👤 Eve R Lang

Alterations in the gut microbiome and a "leaky" gut are associated with Parkinson's disease (PD), which implies the prospect of rebalancing via dietary intervention. Here, we investigate the impact of a diet rich in resistant starch on the gut microbiome through a multi-omics approach. We conducted a randomized, controlled trial with short-term and long-term phases involving 74 PD patients of three groups: conventional diet, supplementation with resistant starch, and high-fibre diet. Our findings reveal associations between dietary patterns and changes in the gut microbiome's taxonomic composition, functional potential, metabolic activity, and host inflammatory proteome response. Resistant starch supplementation led to an increase in Faecalibacterium species and short-chain fatty acids alongside a reduction in opportunistic pathogens. Long-term supplementation also increased blood APOA4 and HSPA5 and reduced symptoms of PD. Our study highlights the potential of dietary interventions to modulate the gut microbiome and improve the quality of life for PD patients. Show less

PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition is a potent cholesterol-lowering strategy. This study examined the effects of PCSK9 monoclonal antibodies (mAbs) and high-intensity statins beyond low-density lipoprotein cholesterol reduction, which are not fully defined, particularly in patients with acute myocardial infarction (MI). Proteomic and lipidomic analyses were conducted on plasma from 265 patients with acute MI from the PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction) randomized, placebo-controlled PCSK9 mAb trial and 34 patients without MI with hyperlipidemia from the Vienna Lipid Clinic registry, also receiving PCSK9 mAbs. Discovery proteomics revealed changes in apolipoproteins and increased PCOLCE (procollagen C-endopeptidase enhancer 1) levels in both the PCSK9 mAb and placebo groups after MI. UK Biobank data confirmed PCOLCE and PCSK9 upregulation as associated with statin use. Hepatoma cell experiments demonstrated a dose-dependent PCOLCE induction on statin treatment. Compared with placebo (statins only), PCSK9 mAb therapy resulted in greater reductions in APOB (apolipoprotein B), APOE (apolipoprotein E), APOC2 (apolipoprotein C2), and APOC3 (apolipoprotein C3), as shown by targeted proteomics. Mediation analysis indicated that these changes were largely explained by low-density lipoprotein cholesterol lowering. Lipidomics identified more pronounced reductions in cholesteryl esters, ceramides, sphingomyelins, phosphatidylcholines, triglycerides, and diglycerides in PCSK9 mAb-treated patients with MI. Results were largely consistent in patients without MI. However, levels of LPA (apolipoprotein[a]), the characteristic protein component of lipoprotein(a), remained unchanged in PCSK9 mAb-treated patients with MI, since a rise of LPA was observed in the placebo group post-MI. Most apolipoprotein changes after PCSK9 mAb therapy following MI were mediated by low-density lipoprotein cholesterol lowering. Statin use is associated with increased circulating PCOLCE, with hepatoma cell experiments supporting a predominant hepatic origin. Combining PCSK9 mAbs with high-intensity statins mitigates post-MI increases in lipoprotein(a). URL: https://www.clinicaltrials.gov; Unique identifier: NCT03067844. Show less

Abdominal aortic aneurysm (AAA) has high mortality and enhanced oxidative stress; autophagy inhibition accelerates its formation. Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase 2 (NOX2) is responsible for generating reactive oxygen species (ROS). The aim is to clarify the mechanism of NOX2-mediated autophagy in AAA. Subcutaneous angiotensin II (AngII) infusion in ApoE Show less

