Glial fibrillary acidic protein levels are associated with global histone H4 acetylation after spinal cord injury in rats

Emerging evidence has suggested global histone H4 acetylation status plays an important role in neural plasticity. For instance, the imbalance of this epigenetic marker has been hypothesized as a key factor for the development and progression of several neurological diseases. Likewise, astrocytic reactivity-a wellknown process that markedly influences the tissue remodeling after a central nervous system injury-is crucial for tissue remodeling after spinal cord injury（SCI）. However, the linkage between the above-mentioned mechanisms after SCI remains poorly understood. We sought to investigate the relation between both glial fibrillary acidic protein（GFAP） and S100 calcium-binding protein B（S100B）（astrocytic reactivity classical markers） and global histone H4 acetylation levels. Sixty-one male Wistar rats（aged ~3 months） were divided into the following groups： sham; 6 hours post-SCI; 24 hours post-SCI; 48 hours post-SCI; 72 hours post-SCI; and 7 days post-SCI. The results suggested that GFAP, but not S100B was associated with global histone H4 acetylation levels. Moreover, global histone H4 acetylation levels exhibited a complex pattern after SCI, encompassing at least three clearly defined phases（first phase： no changes in the 6, 24 and 48 hours post-SCI groups; second phase： increased levels in the 72 hours post-SCI group; and a third phase： return to levels similar to control in the 7 days post-SCI group）. Overall, these findings suggest global H4 acetylation levels exhibit distinct patterns of expression during the first week post-SCI, which may be associated with GFAP levels in the perilesional tissue. Current data encourage studies using H4 acetylation as a possible biomarker for tissue remodeling after spinal cord injury.

Cellular senescence:from anti-cancer weapon to anti-aging target

Cellular senescence(CS)is a state of stable cell cycle arrest characterized by the production and secretion of inflammatory molecules.Early studies described oncogene-induced senescence(OIS)as a barrier to tumorigenesis,such that the therapeutic induction of CS might represent a rational anti-cancer strategy.Indeed,the validity of this approach has been borne out by the development and approval of the cyclin-dependent kinase(CDK)inhibitor palbociclib for the treatment of breast cancer.Apart from tumors,senescent cells have also been shown to accumulate during natural mammalian aging,where they produce detrimental effects on the physiology of surrounding tissues.Thus,pharmacological senescent cell depletion has been proposed as an approach to delay age-related functional decline;this has been formally demonstrated in animal models.In this review article,we describe the current mechanistic understanding of cellular senescence at the molecular level and how it informs the development of new therapeutic strategies to combat cancer and aging.

LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells

LIN28 is an RNA binding protein with important roles in early embryo development,stem cell differentiation/re-programming,tumorigenesis and metabolism.Previous studies have focused mainly on its role in the cytosol where it interacts with Let-7 microRNA precursors or mRNAs,and few have addressed LIN28's role within the nucleus.Here,we show that LIN28 displays dynamic temporal and spatial expression during murine embryo development.Maternal LIN28 expression drops upon exit from the 2-cell stage,and zygotic LIN28 protein is induced at the forming nucleolus during 4-cell to blas-tocyst stage development,to become dominantly expressed in the cytosol after implantation.In cultured pluripotent stem cells(PSCs),loss of LIN28 led to nucleolar stress and activation of a 2-cell/4-cell-like transcriptional program characterized by the expression of endogenous retrovirus genes.Mechanistically,LIN28 binds to small nucleolar RNAs and rRNA to maintain nucleolar integrity,and its loss leads to nucleolar phase separation defects,ribosomal stress and activation of P53 which in turn binds to and activates 2C transcription factor Dux.LIN28 also resides in a complex containing the nucleolar factor Nucleolin(NCL)and the transcrip-tional repressor TRIM28,and LIN28 loss leads to reduced occupancy of the NCL/TRIM28 complex on the Dux and rDNA loci,and thus de-repressed Dux and reduced rRNA expression.Lin28 knockout cells with nucleolar stress are more likely to assume a slowly cycling,translationally inert and anabolically inactive state,which is a part of previously unappreciated 2C-like transcriptional program.These findings elucidate novel roles for nucleolar LIN28 in PSCs,and a new mechanism linking 2C program and nucleolar functions in PSCs and early embryo development.

