The effects of dihydroartemisinin on inflammatory bowel disease-related bone loss in a rat model

Ge, Xingtao; Chen, Zhijian; Xu, Zicheng; Lv, Fang; Zhang, Kewei; Yang, Yu

doi:10.1177/1535370218769420

Cited by 20 publications

(15 citation statements)

References 47 publications

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“…Some artemisinin derivatives have been shown to have good efficacy for the treatment of TNBS- and dextran sulfate sodium-induced colitis [25,26]. However, the artemisinin derivative artesunate was also shown to aggravate OXA-induced colitis, and in this study, all of the artesunate-treated mice died, resulting in a higher mortality rate than that in the model group [27].…”

Section: Discussionmentioning

confidence: 72%

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Dihydroartemisinin Regulates the Th/Treg Balance by Inducing Activated CD4+ T cell Apoptosis via Heme Oxygenase-1 Induction in Mouse Models of Inflammatory Bowel Disease

Yan

Wang

et al. 2019

Molecules

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Dihydroartemisinin (DHA) is a derivative of the herb Artemisia annua L. that has prominent immunomodulatory activity; however, its underlying mechanism remains elusive. Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition characterized as an autoimmune disorder that includes dysfunctions in the T helper (Th)/T regulatory cell (Treg) balance, which normally plays pivotal roles in immune homeostasis. The aim of this study was to explore the potential of DHA to ameliorate IBD by restoring the Th/Treg cell balance. To this end, we established mouse models of colitis induced by oxazolone (OXA) and 2,4,6-trinitro-benzene sulfonic acid (TNBS). We then treated mice with DHA at 4, 8, or 16 mg/kg/day. DHA treatment ameliorated colitis signs and reduced lymphocyte infiltration and tissue fibrosis. Moreover, DHA decreased the numbers of Th1 and Th17 cells and Th9 and Th22 cells in TNBS- or OXA-induced colitis, respectively, and increased Tregs in both models. DHA (0.8 mg/mL) also inhibited activated CD4+ T lymphocytes, which was accompanied by apoptosis induction. Moreover, it promoted heme oxygenase-1 (HO-1) production in vitro and in vivo, concomitant with CD4+ T cell apoptosis and restoration of the Th/Treg balance, and these effects were blocked by treatment with the HO-1 inhibitor Sn-protoporphyrin IX. Overall, these results suggest that DHA is a novel and valuable candidate for IBD therapy or Th/Treg immunoregulation.

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Section: Discussionmentioning

confidence: 72%

“…For IBD, previous research on the mechanisms underlying the activity of the artemisinin family found correlations with anti-inflammatory effects [25,26]. This study highlighted the interaction between DHA and the host immune system to explore its immunoregulatory potency.…”

Section: Discussionmentioning

confidence: 76%

Dihydroartemisinin Regulates the Th/Treg Balance by Inducing Activated CD4+ T cell Apoptosis via Heme Oxygenase-1 Induction in Mouse Models of Inflammatory Bowel Disease

Yan

Wang

et al. 2019

Molecules

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“…Moriyama et al reported that intestinal inflammation in IBD model mice was attenuated by the knockdown of AP-1 [ 36 ]. Previous studies demonstrated (1) the up-regulation of JunB (approximately 1.5-fold) in colon biopsies from CD patients [ 37 ]; (2) the up-regulation of Fra-1 in bone from IBD model rats [ 38 ]; and (3) the up-regulation of c-Fos, but not c-Jun or JunB in the colons of UC patients [ 39 ]. In the present study, c-Fos, FosB, c-Jun, and JunB were expressed at relatively high levels in the CD4 + CD25 − T cells of normal mice, whereas no significant changes were observed in the expression levels of the AP-1 member transcripts that were examined in IBD model mice ( Figure 2 A–G).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylases Enhance Ca2+-Activated K+ Channel KCa3.1 Expression in Murine Inflammatory CD4+ T Cells