Compared with non-left-behind children (NLBC), left-behind children (LBC) face a higher risk of academic stress, depression, and anxiety symptoms due to separation from their parents; however, the heterogeneity of academic stress profiles and their relationships with the symptom network remain insufficiently explored. To address this gap, a cross-sectional survey of 10,524 Chinese children compared LBC (n = 2487) and NLBC. Latent profile analysis (LPA) was first conducted to identify academic stress subgroups among LBC. Subsequently, depression-anxiety symptom networks were estimated using Ising and Gaussian graphical models (GGM), with edge weights derived from regularised logistic regression (Ising) and partial correlation (GGM). Simulated interventions were further evaluated via the NodeIdentifyR algorithm (NIRA). Overall, compared to NLBC, LBC exhibited higher levels of academic stress, depression, and anxiety (ps < 0.001, Cliff's δ = 0.076; Cohen's d = 0.067). LPA revealed three academic stress subgroups: moderate (31.44%), high (9.17%), and low (59.39%). The severity of depression and anxiety symptoms increased with the level of academic stress. The high stress subgroup displayed a sparse network with stronger edges (e.g., A1 'Sudden Fear'-A4 'Physical Symptoms', edge weight = 2.10) compared to moderate- and low-academic stress subgroups. Core nodes with the strongest expected influence were A8 ('Decision Hesitation', moderate subgroup), A2 ('Worry', high subgroup), and D1/D6 ('Sadness' and 'Failure', low subgroup). Simulated interventions indicated that alleviating A8 'Decision Hesitation' or A2 'Worry' most effectively reduced symptom risk (16.66%-30.76%), whereas D8 'Motor' and A7 'Early Departure' were associated with maximal symptom aggravation. Taken together, by integrating LPA-derived academic stress profiles with symptom network analysis, this study reveals distinct symptom associations across subgroups. In the high stress subgroup, symptom A2 ('Worry') is a core intervention target; in the low stress subgroup, A7 ('Early Departure') holds preventive potential. These findings underscore subgroup-specific interventions tailored to individual stress profiles. Show less

Tumor-related metabolites in the tumor microenvironment may induce immune dysfunction, leading to malignant progression and metastasis of tumors. Here, it is demonstrated that tumoral PLA2G16, a phospholipase catalyzes phospholipids to generate free fatty acid (FFA) or lysophosphatidic acid (LPA), is an important contributor to triple-negative breast cancer (TNBC) lung metastasis in an immune-dependent pattern by improving tetracosatetraenoic acid (C24:4 (n-6)) accumulation in the early metastatic niche of lung and impairing immune function of pulmonary CD8 Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become highly prevalent worldwide, largely as a consequence of the global obesity epidemic. This research endeavors to elucidate the role and molecular mechanisms of hepatic glycogen synthase (GS) in MASLD progression. Published transcriptomic data reveal a downward trend in GYS2 gene expression in patients with obesity, MASLD, and metabolic dysfunction-associated steatohepatitis. In mouse models of MASLD, GYS2 gene or protein expression was downregulated, consistent with the human data. Here, GS-deficient mice fed with a normal diet displayed hepatic lipid accumulation and liver injury, whereas hepatic steatosis progression and inflammation were aggravated in mice fed with a high-fat diet. Loss of hepatic GS stimulated fatty acid de novo synthesis through carbohydrate-response element-binding protein and AKT-mTOR1-sterol regulatory element-binding protein 1 axis pathways. In GS-deficient mice, lipid accumulation in the hepatocytes significantly decreased when carbohydrate-response element-binding protein and sterol regulatory element-binding protein 1 levels were suppressed to levels comparable to those of cytotoxic T lymphocyte hepatocytes. Forced expression of hepatic GS by adeno-associated virus in db/db mice ameliorated lipid accumulation in male mice. Our findings provide proof of concept whereby targeting glycogen metabolism in hepatocytes may offer potential therapeutic avenues to treat MASLD. Show less

The mechanisms by which the autosomal dominant disorder tuberous sclerosis complex (TSC) results in liver fibrosis remain poorly understood. KDM6A, a histone demethylase, has been implicated in the pathogenesis of fibrosis in multiple tissues. This study aimed to elucidate the molecular mechanism by which KDM6A contributed to TSC-associated fibrosis. We observed fibrogenesis, epithelial-mesenchymal transition (EMT) induction and upregulation of Kdm6a in vivo and in vitro upon Tsc1 or Tsc2 deficiency. Knockdown of Kdm6a attenuated both fibrosis and EMT phenotypes. Mechanistically, Kdm6a depletion reduced phosphorylation of ERK1/2 and downregulated Snai1 expression. Activation of the MAPK/ERK pathway with PMA restored EMT-related protein expression, confirming the functional involvement of this signaling axis. Furthermore, Tsc1 or Tsc2 deficiency promoted Kdm6a expression via the mTORC1 pathway, while Kdm6a knockdown conversely suppressed mTORC1 activity by reducing mTOR protein expression, suggesting a positive feedback loop between Kdm6a expression and mTORC1. These findings indicate that Kdm6a promotes fibrosis in TSC through the activation of the MAPK/ERK/SNAI1 signaling pathway. Moreover, the combination of mTORC1 and KDM6A inhibitors results in marked regression of fibrosis and liver lesions in TSC models, unveiling a potential treatment for TSC patients with inadequate response to mTORC1 inhibitors. Show less

