Effects of the Amyotrophic Lateral Sclerosis-related Q108P Mutation on the Structural Ensemble Characteristics of CHCHD10.

Introduction: The Q108P pathological variant of the mitochondrial Coiled-Coil-Helix-- Coiled-Coil-Helix Domain-Containing Protein 10 (CHCHD10) has been implicated in amyotrophic lateral sclerosis (ALS). Both the wild-type and CHCHD10Q108P proteins exhibit intrinsically disordered regions, posing challenges for structural studies with conventional experimental tools.

Method: This study presents the foundational characterization of the structural features of CHCHD10Q108P and compares them with those of the wild-type counterpart.

Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury.

Progression of acute traumatic brain injury (TBI) into chronic neurodegeneration is a major health problem with no protective treatments. Here, we report that acutely elevated mitochondrial fission after TBI in mice triggers chronic neurodegeneration persisting 17 months later, equivalent to many human decades. We show that increased mitochondrial fission after mouse TBI is related to increased brain levels of mitochondrial fission 1 protein (Fis1) and that brain Fis1 is also elevated in human TBI.

Crystal Violet Selectively Detects Aβ Oligomers but Not Fibrils In Vitro and in Alzheimer's Disease Brain Tissue.

Deposition of extracellular Amyloid Beta (Aβ) and intracellular tau fibrils in post-mortem brains remains the only way to conclusively confirm cases of Alzheimer's Disease (AD). Substantial evidence, though, implicates small globular oligomers instead of fibrils as relevant biomarkers of, and critical contributors to, the clinical symptoms of AD. Efforts to verify and utilize amyloid oligomers as AD biomarkers in vivo have been limited by the near-exclusive dependence on conformation-selective antibodies for oligomer detection.

Corrigendum: Multi-protection of DL0410 in ameliorating cognitive defects in D-galactose induced aging mice.

[This corrects the article DOI: 10.3389/fnagi.2017.

Flubendazole suppresses VEGF-induced angiogenesis in HUVECs and exerts antitumor effects in PC-3 cells.

Flubendazole, an FDA-approved anthelmintic, has been predicted to show strong VEGFR2 inhibitory activity in silico screening combined with in vitro experimental validation, and it has shown anti-cancer effects on some human cancer cell lines, but little is known about the anti-angiogenesis effects and anti-prostate cancer effects. In this study, we analyzed the binding modes and kinetic analysis of flubendazole with VEGFR2 and first demonstrated that flubendazole suppressed VEGF-stimulated cell proliferation, wound-healing migration, cell invasion and tube formation of HUVEC cells, and decreased the phosphorylation of extracellular signal-regulated kinase and serine/threonine kinase Akt, which are the downstream proteins of VEGFR2 that are important for cell growth. What's more, our results showed that flubendazole decreased PC-3 cell viability and proliferation ability, and suppressed PC-3 cell wound healing migration and invasion across a Matrigel-coated Transwell membrane in a concentration-dependent manner.

Association between Alcohol Consumption and Metabolic Dysfunction-Associated Steatotic Liver Disease Based on Alcohol Flushing Response in Men: The Korea National Health and Nutrition Examination Survey 2019-2021.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is distinguished by the buildup of excessive liver fat unrelated to alcohol consumption. However, the role of alcohol consumption on disease progression is debatable. Recently, alcohol flushing syndrome in Asian populations has gained interest, and its role in the risk of developing MASLD is unknown.

Slingshot homolog-1-mediated Nrf2 sequestration tips the balance from neuroprotection to neurodegeneration in Alzheimer's disease.

Oxidative damage in the brain is one of the earliest drivers of pathology in Alzheimer's disease (AD) and related dementias, both preceding and exacerbating clinical symptoms. In response to oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) is normally activated to protect the brain from oxidative damage. However, Nrf2-mediated defense against oxidative stress declines in AD, rendering the brain increasingly vulnerable to oxidative damage.

The impacts of the mitochondrial myopathy-associated G58R mutation on the dynamic structural properties of CHCHD10.

