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Differential ERK activation during autophagy induced by europium hydroxide nanorods and trehalose: Maximum clearance of huntingtin aggregates through combined treatment.

Accelerating the clearance of intracellular protein aggregates through elevation of autophagy represents a viable approach for the treatment of neurodegenerative diseases. In our earlier report, we have demonstrated the enhanced degradation of mutant huntingtin protein aggregates through autophagy process induced by europium hydroxide nanorods [EHNs: Eu(III)(OH)3], but the underlying molecular mechanism of EHNs mediated autophagy was unclear. The present report reveals that EHNs induced autophagy does not follow the classical AKT-mTOR and AMPK signaling pathways. The inhibition of ERK1/2 phosp

MavN is a Legionella pneumophila vacuole-associated protein required for efficient iron acquisition during intracellular growth.

Iron is essential for the growth and virulence of most intravacuolar pathogens. The mechanisms by which microbes bypass host iron restriction to gain access to this metal across the host vacuolar membrane are poorly characterized. In this work, we identify a unique intracellular iron acquisition strategy used by Legionella pneumophila. The bacterial Icm/Dot (intracellular multiplication/defect in organelle trafficking) type IV secretion system targets the bacterial-derived MavN (more regions allowing vacuolar colocalization N) protein to the surface of the Legionella-containing vacuole where t

G-protein-coupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L.

Autophagy is an important intracellular catabolic mechanism involved in the removal of misfolded proteins. Atg14L, the mammalian ortholog of Atg14 in yeast and a critical regulator of autophagy, mediates the production PtdIns3P to initiate the formation of autophagosomes. However, it is not clear how Atg14L is regulated. In this study, we demonstrate that ubiquitination and degradation of Atg14L is controlled by ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex. Furthermore, we show that a wide range of G-protein-coupled receptor (GPCR) ligands and agonists regulate the levels of Atg14L through …

Lysosomal network proteins as potential novel CSF biomarkers for Alzheimer's disease.

The success of future intervention strategies for Alzheimer's disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i

Listeria phospholipases subvert host autophagic defenses by stalling pre-autophagosomal structures.

Listeria can escape host autophagy defense pathways through mechanisms that remain poorly understood. We show here that in epithelial cells, Listeriolysin (LLO)-dependent cytosolic escape of Listeria triggered a transient amino-acid starvation host response characterized by GCN2 phosphorylation, ATF3 induction and mTOR inhibition, the latter favouring a pro-autophagic cellular environment. Surprisingly, rapid recovery of mTOR signalling was neither sufficient nor necessary for Listeria avoidance of autophagic targeting. Instead, we observed that Listeria phospholipases PlcA and PlcB reduced au

Proteolytic elimination of N-myristoyl modifications by the Shigella virulence factor IpaJ.

Protein N-myristoylation is a 14-carbon fatty-acid modification that is conserved across eukaryotic species and occurs on nearly 1% of the cellular proteome. The ability of the myristoyl group to facilitate dynamic protein-protein and protein-membrane interactions (known as the myristoyl switch) makes it an essential feature of many signal transduction systems. Thus pathogenic strategies that facilitate protein demyristoylation would markedly alter the signalling landscape of infected host cells. Here we describe an irreversible mechanism of protein demyristoylation catalysed by invasion plasm

Neutrophil diversity and function in health and disease.

Neutrophils, the most abundant type of granulocyte, are widely recognized as one of the pivotal contributors to the acute inflammatory response. Initially, neutrophils were considered the mobile infantry of the innate immune system, tasked with the immediate response to invading pathogens. However, recent studies have demonstrated that neutrophils are versatile cells, capable of regulating various biological processes and impacting both human health and disease. Cytokines and other active mediators regulate the functional activity of neutrophils by activating multiple receptors on these cells,

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… Subsequently, neutrophils capture the pathogen by forming phagosomes. … Subsequently, neutrophils capture the pathogen by forming phagosomes. …

Sevoflurane post-conditioning reduces rat myocardial ischemia reperfusion injury through an increase in NOS and a decrease in phopshorylated NHE1 levels.

The protective effects of sevoflurane post-conditioning against myocardial ischemia/reperfusion (I/R) injury (MIRI) have been previously rep … de (NO), NO synthase (NOS) and nicotinamide adenine dinucleotide (NAD+) levels were determined. Autophagosomes and apoptosomes in the myocardium were detected by transmission electron microscopy. The levels of Bcl-2, cleaved caspase-3, Beclin-1, microtubule-associated protein light chain 3 (LC3)‑I/II, Na+/H+ exchanger 1 (NHE1) and phosphorylated NHE1 protein …

Inhibition of autophagy ameliorates acute lung injury caused by avian influenza A H5N1 infection.