Astrocytes are key regulators of neuroinflammation in multiple sclerosis (MS). Electroacupuncture (EA), a safe and cost-effective adjuvant therapy, has shown benefits in neurodegenerative diseases, but its astrocyte-related mechanisms remain unclear. Here, we demonstrated that EA at ST36 alleviated blood-brain barrier (BBB) disruption and neuroinflammation during the peak period of experimental autoimmune encephalomyelitis (EAE). Additionally, EA at ST36 upregulated the expression of α-melanocyte-stimulating hormone (α-MSH) and its receptor melanocortin-4 receptor (MC4R) in spinal astrocytes. Pharmacological studies showed that MC4R agonist RO27-3225 mimicked the therapeutic effects of EA, whereas MC4R antagonist TCMCB07 weakened EA-mediated BBB protection and neuroinflammation suppression. Moreover, astrocyte-specific silencing of MC4R via adeno-associated virus (AAV) weakened EA-mediated BBB protection and neuroinflammation suppression. RNA-sequencing (RNA-seq) and western blot (WB) revealed that EA exerts neuroprotective effects by activating MC4R to inhibit MAPK and NF-κB signaling pathways. Moreover, in MC4R-overexpressing astrocytes, α-MSH and RO27-3225 reduced inflammation responses, while TCMCB07 reversed the effects by MAPK/NF-κB signaling pathways. Collectively, our findings identify astrocytic MC4R as a critical mediator of EA-driven neuroprotection by suppressing MAPK/NF-κB signaling, providing mechanistic insight and a promising therapeutic target for EAE and other neuroinflammatory disorders. Show less

Mammalian opsin 3 (OPN3) is a member of the opsin family of G-protein-coupled receptors with ambiguous light sensitivity. OPN3 was first identified in the brain (and named encephalopsin) and subsequently found to be expressed in other tissues. In adipocytes, OPN3 is necessary for light responses that modulate lipolysis and glucose uptake, while OPN3 in human skin melanocytes regulates pigmentation in a light-independent manner. Despite its initial discovery in the brain, OPN3 functional mechanisms in the brain remain elusive. Here, we investigated the molecular mechanism of OPN3 function in the paraventricular nucleus (PVN) of the hypothalamus. We show that Show less

Neuroinflammation is a key feature of Alzheimer's disease (AD), and stem cell therapies have emerged as promising candidates due to their immunomodulatory properties. Neuro-Cells (NC), a combination of unmodified mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), have demonstrated therapeutic potential in models of central nervous system (CNS) injury and neurodegeneration. Here, we studied the effects of NC in APPswe/PS1dE9 mice, an AD mouse model. Twelve-month-old APPswe/PS1dE9 mice or their wild-type littermates were injected with NC or vehicle into the cisterna magna. Five to six weeks post-injection, cognitive, locomotor, and emotional behaviors were assessed. The brain was stained for amyloid plaque density using Congo red, and for astrogliosis using DAPI and GFAP staining. Gene expression of immune activation markers ( Show less

The proportion of mutations that are dominant is a fundamental genetic parameter affecting the rate of adaptation, the efficacy of selection, and the maintenance of variation in populations. Yet, estimates for this parameter vary greatly. Here we directly quantify the rates and genetic targets of dominant and recessive mutations in the yeast mating pathway by performing parallel genetic screens in haploid ( Show less

