Celastrol ameliorates experimental colitis in IL-10 deficient mice via the up-regulation of autophagy
Jie ZhaoYe SunPeiliang ShiJianning DongLugen ZuoHong‐Gang WangJianfeng GongYi LiLili GuNing LiJieshou LiWeiming Zhu
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Celastrol
Proinflammatory cytokine
Celastrol is a pentacyclic tripterine sourced from Tripterygium wilfordii hook root. Celastrol can exert certain biological functions such as antitumor, anti-inflammatory, and antiproliferative properties. Celastrol was shown from the previous literature to be capable of attenuating many fibrotic diseases. As the effects of various fibrotic diseases such as atherosclerosis, cancer, and ischemia affect more people with devastating repercussions, this warrants celastrol to be exploited as a phytotherapeutic drug. The purpose of this study is to review previous research and identify the proposed therapeutic mechanisms of celastrol in fibrotic diseases focusing on both the in vitro and in vivo experimental models. A systematic literature search on Web of Science (WoS), Scopus, and ScienceDirect that included articles published between 2012 and 2022 was carried out using the keywords “celastrol”, “tripterine”, “fibrotic disease”, and “fibrosis”. After screening the initial search yield of 405 articles, 25 articles were included in this review. The study findings summarize the potential therapeutic mechanism of celastrol in the attenuation of fibrotic diseases in in vivo and in vitro experimental models. It shows that celastrol is useful as a treatment means. However, more studies are needed on the effects of celastrol on humans to carry out clinical trials to verify the long-term benefits of celastrol.
Celastrol
Tripterygium wilfordii
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Celastrol is a novel anti-tumor agent. Ways to further enhance this effect of celastrol has attracted much research attention. Here, we report that celastrol treatment can elevate miR-223 in human breast cancer cell line MCF-7 and prostate cancer PC3. Down-regulating miR-223 could increase the number of viable cells, yet it further reduced viable cells in samples that were treated by celastrol; up-regulation of miR-223 displayed opposite effects. Celastrol's miR-223 induction might be due to NF-κB inhibition and transient mTOR activation: these two events occurred prior to miR-223 elevation in celastrol-treated cells. NF-κB inhibitor, like celastrol, could induce miR-223; the induction of miR-223 by NF-κB inhibitor or celastrol was reduced by the use of mTOR inhibitor. Finally and interestingly, miR-223 also could affect NF-κB and mTOR and the effects were different between cells treated or not treated with celastrol, thus providing an explanation for differing effects of miR-223 alteration on cellular viability in the presence of celastrol or not. For the first time, we disclose that celastrol could induce miR-223 in breast and prostate cancer cells, and that inhibiting miR-223 could further reduce the living cells in celastrol-treated cancer cell lines. We thus provide a novel way to increase celastrol's anti-cancer effects.
Celastrol
MCF-7
Viability assay
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Celastrol
Tripterygium wilfordii
Tripterygium
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Celastrol
PEGylation
PEG 400
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In this study, the effect of celastrol on a rapid HCC model featuring co-activation of AKT/c-Met oncogenes in mice was studied.
Celastrol
Steatosis
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Native Endophytes of Tripterygium wilfordii-Mediated Biotransformation Reduces Toxicity of Celastrol
Celastrol ( 1 ), obtained from the roots of Tripterygium wilfordii Hook F., is most likely to become an antitumor drug, but with severe cytotoxicity. Due to the lack of modifiable sites in the structure of celastrol, the structural diversity of the modified products obtained by synthesis in the previous studies is insufficient, which hinders the pace of its patent medicine. This study describes a method of microbial transformation to increase the modification site of celastrol and reduce its toxicity. The screening of endophytes from native plants was introduced in this context, which led to two novel stereoselective oxidation products such as S -16-hydroxyl celastrol ( 2 ) and A-ring aromatized S -16-hydroxyl celastrol ( 3 ), along with a rare 7,9-octadecadienoic acid ester of celastrol ( 4 ). Their structures were determined by extensive spectroscopic data analysis, especially 1D and 2D NMR. Compared with 1 , compounds 3 and 4 exhibited similar antitumor activity in U251, A549, KG-1, and B16 cell lines. Compound 2 had slightly decreased antitumor activity when compared with compound 1 . Furthermore, compound 2 – 4 showed lower cytotoxicity against BV-2 (about 21-fold lower, 2 : 92.82 μM, 3 : 34.25 μM, and 4 : 74.75 μM vs. celastrol: 4.35 μM), and also identical trends against H9c2 and PC12 cell lines.
Celastrol
Tripterygium wilfordii
Tripterygium
Celastraceae
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Celastrol is a quinone methide triterpenoid extracted from the root bark of the Chinese medicine Tripterygium wilfordii with the most potent antitumor activity among the natural triterpenoids. Celastrol has the abilities to inhibit proliferation, induce apoptosis and suppress invasion and metastasis of tumor cells. Structure and activity analysis based on celastrol semi-synthetic derivatives revealed that the quinone methide moiety is required for its antitumor activity. The heat shock protein HSP90 chaperone machinery and NF-κB signaling are two principal pathways targeted by celastrol. The optimization of solubility and identification of tumor specific targets is required for further developing celastrol and its derivatives as clinically useful anticancer agents. Keywords: Anticancer activity, biosynthesis, celastrol, celastrol semi-synthetic derivatives, quinone methide triterpenoids.
