When Two Worlds Collide: The Contribution and Association Between Genetics (APOEε4) and Neuroinflammation (IL-1β) in Alzheimer's Neuropathogenesis.

Here we consider the collision of a genetic factor and an essential instigator in Alzheimer's neuropathogenesis: (i) the Alzheimer's gene (APOEε4), which downregulates lysosomal autophagy and induces synthesis of (ii) the instigator, interleukin-1β (IL-1β), which drives synthesis of βAPP for Aβ plaques and of MAPKp38 for phosphorylation of tau for formation of neurofibrillary tangles (NFTs), the two cardinal features of AD. RT-PCR, immunoblotting and immunohistochemistry techniques were used to assess the levels of IL-1β and its signaling cascade in ADε4,4, ε3,3, and age-matched controls (AMC3,3) in hippocampal regions of the brain. IL-1β and its downstream signaling proteins TLR-2, MyD88, NFκB, COX-1, and COX-2 were greater in tissues from ADε4,4 than ADε3,3 or AMC3,3.

The Seminal Role of the Proinflammatory Cytokine IL-1β and Its Signaling Cascade in Glioblastoma Pathogenesis and the Therapeutic Effect of Interleukin-1β Receptor Antagonist (IL-1RA) and Tolcapone.

Interleukin-1 beta(IL-1β) is the major driving force in neuroinflammation. Here, we report on (i) the role of (IL-1β) in activating a signaling cascade that leads to proliferation and metastasis in glioblastoma cancer pathogenesis as well as (ii) the therapeutic role for IL-1 Receptor Antagonist (IL-1RA) and Tolcapone against untoward aspects of tumor pathogenesis. Here, we report that IL-1β treatment at 50 ng/mL for 48 h increased proliferation and metastasis by 30-fold ( ≤ 0.

Altered protein homeostasis in cardiovascular diseases contributes to Alzheimer's-like neuropathology.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. CVD is known to increase the risk of subsequent neurodegeneration but the mechanism(s) and proteins involved have yet to be elucidated. We previously showed that myocardial infarction (MI), induced in mice and compared to sham-MI mice, leads to increases in protein aggregation, endoplasmic reticulum (ER) stress in both heart and brain, and changes in proteostatic pathways.

Mitochondria in aging and age-associated diseases.

Mitochondria, essential for cellular energy, are crucial in neurodegenerative disorders (NDDs) and their age-related progression. This review highlights mitochondrial dynamics, mitovesicles, homeostasis, and organelle communication. We examine mitochondrial impacts from aging and NDDs, focusing on protein aggregation and dysfunction.

Metabolomic Profiling and Machine Learning Models for Tumor Classification in Patients with Recurrent IDH-Wild-Type Glioblastoma: A Prospective Study.

Background/objectives: The recurrence of glioblastoma is an inevitable event in this disease's course. In this study, we sought to identify the metabolomic signature in patients with recurrent glioblastomas undergoing surgery and radiation therapy.

Methods: Blood samples collected prospectively from six patients with recurrent IDH-wildtype glioblastoma who underwent one surgery at diagnosis and a second surgery at relapse were analyzed using untargeted gas chromatography-time-of-flight mass spectrometry to measure metabolite abundance.

Epidermal Growth Factor Receptor Inhibitors in Glioblastoma: Current Status and Future Possibilities.

Glioblastoma, a grade 4 glioma as per the World Health Organization, poses a challenge in adult primary brain tumor management despite advanced surgical techniques and multimodal therapies. This review delves into the potential of targeting epidermal growth factor receptor (EGFR) with small-molecule inhibitors and antibodies as a treatment strategy. EGFR, a mutationally active receptor tyrosine kinase in over 50% of glioblastoma cases, features variants like EGFRvIII, EGFRvII and missense mutations, necessitating a deep understanding of their structures and signaling pathways.

Alzheimer's-specific brain amyloid interactome: Neural-network analysis of intra-aggregate crosslinking identifies novel drug targets.

