Induction of IL-2 by interleukin-12 p40 homodimer and IL-12, but not IL-23, in microglia and macrophages: Implications for multiple sclerosis.

The level of IL-2 increases markedly in serum and central nervous system (CNS) of patients with multiple sclerosis (MS) and animals with experimental allergic encephalomyelitis (EAE). However, mechanisms by which IL-2 is induced under autoimmune demyelinating conditions are poorly understood. The present study underlines the importance of IL-12p40 homodimer (p40), the so-called biologically inactive molecule, in inducing the expression of IL-2 in mouse BV-2 microglial cells, primary mouse and human microglia, mouse peritoneal macrophages, RAW264.

Nuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism.

Chemotherapy-induced cardiac damage remains a leading cause of death amongst cancer survivors. Anthracycline-induced cardiotoxicity is mediated by severe mitochondrial injury, but little is known about the mechanisms by which cardiomyocytes adaptively respond to the injury. We observed the translocation of selected mitochondrial tricarboxylic acid (TCA) cycle dehydrogenases to the nucleus as an adaptive stress response to anthracycline-cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes and in vivo.

Increased Type I interferon signaling and brain endothelial barrier dysfunction in an experimental model of Alzheimer's disease.

Blood-brain barrier (BBB) dysfunction is emerging as a key pathogenic factor in the progression of Alzheimer's disease (AD), where increased microvascular endothelial permeability has been proposed to play an important role. However, the molecular mechanisms leading to increased brain microvascular permeability in AD are not fully understood. We studied brain endothelial permeability in female APPswe/PS1∆E9 (APP/PS1) mice which constitute a transgenic mouse model of amyloid-beta (Aβ) amyloidosis and found that permeability increases with aging in the areas showing the greatest amyloid plaque deposition.

Nuclear translocation of Atox1 potentiates activin A-induced cell migration and colony formation in colon cancer.

Background: Colorectal cancer remains a deadly cancer due to metastatic disease. To understand the molecular mechanisms of metastasis in colon cancer, we investigated whether the copper chaperone antioxidant-1 (Atox1) protein plays a role in this process. Recent findings indicate that Atox1 protein has transcription factor activities and plays a vital role in cell proliferation in cancer cells.

Endothelial heterogeneity across distinct vascular beds during homeostasis and inflammation.

Blood vessels are lined by endothelial cells engaged in distinct organ-specific functions but little is known about their characteristic gene expression profiles. RNA-Sequencing of the brain, lung, and heart endothelial translatome identified specific pathways, transporters and cell-surface markers expressed in the endothelium of each organ, which can be visualized at http://www.rehmanlab.

Cinnamon and its Metabolite Protect the Nigrostriatum in a Mouse Model of Parkinson's Disease Via Astrocytic GDNF.

Glial cell line-derived neurotrophic factor (GDNF) has potent neurotrophic effects and is known to promote the dopaminergic (DA) neuronal survival in cellular and animal models of Parkinson's disease (PD). However, long-term ectopic GDNF delivery is associated with long lasting adverse side effects in PD patients. Therefore, finding safer and effective ways to elevate endogenous GDNF levels is an active area of research.

Activin signaling is an essential component of the TGF-β induced pro-metastatic phenotype in colorectal cancer.

Advanced colorectal cancer (CRC) remains a critical health care challenge worldwide. Various TGF-β superfamily members are important in colorectal cancer metastasis, but their signaling effects and predictive value have only been assessed in isolation. Here, we examine cross-regulation and combined functions of the two most prominent TGF-β superfamily members activin and TGF-β in advanced colorectal cancer.

Correction: A Physically-Modified Saline Suppresses Neuronal Apoptosis, Attenuates Tau Phosphorylation and Protects Memory in an Animal Model of Alzheimer's Disease.

[This corrects the article DOI: 10.1371/journal.pone.

NFkB is essential for activin-induced colorectal cancer migration via upregulation of PI3K-MDM2 pathway.

Colorectal cancer (CRC) remains a common and deadly cancer due to metastatic disease. Activin and TGFB (TGFβ) signaling are growth suppressive pathways that exert non-canonical pro-metastatic effects late in CRC carcinogenesis. We have recently shown that activin downregulates p21 via ubiquitination and degradation associated with enhanced cellular migration independent of SMADs.

Expression of an Oncogenic BARD1 Splice Variant Impairs Homologous Recombination and Predicts Response to PARP-1 Inhibitor Therapy in Colon Cancer.

BRCA1-associated RING domain protein 1 (BARD1) stabilizes BRCA1 protein by forming a heterodimeric RING-RING complex, and impacts function of BRCA1, including homologous recombination (HR) repair. Although colon cancer cells usually express wild type BRCA1, presence of an oncogenic BARD1 splice variant (SV) in select cancers may render BRCA1 dysfunctional and allow cells to become sensitive to HR targeting therapies. We previously reported association of loss of full-length (FL) BARD1 with poor prognosis in colon cancer as well as expression of various BARD1 SVs with unknown function.

A physically-modified saline suppresses neuronal apoptosis, attenuates tau phosphorylation and protects memory in an animal model of Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia in the aging population, is characterized by the presence of neuritic plaques, neurofibrillary tangles and extensive neuronal apoptosis. Neuritic plaques are mainly composed of aggregates of amyloid-β (Aβ) protein while neurofibrillary tangles are composed of the hyperphosphorylated tau protein. Despite intense investigations, no effective therapy is currently available to halt the progression of this disease.