The threat of a new influenza pandemic has existed since 1997, when the highly pathogenic H5N1 strain of avian influenza A virus infected hu … his disease pathology is unclear. Here, we used electron microscopy to show the accumulation of autophagosomes in H5N1-infected lungs from a human cadaver and mice, as well as in infected A549 human epithelial lung cells. We also showed that H5N1, but not seasonal H1N1, induced autophagic cell death in alveolar epithelial cells through a pathway involving th …

Type I IFN induction in response to Listeria monocytogenes in human macrophages: evidence for a differential activation of IFN regulatory factor 3 (IRF3).

Listeria monocytogenes is a prototypic bacterium for studying innate and adaptive cellular immunity as well as host defense. Using human monocyte-derived macrophages, we report that an infection with a wild-type strain, but not a listeriolysin O-deficient strain, of the Gram-positive bacterium L. monocytogenes induces expression of IFN-beta and a bioactive type I IFN response. Investigating the activation of signaling pathways in human macrophages after infection revealed that a wild-type strain and a hemolysin-deficient strain of L. monocytogenes activated the NF-kappaB pathway and induced a

HBx induces HepG-2 cells autophagy through PI3K/Akt-mTOR pathway.

Chronic hepatitis B virus infection is the dominant global cause of hepatocellular carcinoma (HCC), especially hepatitis B virus-X (HBx) pla … C. The present study showed that HBx transfection brought about an increase in the formation of autophagosomes and autolysosomes. Microtubule-associated protein light chain 3, Beclin 1, and lysosome-associated membrane protein 2a were up-regulated after HBx transfection. HBx-induced increase in the autophagic level was increased by mTOR inhibitor rapamycin a …

Cholesterol-dependent cytolysins.

The cholesterol-dependent cytolysins (CDCs) are part of a large family of pore-forming proteins that include the human proteins perforin and the complement membrane attack complex. The activity of all family members is focused on membranes, but the proteins are themselves involved in a diverse range of phenomena. An overview of some of these phenomena is provided here, along with an historical perspective of CDCs themselves and how our understanding of their mechanism of action has developed over the years. The way in which pore formation depends on specific characteristics of the membrane und

Delivery of Drugs into Cancer Cells Using Antibody-Drug Conjugates Based on Receptor-Mediated Endocytosis and the Enhanced Permeability and Retention Effect.

Innumerable people worldwide die of cancer every year, although pharmaceutical therapy has actualized many benefits in human health. For background, anti-cancer drug development is difficult due to the multifactorial pathogenesis and complicated pathology of cancers. Cancer cells excrete hydrophobic low-molecular anti-cancer drugs by overexpressed efflux transporters such as multiple drug resistance 1 (MDR1) at the apical membrane. Mutation-driven drug resistance is also developed in cancer. Moreover, the poor distribution of drug to cancer cells is a serious problem, because patients suffer f

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… Phagocytosis, a type of endocytosis, by phagocytes such as macrophages forms phagosomes (1–3 μm in diameter) [ 88 , 89 ]. Macrophages exhibit the highest attachment to particles with a longest dimension of 2–3 μm, which is the same as the size of common bacteria [ 90 ]. … Phagosomal transport depends strongly on phagosome size. Sci. Rep. 2017;7:17068. doi: 10.1038/s41598-017-17183-7. 89. Uribe-Querol E., Rosales C. Phagocytosis: Our Current Understanding of a Universal Biological Process. Front. Immunol. 2020;11:1066. doi: 10.3389/fimmu.2020.01066. 90. …

Dendritic cell biology and its role in tumor immunotherapy.

As crucial antigen presenting cells, dendritic cells (DCs) play a vital role in tumor immunotherapy. Taking into account the many recent advances in DC biology, we discuss how DCs (1) recognize pathogenic antigens with pattern recognition receptors through specific phagocytosis and through non-specific micropinocytosis, (2) process antigens into small peptides with proper sizes and sequences, and (3) present MHC-peptides to CD4+ and CD8+ T cells to initiate immune responses against invading microbes and aberrant host cells. During anti-tumor immune responses, DC-derived exosomes were discovere

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… The degradation of Gram-positive bacterial cell walls by the phagosomes of DCs will lead to the activation of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3), which promotes the release of hexokinase [ 27 ]. … TFEB (transcription factor EB) can also promote lysosome and phagosome acidification and induce protein degradation in DCs [ 59 ]. …

Drugging the efferocytosis process: concepts and opportunities.

