Role of the NLRP3 inflammasome in neurodegenerative diseases and therapeutic implications

Neurodegenerative diseases are a group of neuronal disorders caused by progressive neuronal cell death in different regions of the human brain.Alzheimer's disease(AD)and Parkinson's disease(PD)are the most common types of neurodegenerative diseases that affect millions of people worldwide.There is no cure available for either disease.One of the pathological hallmarks of neurodegenerative diseases is the abnormal protein aggregation in the central nervous system.

Chromosome-scale genome sequence of Suaeda glauca sheds light on salt stress tolerance in halophytes

Soil salinity is a growing concern for global crop production and the sustainable development of humanity.Therefore,it is crucial to comprehend salt tolerance mechanisms and identify salt-tolerance genes to enhance crop tolerance to salt stress.Suaeda glauca,a halophyte species well adapted to the seawater environment,possesses a unique ability to absorb and retain high salt concentrations within its cells,particularly in its leaves,suggesting the presence of a distinct mechanism for salt tolerance.In this study,we performed de novo sequencing of the S.glauca genome.The genome has a size of 1.02 Gb(consisting of two sets of haplotypes)and contains 54761 annotated genes,including alleles and repeats.Comparative genomic analysis revealed a strong synteny between the genomes of S.glauca and Beta vulgaris.Of the S.glauca genome,70.56%comprises repeat sequences,with retroelements being the most abundant.Leveraging the allele-aware assembly of the S.glauca genome,we investigated genome-wide allele-specific expression in the analyzed samples.The results indicated that the diversity in promoter sequences might contribute to consistent allele-specific expression.Moreover,a systematic analysis of the ABCE gene families shed light on the formation of S.glauca’s flower morphology,suggesting that dysfunction of A-class genes is responsible for the absence of petals in S.glauca.Gene family expansion analysis demonstrated significant enrichment of Gene Ontology(GO)terms associated with DNA repair,chromosome stability,DNA demethylation,cation binding,and red/far-red light signaling pathways in the co-expanded gene families of S.glauca and S.aralocaspica,in comparison with glycophytic species within the chenopodium family.Time-course transcriptome analysis under salt treatments revealed detailed responses of S.glauca to salt tolerance,and the enrichment of the transition-upregulated genes in the leaves associated with DNA repair and chromosome stability,lipid biosynthetic process,and isoprenoid metabolic process.Additionally,genome-wide analysis of transcription factors indicated a significant expansion of FAR1 gene family.However,further investigation is needed to determine the exact role of the FAR1 gene family in salt tolerance in S.glauca.

Dual activities of a silencing information regulator complex in yeast transcriptional regulation and DNA-damage response

The Saccharomyces cerevisiae silencing information regulator(SIR)complex contains up to four proteins,namely Sir1,Sir2,Sir3,and Sir4.While Sir2 encodes a NAD-dependent histone deacetylase,other SIR proteins mainly function as structural and scaffold components through physical interaction with various proteins.The SIR complex displays different conformation and composition,including Sir2 homotrimer,Sir1-4 heterotetramer,Sir2-4 heterotrimer,and their derivatives,which recycle and relocate to different chromosomal regions.Major activities of the SIR complex are transcriptional silencing through chromosomal remodeling and modulation of DNA double-strand-break repair pathways.These activities allow the SIR complex to be involved in mating-type maintenance and switching,telomere and subtelomere gene silencing,promotion of nonhomologous end joining,and inhibition of homologous recombination,as well as control of cell aging.This review explores the potential link between epigenetic regulation and DNA damage response conferred by the SIR complex under various conditions aiming at understanding its roles in balancing cell survival and genomic stability in response to internal and environmental stresses.As core activities of the SIR complex are highly conserved in eukaryotes from yeast to humans,knowledge obtained in the yeast may apply to mammalian Sirtuin homologs and related diseases.

Postprandial hyperglycemia and postprandial hypertriglyceridemia in type 2 diabetes

Postprandial glucose level is an independent risk factor for cardiovascular disease that exerts effects greater than glucose levels at fasting state, whereas increase in serum triglyceride level, under both fasting and postprandial conditions, contributes to the development of arteriosclerosis. Insulin resistance is a prevailing cause of abnormalities in postabsorptive excursion of blood glucose and postprandial lipid profile. Excess fat deposition renders a vicious cycle of hyperglycemia and hypertriglyceridemia in the postprandial state, and both of which are contributors to atherosclerotic change of vessels especially in patients with type 2 diabetes mellitus. Several therapeutic approaches for ameliorating each of these abnormalities have been attempted, including various antidiabetic agents or new compounds targeting lipid metabolism.

