Reactive oxygen species in endothelial signaling in COVID-19: Protective role of the novel peptide PIP-2.

Introduction: Recent research suggests that endothelial activation plays a role in coronavirus disease 2019 (COVID-19) pathogenesis by promoting a pro-inflammatory state. However, the mechanism by which the endothelium is activated in COVID-19 remains unclear.

Objective: To investigate the mechanism by which COVID-19 activates the pulmonary endothelium and drives pro-inflammatory phenotypes.

Increased expression of the transforming growth factor β-inducible gene HIC-5 in systemic sclerosis skin and fibroblasts: a novel antifibrotic therapeutic target.

Objective: SSc is a systemic fibrotic disease affecting skin, numerous internal organs and the microvasculature. The molecular pathogenesis of SSc tissue fibrosis has not been fully elucidated, although TGF-β1 plays a crucial role. The Hic-5 protein encoded by the TGF-β1-inducible HIC-5 gene participates in numerous TGF-β-mediated pathways, however, the role of Hic-5 in SSc fibrosis has not been investigated.

Plasma D-Dimer Levels are Elevated in Radiation Oncology Patients.

D-dimer plasma levels were evaluated to determine whether they are altered by radiation. D-dimer levels were measured in radiation oncology patients, who were diagnosed with prostate, breast or lung cancer, or leukemia, as well as in healthy subjects serving as controls. Blood samples from radiotherapy patients were taken at three different time points: pre-, on- and post-radiotherapy.

Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer's disease.

Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by neuropathologic changes involving beta-amyloid (Aβ), tau, neuronal loss, and other associated biological events. While levels of cerebrospinal fluid (CSF) Aβ and tau peptides have enhanced the antemortem detection of AD-specific changes, these two markers poorly reflect the severity of cognitive and functional deficits in people with altered Aβ and tau levels. While multiple previous studies identified non-Aβ, non-tau proteins as candidate neurodegenerative markers to inform the A/T/N biomarker scheme of AD, few have advanced beyond association with clinical AD diagnosis.

Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.

Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene.

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels.

Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer's disease and tauopathies.

Neuronal insulin signaling abnormalities have been associated with Alzheimer's disease (AD). However, the specificity of this association and its underlying mechanisms have been unclear. This study investigated the expression of abnormal serine phosphorylation of insulin receptor substrate 1 (IRS1) in 157 human brain autopsy cases that included AD, tauopathies, α-synucleinopathies, TDP-43 proteinopathies, and normal aging.

Neuroprotective effects of the amylin analogue pramlintide on Alzheimer's disease pathogenesis and cognition.

Amylin is a metabolic peptide hormone that is co-secreted with insulin from beta cells in the pancreas and activates many of the downstream targets of insulin. To investigate the relationship between this hormone and Alzheimer's disease (AD), we measured plasma human amylin levels in 206 subjects with AD, 64 subjects with mild cognitive impairment, and 111 subjects with no cognitive impairment and found significantly lower amylin levels among subjects with AD and mild cognitive impairment compared with the cognitively intact subjects. To investigate mechanisms underlying amylin's effects in the brain, we administered chronic infusions of the amylin analog pramlintide in the senescence-accelerated prone mouse, a mouse model of sporadic AD.

Association of plasma C-reactive protein levels with the diagnosis of Alzheimer's disease.

C-reactive protein (CRP) participates in the systemic response to inflammation. Previous studies report inconsistent findings regarding the relationship between plasma CRP and Alzheimer's disease (AD). We measured plasma CRP in 203 subjects with AD, 58 subjects with mild cognitive impairment (MCI) and 117 normal aging subjects and administered annual Mini-Mental State Examinations (MMSE) during a 3-year follow-up period to investigate CRP's relationship with diagnosis and progression of cognitive decline.

Cellular, synaptic, and biochemical features of resilient cognition in Alzheimer's disease.

Although neuritic plaques and neurofibrillary tangles in older adults are correlated with cognitive impairment and severity of dementia, it has long been recognized that the relationship is imperfect, as some people exhibit normal cognition despite high levels of Alzheimer's disease (AD) pathology. We compared the cellular, synaptic, and biochemical composition of midfrontal cortices in female subjects from the Religious Orders Study who were stratified into three subgroups: (1) pathological AD with normal cognition ("AD-Resilient"), (2) pathological AD with AD-typical dementia ("AD-Dementia"), and (3) pathologically normal with normal cognition ("Normal Comparison"). The AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared with the AD-Dementia group, and increased densities of glial fibrillary acidic protein astrocytes compared with both the AD-Dementia and Normal Comparison groups.

Synaptic dysbindin-1 reductions in schizophrenia occur in an isoform-specific manner indicating their subsynaptic location.

Background: An increasing number of studies report associations between variation in DTNBP1, a top candidate gene in schizophrenia, and both the clinical symptoms of the disorder and its cognitive deficits. DTNBP1 encodes dysbindin-1, reduced levels of which have been found in synaptic fields of schizophrenia cases. This study determined whether such synaptic reductions are isoform-specific.

Chronic corticosterone exposure alters postsynaptic protein levels of PSD-95, NR1, and synaptopodin in the mouse brain.

