Результаты поиска

FKBP10 mitigates osteoporosis by restraining the HSPA5-coupled ERS-pyroptosis axis to enhance osteogenic differentiation in BMSCs.

BACKGROUND: Osteoporosis is characterized by progressive bone deterioration and is closely associated with impaired osteogenic differentiati … nd promoted HSPA5 lysosomal degradation, thereby alleviating HSPA5-associated sustained endoplasmic reticulum stress (ERS) and subsequent pyroptosis. CONCLUSIONS: Our findings identify FKBP10 as a protective regulator that preserves the osteogenic differentiation capacity of BMSCs and attenuates osteoporosis progression by restraining the HSPA5-associated …

Вирус Западного Нила и вирусные инфекции Зики вызывают резкие образования в гениальных потомках человека и в клетках A549.

UNLABELELED: Ранее было замечено, что вирусные репликации зики (VRV) имеют асимметричное скопление с одной стороны ядра в инфицированных Huh7, A549 и h-NPC. Инфекции вируса Западного Нила (ВНВ) в этих клетках также вызывают асимметричное группирование VRV. Были исследованы последовательные ответы ячеек, ведущие к асимметричной группировке ВНВ и ЗИКВ VRV. Обе инфекции активировали белковую реакцию на клетку (УПО), о чем свидетельствует усиление ПРФ78, главного регулятора УПО, и активация отделения ПЕРК УПО (p-PERK-p-eIF2α-GADD34). Кроме того, был вызван рост ацетилации микротубуля (MT). По мере

Совпадение в аннотации оригинала
UNLABELLED: Zika viral replication vesicles (VRVs) were previously observed to cluster asymmetrically on one side of the nucleus in infected … increased and GRP78, ubiquitinated proteins, the deacetylase HDAC6, VRVs, and modified endoplasmic reticulum clustered at the cellular microtubule-organizing center (MTOC) and became surrounded by a vimentin "cage." The components involved in the formation of asymmetric VRVs are characteristic of aggresome formation, an additional cellular response that co …

Ubiquitination by HRD1 is essential for TLR3 trafficking and its innate immune signaling.

Toll-like receptor 3 (TLR3), an innate immune sensor for double-stranded RNA (dsRNA), traffics from the endoplasmic reticulum (ER) after synthesis to endolysosomes for proteolytic cleavage and activation. However, the molecular mechanisms governing TLR3 trafficking remain largely unclear. Here, we identify the ER-resident E3 ligase HMG-CoA reductase degradation protein 1 (HRD1), a core component of ER-associated degradation (ERAD), as a key regulator that promotes TLR3 trafficking and downstream signaling. HRD1 deficiency in macrophages significantly impairs poly(I:C)-induced TLR3 signaling an…

B-Cell Receptor-Associated Protein 31 Deficiency Aggravates Ethanol-Induced Liver Steatosis and Liver Injury via Attenuating Fatty Acid Oxidation and Glycogen Synthesis.

Alcoholic liver disease (ALD) is a spectrum of alcohol-induced disorders and represents a major global health challenge. B-cell receptor-associated protein 31 (BAP31) is an endoplasmic reticulum-resident chaperone involved in protein transport, apoptosis, cancer biology, and lipid metabolism. To explore its role in ALD, we used hepatocyte-specific BAP31 knockout mice (BAP31-LKO) and wild-type (WT) littermates exposed to ethanol to assess BAP31's biochemical and metabolic impact. Following ethanol exposure, BAP31-LKO mice exhibited elevated serum alanine transaminase (23.2%, p < 0.05) and aspar…

The protective role of the IRE1α/XBP1 signaling cascade in autophagy during ischemic stress and acute kidney injury.

Acute kidney injury (AKI) is a common and serious complication resulting from ischemia and hypoxia, leading to significant morbidity and mor … conditions, and I/R injury was induced in mice. The expression of autophagy-related and endoplasmic reticulum stress markers (IRE1α, XBP1, GRP78, Beclin1, LC3I/II, and P62) was assessed using immunoblotting and immunofluorescence. Additionally, the impacts of IRE1α overexpression and pharmacological agents, IXA6 (IRE1α agonist), and STF083010 (IRE1α inhibit …

GRP78 alleviates secondary brain injury by regulating phenotype polarization in astrocytes via JAK2-STAT3 pathway after intracerebral hemorrhage.

BACKGROUND: Astrocytes, exhibiting dual phenotypes (A1 neurotoxic and A2 neuroprotective), play a pivotal role in secondary brain injury (SBI) subsequent to intracerebral hemorrhage (ICH). However, the underlying mechanisms remain elusive. This study sought to explore whether Glucose-regulated protein 78 (GRP78), an essential chaperone involved in endoplasmic reticulum stress, alleviates SBI by influencing astrocytic polarization and to elucidate the underlying mechanisms. METHODS: An autologous blood intracerebral hemorrhage model was established in C57BL/6 mice (8-10 weeks old, 25-30 g), an…

Glabridin Alleviates Metabolic Disorders in Diet-Induced Diabetic Mice.