Neuronal protein-tyrosine phosphatase 1B hinders sensory-motor functional recovery and causes affective disorders in two different focal ischemic stroke models

Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.

Insensitivity of PI3K/Akt/GSK3 signaling in peripheral blood mononuclear cells of age-related macular degeneration patients

Our recent studies with cultured retinal pigment epithelium cells suggested that overexpression of interleukin 17 receptor C（IL-17RC）,a phenomenon observed in peripheral blood and chorioretinal tissues with age-related macular degeneration（AMD）,was associated with altered activation of phosphatidylinositide 3-kinase（PI3K）,Akt,and glycogen synthase kinase 3（GSK3）.We wondered whether or not altered PI3 K,Akt,and GSK3 activities could be detected in peripheral blood mononuclear cells（PBMC） obtained from AMD patients.In the patients＇ PBMC,absent or reduced serine-phosphorylation of GSK3α or GSK3β was observed,which was accompanied with increased phosphorylation of GSK3 substrates（e.g.CCAAT enhancer binding protein a,insulin receptor substrate 1,and TAU）,indicative of enhanced GSK3 activation.In addition,decreased protein mass of PI3K85α and tyrosinephosphorylation of PI3K50α was present in PBMC of the AMD patients,suggesting impaired PI3 K activation.Moreover,abnormally lowered molecular weight forms of Akt and GSK3 were detected in PBMC of the AMD patients.These data demonstrate that despite the presence of high levels of IL-17 RC,Wnt-3a and vascular endothelial growth factor,the PI3K/Akt/GSK3 signaling pathway is insensitive to these stimuli in PBMC of the AMD patients.Thus,measurement of PI3K/Akt/GSK3 expression and activity in PBMC may serve as a surrogate biomarker for AMD.

Nef-M1, a CXCR4 Peptide Antagonist, Enhances Apoptosis and Inhibits Primary Tumor Growth and Metastasis in Breast Cancer

Results from studies with animal models suggest that, in many cancers, CXCR4 is an important therapeutic target and that CXCR4 antagonists may be promising treatments for primary cancers and for metastases. The Nef protein effectively competes with CXCR4’s natural ligand, SDF-1α, and induces apoptosis. As described in this report, the Nef-M1 peptide (Nef protein amino acids 50 - 60) inhibits primary tumor growth and metastasis of breast cancer (BC). Four BC cell lines (MDA-MB-231, MDA-MB-468, MCF 7, and DU4475) and primary human mammary epithelium (HME) cells were evaluated for their response to the Nef protein and to the Nef-M1 peptide. The presence of CXCR4 receptors in these cells was determined by RT-PCR, Western blot (WB), and immunohistochemical analyses. The apoptotic effect of Nef-M1 was assessed by terminal transferase dUTP nick-end labeling (TUNEL). WBs was used to assess caspase 3 activation. BC xenografts grown in SCID mice were evaluated for the presence of CXCR4 and for their metastatic potential. CXCR4 was presented in MDA-MB-231, MCF 7, and DU 4475 BC cells but not in MDA-MB-468 BC or HME cells. Cells expressing CXCR4 and treated with Nef-M1 peptide or the Nef protein had higher rates of apoptosis than untreated cells. Caspase-3 activation increased in MDA-MB 231 cells treated with the Nef protein, the Nef 41 - 60 peptide, or Nef-M1. Nef-M1, administered to mice starting at the time of xenograft implantation, inhibited growth of primary tumors and metastatic spread. Untreated mice developed diffuse intraperitoneal metastases. We conclude that, in BCs, Nef-M1, through interaction with CXCR4, inhibits primary tumor growth and metastasis by causing apoptosis.