Alzheimer's disease (AD) is characterized by peri-neuronal amyloid plaque and intra-neuronal neurofibrillary tangles. These aggregates are identified by the immunodetection of "seed" proteins (Aβ and hyperphosphorylated tau, respectively), but include many other proteins incorporated nonrandomly. Using click-chemistry intra-aggregate crosslinking, we previously modeled amyloid "contactomes" in SY5Y-APP neuroblastoma cells, revealing that aspirin impedes aggregate growth and complexity.

Rescue of ApoE4-related lysosomal autophagic failure in Alzheimer's disease by targeted small molecules.

Homozygosity for the ε4 allele of APOE increases the odds of developing Alzheimer's by 12 to 15 times relative to the most common ε3;ε3 genotype, and its association with higher plaque loads comports with evidence that APOEε4 compromises autophagy. The ApoE4 protein specifically binds a cis element ("CLEAR") in the promoters of several autophagy genes to block their transcription. We used a multifaceted approach to identify a druggable site in ApoE4, and virtual screening of lead-like compounds identified small molecules that specifically bind to this site to impede ApoE4::DNA binding.

Myocardial infarction elevates endoplasmic reticulum stress and protein aggregation in heart as well as brain.

Cardiovascular diseases, including myocardial infarction (MI), constitute the leading cause of morbidity and mortality worldwide. Protein-aggregate deposition is a hallmark of aging and neurodegeneration. Our previous study reported that aggregation is strikingly elevated in hearts of hypertensive and aged mice; however, no prior study has addressed MI effects on aggregation in heart or brain.

Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend Life- and Healthspan.

Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer's disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's diseases. We screened a panel of bioactive thiadiazolidinones (TDZDs) from our in-house library for rescue of protein aggregation in human-cell and models of neurodegeneration.

In silico analysis of TUBA4A mutations in Amyotrophic Lateral Sclerosis to define mechanisms of microtubule disintegration.

Amyotrophic lateral sclerosis (ALS) is an inexorably progressive and degenerative disorder of motor neurons with no currently-known cure. Studies to determine the mechanism of neurotoxicity and the impact of ALS-linked mutations (SOD1, FUS, TARDP, C9ORF72, PFN1, TUBA4A and others) have greatly expanded our knowledge of ALS disease mechanisms and have helped to identify potential targets for ALS therapy. Cellular pathologies (e.

Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases.

The mammalian 14-3-3 family comprises seven intrinsically unstructured, evolutionarily conserved proteins that bind >200 protein targets, thereby modulating cell-signaling pathways. The presence of 14-3-3 proteins in cerebrospinal fluid provides a sensitive and specific biomarker of neuronal damage associated with Alzheimer’s disease (AD), Creutzfeldt−Jakob disease (CJD), spongiform encephalitis, brain cancers, and stroke. We observed significant enrichment of 14-3-3 paralogs G, S, and Z in human brain aggregates diagnostic of AD.

Machine-learning analysis of intrinsically disordered proteins identifies key factors that contribute to neurodegeneration-related aggregation.

Protein structure is determined by the amino acid sequence and a variety of post-translational modifications, and provides the basis for physiological properties. Not all proteins in the proteome attain a stable conformation; roughly one third of human proteins are unstructured or contain intrinsically disordered regions exceeding 40% of their length. Proteins comprising or containing extensive unstructured regions are termed intrinsically disordered proteins (IDPs).

Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer's Disease.

Glial fibrillary acidic protein (GFAP) is an intermediate filament structural protein involved in cytoskeleton assembly and integrity, expressed in high abundance in activated glial cells. GFAP is neuroprotective, as knockout mice are hypersensitive to traumatic brain injury. GFAP in cerebrospinal fluid is a biomarker of Alzheimer's disease (AD), dementia with Lewy bodies, and frontotemporal dementia (FTD).

Intrinsically disordered proteins identified in the aggregate proteome serve as biomarkers of neurodegeneration.

A protein's structure is determined by its amino acid sequence and post-translational modifications, and provides the basis for its physiological functions. Across all organisms, roughly a third of the proteome comprises proteins that contain highly unstructured or intrinsically disordered regions. Proteins comprising or containing extensive unstructured regions are referred to as intrinsically disordered proteins (IDPs).

Novel hydroxybenzylamine-deoxyvasicinone hybrids as anticholinesterase therapeutics for Alzheimer's disease.