Animal models provide compelling evidence that chronic stress is associated with biochemical and morphological changes in the brain, many of which are mediated by corticosterone, a principal glucocorticoid synthesized in the rodent adrenal cortex and secreted in response to stress. To better characterize the effects of chronic corticosterone at the synaptic and subsynaptic level, we implanted three-month-old male C57B/6 mice with 2 × 5 mg corticosterone pellets (CORT group, n = 14), 21 day release formulation (20 mg/kg/day dose) or placebo pellets (Placebo group, n = 14), 21-day release formulation. After 20 days, brains were removed.

Persistent activation of dermal fibroblasts from patients with gadolinium-associated nephrogenic systemic fibrosis.

Background: Nephrogenic systemic fibrosis (NSF) is a systemic fibrotic disorder occurring in some patients with renal insufficiency after exposure to gadolinium-based contrast agents (GdBCA).

Objectives: To examine cultured NSF dermal fibroblast production and expression of collagens I and III, fibronectin, hyaluronic acid and α-smooth muscle actin (α-SMA) during serial passages and the effects of two GdBCA on collagen gene expression and production by normal dermal fibroblasts.

Methods: NSF fibroblasts were analysed for expression and production of types I and III collagen, fibronectin, hyaluronic acid and α-SMA.

Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression.

DTNBP1 (dystrobrevin binding protein 1) remains a top candidate gene in schizophrenia. Reduced expression of this gene and of its encoded protein, dysbindin-1, have been reported in the brains of schizophrenia cases. It has not been established, however, if the protein reductions encompass all dysbindin-1 isoforms or if they are associated with decreased DTNBP1 gene expression.

Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer's disease.

Progressive synaptic degeneration and neuron loss are major structural correlates of cognitive impairment in Alzheimer's disease (AD). The mechanisms by which synaptic degeneration in AD occurs have not been established. The activation of proteins within the caspase family has been implicated in AD-associated neurodegeneration, and synaptically localized caspase activity could play a role in the synaptic degeneration and loss found in AD.

Inhibition of systemic sclerosis dermal fibroblast type I collagen production and gene expression by simvastatin.

Objective: To examine whether statins are capable of modulating collagen gene expression in cultured systemic sclerosis dermal fibroblasts.

Methods: Cultured dermal fibroblasts from 3 patients with diffuse systemic sclerosis of recent onset were treated with 5 microM and 10 microM of simvastatin for 3 or 4 days. Morphologic features, cytotoxicity, and type I collagen production and messenger RNA (mRNA) levels in the fibroblasts were examined.

Transcriptional inhibition of type I collagen gene expression in scleroderma fibroblasts by the antineoplastic drug ecteinascidin 743.

We previously showed that COL1A1 expression is up-regulated at the transcriptional level in systemic sclerosis (SSc) fibroblasts and that the CCAAT-binding factor (CBF) is involved in this increased expression. Ecteinascidin 743 (ET-743) is a chemotherapeutic agent that binds with sequence specificity to the minor groove of DNA and inhibits CBF-mediated transcriptional activation of numerous genes. Therefore, we examined the effects of ET-743 on the increased COL1A1 expression in SSc fibroblasts.

A monoclonal antibody and an enzyme immunoassay for human Ala-IL-8(77).

Interleukin-8 (IL-8) plays a central role in neutrophil chemotaxis and exerts a wide range of effects on various cells, ranging from tumor angiogenesis to impairment of neuronal signaling. Two main forms of IL-8 exist, one containing 77 amino acids (Ala-IL-8(77)) and a second containing 72 amino acids (Ser-IL-8(72)), which comprise more than 90% of IL-8 protein in cell cultures. IL-8(77) was reported to be produced predominantly by endothelial cells and is known as "endothelial" IL-8.

Site-specific interaction of bone morphogenetic protein 2 with procollagen II.

Bone morphogenetic proteins (BMPs) play a critical role in embryo development, organogenesis, and regeneration of damaged tissues. Biological activity of BMPs depends on their local concentration, which is regulated by intracellular enzymatic processing of pro-BMPs, and then the binding of secreted BMPs to antagonizing extracellular proteins. It has been suggested that BMPs interact with structural proteins of the extracellular matrix, but this process is poorly understood.

trans-Lesion synthesis past bulky benzo[a]pyrene diol epoxide N2-dG and N6-dA lesions catalyzed by DNA bypass polymerases.

The effectiveness of in vitro primer elongation reactions catalyzed by human bypass DNA polymerases kappa (hDinB1), pol eta (hRad30A), pol iota (hRad30B), and yeast pol zeta (Rev3 and Rev7) in site-specifically modified template oligonucleotide strands were studied in vitro. The templates contained single bulky lesions derived from the trans-addition of the mutagenic (+)- or (-)-enantiomers of r7,t8-dihydroxy-t9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (a metabolite of the environmental carcinogen benzo[a]pyrene), to the exocyclic amino groups of guanine or adenine in oligonucleotide templates 33, or more, bases long. In "running start" primer extension reactions, pol kappa effectively bypassed both the stereoisomeric (+)- and (-)-trans-guanine adducts but not the analogous adenine adducts.