Non-alcoholic fatty liver disease: a narrative review of genetics

Non-alcoholic fatty liver disease(NAFLD) is now the most common cause of chronic liver diseases worldwide. It encompasses a spectrum of disorders ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis(NASH),fibrosis, cirrhosis, and hepatocellular carcinoma. One of the key challenges in NAFLD is identifying which patients will progress. Epidemiological and genetic studies indicate a strong pattern of heritability that may explain some of the variability in NAFLD phenotype and risk of progression. To date, at least three common genetic variants in the PNPLA3, TM6 SF2, and GCKR genes have been robustly linked to NAFLD in the population. The function of these genes revealed novel pathways implicated in both the development and progression of NAFLD. In addition,candidate genes previously implicated in NAFLD pathogenesis have also been identified as determinants or modulators of NAFLD phenotype including genes involved in hepatocellular lipid handling, insulin resistance,inflammation, and fibrogenesis. This article will review the current understanding of the genetics underpinning the development of hepatic steatosis and the progression of NASH. These newly acquired insights may transform our strategy to risk-stratify patients with NAFLD and to identify new potential therapeutic targets.

Re-evaluating the role of epithelial-mesenchymal-transition in cancer progression

Epithelial-mesenchymal transition（EMT） and mesenchymal-epithelial transition（MET） are essential for embryonic development and also important in cancer progression. In a conventional model, epithelial-like cancer cells transit to mesenchymal-like tumor cells with great motility via EMT transcription factors; these mesenchymallike cells migrate through the circulation system, relocate to a suitable site and then convert back to an epithelial-like phenotype to regenerate the tumor. However, recent findings challenge this conventional model and support the existence of a stable hybrid epithelial/mesenchymal（E/M） tumor population. Hybrid E/M tumor cells exhibit both epithelial and mesenchymal properties, possess great metastatic and tumorigenic capacity and are associated with poorer patient prognosis. The hybrid E/M model and associated regulatory networks represent a conceptual change regarding tumor metastasis and organ colonization. It may lead to the development of novel treatment strategies to ultimately stop cancer progression and improve disease-free survival.

N-methyl-D-aspartate receptor functions altered by neuronal PTP1B activation in Alzheimer’s disease and schizophrenia models

Glutamate is the main exc i tatory neurotransmitter in the brain and binds to two major classes of receptors,theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)and the N-methyl-D-aspartate(NMDA)receptors.Unlike AMPA receptors that are immediately activated by glutamate release,NMDA receptors are blocked by magnesium and can only be activated by glutamate after membrane depolarization.Thus,NMDA receptors are only activated after repeated AMPA receptor activation by glutamate.NMDA receptors are,for the most part,calcium-permeable channels.Calcium influx through NMDA receptors modulates synaptic transmission in neurons based on prior history of excitation,and provides a means of scaling the strength of synapses required for Hebbian plasticity.

Unraveling complexity of interconnected regulatory circuits in lipid metabolism

In this issue of Journal of Biomedical Research,3review articles are published that cover a broad range of topics addressing current understanding on regulation of nutrient metabolism through protein phosphatases,homeostatic regulation of cellular lipid droplets by small GTPases,and mechanisms by which hepatic assembly and secretion of triglyceride-rich lipoproteins are regulated.

Lipoprotein metabolism in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease （NAFLD）, an pathologies characterized by fatty accumulation in escalating health problem worldwide, covers a spectrum of hepatocytes in early stages, with potential progression to liver inflammation, fibrosis, and failure. A close, yet poorly understood link exists between NAFLD and dyslipidemia, a constellation of abnormalities in plasma lipoproteins including triglyceride-rich very low density lipoproteins. Apolipoproteins are a group of primarily liver-derived proteins found in serum lipoproteins; they not only play an extracellular role in lipid transport between vital organs through circulation, but also play an important intracellu- lar role in hepatic lipoprotein assembly and secretion. The liver functions as the central hub for lipoprotein metab- olism, as it dictates lipoprotein production and to a significant extent modulates lipoprotein clearance. Lipoprotein metabolism is an integral component of hepatocellular lipid homeostasis and is implicated in the pathogenesis, potential diagnosis, and treatment of NAFLD.

Mapping the human protein interactome

Interactions are the essence of all biomolecules because they cannot fulfill their roles without interacting with other molecules. Hence, mapping the interactions of biomolecules can be useful for understanding their roles and functions. Furthermore, the development of molecular based systems biology requires an understanding of the biomolecular interactions. In recent years, the mapping of protein-protein interactions in different species has been reported, but few reports have focused on the large-scale mapping of protein-protein interactions in human. Here, we review the developments in protein interaction mapping and we discuss issues and strategies for the mapping of the human protein interactome.

