The endoplasmic reticulum is responsible for much of a cell's protein synthesis and folding, but it also has an important role in sensing cellular stress. Recently, it has been shown that the endoplasmic reticulum mediates a specific set of intracellular signalling pathways in response to the accumulation of unfolded or misfolded proteins, and these pathways are collectively known as the unfolded-protein response. New observations suggest that the unfolded-protein response can initiate inflammation, and the coupling of these responses in specialized cells and tissues is now thought to be fundamental in the pathogenesis of inflammatory diseases. The knowledge gained from this emerging field will aid in the development of therapies for modulating cellular stress and inflammation.

From endoplasmic reticulum stress to the inflammatory response.

Radical-mediated 1,2-difunctionalization of olefins is a well-established synthetic technique widely used in the rapid construction of structurally diverse molecular entities. However, radical-mediated 1,3-difunctionalization reactions are rare, and the substrates are generally limited to strained skeletons. Here, we report a practical approach for 1,3-difunctionalization of available β,γ-unsaturated ketones via a radical cascade process including visible light–irradiated radical addition, thermodynamic stability–driven 1,2-carbonyl migration from unactivated all-carbon quaternary center, and terminal C-radical varied transformations. Various highly functionalized alkyl skeletons with different valuable functional groups at positions 1 and 3 and the carbonyl group at position 2 have been synthesized through a radical chain pathway or Cu-catalyzed Ritter-type reaction. Moreover, this protocol provides a real case of diversity-oriented radical rearrangement for drug discovery. We identified a previously unknown chemotype of dual inhibitors for hypoxia-inducible factor (HIF) and WNT signaling pathways from products. These small-molecule inhibitors could suppress HIF and WNT signaling–dependent HCT116 cell growth in 2D and 3D culture systems.

Visible light–initiated radical 1,3-difunctionalization of β,γ-unsaturated ketones

Type I interferon signaling facilitates resolution of acute liver injury by priming macrophage polarization

Rheumatoid arthritis (RA) occurs in about 5 per 1,000 people and can lead to severe joint damage and disability. However, the knowledge of pathogenesis and treatment for RA remains limited. Here, we found that histone demethylase inhibitor GSK-J4 relieved collagen induced arthritis (CIA) symptom in experimental mice model, and the underlying mechanism is related to epigenetic transcriptional regulation in macrophages. The role of epigenetic regulation has been introduced in the process of macrophage polarization and the pathogenesis of inflammatory diseases. As a repressive epigenetic marker, tri-methylation of lysine 27 on histone H3 (H3K27me3) was shown to be important for transcriptional gene expression regulation. Here, we comprehensively analyzed H3K27me3 binding promoter and corresponding genes function by RNA sequencing in two differentially polarized macrophage populations. The results revealed that H3K27me3 binds on the promoter regions of multiple critical cytokine genes and suppressed their transcription, such as IL6, specifically in M-CSF derived macrophages but not GM-CSF derived counterparts. Our results may provide a new approach for the treatment of inflammatory and autoimmune disorders.

/pdf/inhibition-of-histone-h3-lysine-27-demethylase-activity-1y02vfx9.pdf

Inhibition of Histone H3 Lysine-27 Demethylase Activity Relieves Rheumatoid Arthritis Symptoms via Repression of IL6 Transcription in Macrophages

Fatty acid transport protein 4 (FATP4) belongs to a family of acyl-CoA synthetases which activate long-chain fatty acids into acyl-CoAs subsequently used in specific metabolic pathways. Patients with FATP4 mutations and Fatp4-null mice show thick desquamating skin and other complications, however, FATP4 role on macrophage functions has not been studied. We here determined whether the levels of macrophage glycerophospholipids, sphingolipids including ceramides, triacylglycerides, and cytokine release could be altered by FATP4 inactivation. Two in vitro experimental systems were studied: FATP4 knockdown in THP-1-derived macrophages undergoing M1 (LPS + IFNγ) or M2 (IL-4) activation and bone marrow-derived macrophages (BMDMs) from macrophage-specific Fatp4-knockout (Fatp4M-/-) mice undergoing tunicamycin (TM)-induced endoplasmic reticulum stress. FATP4-deficient macrophages showed a metabolic shift towards triacylglycerides and were protected from M1- or TM-induced release of pro-inflammatory cytokines and cellular injury. Fatp4M-/- BMDMs showed specificity in attenuating TM-induced activation of inositol-requiring enzyme1α, but not other unfolded protein response pathways. Under basal conditions, FATP4/Fatp4 deficiency decreased the levels of ceramides and induced an up-regulation of mannose receptor CD206 expression. The deficiency led to an attenuation of IL-8 release in THP-1 cells as well as TNF-α and IL-12 release in BMDMs. Thus, FATP4 functions as an acyl-CoA synthetase in macrophages and its inactivation suppresses the release of pro-inflammatory cytokines by shifting fatty acids towards the synthesis of specific lipids.

