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Thorax ◽  
2022 ◽  
pp. thoraxjnl-2020-216807
Author(s):  
Koralia Paschalaki ◽  
Christos Rossios ◽  
Charis Pericleous ◽  
Mairi MacLeod ◽  
Stephen Rothery ◽  
...  

Cellular senescence contributes to the pathophysiology of chronic obstructive pulmonary disease (COPD) and cardiovascular disease. Using endothelial colony-forming-cells (ECFC), we have demonstrated accelerated senescence in smokers and patients with COPD compared with non-smokers. Subgroup analysis suggests that ECFC from patients with COPD on inhaled corticosteroids (ICS) (n=14; eight on ICS) exhibited significantly reduced senescence (Senescence-associated-beta galactosidase activity, p21CIP1), markers of DNA damage response (DDR) and IFN-γ-inducible-protein-10 compared with patients with COPD not on ICS. In vitro studies using human-umbilical-vein-endothelial-cells showed a protective effect of ICS on the DDR, senescence and apoptosis caused by oxidative stress, suggesting a protective molecular mechanism of action of corticosteroids on endothelium.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Satoshi Yamanaka ◽  
Yuto Horiuchi ◽  
Saya Matsuoka ◽  
Kohki Kido ◽  
Kohei Nishino ◽  
...  

AbstractProteolysis-targeting chimaeras (PROTACs) as well as molecular glues such as immunomodulatory drugs (IMiDs) and indisulam are drugs that induce interactions between substrate proteins and an E3 ubiquitin ligases for targeted protein degradation. Here, we develop a workflow based on proximity-dependent biotinylation by AirID to identify drug-induced neo-substrates of the E3 ligase cereblon (CRBN). Using AirID-CRBN, we detect IMiD-dependent biotinylation of CRBN neo-substrates in vitro and identify biotinylated peptides of well-known neo-substrates by mass spectrometry with high specificity and selectivity. Additional analyses reveal ZMYM2 and ZMYM2-FGFR1 fusion protein—responsible for the 8p11 syndrome involved in acute myeloid leukaemia—as CRBN neo-substrates. Furthermore, AirID-DCAF15 and AirID-CRBN biotinylate neo-substrates targeted by indisulam and PROTACs, respectively, suggesting that this approach has the potential to serve as a general strategy for characterizing drug-inducible protein–protein interactions in cells.


2022 ◽  
Author(s):  
Wei-Jia Luo ◽  
Sung-Liang Yu ◽  
Chia-Ching Chang ◽  
Min-Hui Chien ◽  
Keng-Mao Liao ◽  
...  

Heat shock protein (HSP) 40 has emerged as a key actor in both innate and adaptive immunity, whereas the role of HLJ1, a molecular chaperone in HSP40 family, in modulating endotoxin–induced sepsis severity is still unclear. Here, we use single-cell RNA sequencing to characterize mouse liver nonparenchymal cell populations under LPS (lipopolysaccharide) stimulation, and show that HLJ1 deletion affected IFN-γ-related gene signatures in distinct immune cell clusters. HLJ1 deficiency also leads to reduced serum levels of IL-12 in LPS-treated mice, contributing to dampened production of IFN-γ in natural killer cells but not CD4+ or CD8+ T cells, and subsequently to improved survival rate. Adoptive transfer of HLJ1-deleted macrophages into LPS-treated mice results in reduced IL-12 and IFN-γ levels and protects the mice from IFN-γ–dependent mortality. In the context of molecular mechanisms, HLJ1 is an LPS-inducible protein in macrophages and converts misfolded IL-12p35 homodimers to monomers, which maintains bioactive IL-12p70 heterodimerization and secretion. This study suggests HLJ1 causes IFN-γ–dependent septic lethality by promoting IL-12 heterodimerization, and targeting HLJ1 has therapeutic potential in inflammatory diseases involving activating IL-12/IFN-γ axis.


2021 ◽  
Vol 8 ◽  
Author(s):  
Chenyi Liu ◽  
Shian Zhang ◽  
Xinyi Deng ◽  
Yijing Chen ◽  
Lijun Shen ◽  
...  

Purpose: To investigate and compare the aqueous concentrations of vascular endothelial growth factor (VEGF) and other inflammatory cytokines in various choroidal neovascularization (CNV) diseases and types.Methods: This observational study included 127 naive eyes with CNV and 43 control eyes with cataracts. Aqueous humor (AH) samples were obtained prior to intravitreal anti-VEGF injection or cataract surgery. Multiple inflammatory cytokines, including VEGF, interleukin (IL) 6, IL-8, IL-10, interferon-inducible protein 10 (IP-10), and monocyte chemotactic protein 1 (MCP-1) levels, were measured using a multiplex bead assay. The angiogenesis index was defined as the ratio of IP-10 to MCP-1. In addition, the relationship among AH cytokine levels, central macular thickness (CMT), and CNV size on optical coherence tomography angiography (OCTA) was evaluated.Results: Except in the myopic CNV group (P = 0.452), the AH concentration of VEGF was significantly higher in all other CNV groups than in the control group (P < 0.05 for all comparisons). IL-8, IL-10, IP-10, and MCP-1 levels (P < 0.05 for all groups) were significantly higher in all CNV diseases except those with neovascular central serous chorioretinopathy. The angiogenesis index was significantly higher in all CNV diseases (P < 0.05 for all comparisons). The VEGF level may be associated with the size of the CNV on OCTA (p = 0.043).Conclusions: The level of intraocular inflammatory cytokines varied among different CNV diseases and CNV types. Therefore, the angiogenesis index may be a more sensitive indicator of angiogenesis.