Glabridin (GLD) is a flavonoid derived from licorice. This study aims to evaluate GLD's therapeutic potential in ameliorating type 2 diabete … s of glycogen synthesis, gluconeogenesis, lipid metabolism, mitochondrial function, and endoplasmic reticulum (ER) stress. GLD significantly lowered blood glucose levels in the diabetic mice. It suppressed gluconeogenesis by inhibiting PEPCK and G6P, while promoting glycogen synthesis by activating GCK and inhibiting GSK-3β. Additionally, GLD enhanced insul …

HERC3 facilitates ERAD of select membrane proteins by recognizing membrane-spanning domains.

Aberrant proteins located in the endoplasmic reticulum (ER) undergo rapid ubiquitination by multiple ubiquitin (Ub) E3 ligases and are retrotranslocated to the cytosol as part of the ER-associated degradation (ERAD). Despite several ERAD branches involving different Ub E3 ligases, the molecular machinery responsible for these ERAD branches in mammalian cells remains not fully understood. Through a series of multiplex knockdown/knockout experiments with real-time kinetic measurements, we demonstrate that HERC3 operates independently of the ER-embedded ubiquitin ligases RNF5 and RNF185 (RNF5/185…

Protective effect of metformin against rotenone-induced parkinsonism in mice.

Rotenone is a mitochondrial complex I inhibitor, which can cause the death of dopaminergic (DA) neurons and Parkinson's disease (PD). Curren … he mRNA levels of proinflammatory cytokines (TNF-α and IL-1β) and molecules involved in endoplasmic reticulum (ER) stress (ATF4, ATF6, XBP1, Grp78, and CHOP) in the midbrain were detected by Quantitative real-time PCR. This study showed that 50 mg/kg metformin given orally daily, beginning 3 d before rotenone injection and continuing for 4 weeks following r …

Probing the Global Cellular Responses to Lipotoxicity Caused by Saturated Fatty Acids.

Excessive levels of saturated fatty acids are toxic to cells, although the basis for this lipotoxicity remains incompletely understood. Here, we analyzed the transcriptome, lipidome, and genetic interactions of human leukemia cells exposed to palmitate. Palmitate treatment increased saturated glycerolipids, accompanied by a transcriptional stress response, including upregulation of the endoplasmic reticulum (ER) stress response. A comprehensive genome-wide short hairpin RNA (shRNA) screen identified >350 genes modulating lipotoxicity. Among previously unknown genetic modifiers of lipotoxicity,…

[Thioridazine Sensitizes Apoptotic Effect of TRAIL in Human Lung Cancer PC9 Cells Through ER Stress Mediated Up-regulation of DR5].

BACKGROUND: Tumor necrosis factor-related apoptosis-inducting ligand (TRAIL) can induce apoptosis of tumor cells, however, various of tumor cells may survive because of resistance to TRAIL-mediated apoptosis. This study is to observe the proliferation inhibition effect of TRAIL sensitized by thioridazine on PC9 cells through endoplasmic reticulum (ER) stress mediated up-regulation of death receptor 5 (DR5) and investigate its mechanism. METHODS: PC9 cells were treated with different concentrations of thioridazine and TRAIL alone or in combination. Cell proliferation was measured by MTT assay,…

CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy.

BACKGROUND & AIMS: CXC chemokine receptor 3 (CXCR3) is involved in virus-related chronic liver inflammation. However, the role of CXCR3 in n … pogenic genes. Moreover, CXCR3 is associated with autophagosome-lysosome impairment and endoplasmic reticulum (ER) stress in steatohepatitis as evidenced by LC3-II and p62/SQSTM1 accumulation and the induction of GRP78, phospho-PERK and phospho-eIF2α. Inhibition of CXCR3 using CXCR3 antagonist significantly suppressed MCD-induced steatosis and hepatocytes i …

Oxidative stress-dependent activation of the eIF2α–ATF4 unfolded protein response branch by skin sensitizer 1-fluoro-2,4-dinitrobenzene modulates dendritic-like cell maturation and inflammatory status in a biphasic manner [corrected].