Supramolecular organizing centers(SMOCs) as signaling machines in innate immune activation

Innate immunity offers the first line of defense against infections and other types of danger such as tumorigenesis. Its discovery provides tremendous therapeutic opportunities for numerous human diseases. Delving into the structural basis of signal transduction by innate immune receptors, our lab has recently helped to establish the new paradigm in which innate immune receptors transduce ligand-binding signals through formation of higher-order assemblies containing intracellular adapters, signaling enzymes and their substrates. These large signalosome assemblies may be visible under light microscopy as punctate structures in the μm scale, connecting to the underlying molecular structures in the nm scale. They drive proximity-induced enzyme activation, and provide a mechanism for signaling amplification by nucleated polymerization. These supramolecular signaling complexes also open new questions on their cellular organization and mode of regulation, pose challenges to our methodology, and afford valuable implications in drug discovery against these medically important pathways.

The role of Nkx3.2 in chondrogenesis

Transcription factor, Nkx3.2, is a member of the NK family of developmental genes and is expressed during embryogenesis in a variety of mammalian model organisms, including chicken and mouse. It was first identified in Drosophila as the Bagpipe （bap） gene, where it has been demonstrated to be essential during formation of the midgut musculature. However, mammalian homolog Nkx3.2 has been shown to play a significant role in axial and limb skeletogenesis; in particular, the human skeletal disease, spondylo-megaepiphyseal-metaphyseal dysplasia （SMMD）, is associated with mutations of the Nkx3.2 gene. In this review, we highlight the role of Nkx3.2 during musculoskeletal development, with an emphasis on the factor＇s role in determining chondrogenic cell fate and its subsequent role in endochondral ossification and chondrocyte survival.

Higher-order assemblies in immune signaling:supramolecular complexes and phase separation

Signaling pathways in innate and adaptive immunity play vital roles in pathogen recognition and the functions of immune cells.Higher-order assemblies have recently emerged as a central principle that governs immune signaling and,by extension,cellular communication in general.There are mainly two types of higher-order assemblies:1)ordered,solid-like large supramolecular complexes formed by stable and rigid protein-protein interactions,and 2)liquid-like phase-separated condensates formed by weaker and more dynamic intermolecular interactions.This review covers key examples of both types of higher-order assemblies in major immune pathways.By placing emphasis on the molecular structures of the examples provided,we discuss how their structural organization enables elegant mechanisms of signaling regulation.

Resistance mechanism to cisplatin in NCI-H460 non-small cell lung cancer cell line:investigating apoptosis,autophagy,and cytogenetic damage

Aim:To investigate the effects of cisplatin on the human non-small cell lung carcinoma(NCI-H460)cell line regarding cytotoxicity,genotoxicity,and expression of genes associated with apoptosis(BIRC5)and autophagy(BECN1).Methods:Cell cultures were treated with cisplatin concentrations(0.16-33.3μmol/L)for 48 h.Mutagenicity and acute and chronic cytotoxicities were assessed using the MTT,clonogenic,and cytokinesis-block micronucleus assays.Gene expression of BIRC5 and BECN1 was evaluated by reverse transcription-polymerase chain reaction.Results:Cisplatin IC50(0.33μmol/L)increased micronucleus frequency 2.50 times.Cisplatin was also cytotoxic in the 0.6-33.3μmol/L range,with reduced expression of the BIRC5 gene,suggesting induction of apoptosis.Besides reducing the expression of the BIRC5 gene,33.3μmol/L cisplatin increased the expression of the BECN1 gene,suggesting that autophagy can be related to cisplatin resistance.Conclusion:Cisplatin inhibited NCI-H460 growth,and cisplatin IC50 induced genotoxic damage.When higher cisplatin concentrations are used,the expression of genes associated with apoptosis and autophagy was changed.This results points to a further investigation of the role of autophagy in cisplatin resistance.

Neural regulation of CNS angiogenesis during development

Vertebrates have evolved a powerful vascular system that involves close interactions between blood vessels and target tissues. Vascular biology had been mostly focused on the study of blood vessels for decades, which has generated large bodies of knowledge on vascular cell development, function and pathology. We argue that the prime time has arrived for vascular research on vessel-tissue interactions, especially target tissue regulation of vessel development. The central nervous system （CNS） requires a highly efficient vascular system for oxygen and nutrient transport as well as waste disposal. Therefore, neurovascular interaction is an excellent entry point to understanding target tissue regulation of blood vessel development. In this review, we summarize signaling pathways that transmit information from neural cells to blood vessels during development and the mechanisms by which they regulate each step of CNS angiogenesis. We also review important mechanisms of neural regulation of blood-brain barrier establishment and maturation, highlighting different functions of neural progenitor cells and pericytes. Finally, we evaluate potential contribution of malfunctioning neurovascular signaling to the development of brain vascular diseases and discuss how neurovascular interactions could be involved in brain tumor angiogenesis.