The mitochondria are responsible for producing energy within the cell, and in mitochondrial myopathy, there is a defect in the energy production process. The CHCHD10 gene codes for a protein called coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10), which is found in the mitochondria and is involved in the regulation of mitochondrial function. G58R mutation has been shown to disrupt the normal function of CHCHD10, leading to mitochondrial dysfunction and ultimately to the development of mitochondrial myopathy.

Frontotemporal Dementia-Related V57E Mutation Impairs Mitochondrial Function and Alters the Structural Properties of CHCHD10.

The V57E pathological variant of the mitochondrial coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10) plays a role in frontotemporal dementia. The wild-type and V57E mutant CHCHD10 proteins contain intrinsically disordered regions, and therefore, these regions hampered structural characterization of these proteins using conventional experimental tools. For the first time in the literature, we represent that the V57E mutation is pathogenic to mitochondria as it increases mitochondrial superoxide and impairs mitochondrial respiration.

Enhanced cell growth, production, and mAb quality produced in Chinese hamster ovary-K1 cells by supplementing polyamine in the media.

Polyamines such as putrescine (PUT), spermidine (SPD), and spermine (SPM) are amine group-containing biomolecules that regulate multiple intracellular functions such as proliferation, differentiation, and stress response in mammalian cells. Although these biomolecules can be generated intracellularly, lack of polyamine-synthesizing activity has occasionally been reported in a few mammalian cell lines such as Chinese hamster ovary (CHO)-K1; thus, polyamine supplementation in serum-free media is required to support cell growth and production. In the present study, the effects of biogenic polyamines PUT, SPD, and SPM in media on cell growth, production, metabolism, and antibody quality were explored in cultures of antibody-producing CHO-K1 cells.

A Par3/LIM Kinase/Cofilin Pathway Mediates Human Airway Smooth Muscle Relaxation by TAS2R14.

TAS2Rs (bitter taste receptors) are GPCRs (G protein-coupled receptors) expressed on human airway smooth muscle (HASM) cells; when activated by receptor agonists they evoke marked airway relaxation. In both taste and HASM cells, TAS2Rs activate a canonical G-mediated stimulation of Ca release from intracellular stores by activation of PLCβ (phospholipase Cβ). Alone, this [Ca] signaling does not readily account for relaxation, particularly since bronchoconstrictive agonists acting at G-coupled receptors also increase [Ca].

Effects of the Jokela type of spinal muscular atrophy-related G66V mutation on the structural ensemble characteristics of CHCHD10.

The G66V pathological variant of the coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10), mitochondrial, plays a role in Jokela type spinal muscular atrophy. The wild-type and G66V mutant-type CHCHD10 proteins contain intrinsically disordered regions, and therefore, their structural ensemble studies have been experiencing difficulties using conventional tools. Here, we show our results regarding the first characterization of the structural ensemble characteristics of the G66V mutant form of CHCHD10 and the first comparison of these characteristics with the structural ensemble properties of wild-type CHCHD10.

X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women.

Although women experience significantly higher tau burden and increased risk for Alzheimer's disease (AD) than men, the underlying mechanism for this vulnerability has not been explained. Here, we demonstrate through in vitro and in vivo models, as well as human AD brain tissue, that X-linked ubiquitin specific peptidase 11 (USP11) augments pathological tau aggregation via tau deubiquitination initiated at lysine-281. Removal of ubiquitin provides access for enzymatic tau acetylation at lysines 281 and 274.

Age-Related Clinical Characteristics, Inflammatory Features, Phenotypes, and Treatment Response in Asthma.

Background: Emerging evidence suggests that aging affects asthma outcomes, but the mechanism remains largely unexplored.

Objective: To explore age-related clinical characteristics, inflammatory features, phenotypes, and treatment response in asthma.

Methods: This was a prospective cohort study of asthmatic patients with a 12-month follow-up in a real-world setting.

Slingshot homolog-1 mediates the secretion of small extracellular vesicles containing misfolded proteins by regulating autophagy cargo receptors and actin dynamics.