There is currently limited information about sensory and perceptual abilities across the progression of CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis; Batten disease), a recessively inherited lysosomal storage disorder and a leading cause of childhood neurodegeneration. Clinical symptoms include vision loss, motor impairments, and cognitive challenges, making it difficult to accurately assess neurocognitive and perceptual abilities. Thus, there is a critical need to identify objective biomarkers that can be used to inform disease progression and track treatment response in this population. This exploratory study investigates longitudinal changes in auditory sensory perceptual processing in a small sample of individuals with genetically confirmed CLN3 disease (N=4; 3 male) compared to a cross-sectional sample of 60 neurotypical (NT) controls using high-density electroencephalography (EEG). We utilized a duration mismatch negativity (MMN) paradigm, identical to what has been used in our previous cross-sectional study. We examined the auditory evoked potentials (AEPs) of the standard tones across three different stimulus onset asynchrony conditions and examined the N1 and P2 components of the AEP. We found age related differences in the amplitudes of the N1 and P2 components in individuals with CLN3 disease relative to NT controls. These amplitude differences were most notable in CLN3 disease when participants were presented with standard tones that had the slowest presentation rate. Specifically, N1 and P2 amplitudes were more negative than NT controls in childhood and adolescence and as CLN3 disease participants aged, the amplitude of the AEPs was greater than controls. Further, a more positive N1 amplitude during the longest stimulus presentation condition was associated with both reduced verbal intelligence and working memory abilities in CLN3 disease participants. Our preliminary findings parallel recently published work in a mouse model of CLN3 disease that showed both sex- and age-dependent disruptions in central auditory processing. Taken together, we demonstrate the utility of auditory EEG measures as a sensitive, objective and translational measure in CLN3 disease that may serve as a potential outcome measure useful in tracking disease progression. Continued work is needed in humans focused on sex-based differences and longitudinal changes of auditory processing in CLN3 disease. Show less

The aim of this study was to investigate the improving effect of Schisandrin B (Sch B) on metabolic associated fatty liver disease (MAFLD) by regulating the PPARγ signaling pathway and gut microbiota, and its mechanism in mice. Male C57BL/6 mice were fed with a high-fat diet (HFD) continuously for 16 weeks to establish a MAFLD model. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and lipopolysaccharide (LPS) in serum, as well as the level of malondialdehyde (MDA), and the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in the liver tissue were measured. Changes in the gut microbiota of mice was analyzed by 16S rRNA sequencing technology. The expression levels of PPARγ, Plin2, Pck1, Acsl4, and Fads1 proteins, as well as those of zonula occludins 1 (ZO-1) and Occludin proteins in the colon tissue were detected by Western Blot. The results showed that Sch B could alleviate the structure disorder, ballooning degeneration, inflammatory cell infiltration, liver lipid droplets, and fibrosis in liver tissue, lower the levels of AST, ALT, TG, TC, LDL-C, and LPS, increase the level of HDL-C and lower the levels of TNF-α and IL-6 in serum, increase the level of IL-10, and lower the level of MDA and increase the activities of SOD and GSH-Px in liver tissue in MAFLD mice. Sch B could increase the expression levels of PPARγ, Pck1, and Fads1 proteins, but decrease Plin2 and Acsl4 proteins in liver tissue. Sch B could improve the diversity and abundance of the gut microbiota, restore the normal composition of the gut microbiota at the phylum and genus levels, alleviate the disruption of the gut barrier caused by HFD, and enhance the expression of ZO-1 and Occludin proteins in colon tissue in MAFLD mice. This study showed Sch B can improve HFD-induced MAFLD, and the mechanism may be through regulating the PPARγ, Plin2, PCk1, Acsl4 and Fads1 signaling pathway, restoring the diversity of gut microbiota, and improving the gut barrier to delay the progression of MAFLD. Show less

Hypertrophic cardiomyopathy (HCM) is a hereditary disease of the myocardium characterized by asymmetric hypertrophy (mainly the left ventricle) not caused by pressure or volume load. Most cases of HCM are caused by genetic mutations, particularly in the gene encoding cardiac myosin, such as Show less