Stroke-like onset of brain stem degeneration presents with unique MRI sign and heterozygous NMNAT2 variant:a case report

Background:Acute-onset neurodegenerative diseases in older patients are rare clinical cases,especially when the degeneration only affects specific regions of the nervous system.Several neurological disorders have been described in which the degeneration of brain parenchyma originates from and/or primarily affects the brain stem.Clinical diagnosis in these patients,however,is often complicated due to a poor understanding of these diseases and their underlying mechanisms.Case presentation:In this manuscript we report on a 73-year-old female who had experienced a sudden onset of complex neurological symptoms that progressively worsened over a period of 2 years.Original evaluation had suggested a MRI-negative stroke as underlying pathogenesis.The combination of patient’s medical history,clinical examination and exceptional pattern of brain stem degeneration presenting as“kissing swan sign”in MR imaging was strongly suggestive of acute onset of Alexander’s disease.This leukoencephalopathy is caused by GFAP(glial fibrilary acidic protein)gene mutations and may present with brain stem atrophy and stroke-like onset of symptoms in elderly individuals.However,a pathognomonic GFAP gene mutation could not be identified by Sanger sequencing.Conclusions:After an extended differential diagnosis and exclusion of other diseases,a definite diagnosis of the patient’s condition presently remains elusive.However,whole-exome sequencing performed from patient’s blood revealed 12 potentially disease-causative heterozygous variants,amongst which several have been associated with neurological disorders in vitro and in vivo–in particular the axon degeneration-related NMNAT2 gene.

Computational approaches to understanding protein aggregation in neurodegeneration

有毒的外国人蛋白质 conformers 的产生作为一个统一线程出现在象 Alzheimer'sdisease， Parkinson 的疾病，和 amyotrophic 那样的混乱之中侧面的硬化。关于动态变化的原子水平的详细那 facilitateprotein 聚集，以及大规模订的总数和可溶的外国人 oligomers 的结构的特征，将为细胞毒素的种类的 inhibitingformation 显著地作出贡献到这些复杂现象和提议潜力策略的当前的理解。然而，试验性的限制经常预防高分辨率的 structuraland 的获得为聚集系统的机械学的信息。计算方法，特别地，那些联合所有原子和 coarse-grainedsimulations 盖住大量时间和长度规模，因此为调查 proteinaggregation 作为关键工具出现了。这里，我们为蛋白质的学习考察计算方法论的当前的状态自己组装，与向在人的 neurodegenerative 混乱的蛋白质总数的理解的这些方法的申请上的 afocus。

Interleukins in Epilepsy:Friend or Foe

Epilepsy is a chronic neurological disorder with recurrent unprovoked seizures,affecting~65 million worldwide.Evidence in patients with epilepsy and animal models suggests a contribution of neuroinflammation to epileptogenesis and the development of epilepsy.Interleukins(ILs),as one of the major contributors to neuroinflammation,are intensively studied for their association and modulatory effects on ictogenesis and epileptogenesis.ILs are commonly divided into pro-and anti-inflammatory cytokines and therefore are expected to be pathogenic or neuroprotective in epilepsy.However,both protective and destructive effects have been reported for many ILs.This may be due to the complex nature of ILs,and also possibly due to the different disease courses that those ILs are involved in.In this review,we summarize the contributions of different ILs in those processes and provide a current overview of recent research advances,as well as preclinical and clinical studies targeting ILs in the treatment of epilepsy.

Prostate cancer and chemoprevention by natural dietary phytochemicals

Prostate cancer is the second leading cancer among men in the United States. Several studies have correlated the development of prostate cancer with diet and life-style. Therefore, a balanced diet and improved life style might inhibit prostate cancer progression. Cancer chemoprevention has emerged as an important factor in controlling cancer development through natural or synthetic compounds. Oxidative stress is among the factors contributing to prostate cancer development. The transcription factor nuclear factor(erythroid-derived 2)-like 2(Nrf2) controls detoxifying antioxidant enzymes expression by binding to the antioxidant response element(ARE) in the promoter of these genes to activate their expression. Many natural products can fight oxidative stress and protects cells from DNA damage by activating the Nrf2/ARE pathway. High consumption of fruits and vegetables can reduce disease incidence and invasive tumors. In this review, the roles of important fruit and vegetable phytochemicals in regulating prostate cancer progression and tumor growth are discussed.