY294002 on adriamycin-induced epithelial-mesenchymal transition in human breast carcinoma cells.

OBJECTIVE: To study the effect of LY294002 on the adriamycin- induced epithelial-mesenchymal transition in human breast carcinoma cells. METHODS: Human breast carcinoma cells MCF-7 was cultured in vitro and then exposed to adriamycin with or without LY294002. The protein expression levels of Akt, phosphorylated-Akt (p-Akt), Snail, and E-cadherin was detected by Western blot analysis. The mRNA expressions of Snail and E-cadherin were determined by RT-PCR. RESULTS: Adriamycin significantly increased the protein expression of Snail and depressed the protein expression of E-cadherin (P<0.05). The pre-treatment with LY294002 significantly reversed the changes of activities and levels of the above proteins (P<0.05). CONCLUSION: LY294002 could reverse the adriamycin-induced epithelial-mesenchymal transition in human breast carcinoma cells by regulating the expressions of Snail and E-cadherin through suppressing PI3K/Akt signaling pathway.