The pathogenesis of allergic contact dermatitis, the most common manifestation of immunotoxicity in humans, is intimately connected to hapten-induced maturation of dendritic cells (DC). The molecular mechanisms driving this maturational program are not completely known; however, initial danger signals such as the generation of reactive oxygen species (ROS) were shown to play a critical role. Recent evidence linking ROS production, endoplasmic reticulum (ER) stress, and the pathogenesis of several inflammatory diseases led us to analyze, in the present work, the ability of the skin sensitizer 1…

Possible Involvement of Multidrug-Resistant Hepatitis B Virus sW172* Truncation Variant in the ER Stress Signaling Pathway during Hepatocarcinogenesis.

We investigated the biological effect of hepatitis B virus (HBV) rtA181T/sW172* point mutation on HBsAg secretion and the potential mechanisms involved in hepatocarcinogenesis. Full-length HBV wild type (wt) and HBV rtA181T/sW172* expression plasmids were transfected into HepG2 cell lines or were injected into C57BL/6 mice. The extracellular and intracellular expression levels of HBsAg and HBeAg proteins, in mouse serum and liver tissues were detected by ELISA. The localization of the truncated protein was characterized in vitro. The mRNA expression of endoplasmic reticulum (ER) stress gene GR…

The lumpy skin disease virus protein LSDV003 regulates MHC-I trafficking and surface expression.

Lumpy skin disease (LSD) is a severe transboundary disease of cattle caused by lumpy skin disease virus (LSDV), which is highly transmissibl … ly, LSDV003 interacts with both the MHC-I heavy chain and β2-microglobulin and mediates endoplasmic reticulum (ER) retention of MHC-I via a C-terminal HNEL motif, thereby preventing its transport to the cell surface. Mutational analyses demonstrated that disruption of the HNEL motif impaired the ability of LSDV003 to alter MHC-I localization and surface exp …

Knockout of the Intracellular Calcium Conducting Ion Channel Mitsugumin 23 (MG23) Protects Against Pressure Overload Induced Left Ventricular Hypertrophy and Cardiac Dysfunction.

In cardiac dysfunction, intracellular Ca2+-dynamics are disrupted leading to leakage of Ca2+ from the sarcoplasmic reticulum (SR). This results in diminished cardiac contractility and impaired cardiac function. In cardiac tissue, the underlying molecular mechanisms responsible for RyR2-independent Ca2+-leak are poorly understood. Mitsugumin 23 (MG23) is an intracellular Ca2+-conducting ion channel located on endoplasmic/sarcoplasmic reticulum (ER/SR) and nuclear membranes. We propose that MG23 contributes to regulation of intracellular Ca2+-homeostasis, and that altered MG23 function may drive…

PTK2/FAK inhibition triggers TMED9-mediated protective autophagy in pancreatic cancer cell via enhancing ERGIC-ERES contact.

Macroautophagy/autophagy represents a promising therapeutic target in oncology, exhibiting context-dependent roles in tumor progression. Kin … AMPK: AMP-activated protein kinase; BAF: bafilomycin A1; ECM: extracellular matrix; ER: endoplasmic reticulum; ERES: endoplasmic reticulum exit sites; ERGIC: ER-Golgi intermediate compartment; GSK: GSK2256098; MTOR: mechanistic target of rapamycin kinase; PDAC: pancreatic ductal adenocarcinoma; PI3K: phosphoinositide 3-kinase; PI4KB: phosphatidylinositol 4- …

Membrane ATG8ylation in secretory autophagy.

Mammalian Atg8-family (ATG8) proteins are crucial for macroautophagic/autophagic degradation in the lysosome and facilitate non-degradative … diazepam binding inhibitor, acyl-CoA binding protein; DSS, dextran sodium sulfate; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum intermediate compartment; ESCRT, endosomal complexes required for transport; EVs, extracellular vesicles; EVPs, extracellular vesicles and particles; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IFNB …

Oxidative protein folding and Ca2+ homeostasis under redox control.

Secretory and membrane proteins undergo oxidative folding, the process of forming disulfide bonds between cysteine side chains to construct a stable higher-order structure, primarily in the endoplasmic reticulum (ER) followed by further post-translational modification in the Golgi apparatus, after which proteins proceed to pathways for secretion and membrane localization. Proteins involved in transferring oxidizing power to target proteins possess a pair of highly reactive forms of cysteine residue that mediate reduction-oxidation (redox) reactions. Oxidizing power, which is generally provided…

Mitochondrial proteomic signatures of postcardiac arrest brain injury reveal potential therapeutic targets.

Mitochondrial dysfunction is central to postcardiac arrest brain injury (PCABI); however, the underlying protein networks involved remain po … logical signature comprising complex I deficiency (NDUFB4), oxidative stress (NDUFB11), endoplasmic reticulum stress (RPN2), and lipid dysregulation (PLA2). SRT1720 treatment was associated with the reversal of these proteomic alterations and the re-establishment of metabolic homeostasis. Collectively, this multilevel analysis identifies a mitochondrial pro …