Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

Abstract

Hedyotis hedyotidea has been used in traditional Chinese medicine for the treatment of autoimmune diseases. However, the mechanisms underlying for the effect remain unknown. We previously showed that, among 11 compounds extracted from H hedyotidea, betulin produced the strongest suppressive effect on T cell activation. Here, we examined the hepatoprotective effects of betulin against acute autoimmune hepatitis in mice and the mechanisms underlying the effects. Freshly isolated mouse splenocytes were stimulated with concanavalin A (Con A, 5 μg/mL) in the presence of betulin, the cell proliferation was assessed with CSFE-dilution assay. Mice were injected with betulin (10, 20 mg· kg -1 ·d -1 , ip) for 3 d. One hour after the last injection, the mice were injected with Con A (15 mg/kg, iv) to induce acute hepatitis. Blood samples and liver tissues were harvested at 10 h after Con A injection, and serum transaminase levels and liver histopathology were detected; serum levels of proinflammatory cytokines, hepatic T lymphocyte ratios, and functional statuses of conventional T and NKT cells were also analyzed. Betulin (16 and 32 μmol/L) dose-dependently suppressed the proliferation of Con A-stimulated mouse splenocytes in vitro. In Con A-challenged mice, preinjection with betulin (20 mg· kg -1 ·d -1 ) significantly decreased the levels of proinflammatory cytokines IFN-γ, TNF-α and IL-6, and ameliorated liver injury. Furthermore, pretreatment with betulin (20 mg· kg -1 ·d -1 ) significantly inhibited the Con A-induced activation of NKT and conventional T cells, and decreased production of proinflammatory cytokines IFN-γ, TNF-α and IL-6 in these two cell populations. Betulin has immunomodulatory effect on overly activated conventional T and NKT cells and exerts hepatoprotective action in mouse autoimmune hepatitis. The findings provide evidence for the use of H hedyotidea and its constituent betulin in the treatment of autoimmune diseases.

Betulin Inhibits Lung Metastasis by Inducing Cell Cycle Arrest, Autophagy, and Apoptosis of Metastatic Colorectal Cancer Cells

“…Pharmacokinetic research in rats has showed that daily intraperitoneal administration of 60 mg/kg of betulin for 28 days does not result in toxicity [37]. Oral administration of 5 and 10 mg/kg betulin improved the scopolamine-induced amnesia in mouse models, and intraperitoneal administration of betulin (10 and 20 mg/kg) improved autoimmune hepatitis in mice [11,38]. Additionally, betulin administration (10 mg/kg) significantly decreased lung metastasis of CT26 cells.…”

Taraxasterol from Taraxacum prevents concanavalin A-induced acute hepatic injury in mice via modulating TLRs/NF-κB and Bax/Bc1-2 signalling pathways

“…Accordingly, great attraction is paid to the use of natural products as new therapeutic and preventive drugs against immune-mediated hepatic injury due to their high efficiency, high safety, and low cost. Some compounds of natural products have been investigated to possess protective effects on immune hepatic injury [5][6][7].…”

Gui-ling-gao inhibits Concanavalin A-induced inflammation by suppressing the expressions of iNOS and proinflammatory cytokines in mice isolated splenocytes

“…Other studies have shown that Con A can induce production of several proinflammatory factors, such as iNOS and a variety of proinflammatory cytokines including IL‐4, IL‐6, IL‐1β, IFN‐γ, and TNF‐α (Bai et al, , Liang et al, ). Since Con A challenge mimics the inflammation condition, Con A‐induced splenocytes proliferation model is commonly used to study immune‐mediated diseases (Demenesku et al, , Sharma & Tiku, , Zhou et al, ). GLG was found to concentration‐dependently inhibit Con A‐induced cell proliferation in isolated mice splenocytes, suggesting that GLG suppressed the activation of T‐lymphocytes under inflammatory conditions.…”

“…It is generally known that LPS stimulates B‐lymphocyte proliferation response (Liu et al, ). However, inflammation involves both B‐lymphocyte and T‐lymphocyte proliferation (Xu et al, , Zhou et al, ). In order to investigate whether GLG's antiinflammatory and immunomodulatory effects involve T‐lymphocyte proliferation, the present study evaluated its effects on in vitro concanavalin A (Con A)‐induced proliferation/inflammation in BALB/c mice isolated splenocytes.…”