Transcriptional analysis of the endothelial response to diabetes reveals a role for galectin-3

To characterize the endothelial dysfunction associated with Type II diabetes, we surveyed transcriptional responses in the vascular endothelia of mice receiving a diabetogenic, high-fat diet. Tie2-GFP mice were fed a diet containing 60% fat calories (HFD); controls were littermates fed normal chow. Following 4, 6, and 8 wk, aortic and leg muscle tissues were enzymatically dispersed, and endothelial cells were obtained by fluorescence-activated cell sorting. Relative mRNA abundance in HFD vs. control endothelia was measured with long-oligo microarrays; highly dysregulated genes were confirmed by real-time PCR and protein quantification. HFD mice were hyperglycemic by 2 wk and displayed vascular insulin resistance and decreased glucose tolerance by 5 and 6 wk, respectively. Endothelial transcripts upregulated by HFD included galectin-3 ( Lgals3), 5-lipoxygenase-activating protein, and chemokine ligands 8 and 9. Increased LGALS3 protein was detected in muscle endothelium by immunohistology accompanied by elevated LGALS3 in the serum of HFD mice. Our comprehensive analysis of the endothelial transcriptional response in a model of Type II diabetes reveals novel regulation of transcripts with roles in inflammation, insulin sensitivity, oxidative stress, and atherosclerosis. Increased endothelial expression and elevated humoral levels of LGALS3 supports a role for this molecule in the vascular response to diabetes, and its potential as a direct biomarker for the inflammatory state in diabetes.

Download Full-text

Transcriptional analysis of lymphoid tissues from infected nonhuman primates reveals the basis for attenuation and immunogenicity of an Ebola virus encoding a mutant VP35 protein

Journal of Virology ◽

10.1128/jvi.01995-20 ◽

2021 ◽

Author(s):

Amanda Pinski ◽

Courtney Woolsey ◽

Allen Jankeel ◽

Robert Cross ◽

Christopher F. Basler ◽

...

Keyword(s):

Immune Response ◽

Nonhuman Primates ◽

Ebola Virus ◽

Transcriptional Response ◽

Transcriptional Analysis ◽

Lymphoid Tissues ◽

High Dose ◽

Type I ◽

Wild Type ◽

Transcriptional Responses

Infection with Zaire ebolavirus (EBOV), a member of the Filoviridae family, causes a disease characterized by high levels of viremia, aberrant inflammation, coagulopathy, and lymphopenia. EBOV initially replicates in lymphoid tissues and disseminates via dendritic cells (DCs) and monocytes to liver, spleen, adrenal gland and other secondary organs. EBOV protein VP35 is a critical immune evasion factor that inhibits type I interferon signaling and DC maturation. Nonhuman primates immunized with a high dose (5x105 PFU) of recombinant EBOV containing a mutated VP35 (VP35m) are protected from challenge with wild-type (wt)EBOV. This protection is accompanied by a transcriptional response in the peripheral blood reflecting a regulated innate immune response and a robust induction of adaptive immune genes. However, the host transcriptional response to VP35m in lymphoid tissues has not been evaluated. Therefore, we conducted a transcriptional analysis of axillary and inguinal lymph nodes, and spleen tissues of NHPs infected with a low dose (2x104 PFU) of VP35m and then backchallenged with a lethal dose of wtEBOV. VP35m induced early transcriptional responses in lymphoid tissues that are distinct from those observed in wtEBOV challenge. Specifically, we detected robust antiviral innate and adaptive responses and fewer transcriptional changes in genes with roles in angiogenesis, apoptosis and inflammation. Two of three macaques survived wtEBOV backchallenge, with only the nonsurvivor displaying a transcriptional response reflecting Ebola virus disease. These data suggest that VP35 is a key modulator of early host responses in lymphoid tissues, thereby regulating disease progression and severity following EBOV challenge. IMPORTANCE Zaire Ebola virus (EBOV) infection causes a severe and often fatal disease characterized by inflammation, coagulation defects, and organ failure driven by a defective host immune response. Lymphoid tissues are key sites of EBOV pathogenesis and generation of an effective immune response to infection. A recent study demonstrated that infection with an EBOV encoding a mutant VP35, a viral protein that antagonizes host immunity, can protect nonhuman primates (NHPs) against lethal EBOV challenge. However, no studies have examined the response to this mutant EBOV in lymphoid tissues. Here, we characterize the gene expression of lymphoid tissues from NHPs challenged with the mutant EBOV and subsequently with wild-type EBOV to identify signatures of a protective host response. Our findings are critical for elucidating viral pathogenesis, mechanisms of host antagonism and the role of lymphoid organs in protective responses to EBOV to improve the development of antivirals and vaccines against EBOV.

Download Full-text

Genome-scale transcriptional analysis reveals key genes associated with the development of type II diabetes in mice

Experimental and Therapeutic Medicine ◽

10.3892/etm.2017.4042 ◽

2017 ◽

Vol 13 (3) ◽

pp. 1044-1150 ◽

Cited By ~ 2

Author(s):

Yuchi Zhang ◽

Dongwei Han ◽

Pengyang Yu ◽

Qijing Huang ◽

Pengling Ge

Keyword(s):

Type Ii Diabetes ◽

Transcriptional Analysis ◽

Type Ii ◽

Diabetes In Mice ◽

Key Genes ◽

Genome Scale

Download Full-text

Physical activity, exercise and low-grade systemic inflammation

Proceedings of The Nutrition Society ◽

10.1017/s0029665110001928 ◽

2010 ◽

Vol 69 (3) ◽

pp. 400-406 ◽

Cited By ~ 43

Author(s):

Julia Wärnberg ◽

Karen Cunningham ◽

Javier Romeo ◽

Ascension Marcos

Keyword(s):

Physical Activity ◽

Type Ii Diabetes ◽

The Body ◽

Low Grade ◽

Type Ii ◽

Active Lifestyle ◽

Physically Active ◽

Inflammatory State ◽

Physical Activity And Exercise ◽

Low Grade Inflammation

Prospective studies have shown that chronic low-grade inflammation may contribute to the pathogenesis of the most common chronic diseases and in particular CVD. Obesity has repeatedly been associated with moderately raised levels of inflammation, and this observation has led to the view that obesity is characterised by a state of chronic low-grade inflammation. There is now great interest in elucidating how physical activity and exercise modulate inflammation. This review summarises the current research addressing the influence of physical activity and exercise in mitigating the risks of obesity and diseases such as type-II diabetes and CVD, through its action on the low-grade inflammatory state. Most research on this topic hypothesised that the association between physical activity and inflammatory markers is independent of fatness, but very few studies have proven this. Given that physical activity and obesity are often inversely related, it is not clear as to whether the anti-inflammatory health benefits of a physically active lifestyle are due to exercise per se or result from favourable changes in the body composition.

Download Full-text