Heart failure (HF) is associated with cytokine activation and inflammation. Experimental evidence suggests that plasma interleukin-17 (IL-17) is associated with myocardial fibrosis and cardiac dysfunction in HF. IL-17D, a subtype of IL-17 originates from particular tissues such as the heart. However, there is very limited data on the IL-17 cytokine family in patients with HF. Therefore, we investigated the association between circulating IL-17D levels, clinical characteristics and outcome in a large cohort of patients with heart failure. Plasma IL-17D was measured in 2032 patients with HF from 11 European countries using a proximity extension assay. The primary outcome was a composite of HF hospitalization or all-cause mortality. Patients with higher plasma IL-17D concentrations were more likely to have atrial fibrillation (AF), renal dysfunction and heart failure with preserved ejection fraction (HFpEF) and had higher plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations (all p < 0.001). IL-17D was not associated with interleukin-6 (IL-6) or C-reactive protein (CRP) concentrations. After adjustment for confounders in a multivariable Cox regression analysis, patients in the highest quartile of plasma IL-17D had a significantly increased risk of the composite outcome of HF hospitalization or all-cause mortality compared to patients in the lowest quartile [Hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.05-1.57]. In patients with HF, elevated plasma IL-17D concentrations are associated with higher plasma NT-proBNP concentrations and a higher prevalence of AF and renal dysfunction. High IL-17D concentrations are independently associated with worse outcome. Show less

Lipid-lowering agents are relevant in stroke prevention. Probucol (PU) is an antioxidative and lipid-lowering drug that has been used to treat atherosclerotic cardiovascular diseases and xanthomas. The drug penetrates the core of low-density lipoprotein cholesterol (LDL-C) particles, enhancing the activity of plasma cholesterol l ester transfer protein (CETP) and strengthening the liver scavenger receptor type I, resulting in reducing LDL-C; by increasing the activity of paraoxonase 1, upregulating the antioxidant function of high-density lipoprotein (HDL), and it decreases the serum HDL-cholesterol (HDL-C) level. This drug has been retired from the Western markets for lowering HDL-C levels and Q-interval prolongation. The latter side effect has been rarely reported and may be transient. Recent clinical evidence supports the effectiveness of PU in preventing cardiovascular events and in reducing mortality, irrespective of the reduction of HDL-C. Based on basic research and clinical studies, it appears that PU might be a valuable alternative when statins are ineffective or contraindicated, in patients at high risk of recurrence of cerebral ischemia and hemorrhage. Show less

The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. Show less

The structural-functional organization of ammonia and glutamine metabolism in the liver acinus involves highly specialized hepatocyte subpopulations like glutamine synthetase (GS) expressing perivenous hepatocytes (scavenger cells). However, this cell population has not yet been characterized extensively regarding expression of other genes and potential subpopulations. This was investigated in the present study by proteome profiling of periportal GS-negative and perivenous GS-expressing hepatocytes from mouse and rat. Apart from established markers of GS Show less

Intestinal microbes and their metabolites affect the development of colorectal cancer (CRC). Short-chain fatty acids are metabolites generated by intestinal microbes from dietary fiber. We investigated the mechanisms by which free fatty acid receptor 2 (FFAR2), a receptor for short-chain fatty acids that can affect the composition of the intestinal microbiome, contributes to the pathogenesis of CRC. We performed studies with Apc Apc Loss of FFAR2 promotes colon tumorigenesis in mice by reducing gut barrier integrity, increasing tumor bacterial load, promoting exhaustion of CD8 Show less

Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. The overexpression of COUP-TFII has been observed in several types of malignancies. However, its role in ICC progression remains unclear. In this study, we found that the protein level of COUP-TFII was increased, but the mRNA level was unchanged in ICC tissues. High protein expression was positively associated with tumor size, lymph node metastasis, and poor prognosis in ICC patients. Furthermore, the overexpression of COUP-TFII promoted the proliferation, migration, and invasion of ICC cells in vitro and enhanced tumor growth and metastasis in nude mouse models. Mechanistic studies revealed that COUP-TFII induced epithelial-to-mesenchymal transition in ICC cells by upregulating Snail expression. Moreover, the activation of PI3K/AKT signaling led to the upregulation of COUP-TFII protein expression in ICC. Together, these findings indicate that COUP-TFII promotes epithelial-to-mesenchymal transition and metastasis in ICC and suggest that this protein is a potential target for adjuvant therapy for these patients. Show less

Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass. Show less

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions, difficulty with communication, and repetitive behavior patterns. In humans affected by ASD, there is a male pre-disposition towards the condition with a male to female ratio of 4:1. In part due to the complex etiology of ASD including genetic and environmental interplay, there are currently no available medical therapies to improve the social deficits of ASD. Studies in rodent models and humans have shown promising therapeutic effects of oxytocin in modulating social adaptation. One pharmacological approach to stimulating oxytocinergic activity is the melanocortin receptor 4 agonist Melanotan-II (MT-II). Notably the effects of oxytocin on environmental rodent autism models has not been investigated to date. We used a maternal immune activation (MIA) mouse model of autism to assess the therapeutic potential of MT-II on autism-like features in adult male mice. The male MIA mice exhibited autism-like features including impaired social behavioral metrics, diminished vocal communication, and increased repetitive behaviors. Continuous administration of MT-II to male MIA mice over a seven-day course resulted in rescue of social behavioral metrics. Normal background C57 male mice treated with MT-II showed no significant alteration in social behavioral metrics. Additionally, there was no change in anxiety-like or repetitive behaviors following MT-II treatment of normal C57 mice, though there was significant weight loss following subacute treatment. These data demonstrate MT-II as an effective agent for improving autism-like behavioral deficits in the adult male MIA mouse model of autism. Show less

Synaptic damage precedes neuron death in Alzheimer's disease (AD). Neurexins, NRXN1, NRXN2, and NRXN3, are presynaptic adhesion molecules that specify neuron synapses and regulate neurotransmitter release. Neurexins and postsynaptic neuroligins interact with amyloid beta oligomer (AβO) deposits in damaged synapses. NRXN3 gene variants have been associated with autism, addiction, and schizophrenia, however, not fully investigated in Alzheimer's disease. In the present study, we investigated an AD association of a 3'-splicing allele of rs8019381 that produces altered expression of transmembrane or soluble NRXN3 isoforms. We carried out RT-PCR (reverse transcription polymerase chain reaction), PCR-RFLP (PCR and restriction fragment length polymorphism), Sanger sequencing, and in situ hybridization (ISH) assays for NRXN3 neuron expression and genotyping. Genetic associations were analyzed by χ We previously identified a functional haplotype in the 3' region of neurexin 3 (NRXN3) gene that alters the expression ratios between NRXN3 transmembrane and soluble isoforms. In this study, we found that expression and ratio of transmembrane and soluble NRXN3 isoforms were reduced in AD postmortem brains and inversely correlated with inflammasome component NLRP3 in AD brain regions. The splicing haplotype related to the transmembrane and soluble NRXN3 expression was associated with AD samples with P = 6.3 × 10 We found that the SNP rs8019381 of NRXN3 that is located adjacent to splicing site #5 (SS#5) interacts with the APOE ε4 haplotype and alters NRXN3 transmembrane or soluble isoform expression in AD postmortem cortex. Dysregulation of presynaptic NRXN3 expression and splicing might increase neuron inflammation in AD brain. Show less

To investigate whether angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) are differentially associated with the severity of retinopathy in patients with type 2 diabetes mellitus (T2DM). Cross-sectional study. Serum levels of ANGPTL3, ANGPTL4, high-sensitivity C-reactive protein (CRP), vascular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and vascular endothelial growth factor (VEGF) were quantified by ELISA. Retinal images were recorded to assess the grade of diabetic retinopathy (DR). Multivariable-adjusted logistic analysis was performed to estimate the association of each biomarker and DR stage. Among 1192 T2DM patients, 426 (35.7%) had nonproliferative diabetic retinopathy (NPDR) and 56 (4.5%) had proliferative diabetic retinopathy (PDR). After adjusting for covariables, the odds ratios expressing the risk of having DR vs no DR (n = 710 vs 482) were 1.23 (95% confidence interval [CI], 1.08-1.40, P = .002) for ANGPTL3; 0.90 (95% CI, 0.79-1.02; P = .095) for ANGPTL4; and 1.14 (95% CI, 1.00-1.29; P = .044) for VEGF. The risk of having no DR vs NPDR (n = 710 vs 426) was 1.16 (95% CI, 1.01-1.32; P = .036) for ANGPTL3; 0.90 (95% CI, 0.79-1.04; P = .15) for ANGPTL4; and 1.14 (95% CI, 1.00-1.31; P = .045) for VEGF. The odds ratios of having NPDR vs PDR (n = 426 vs 56) was 1.47 (95% CI, 1.03-2.10; P = .035) for serum ANGPTL3; 0.96 (95% CI, 0.69-1.35; P = .83) for ANGPTL4; and 1.05 (95% CI, 0.77-1.45; P = .74) for VEGF. ANGPTL3 is independently and strongly associated with DR progression in all stages. Blockade of ANGPTL3 signal in retina might postpone the onset and development of DR in T2DM patients. Show less