2021 ◽  
Author(s):  
Liping Zeng ◽  
Hao Chen ◽  
Yaqi Wang ◽  
Derrick Hicks ◽  
Haiyan Ke ◽  
...  

Transcriptional regulators of general stress response (GSR) reprogram expression of selected genes to transduce informational signals into cellular events, ultimately manifested in plant's ability to cope with environmental challenges. Identification of the core GSR regulatory proteins will uncover the principal modules and their mode of action in the establishment of adaptive responses. To define the GSR regulatory components, we employed a yeast-one-hybrid assay to identify the protein(s) that binds to the previously established functional GSR motif, coined Rapid Stress Response Element (RSRE). This led to the isolation of ORA47 (octadecanoid-responsive AP2/ERF-domain transcription factor 47), a Methyl jasmonate (MeJA) inducible protein. Subsequently, the ORA47 transcriptional activity was confirmed using RSRE-driven Luciferase (LUC) activity assay performed in the ORA47 loss- and gain-of-function lines introgressed into the 4xRSRE::Luc background. In addition, the prime contribution of CALMODULIN-BINDING TRANSCRIPTIONAL ACTIVATOR3 (CAMTA3) protein in induction of RSRE was reaffirmed by genetic studies. Moreover, exogenous application of MeJA led to enhanced levels of ORA47 and CAMTA3 transcripts, and the induction of RSRE::LUC activity. Metabolic analyses illustrated the reciprocal functional inputs of ORA47 and CAMTA3 in increasing JA levels. Lastly, transient assays identified JASMONATE ZIM-domain1 (JAZ1) as a repressor of RSRE::LUC activity.


Author(s):  
Johannes Thorman ◽  
Per Björkman ◽  
Gaetano Marrone ◽  
Taye Tolera Balcha ◽  
Fregenet Tesfaye ◽  
...  

To reach the goal of elimination of HIV as public health threat, access to antiretroviral treatment (ART) has to be further scaled up. To ensure viral suppression in individuals receiving ART, novel and robust systems for treatment monitoring are required.


2021 ◽  
Author(s):  
Alyson Sujkowski ◽  
Kristin Richardson ◽  
Matthew V. Prifti ◽  
R. J. Wessells ◽  
Sokol V. Todi

AbstractEndurance exercise is a potent intervention with widespread benefits proven to reduce disease incidence and impact across species. While endurance exercise supports neural plasticity, enhanced memory, and reduced neurodegeneration, less is known about the effect of chronic exercise on the progression of movement disorders such as ataxias. Here, we focused on three different types of ataxias, Spinocerebellar Ataxias Type (SCAs) 2, 3, and 6, belonging to the polyglutamine (polyQ) family of neurodegenerative disorders. In Drosophila models of these SCAs, flies progressively lose motor function. Here, we observe marked protection of speed and endurance in exercised SCA2 flies and modest protection in exercised SCA6 models, while no benefit is observed in SCA3 flies. Causative protein levels are reduced in SCA2 flies after chronic exercise, but not in SCA3 models, linking protein levels to exercise-based benefits. Additional investigations indicate that the exercise-inducible protein, Sestrin (Sesn) suppresses mobility decline and improves early death in SCA2 flies, even without exercise, coincident with disease protein level reduction and increased autophagic flux. These improvements depend on previously established functions of Sesn that reduce oxidative damage and modulate mTOR activity. Our study suggests differential responses of polyQ SCAs to exercise, highlighting the potential for more extensive application of exercise-based therapies in the prevention of polyQ neurodegeneration. Defining the mechanisms by which endurance exercise suppresses polyQ SCAs will open the door for more effective treatment for these diseases.


2021 ◽  
Author(s):  
Yuki Hatoyama ◽  
Yuta Homma ◽  
Shu Hiragi ◽  
Mitsunori Fukuda

Two small GTPases, Rab1 and Rab5, are key membrane trafficking regulators that are conserved in all eukaryotes. Since they have recently been shown to be essential for cell survival and/or growth in cultured mammalian cells, thereby precluding the establishment of Rab1-knockout (KO) and Rab5-KO cells, it has been extremely difficult to assess the impact of complete Rab1 or Rab5 protein depletion on cellular functions. Here, we generated and analyzed conditional KO (CKO) cells for Rab1 (Rab1A/1B) and Rab5 (Rab5A/5B/5C) by using the auxin-inducible protein degradation system. Rab1-CKO and Rab5-CKO led to eventual cell death >18 h and >48 h, respectively, after auxin exposure. After acute Rab1 protein depletion, the Golgi stack and ribbon structures were completely disrupted, and ER-to-Golgi trafficking was severely inhibited. Moreover, we discovered a novel Rab1-depletion phenotype: perinuclear clustering of early endosomes and delayed transferrin recycling. In contrast, acute Rab5 protein depletion resulted in loss of early endosomes and late endosomes, but lysosomes appeared to be normal. We also observed a dramatic reduction in the intracellular signals of endocytic cargos via receptor-mediated or fluid-phase endocytosis in Rab5-depleted cells.


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