Is vitamin D receptor a druggable target for non-alcoholic steatohepatitis?

Nonalcoholic steatohepatitis(NASH)is a progressed stage of non-alcoholic fatty liver disease,and available therapeutic strategies for NASH are limited.Vitamin D receptor(VDR)is proposed as a druggable target for NASH due to the discovery of vitamin D deficiency in NASH patients.To date,vitamin D supplementation has not consistently conferred expected therapeutic benefits,raising the question of whether VDR can serve as a proper drug target for NASH.It is known that VDR can interact with other ligands such as bile acids in addition to vitamin D,and its expression can be induced by fatty acids,and insulin.It has also been shown that while activation of VDR in hepatic macrophages and hepatic stellate cells resulted in attenuation of hepatic inflammation and fibrosis,activation of VDR in hepatocytes could accelerate lipid accumulation.Thus,the multiplicity of VDR ligands,together with the cell type-specificity of VDR activation,must be taken into consideration in assessing the validity of VDR being a potential druggable target for NASH treatment.To this end,we have evaluated the relationship between VDR activation and various contributing factors,such as gut microbiota,bile acid,fatty acids,and insulin,in addition to vitamin D,with an expectation that a potential drug might be identified that can elicit VDR activation in a tissue-and/or cell type-specific manner and therefore achieving therapeutic benefits in NASH.

Functional phenotypes of CCR5 on CD4+ T cells of relevance to its genetic and epigenetic associations with HIV infection

The article by Kulkarni et al.provides a description of some genetic and epigenetic interactions that determine the functional phenotypes of the chemokine receptor CCR5,which is critical to human immunodeficiency virus type 1(HIV-1)infection.1 Significant advances in the genetic regulation of human diseases have been made through the use of genome-wide association studies(GWASs)over the past several years.The daunting task of elucidating the cellular pathways that are critical to human disease regulation remains for many disease-associated coding genetic variants.

水动力尾静脉注射介导Akt/β-catenin/Yap质粒转染建立小鼠肝癌模型

目的通过应用水动力尾静脉注射(hydrodynamic tail vein injection,HTVi)Sleeping Beauty(SB)质粒及促癌基因质粒,构建一种新型小鼠肝癌模型。方法6周龄雄性C57BL/6J小鼠,按照体重随机分为对照组和模型组。将冻存的SB、Akt、β-catenin、Yap质粒转化入感受态E.coli DH5α大肠杆菌,于LB培养基扩增后提取质粒。每只模型组小鼠尾静脉快速注射上述质粒混合溶液2 mL,包含SB质粒5μg,Akt、β-catenin、Yap质粒分别15μg,对照组小鼠给予等量PBS尾静脉注射。继续饲养8周后处死小鼠,观察小鼠情况,记录体重、肝重。观察小鼠肝脏病理学变化,并应用Western blot法检测小鼠肝组织中Akt、β-catenin、Yap基因表达水平。结果高压注射质粒8周后,对照组小鼠活动度好,皮毛光亮;小鼠肝脏形态正常;肝组织HE染色显示,对照组小鼠肝小叶结构完整。模型组小鼠活动减少,皮毛无光泽。与对照组比较,模型组小鼠体重下降、肝重增加、肝体比显著上调;模型组小鼠肝脏体积增大,质地较硬,表面出现颗粒状、结节样改变;肝组织HE染色显示,模型组小鼠肝组织结构紊乱,并出现多个肿瘤结节。此外,与对照组相比,模型组小鼠肝组织中Akt、β-catenin、Yap基因表达均明显上调。结论应用水动力尾静脉注射SB质粒及Akt/β-catenin/Yap质粒的方法可成功建立小鼠肝癌模型,为肝癌发病机制及药物研发提供快速、经济的动物模型。

Integrated miRNA and mRNA Analysis Identified Potential Mechanisms and Targets of Qianggan Extracts in Preventing Nonalcoholic Steatohepatitis

