Investigation of Griffithsin's Interactions with Human Cells Confirms Its Outstanding Safety and Efficacy Profile as a Microbicide Candidate

Many natural product-derived lectins such as the red algal lectin griffithsin (GRFT) have potent in vitro activity against viruses that display dense clusters of oligomannose N-linked glycans (NLG) on their surface envelope glycoproteins. However, since oligomannose NLG are also found on some host proteins it is possible that treatment with antiviral lectins may trigger undesirable side effects. For other antiviral lectins such as concanavalin A, banana lectin and cyanovirin-N (CV-N), interactions between the lectin and as yet undescribed cellular moieties have been reported to induce undesirable side effects including secretion of inflammatory cytokines and activation of host T-cells. We show that GRFT, unlike CV-N, binds the surface of human epithelial and peripheral blood mononuclear cells (PBMC) through an exclusively oligosaccharide-dependent interaction. In contrast to several other antiviral lectins however, GRFT treatment induces only minimal changes in secretion of inflammatory cytokines and chemokines by epithelial cells or human PBMC, has no measureable effect on cell viability and does not significantly upregulate markers of T-cell activation. In addition, GRFT appears to retain antiviral activity once bound to the surface of PBMC. Finally, RNA microarray studies show that, while CV-N and ConA regulate expression of a multitude of cellular genes, GRFT treatment effects only minimal alterations in the gene expression profile of a human ectocervical cell line. These studies indicate that GRFT has an outstanding safety profile with little evidence of induced toxicity, T-cell activation or deleterious immunological consequence, unique attributes for a natural product-derived lectin

Mönckeberg sclerosis with giant cells as a masquerade of giant cell arteritis

Giant cell arteritis (GCA) is the most common type of vasculitis in adults, which is classified as a large/medium vessel vasculitis. It has a predilection for the ophthalmic circulation and extracranial carotid system. Temporal artery biopsy specimens can show the presence of inflammatory multinucleated giant cells. Here, we report just the third case of Mönckeberg sclerosis with multinucleated giant cells affecting the temporal artery and mimicking GCA. This rare finding in the evaluation of a common vasculitis is important for rheumatologists to be aware of and emphasizes close collaboration between clinicians and pathologists

Altered skeletal muscle metabolic pathways, age, systemic inflammation, and low cardiorespiratory fitness associate with improvements in disease activity following high-intensity interval training in persons with rheumatoid arthritis

BACKGROUND: Exercise training, including high-intensity interval training (HIIT), improves rheumatoid arthritis (RA) inflammatory disease activity via unclear mechanisms. Because exercise requires skeletal muscle, skeletal muscle molecular pathways may contribute. The purpose of this study was to identify connections between skeletal muscle molecular pathways, RA disease activity, and RA disease activity improvements following HIIT. METHODS: RA disease activity assessments and vastus lateralis skeletal muscle biopsies were performed in two separate cohorts of persons with established, seropositive, and/or erosive RA. Body composition and objective physical activity assessments were also performed in both the cross-sectional cohort and the longitudinal group before and after 10 weeks of HIIT. Baseline clinical assessments and muscle RNA gene expression were correlated with RA disease activity score in 28 joints (DAS-28) and DAS-28 improvements following HIIT. Skeletal muscle gene expression changes with HIIT were evaluated using analysis of covariance and biological pathway analysis. RESULTS: RA inflammatory disease activity was associated with greater amounts of intramuscular adiposity and less vigorous aerobic exercise (both p < 0.05). HIIT-induced disease activity improvements were greatest in those with an older age, elevated erythrocyte sedimentation rate, low cardiorespiratory fitness, and a skeletal muscle molecular profile indicative of altered metabolic pathways (p < 0.05 for all). Specifically, disease activity improvements were linked to baseline expression of RA skeletal muscle genes with cellular functions to (1) increase amino acid catabolism and interconversion (GLDC, BCKDHB, AASS, PYCR, RPL15), (2) increase glycolytic lactate production (AGL, PDK2, LDHB, HIF1A), and (3) reduce oxidative metabolism via altered beta-oxidation (PXMP2, ACSS2), TCA cycle flux (OGDH, SUCLA2, MDH1B), and electron transport chain complex I function (NDUFV3). The muscle mitochondrial glycine cleavage system (GCS) was identified as critically involved in RA disease activity improvements given upregulation of multiple GCS genes at baseline, while GLDC was significantly downregulated following HIIT. CONCLUSION: In the absence of physical activity, RA inflammatory disease activity is associated with transcriptional remodeling of skeletal muscle metabolism. Following exercise training, the greatest improvements in disease activity occur in older, more inflamed, and less fit persons with RA. These exercise training-induced immunomodulatory changes may occur via reprogramming muscle bioenergetic and amino acid/protein homeostatic pathways. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02528344. Registered on 19 August 2015. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-021-02570-3