Celastrol
Tripterygium wilfordii
Quinone methide
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Celastrol은 미역줄나무의 뿌리에서 얻은 추출물로 오래전부터 관절염 및 자가면역 같은 염증반응 질병들을 치료하기 위하여 쓰여져 왔다. 이외에도 많은 연구들에서 celastrol이 신경보호, 항산화 및 알츠하이머 치료에 사용될 수 있으며 특히, 암 치료에 효과적이라고 밝혀 졌다(Table 1). 따라서 많은 연구자들이 생리학적, 생화학적 및 면역학적 관점에서 celastrol의 항암효과를 규명하고자 노력을 기울이고 있으며, 다양한 관점에서 신호전달체계를 조절한다는 사실을 밝혀냈다(Fig. 1). 특히, celastrol은 $NF-{\kappa}B$ 를 억제함으로서 암의 발달 및 전이를 저해함을 물론, 암의 치료에 동반되는 면역 반응을 조절 할 수 있다(Fig. 2). 또한 세포사멸과 관계된 유전자들을 활성화 시키고, 항세포사멸 유전자들을 억제시킴으로서 세포 주기를 조절한다. 유전자 조절 외에도 heat shock protein과 같은 단백질의 변조와 자가소화작용(autophagy)를 유도한다. 이처럼 celastrol의 다양한 효과는 암의 성공적 치료에 한발 더 가까워지게 만든다. 이외에도 celastrol의 항 비만 효과가 알려지면서 향후 비만 및 비만과 연계된 암 환자들이 가질 수 있는 부작용, 오남용 및 비용절감 측면에서 좋은 결과를 나타낼 것이라 예상 된다. Celastrol의 다양한 기작이 밝혀짐에도 불구 하고 직접적인 결합 부위에 대한 연구 결과는 아직 없으며, 임상적용 하기에 앞서 다양한 동물모델 in vivo 실험이 필요하다. 또한 임상치료 시도에 있어 안전성을 확보 하기 위해서는 celastrol의 단기간 및 장기간의 효과에 대한 깊은 연구가 요구된다. 【It has been generally accepted that obesity and overweight are associated with metabolic diseases and cancer incidence. In fact, obesity increased risks of cancers i.e. breast, liver, pancreatic and prostate. Celastrol is a pentacyclic triterpenoid isolated from Thunder god vine, was used as a Chinese traditional medicine for treatment of inflammatory disorders such as arthritis, lupus erythematosus and Alzheimer's disease. Also, celastrol has various biological properties of chemo-preventive, neuro-protective, and anti-oxidant effects. Recent studies demonstrated that celastrol has anti-proliferation effects in different type of obesity-related cancers and suppresses tumor progression and metastasis. Anticancer effects of celastrol include regulation of $NF-{\kappa}B$ , heat shock protein, JNK, VEGF, CXCR4, Akt/mTOR, MMP-9 and so on. For these reasons, celastrol has shown to be a promising anti-tumor agent. In this review, we will address the anticancer activities and multiple mechanisms of celastrol in obesity-related cancers.】
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Neutrophil-myeloperoxidase (MPO) is a heme-containing peroxidase which produces excess amounts of hypochlorous acid during inflammation. While pharmacological MPO inhibition mitigates all indices of experimental colitis, no studies have corroborated the role of MPO using knockout (KO) models. Therefore, we investigated MPO deficient mice in a murine model of colitis. Wild type (Wt) and MPO-deficient mice were treated with dextran sodium sulphate (DSS) in a chronic model of experimental colitis with three acute cycles of DSS-induced colitis over 63 days, emulating IBD relapse and remission cycles. Mice were immunologically profiled at the gut muscoa and the faecal microbiome was assessed via 16S rRNA amplicon sequencing. Contrary to previous pharmacological antagonist studies targeting MPO, MPO-deficient mice showed no protection from experimental colitis during cyclical DSS-challenge. We are the first to report drastic faecal microbiota shifts in MPO-deficient mice, showing a significantly different microbiome profile on Day 1 of treatment, with a similar shift and distinction on Day 29 (half-way point), via qualitative and quantitative descriptions of phylogenetic distances. Herein, we provide the first evidence of substantial microbiome shifts in MPO-deficiency, which may influence disease progression. Our findings have significant implications for the utility of MPO-KO mice in investigating disease models.
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The radiosensitizing activity of celastrol, a quinone methide triterpene was examined. We found that celastrol treatment of the NCI-H460 lung cancer cell line increased radiation-induced cell killing. The increased radiosensitivity was correlated with decreased levels of Hsp90 clients, such as EGFR, ErbB2 and survivin as well as with increased p53 expression. Celastrol inhibited the ATP-binding activity of Hsp90. Furthermore, celastrol treatment dissociated an Hsp90 client protein, EGFR, and this in turn resulted in degradation of the client protein. These results were not observed with another structurally similar triterpenoid, 6β-acetonyl-22β-hydroxytingenol (TG), suggesting that a specific structural feature of the triterpenoid is required for radiosensitization. Moreover celastrol treatment increased p53 levels by phosphorylating Ser15 and Ser20 residues as well as by inhibiting its proteasomal degradation. Celastrol may be considered an effective radiosensitizer acting as an inhibitor of Hsp90 and a p53 activator. The two activities could be applicable to a broad range of cancer cells with either wild-type or mutant p53 because either activity could be effective for the enhancement of radiation cell killing. Further analysis with other triterpenoids should identify the functional moiety of the structure and additional candidates for effective radiosensitizers, which can be used in combined radiotherapy.
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Radiosensitizer
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