FATP4 inactivation in cultured macrophages attenuates M1- and ER stress-induced cytokine release via a metabolic shift towards triacylglycerides.

Cellular stress responses are often engaged at sites of inflammation and can alter macrophage cytokine production. We now report that macrophages in distinct states of differentiation or in different temporal stages of inflammatory response exhibit differential sensitivity to cell stress mediated alterations in M1-like polarized inflammatory cytokine production. Tunicamycin (Tm) treatment of bone marrow derived macrophages (BMDM) cultured with M-CSF cultured bone marrow derived macrophages (M-BMDM) had markedly amplified M1-like responses to LPS, exhibiting higher levels of IL12p40 and IL12p35 mRNAs while BMDM cultured with GM-CSF, which normally express high IL12 subunit production in response to LPS, were relatively unaltered. Anti-inflammatory IL10 mRNA production in LPS-stimulated M-BMDM was greatly reduced by cell stress. These changes in cytokine mRNA levels resulted from altered rates of transcription and mRNA decay. Stress also altered cytokine protein production. Resident liver macrophages isolated from mice treated with Tm showed elevated levels of IL12 subunit mRNA production following LPS stimulation. Furthermore, macrophages infiltrating the liver during the early phase of acetaminophen injury (24 h) had little stress-mediated change in cytokine mRNA production while cells isolated in the later phase (48-72 h) exhibited higher sensitivity for stress elevated cytokine production. Hence cultured macrophages developed using different growth/differentiation factors and macrophages from different temporal stages of injury in vivo show markedly different sensitivity to cell stress for altered inflammatory cytokine production. These findings suggest that cellular stress can be an important modulator of the magnitude and character of myeloid inflammatory activity.

/pdf/unfolded-protein-response-differentially-regulates-tlr4-1so13wrzmt.pdf

Unfolded Protein Response Differentially Regulates TLR4-Induced Cytokine Expression in Distinct Macrophage Populations.

The Wnt/β-catenin signaling pathway plays an important role in tissue homeostasis, and its malignant activation is closely related to the occurrence and development of many cancers, especially colorectal cancer with adenomatous polyposis coli (APC) and CTNNB1 mutations. By applying a TCF/lymphoid-enhancing factor (LEF) luciferase reporter system, the high-throughput screening of 18 840 small-molecule compounds was performed. A novel scaffold compound, C644-0303, was identified as a Wnt/β-catenin signaling inhibitor and exhibited antitumor efficacy. It inhibited both constitutive and ligand activated Wnt signals and its downstream gene expression. Functional studies showed that C644-0303 causes cell cycle arrest, induces apoptosis, and inhibits cancer cell migration. Moreover, transcription factor array indicated that C644-0303 could suppress various tumor-promoting transcription factor activities in addition to Wnt/β-catenin. Finally, C644-0303 suppressed tumor spheroidization in a 3-dimensional cell culture model and inhibited xenograft tumor growth in mice. In conclusion, we report a novel structural small molecular inhibitor targeting the Wnt/β-catenin signaling pathway that has therapeutic potential for colorectal cancer treatment.

C644-0303, a small-molecule inhibitor of the Wnt/β-catenin pathway, suppresses colorectal cancer growth.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Wei Wei

Author Tools

Chat about Author

Papers

Unfolded Protein Response Differentially Regulates TLR4-Induced Cytokine Expression in Distinct Macrophage Populations.

C644-0303, a small-molecule inhibitor of the Wnt/β-catenin pathway, suppresses colorectal cancer growth.