A series of novel 2-hydroxybenzylamine-deoxyvasicinone hybrid analogs (8a-8n) have been synthesized and evaluated as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and as inhibitors of amyloid peptide (Aβ) aggregation, for treatment of Alzheimer's disease (AD). These dual acting compounds exhibited good AChE inhibitory activities ranging from 0.34 to 6.

Antitumor properties of novel sesquiterpene lactone analogs as NFκB inhibitors that bind to the IKKβ ubiquitin-like domain (ULD).

Melampomagnolide B (MMB, 3) is a parthenolide (PTL, 1) based sesquiterpene lactone that has been used as a template for the synthesis of a plethora of lead anticancer agents owing to its reactive C-10 primary hydroxyl group. Such compounds have been shown to inhibit the IKKβ subunit, preventing phosphorylation of the cytoplasmic IκB inhibitory complex. The present study focuses on the synthesis and in vitro antitumor properties of novel benzyl and phenethyl carbamates of MMB (7a-7k).

"Protein aggregates" contain RNA and DNA, entrapped by misfolded proteins but largely rescued by slowing translational elongation.

All neurodegenerative diseases feature aggregates, which usually contain disease-specific diagnostic proteins; non-protein constituents, however, have rarely been explored. Aggregates from SY5Y-APP neuroblastoma, a cell model of familial Alzheimer's disease, were crosslinked and sequences of linked peptides identified. We constructed a normalized "contactome" comprising 11 subnetworks, centered on 24 high-connectivity hubs.

Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs.

Glycogen synthase kinase-3β (GSK3β) controls many physiological pathways, and is implicated in many diseases including Alzheimer's and several cancers. GSK3β-mediated phosphorylation of target residues in microtubule-associated protein tau (MAPTAU) contributes to MAPTAU hyperphosphorylation and subsequent formation of neurofibrillary tangles. Inhibitors of GSK3β protect against Alzheimer's disease and are therapeutic for several cancers.

Computational target-based drug repurposing of elbasvir, an antiviral drug predicted to bind multiple SARS-CoV-2 proteins.

Coronavirus disease 19 (COVID-19) is a severe acute respiratory syndrome caused by SARS-CoV-2 (2019-nCoV). While no drugs have yet been approved to treat this disease, small molecules effective against other viral infections are under clinical evaluation for therapeutic abatement of SARS-CoV-2 infections. Ongoing clinical trials include Kaletra (a combination of two protease inhibitors approved for HIV treatment), remdesivir (an investigational drug targeting RNA-dependent RNA polymerase [RdRP] of SARS-CoV-2), and hydroxychloroquine (an approved anti-malarial and immuno-modulatory drug).

Computational and in vitro characterization of ICY-5: A potential candidate promoting mitochondrial apoptosis via the c-MET and STAT3 pathways.

Targeted chemotherapy remains the primary choice in controlling various forms of breast cancer (BC) due to its heterogenous gene expressions in various subtypes. In silico and in vitro evaluation of ICY-5, a novel arylidene analogue against c-MET, was performed. ICY-5 exhibited a docking score of -9.

FCX-146, a potent allosteric inhibitor of Akt kinase in cancer cells: Lead optimization of the second-generation arylidene indanone scaffold.

Akt, a serine-threonine protein kinase, is regulated by class-I PI3K signaling. Akt regulates a wide variety of cell processes including cell proliferation, survival, and angiogenesis through serine/threonine phosphorylation of downstream targets including mTOR and glycogen-synthase-kinase-3-beta (GSK3β). Targeting cancer-specific overexpression of Akt protein could be an efficient way to control cancer-cell proliferation.

A Novel Microtubule-Binding Drug Attenuates and Reverses Protein Aggregation in Animal Models of Alzheimer's Disease.

Age-progressive neurodegenerative pathologies, including Alzheimer's disease (AD), are distinguished and diagnosed by disease-specific components of intra- or extra-cellular aggregates. Increasing evidence suggests that neuroinflammation promotes protein aggregation, and is involved in the etiology of neurological diseases. We synthesized and tested analogs of the naturally occurring tubulin-binding compound, combretastatin A-4.