Synthesis and discovery of a drug candidate for treatment of idiopathic pulmonary fibrosis through inhibition of TGF-β1 pathway

Li, Xiaohe; Cheng, Lü; Liu, Shuangwei; ShuaiShuai, Liu; Su, Chengcheng; Tu, Xiao; Bi, Zhun; Sheng, Pengzhen; Huang, Mengying; Liu, Xinhua; Yue, Wei; Zhao, Lin; Miao, Shengxiang; Mao, Jiahe; Huang, Kai; Gao, Shaoyan; Liu, Ning; Qi, Min; Liu, Tongtong; Qin, Shuanglin; Wei, Luqing; Sun, Tao; Ning, Wen; Yang, Guang; Yang, Cheng

doi:10.1016/j.ejmech.2018.07.074

Cited by 21 publications

(47 citation statements)

References 20 publications

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“…The novel compounds shared alantolactone's anti-inflammatory mechanisms. Another noteworthy study involving alantolactone (1) derivatives was published in 2018 by Li et al [54], testing 44 derivatives for their ability to inhibit induced pulmonary fibrosis in mice. The results showed that 2 of these compounds are particularly active at 100 mg/kg (b.w.…”

Section: Alantolactonementioning

confidence: 99%

Applications of Sesquiterpene Lactones: A Review of Some Potential Success Cases

et al. 2020

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Sesquiterpene lactones, a vast range of terpenoids isolated from Asteraceae species, exhibit a broad spectrum of biological effects and several of them are already commercially available, such as artemisinin. Here the most recent and impactful results of in vivo, preclinical and clinical studies involving a selection of ten sesquiterpene lactones (alantolactone, arglabin, costunolide, cynaropicrin, helenalin, inuviscolide, lactucin, parthenolide, thapsigargin and tomentosin) are presented and discussed, along with some of their derivatives. In the authors’ opinion, these compounds have been neglected compared to others, although they could be of great use in developing important new pharmaceutical products. The selected sesquiterpenes show promising anticancer and anti-inflammatory effects, acting on various targets. Moreover, they exhibit antifungal, anxiolytic, analgesic, and antitrypanosomal activities. Several studies discussed here clearly show the potential that some of them have in combination therapy, as sensitizing agents to facilitate and enhance the action of drugs in clinical use. The derivatives show greater pharmacological value since they have better pharmacokinetics, stability, potency, and/or selectivity. All these natural terpenoids and their derivatives exhibit properties that invite further research by the scientific community.

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Section: Alantolactonementioning

confidence: 99%

Applications of Sesquiterpene Lactones: A Review of Some Potential Success Cases

et al. 2020

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“…Previous studies have suggested that mechanical stress was the initial cause of HLF (Fukuyama et al, 1995;Nakatani et al, 2002) and could induce several cytokines espression in fibroblasts, such as transforming growth factor (TGF-β1) and IL-6 (Koyama and Aizawa, 2002;Nakatani et al, 2002;Jacobs et al, 2014). Although these cytokines have been reported to induce fibrosis in a variety of soft tissues (Mozaffarian et al, 2008;Diaz et al, 2009;Gonzalez et al, 2016;Li et al, 2019), the key cytokines and precise mechanism of the pathology of HLF has not been fully elucidated. To identify genes that may contribute to the pathogenesis of HLF, we performed isobaric tags for relative and absolute quantification (iTRAQ) analysis and integrated proteome and transcriptome data.…”

Section: Introductionmentioning

confidence: 99%

CRLF1 Is a Key Regulator in the Ligamentum Flavum Hypertrophy

Zheng

Lian

et al. 2020

Front. Cell Dev. Biol.

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Hypertrophy of the ligamentum flavum (HLF) is one of the common causes of lumbar spinal stenosis (LSS). The key molecules and mechanisms responsible for HLF remain unclear. Here, we used an integrated transcriptome and proteomics analysis of human ligamentum flavum (LF), and subsequent immunohistochemistry and real-time PCR assays, to show upregulation of CRLF1 to be the dominant response to HLF. TGF-β1 significantly increased mRNA expression of CRLF1 through SMAD3 pathway. CRLF1 enhanced LF fibrosis via ERK signaling pathway at the post-transcriptional level and was required for the pro-fibrotic effect of TGF-β1. Knockdown of CRLF1 was shown here to reduce fibrosis caused by inflammatory cytokines and mechanical stress. Furthermore, we found that bipedal standing posture can cause HLF and upregulation of CRLF1 expression in mice LF. Overexpression of CRLF1 was indicated to cause HLF in vivo, whereas CRLF1 knockdown impeded the formation of HLF in bipedal standing mice. These results revealed a crucial role of CRLF1 in LF hypertrophy. We propose that inhibition of CRLF1 is a potential therapeutic strategy to treat HLF.

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“…In this review, the multiple pharmacological effects of Ala, including antitumor, antifungal, antibacterial, antiinflammatory, neuroprotective activities, and associated mechanisms were summarized. Currently, lots of analogs have been synthesized chemically or transformed microbiologically, among which many retain the bioactivity of Ala while some even attain new bioactivities absent from Ala, such as the inhibition of pulmonary fibrosis through TGF-β1 pathway (Cantrell et al, 2010;Kumar et al, 2019;Li et al, 2018;Xin et al, 2008). Through Michael reaction, Ala can also be conjugated to substituted piperazines or antibiotics to enhance the efficacy and reduce the cytotoxicity of drugs, such as daunorubicin and doxorubicin (Pukhov et al, 2019;Semakov et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Alantolactone: A sesquiterpene lactone with diverse pharmacological effects

et al. 2021

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Alantolactone (Ala) is a sesquiterpene lactone that can be isolated from many herbal plants belonging to Asteraceae. Besides the antimicrobial activities against bacteria, fungi and viruses, Ala has also demonstrated significant antiinflammatory effects in various models by inhibiting NF-κB and MAPKs to decrease the pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. The antitumor effects of Ala have been demonstrated in vitro and in vivo via inducing intrinsic apoptosis, oxidative stress, ER stress, cell cycle arrest and inhibiting autophagy and STAT3 phosphorylation, which are also involved in its combination or synergy with other antitumor drugs. Ala also has neuroprotective activity through attenuating oxidative stress and inflammation, besides its modulation of glucose and lipid metabolism. This review summarizes the recent advances of the pharmacological effects of Ala, including anti-inflammatory, antitumor, antimicrobial, neuroprotective activities, as well as the underlying mechanisms.Ala might be employed as a potential lead to develop drugs for multiple diseases.

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Synthesis and discovery of a drug candidate for treatment of idiopathic pulmonary fibrosis through inhibition of TGF-β1 pathway

Cited by 21 publications

References 20 publications

Applications of Sesquiterpene Lactones: A Review of Some Potential Success Cases

Applications of Sesquiterpene Lactones: A Review of Some Potential Success Cases

CRLF1 Is a Key Regulator in the Ligamentum Flavum Hypertrophy

Alantolactone: A sesquiterpene lactone with diverse pharmacological effects

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