Interleukin-12 (IL-12), but not IL-23, induces the expression of IL-7 in microglia and macrophages: implications for multiple sclerosis.

Interleukin-12 (IL-12) p70 and IL-23 are bioactive cytokines and their biological functions are becoming clear. Increased expression of IL-7 in the central nervous system as well as in peripheral immune cells is associated with multiple sclerosis and experimental allergic encephalomyelitis. Here, we describe the induction of IL-7 in primary mouse and human microglia, BV-2 microglial cells, mouse peritoneal macrophages and astrocytes by IL-12p70.

Up-regulation of neurotrophic factors by cinnamon and its metabolite sodium benzoate: therapeutic implications for neurodegenerative disorders.

This study underlines the importance of cinnamon, a widely-used food spice and flavoring material, and its metabolite sodium benzoate (NaB), a widely-used food preservative and a FDA-approved drug against urea cycle disorders in humans, in increasing the levels of neurotrophic factors [e.g., brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3)] in the CNS.

Suppression of nuclear factor-κB activation and inflammation in microglia by physically modified saline.

Chronic inflammation involving activated microglia and astroglia is becoming a hallmark of many human diseases, including neurodegenerative disorders. Although NF-κB is a multifunctional transcription factor, it is an important target for controlling inflammation as the transcription of many proinflammatory molecules depends on the activation of NF-κB. Here, we have undertaken a novel approach to attenuate NF-κB activation and associated inflammation in activated glial cells.

Sodium phenylbutyrate controls neuroinflammatory and antioxidant activities and protects dopaminergic neurons in mouse models of Parkinson's disease.

Neuroinflammation and oxidative stress underlie the pathogenesis of various neurodegenerative disorders. Here we demonstrate that sodium phenylbutyrate (NaPB), an FDA-approved therapy for reducing plasma ammonia and glutamine in urea cycle disorders, can suppress both proinflammatory molecules and reactive oxygen species (ROS) in activated glial cells. Interestingly, NaPB also decreased the level of cholesterol but involved only intermediates, not the end product of cholesterol biosynthesis pathway for these functions.

Testing NF-κB-based therapy in hemiparkinsonian monkeys.

Parkinson's disease (PD) is the most common human neurodegenerative disorder affecting movement, balance, flexibility, and coordination. Despite intense investigation, no effective therapy is available to stop the onset PD or halt its progression. The primate model of PD is considered to be one of the best available models for human PD.

Fibrillar amyloid-beta-activated human astroglia kill primary human neurons via neutral sphingomyelinase: implications for Alzheimer's disease.

Glial activation plays an important role in the pathogenesis of various neurodegenerative disorders including Alzheimer's disease. However, molecular mechanisms by which activated glia could kill neurons are poorly understood. The present study underlines the importance of neutral sphingomyelinase (N-SMase) in mediating the damaging effect of fibrillar amyloid-β 1-42 (Aβ1-42) peptide-activated astroglia on neurons.

Sphingolipids in multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the CNS. Oligodendrocytes, the myelin-forming cells of the central nervous system (CNS), are target cells in MS. Although the etiology of MS is poorly known, new insights suggest oligodendrocyte apoptosis as one of the critical events followed by glial activation and infiltration of lymphocytes and macrophages.

Sodium benzoate, a metabolite of cinnamon and a food additive, reduces microglial and astroglial inflammatory responses.

Upon activation, microglia and astrocytes produce a number of proinflammatory molecules that participate in the pathophysiology of several neurodegenerative disorders. This study explores the anti-inflammatory property of cinnamon metabolite sodium benzoate (NaB) in microglia and astrocytes. NaB, but not sodium formate, was found to inhibit LPS-induced expression of inducible NO synthase (iNOS), proinflammatory cytokines (TNF-alpha and IL-1beta) and surface markers (CD11b, CD11c, and CD68) in mouse microglia.

Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death.

Neurodegenerative disorders are marked by extensive neuronal apoptosis and gliosis. Although several apoptosis-inducing agents have been described, understanding of the regulatory mechanisms underlying modes of cell death is incomplete. A major breakthrough in delineation of the mechanism of cell death came from elucidation of the sphingomyelin (SM)-ceramide pathway that has received worldwide attention in recent years.

Reactive oxygen species up-regulate CD11b in microglia via nitric oxide: Implications for neurodegenerative diseases.

Microglial activation is considered as a hallmark of several neurodegenerative disorders. During microglial activation, the expression of CD11b, the beta-integrin marker of microglia, is increased. However, the molecular mechanism behind increased microglial CD11b expression is poorly understood.

Oxidative stress kills human primary oligodendrocytes via neutral sphingomyelinase: implications for multiple sclerosis.

Multiple sclerosis (MS) is the most common human demyelinating disease of the central nervous system where oxidative stress has been proposed to play an important role in oligodendroglial death. However, molecular mechanisms that couple oxidative stress to the loss of oligodendrocytes are poorly understood. This study underlines the importance of neutral sphingomyelinase-ceramide pathway in mediating oxidative stress-induced apoptosis and cell death of human primary oligodendrocytes.