Increasing evidence indicates that the accumulation misfolded proteins in Alzheimer's disease (AD) arises from clearance defects in the autophagy-lysosome pathway. Misfolded proteins such as Aβ and tau are secreted in small extracellular vesicles (i.e.

Modulation of synaptic plasticity, motor unit physiology, and TDP-43 pathology by CHCHD10.

Mutations in CHCHD10, a gene coding for a mitochondrial intermembrane space protein, are associated with Frontotemporal dementia (FTD)-Amyotrophic lateral sclerosis (ALS) spectrum disorders, which are pathologically characterized by cytoplasmic inclusions containing TDP-43. FTD/ALS-linked CHCHD10 mutations and TDP-43 inclusions similarly induce mitochondrial defects in respiration, fusion/fission, mtDNA stability, and cristae structure, while sizeable amounts of cytoplasmic TDP-43 aggregates are found in mitochondria. However, the mechanistic link between CHCHD10 and TDP-43 pathogenesis remains unclear.

Pathological characterization of a novel mouse model expressing the PD-linked CHCHD2-T61I mutation.

Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) is a mitochondrial protein that plays important roles in cristae structure, oxidative phosphorylation and apoptosis. Multiple mutations in CHCHD2 have been associated with Lewy body disorders (LBDs), such as Parkinson's disease (PD) and dementia with Lewy bodies, with the CHCHD2-T61I mutation being the most widely studied. However, at present, only CHCHD2 knockout or CHCHD2/CHCHD10 double knockout mouse models have been investigated.

Identification of multi-target anti-cancer agents from TCM formula by in silico prediction and in vitro validation.

Cancer is a complex disease associated with multiple gene mutations and malignant phenotypes, and multi-target drugs provide a promising therapy idea for the treatment of cancer. Natural products with abundant chemical structure types and rich pharmacological characteristics could be ideal sources for screening multi-target antineoplastic drugs. In this paper, 50 tumor-related targets were collected by searching the Therapeutic Target Database and Thomson Reuters Integrity database, and a multi-target anti-cancer prediction system based on mt-QSAR models was constructed by using naïve Bayesian and recursive partitioning algorithm for the first time.

Structures of the Wild-Type and S59L Mutant CHCHD10 Proteins Important in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia.

The S59L genetic mutation of the mitochondrial coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10) is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The wild-type and mutant forms of this protein contain intrinsically disordered regions, and their structural characterization has been facing challenges. Here, for the first time in the literature, we present the structural ensemble properties of the wild-type and S59L mutant form of CHCHD10 in an aqueous solution environment at the atomic level with dynamics.

Atorvastatin combined with dexamethasone in chronic subdural haematoma (ATOCH II): study protocol for a randomized controlled trial.

Background: Chronic subdural haematoma (CSDH) is a common condition in the elderly that often requires neurosurgical management. For small CSDH, evidence has emerged that statins may reduce haematoma volume and improve outcomes, presumably by reducing local inflammation and promoting vascular repair. We wish to extend this evidence in a study that aims to determine the efficacy and safety of atorvastatin combined with low-dose dexamethasone in patients with CSDH.

β-arrestin1 promotes tauopathy by transducing GPCR signaling, disrupting microtubules and autophagy.

G protein-coupled receptors (GPCRs) have been shown to play integral roles in Alzheimer's disease pathogenesis. However, it is unclear how diverse GPCRs similarly affect Aβ and tau pathogenesis. GPCRs share a common mechanism of action via the β-arrestin scaffolding signaling complexes, which not only serve to desensitize GPCRs by internalization, but also mediate multiple downstream signaling events.

Interaction effects of asthma and rhinitis control on work productivity and activity impairment: A cross-sectional study.

Symptomatic asthma and rhinitis negatively impact patients' work productivity and activity. However, little is known about the potential interaction effect of both asthma and rhinitis control on work productivity and activity impairment. This study aimed to explore whether there are interaction effects of asthma and rhinitis control on work productivity and activity impairment in patients with asthma and with rhinitis.