Biology subjects

Lund, G.

Publications and source records attributed to Lund, G..

3 recordsLinked to original sources

bioRxiv2023

Macrophage-targeted DNA methyltransferase inhibitor SGI-1027 decreases atherosclerosis in ApoE-null mice

Background and aimsCorrection of vascular DNA hypermethylation may slow atherogenesis. We tested the anti-inflammatory and anti-atherogenic activity of macrophage-targeted DNA methyltransferase (DNMT) inhibitor SGI-1027. Methods, ResultsSGI-1027 was encapsulated into human serum albumin (HSA) nanoparticles (HSANP) functionalized with the PP1 peptide, a macrophage scavenger receptor 1 ligand, fused to a FLAG epitope (S-HSANP-FLAGPP1). Nanoparticle physico-chemical characteristics predicted good marginalization towards the vascular wall, although SGI-1027 encapsulation efficiency was relatively low ([~]23%). S-HSANP-FLAGPP1 were rapidly internalized compared to non-functionalized and, surprisingly, functionalized void controls, and induced a shift towards an anti-inflammatory profile of secreted cytokines in human THP-1 macrophages. S-HSANP-FLAGPP1 colonized the atheroma and induced a significant [~]44% reduction of atherosclerosis burden in the aortic tree of ApoE-null mice compared to controls. A reduction in aortic root atherosclerosis was observed, although primarily induced by HSANP irrespective of loading or functionalization. No alteration of body weight, non-vascular tissue gross histology, plasma glucose, triglyceride or cholesterol were observed. HSA whether free or structured in nanoparticles, induced a 3-4-fold increase in HDL compared to vehicle. ConclusionsWe confirm that DNMT inhibition is anti-atherogenic and provide proof of principle that targeted HSANP are effective carriers for those molecules. SGI-1027 displayed a novel anti-inflammatory activity that is independent of cell proliferation and therefore likely unrelated to DNMT inhibition. HDL elevation may represent an additional advantage of HSA-based nanocarriers.

pathology↗

bioRxiv2023

A Distinct Phenotype of Polarized Memory B cell holds IgE Memory

Allergen-specific IgE antibodies mediate allergic pathology in diseases such as allergic rhinitis and food allergy. Memory B cells (MBCs) contribute to circulating IgE by regenerating IgE-producing plasma cells upon allergen encounter. We report a population of type 2 polarized MBCs defined as CD23hi, IL-4Rhi, CD32low at the transcriptional and surface protein levels. These "MBC2s" are enriched in IgG1 and IgG4-expressing cells, while constitutively expressing germline transcripts for IgE. Allergen-specific B cells from patients with allergic rhinitis and food allergy were enriched in MBC2s. MBC2s generated allergen specific-IgE during sublingual immunotherapy, thereby identifying these cells as the primary reservoir of IgE. The identification of MBC2s provides insights into the maintenance of IgE memory, which is detrimental in allergic diseases, but which could be beneficial in protection against venoms and helminths. One-Sentence SummaryIdentification of a novel memory B cell subset which holds allergen specific IgE memory.

immunology↗

bioRxiv2022

Differential RNA-silencing and plasmodesmata callose deposition in leaves and stems of transgenic tobacco plants during Tobacco etch virus infection recovery

Viruses are amongst the most prevalent pathogens that threaten plants. Plants have evolved a sequence-specific defense mechanism against viruses to ensure survival, known as RNA silencing, which includes transcriptional and post-transcriptional gene silencing. After a viral infection, some plants undergo recovery and become further resistant to viral infection. To identify additional mechanisms underlying disease recovery besides the known RNA silencing, we analyzed transgenic tobacco plants expressing a transcript derived from the Nuclear Inclusion "a" protein (NIa) cistron of the tobacco etch virus (TEV), which had recovered from infection three weeks following viral inoculation. Using in situ hybridizations and qRT-PCR, we detected the viral RNA and the transgene-derived transcript in stem sections adjacent to the recovered leaves. To further characterize the silenced and non-silenced conditions, we undertook tissue-specific RNA-Seq and small RNA-Seq analyses in leaf and stem. We found more differentially expressed genes (DEGs) in the recovered leaf, primarily related to defense, silencing, and hormone signaling responses. Finally, we observed differences in plasmodesmata callose deposition and callose-related genes. Overall, our findings suggest that cell-to-cell viral restriction movement also participates in the recovery of TEV infection in transgenic tobacco plants, besides the key function of RNA silencing.

plant biology↗