The daily removal of billions of apoptotic cells in the human body via the process of efferocytosis is essential for homeostasis. To allow for this continuous efferocytosis, rapid phenotypic changes occur in the phagocytes enabling them to engulf and digest the apoptotic cargo. In addition, efferocytosis is actively anti-inflammatory and promotes resolution. Owing to its ubiquitous nature and the sheer volume of cell turnover, efferocytosis is a point of vulnerability. Aberrations in efferocytosis are associated with numerous inflammatory pathologies, including atherosclerosis, cancer and infe

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… The fusion of the apoptotic cell-containing phagosome with lysosomes, where many pH-sensitive degradative enzymes reside, aids in the breakdown of the biomolecular content of the apoptotic cargo. How the phagosomes traffic inside phagocytes has been reviewed extensively elsewhere 1 , 2 . … The canonical phagocytosis pathway involves the maturation of the early phagosome to late phagosome with eventual fusion with the lysosomal compartment. …

The interplay of CD150 and CD180 receptor pathways contribute to the pathobiology of chronic lymphocytic leukemia B cells by selective inhibition of Akt and MAPK signaling.

Cell surface expression of CD150 and CD180 receptors in chronic lymphocytic leukemia (CLL) associates with mutational IGHV status and favourable prognosis. Here we show a direct correlation between cell surface expression and colocalization of these receptors on CLL B cells. In the absence of CD150 and CD180 on the cell surface both receptors were expressed in the cytoplasm. The CD150 receptor was colocalized with markers of the endoplasmic reticulum, the Golgi apparatus and early endosomes. In contrast, CD180 was detected preferentially in early endosomes. Analysis of CD150 isoforms different

Эпигенетические достижения в педиатрическом многоразовом склерозе: ДНК-метилирование примечательно участие Эпштейна-Барра заражённых вирусом и принимающих иммунных сетей.

СПРАВОЧНАЯ ИНФОРМАЦИЯ И ЦЕЛИ: Педиатрический множественный склероз (PedMS) предоставляет уникальную возможность для изучения патогенеза MS с учетом короткого интервала между воздействием на окружающую среду и возникновением заболеваний. Цель этого исследования состояла в том, чтобы выявить различные метилированные регионы (ДМР), которые способствуют взаимодействию между экологическими факторами и геномными факторами на ранних этапах заболевания. В этом многоцентровом исследовании мы проанализировали периферическую ДНК крови. 175 Итальянские предметы122 Пациенты педиатрии, 53 - здоровый контрол

TMED2/9/10 Serve as Biomarkers for Poor Prognosis in Head and Neck Squamous Carcinoma.

Background: Head and neck squamous carcinoma (HNSC) is one of the most common malignant tumors with high incidence and poor prognosis. Transmembrane emp24 structural domain (TMED) proteins are involved in protein transport and vesicle budding processes, which have implicated various malignancies' progression. However, the roles of TMEDs in HNSC, especially in terms of development and prognosis, have not been fully elucidated. Methods: We applied TIMER 2.0, UALCAN, GEPIA 2, Kaplan-Meier plotter, GEO, The Human Protein Atlas (HPA), cBioPortal, Linkedomics, Metascape, GRNdb, STRING, and Cytoscape

The role of abnormal epigenetic regulation of small GTPases in glioma (Review).

Brain tumors are one of the most severe types of malignant tumors and glioma accounts for ~80% of malignant brain tumors. The current treatment methods for glioma are limited and patients with glioma often experience relapse following treatment, which leads to a poor prognosis for these patients. Therefore, novel therapeutic targets and methods urgently need to be explored. The present review screened studies that mainly focused on the epigenetic regulation of small guanosine triphosphate (GTP)ase in glioma. These small GTPases participate in most cellular biological processes, including diffe

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… Moreover, it is associated with endosomes/phagosomes and primary cilia ( 186 , 187 ). RAB10 is mainly involved in regulating ER dynamics and morphology, polarized trafficking, establishment of basement membrane polarity and tubular endosome formation ( 183 , 188 - 190 ). … maturation and its overexpression rescues Mycobacterium-containing phagosomes maturation Traffic 11 221 235 2010 10.1111/j.1600-0854.2009.01013.x 20028485 187 Babbey CM Bacallao RL Dunn KW Rab10 associates with primary cilia and the exocyst complex in renal epithelial cells Am J Physiol Renal Physiol …

Comprehensive analysis of plasma cell heterogeneity and immune interactions in multiple myeloma.

This study focused on the role of plasma cells in multiple myeloma (MM) and the associated potential mechanisms. Transcriptomic data of MM and various gene sets from several public databases were downloaded for subsequent analyses. Through single-cell sequencing, 10 major cell types were identified and annotated. The differential gene expression and pathway enrichment between different plasma cell subtypes as well as cell communication analysis, transcriptional regulation analysis, and enrichment analysis in conjunction with the malignant subpopulation were performed. Next, the samples were cl