Matsui

Terasawa

Kajikuri

et al. 2018

IJMS

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The up-regulated expression of the Ca2+-activated K+ channel KCa3.1 in inflammatory CD4+ T cells has been implicated in the pathogenesis of inflammatory bowel disease (IBD) through the enhanced production of inflammatory cytokines, such as interferon-γ (IFN-γ). However, the underlying mechanisms have not yet been elucidated. The objective of the present study is to clarify the involvement of histone deacetylases (HDACs) in the up-regulation of KCa3.1 in the CD4+ T cells of IBD model mice. The expression levels of KCa3.1 and its regulators, such as function-modifying molecules and transcription factors, were quantitated using a real-time polymerase chain reaction (PCR) assay, Western blotting, and depolarization responses, which were induced by the selective KCa3.1 blocker TRAM-34 (1 μM) and were measured using a voltage-sensitive fluorescent dye imaging system. The treatment with 1 μM vorinostat, a pan-HDAC inhibitor, for 24 h repressed the transcriptional expression of KCa3.1 in the splenic CD4+ T cells of IBD model mice. Accordingly, TRAM-34-induced depolarization responses were significantly reduced. HDAC2 and HDAC3 were significantly up-regulated in the CD4+ T cells of IBD model mice. The down-regulated expression of KCa3.1 was observed following treatments with the selective inhibitors of HDAC2 and HDAC3. The KCa3.1 K+ channel regulates inflammatory cytokine production in CD4+ T cells, mediating epigenetic modifications by HDAC2 and HDAC3.

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“…Following the last treatment of probiotics or IPA, colons were collected and fixed in 10% neutral buffered formalin for 24 h. Subsequently, colon samples were dehydrated, embedded in paraffin, sectioned at six μm, and stained with hematoxylin and eosin (H&E). H&E-stained colon sections were imaged using phase-contrast microscopy and then scored as described previously 34 . Briefly, histopathological lesions were evaluated using the disease activity index (DAI), as previously described 34 .…”

Section: Methodsmentioning

confidence: 99%

“…H&E-stained colon sections were imaged using phase-contrast microscopy and then scored as described previously 34 . Briefly, histopathological lesions were evaluated using the disease activity index (DAI), as previously described 34 . The DAI includes the degree of mucosal damage (0: none, 1: mucous layer, 2: submucosa, 3: muscularis and serosa), and crypt damage (0: none, 1: basal, 1/3: damaged, 2: basal, 2/3: damaged, 3: entire crypt damaged, 4: epithelium lost).…”

Section: Methodsmentioning

confidence: 99%

Probiotics Stimulate Bone Formation in Obese Mice via Histone Methylations

Behera¹,

Ison²,

Voor³

et al. 2021

Theranostics

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Rationale: Manipulation of the gut microbiome can prevent pathologic bone loss. However, the effects of probiotics on mitochondrial epigenetic remodeling and skeletal homeostasis in the high-fat diet (HFD)-linked obesity remains to be explored. Here, we examined the impact of probiotics supplementation on mitochondrial biogenesis and bone homeostasis through the histone methylation mechanism in HFD fed obese mice. Methods: 16S rRNA gene sequencing was performed to study the microbiota composition in the gut and microbial dysbiosis in obese mouse model. High resolution (microPET/CT) imaging was performed to demonstrate the obese associated colonic inflammation. Obese-associated upregulation of target miRNA in osteoblast was investigated using a microRNA qPCR array. Osteoblastic mitochondrial mass was evaluated using confocal imaging. Overexpression of mitochondrial transcription factor (Tfam) was used to investigate the glycolysis and mitochondrial bioenergetic metabolism using Tfam-transgenic (Tg) mice fed on HFD. The bone formation and mechanical strength was evaluated by microCT analysis and three-point bending analysis. Results: High-resolution imaging (µ-CT) and mechanical testing revealed that probiotics induced a significant increase of trabecular bone volume and bone mechanical strength respectively in obese mice. Probiotics or Indole-3-propionic acid (IPA) treatment directly to obese mice, prevents gut inflammation, and improved osteoblast mineralization. Mechanistically, probiotics treatment increases mitochondrial transcription factor A (Tfam) expression in osteoblasts by promoting Kdm6b/Jmjd3 histone demethylase, which inhibits H3K27me3 epigenetic methylation at the Tfam promoter. Furthermore, Tfam-transgenic (Tg) mice, fed with HFD, did not experience obesity-linked reduction of glucose uptake, mitochondrial biogenesis and mineralization in osteoblasts. Conclusions: These results suggest that the probiotics mediated changes in the gut microbiome and its derived metabolite, IPA are potentially be a novel agent for regulating bone anabolism via the gut-bone axis.

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The effects of dihydroartemisinin on inflammatory bowel disease-related bone loss in a rat model

Cited by 20 publications

References 47 publications

Dihydroartemisinin Regulates the Th/Treg Balance by Inducing Activated CD4+ T cell Apoptosis via Heme Oxygenase-1 Induction in Mouse Models of Inflammatory Bowel Disease

Dihydroartemisinin Regulates the Th/Treg Balance by Inducing Activated CD4+ T cell Apoptosis via Heme Oxygenase-1 Induction in Mouse Models of Inflammatory Bowel Disease

Histone Deacetylases Enhance Ca2+-Activated K+ Channel KCa3.1 Expression in Murine Inflammatory CD4+ T Cells

Probiotics Stimulate Bone Formation in Obese Mice via Histone Methylations

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