Objective: Qianggan(QG) extract is a patented traditional Chinese medicine that has been widely used for the clinical treatment of nonalcoholic steatohepatitis(NASH). However, its mechanism remains unclear. Methods: The efficacy of QG was evaluated in mice with methionine-and-choline-deficient diet-induced NASH by measuring serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels and by H and E staining of liver sections. Microarray and bioinformatics analyses were performed to obtain hepatic micro RNA(mi RNA) and m RNA expression profiles and to mine potential mechanisms and therapeutic targets. Furthermore, representative mi RNA and m RNA expression levels were validated by quantitative real-time polymerase chain reaction(q RT-PCR). Results: QG extract significantly improved NASH. Twelve differentially expressed mi RNAs and 1124 differentially changed m RNAs were identified as potential targets of QG extract. Integrated analysis detected 976 mi RNA–m RNA regulatory pairs, and networks including 11 mi RNAs and 427 m RNAs were constructed by Cytoscape. Hub nodes including mi R-7050-5p, mi R-212-3p, Bcl2l11, and Kras were filtered out. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that 427 m RNAs were enriched in pathways including apoptotic process, immune response, Fox O signaling pathway, and natural killer cell-mediated cytotoxicity. We also constructed a protein–protein interaction network with 254 nodes, and identified hub genes including Kras, Fasl, and Ncam1. Finally, the results of q RT-PCR were in good accordance with microarray data. Conclusion: This study identified important hub mi RNAs and m RNAs involved in the mechanism of QG extract and which might provide potential therapeutic targets for patients with NASH.

Distinct strengths of mTORC1 control T-cell memory via transcriptional FOXO1 and metabolic AMPKα1 pathways in linear cell differentiation and asymmetric cell division models

CD8^(+)effector T(T_(E))cells play a critical role in immunity against infections.In response to a pathogenic stimulus,antigenpresenting cells(APCs)deliver three signals[via T-cell receptor(TCR),costimulation,and cytokines]to naive CD8^(+)T cells,stimulating their entry into a developmental program characterized by T-cell expansion followed by a contraction phase.During the contraction phase,90-95%of IL-7R^(-)CD62L^(-)KLRG1^(+)T_(E)cells undergo cell apoptosis.

Efficacy of polyphenolic ingredients of Chinese herbs in treating dyslipidemia of metabolic syndromes

There is an increasing interest and popularity of Chinese herbal medicine worldwide, which is accompanied by increasing concerns about its effectiveness and potential toxicity. Several ingredients, such as polyphenolic compounds berberine, flavonoids, and curcumin, have been studied extensively by using various animal models. Effectiveness of treatment and amelioration of metabolic syndromes, including insulin resistance and dyslipidemia, has been demonstrated. This review summarizes the major checkpoints and contributing factors in regulation of exogenous and endogenous lipid metabolism, with particular emphasis centered on triglyceride-rich and cholesterol-rich lipoproteins. Available experimental evidence demonstrating the lipid-lowering effect of berberine, flavonoids and curcumin in cell culture and animal models is compiled, and the strengths and shortcomings of experimental designs in these studies are discussed.

Maternal and fetal T cells in term pregnancy and preterm labor

Pregnancy is a state of immunological balance during which the mother and the developing fetus must tolerate each other while maintaining sufficient immunocompetence to ward off potential threats.The site of closest contact between the mother and fetus is the decidua,which represents the maternal–fetal interface.Many of the immune cell subsets present at the maternal–fetal interface have been well described;however,the importance of the maternal T cells in this compartment during late gestation and its complications,such as preterm labor and birth,has only recently been established.Moreover,pioneer and recent studies have indicated that fetal T cells are activated in different subsets of preterm labor and may elicit distinct inflammatory responses in the amniotic cavity,leading to preterm birth.In this review,we describe the established and proposed roles for maternal T cells at the maternal–fetal interface in normal term parturition,as well as the demonstrated contributions of such cells to the pathological process of preterm labor and birth.We also summarize the current knowledge of and proposed roles for fetal T cells in the pathophysiology of the preterm labor syndrome.It is our hope that this review provides a solid conceptual framework highlighting the importance of maternal and fetal T cells in late gestation and catalyzes new research questions that can further scientific understanding of these cells and their role in preterm labor and birth,the leading cause of neonatal mortality and morbidity worldwide.