To explore the genetic basis for a neonate featuring hyperammonemia. The patient was examined and tested by tandem mass spectrometry and next generation sequencing (NGS). Suspected mutations were confirmed by Sanger sequencing of the proband and her parents. Potential impact of the mutation was predicted with SIFT, PolyPhen-2 and MutationTaste software. Plasma ammonia and alanine were significantly increased in the proband, while serum citrulline was decreased. The neonate was found to harbor compound heterozygous mutations of the CPS1 gene [c.1631C>T(p.T544M) and c.1981G>T(p.G661C)], which were respectively inherited from her father and mother. The carbamoyl phosphate synthetase I deficiency of the proband can probably be attributed to the mutations of the CPS1 gene. Above finding has expanded the spectrum of CPS1 mutations in association with carbamoyl phosphate synthetase I deficiency. Show less

ANGPTL4 (angiopoietin-like protein 4) is a LPL (lipoprotein lipase) inhibitor and is present in high-density lipoprotein (HDL). However, it is not defined whether ANGPTL4 in HDLs could affect HDL metabolism and function in type 2 diabetes mellitus (T2DM). ANGPTL4 levels in the circulation and HDLs were quantified in nondiabetic participants (n=201, 68.7% females) and T2DM patients (n=185, 66.5% females). HDLs were isolated from nondiabetic controls and T2DM patients to assess cholesterol efflux Physically, ANGPTL4 in HDLs protected HDLs from hydrolysis. Resulting from increased circulating ANGPTL4 levels in T2DM, ANGPTL4 levels in HDLs were elevated but with compromised inhibitory effect on EL, leading to increased HDL hydrolysis and dysfunction. Show less

Excessive alcohol (EtOH) consumption causes an imbalance in protein metabolism. EtOH impairs protein synthesis in C2C12 myoblasts via a FoxO1-AMPK-TSC2-mTORC1 pathway and also induces protein degradation. As the underlying regulatory signaling cascades for these processes are currently poorly defined, we tested the hypothesis that alcohol-induced autophagy is mediated via activation of the PIK3C3 complex that is regulated by FoxO1-AMPK. C2C12 myoblasts were incubated with EtOH for various periods of time, and autophagy pathway-related proteins were assessed by Western blotting and immunoprecipitation. Expression of targeted genes was suppressed using electroporation of specific siRNAs and chemical inhibitors. Incubation of C2C12 myoblasts with 100 mM EtOH increased the autophagy markers LC3B-II and ATG7, whereas levels of SQSTM1/p62 decreased. The lysosomal inhibitor bafilomycin A1 caused a similar response, although there was no additive effect when combined with EtOH. EtOH altered ULK1 S555 and S757 phosphorylation in a time- and AMPK-dependent manner. The activation of AMPK and ULK1 was associated with increased BECN1 (S93, S14) and PIK3C3/VPS34 (S164) phosphorylation as well as increased total ATG14 and PIK3C3. These changes promoted formation of the ATG14-AMBRA1-BECN1-PIK3C3 proautophagy complex that is important in autophagosome formation. EtOH-induced changes were not associated with increased production of PtdIns3P, which may be due to enhanced PIK3C3 complex binding with 14-3-3θ. Reduction of AMPK using siRNA suppressed the stimulatory effect of EtOH on BECN1 S93, BECN1 S14, and PIK3C3 S164 phosphorylation in a time-dependent manner. Likewise, knockdown of AMPK or chemical inhibition of FoxO1 attenuated phosphorylation of ULK1 at both residues. Knockdown of ULK1 or BECN1 antagonized the effect of EtOH on LC3B-II, SQSTM1, and ATG7 protein expression. EtOH-induced autophagy is mediated through changes in phosphorylation and interaction of various PIK3C3 complex components. This, in turn, is regulated either directly via FoxO1-AMPK or indirectly via the FoxO1-AMPK-ULK1 signaling cascade in a mTORC1-independent or mTORC1-dependent manner. Show less