Natural product mogrol attenuates bleomycin-induced pulmonary fibrosis development through promoting AMPK activation

Liu, Bei; Yang, Jinyu; Hao, Jiatong; Xie, Haifeng; Shimizu, Kuniyoshi; Li, Renshi; Zhang, Chaofeng

doi:10.1016/j.jff.2020.104280

Cited by 13 publications

(13 citation statements)

References 28 publications

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“…Many studies have shown that mogrol can effectively reduce blood glucose to contribute to antihyperglycemia and antilipidemia by activating AMP-activated protein kinase ( Harada et al, 2016 ; Wang H. et al, 2020 ; Liang et al, 2021 ). Further studies have identified that it could attenuate pulmonary fibrosis, memory impairment, neuroinflammation, and apoptosis ( Chen et al, 2018 ; Wang J. et al, 2020 ; Liu et al, 2021 ). Additionally, mogrol can also suppress leukemic cell growth by inhibiting the extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription three pathways (STAT3) implicated in leukemia carcinogenesis ( Liu et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Construction and Optimization of the de novo Biosynthesis Pathway of Mogrol in Saccharomyces Cerevisiae

Wang

Liu

et al. 2022

Front. Bioeng. Biotechnol.

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Mogrol plays important roles in antihyperglycemic and antilipidemic through activating the AMP-activated protein kinase pathway. Although the synthesis pathway of mogrol in Siraitia grosvenorii has been clarified, few studies have focused on improving mogrol production. This study employed a modular engineerin g strategy to improve mogrol production in a yeast chassis cell. First, a de novo synthesis pathway of mogrol in Saccharomyces cerevisiae was constructed. Then, the metabolic flux of each synthetic module in mogrol metabolism was systematically optimized, including the enhancement of the precursor supply, inhibition of the sterol synthesis pathway using the Clustered Regularly Interspaced Short Palindromic Repeats Interference system (CRISPRi), and optimization of the expression and reduction system of P450 enzymes. Finally, the mogrol titer was increased to 9.1 μg/L, which was 455-fold higher than that of the original strain. The yeast strains engineered in this work can serve as the basis for creating an alternative way for mogrol production in place of extraction from S. grosvenorii.

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Section: Introductionmentioning

confidence: 99%

Construction and Optimization of the de novo Biosynthesis Pathway of Mogrol in Saccharomyces Cerevisiae

Wang

Liu

et al. 2022

Front. Bioeng. Biotechnol.

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“…In the bleomycin-induced PF mice group, an increase in pulmonary index and a decrease in weight and survival rate were observed. Mogrol treatment significantly reduced weight loss and pulmonary index compared to the bleomycin group at both doses (5 or 10 mg/kg), similar to the antifibrotic effects of the nintedanib (a positive drug at a dose of 40 mg/kg) group [ 26 , 45 ]. The histology of the lungs in the staining study revealed bleomycin-induced alveolar wall thickening, neutrophil infiltration, edema, and higher collagen production in the lung tissues compared to normal.…”

Section: Pharmacological Activities Of Mogrolmentioning

confidence: 75%

“…Limited toxicology studies have been conducted on mogrol and its synthetic derivatives, but toxicology studies on mogrosides extracted from the fruits are available. In cell proliferation assays, mogrol has no effect on the viability of 3T3-L1, mouse type II alveolar epithelial cell MLE-12, and bone marrow macrophages at the concentration up to 50, 40, and 10 μM, respectively [ 4 , 25 , 26 ]. Similarly, mogrosides were found to be safe in the study conducted on dogs for 28 and 90 days of oral administration at a dose (3000 mg/kg bw/day).…”

Section: Mogrol Structure and Propertiesmentioning

confidence: 99%

“…Similarly, in primary lung fibroblasts (PLFs) cells, the up-regulated protein levels of α-SMA, Lysyl oxidase-like protein 2 (LOXL2), collagen I, and phosphorylation forms of Smad2/3 due to TGF-β1 were restored with the mogrol treatment at 10 μM concentration ( Table 1 ). AMPK activation and NOX4 activity can stimulate lung myofibroblast differentiation, and mogrol also significantly restored the unusually decreased p-AMPK and amplified NOX4 protein expression in TGF-β1-treated PLFs [ 26 ].…”

Section: Pharmacological Activities Of Mogrolmentioning

confidence: 99%

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Pharmacological Activities of Mogrol: Potential Phytochemical against Different Diseases

Jaiswal

Lee

2023

Life

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Recently, mogrol has emerged as an important therapeutic candidate with multiple potential pharmacological properties, including neuroprotective, anticancer, anti-inflammatory, antiobesity, antidiabetes, and exerting a protective effect on different organs such as the lungs, bone, brain, and colon. Pharmacokinetic studies also highlighted the potential of mogrol as a therapeutic. Studies were also conducted to design and synthesize the analogs of mogrol to achieve better activities against different diseases. The literature also highlighted the possible molecular mechanism behind pharmacological activities, which suggested the role of several important targets, including AMPK, TNF-α, and NF-κB. These important mogrol targets were verified in different studies, indicating the possible role of mogrol in other associated diseases. Still, the compilation of pharmacological properties, possible molecular mechanisms, and important targets of the mogrol is missing in the literature. The current study not only provides the compilation of information regarding pharmacological activities but also highlights the current gaps and suggests the precise direction for the development of mogrol as a therapeutic against different diseases.

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“…BDG is a cucurbitane-type triterpene compound with antitumor and anti-inflammatory activities (Ukiya et al, 2002). In our previous study, mogrol (10 mg/kg/day), an analog of BDG has been demonstrated to reduce lung fibrosis in mice by activating AMPK (Liu et al, 2021). Of note, the structure of BDG is similar to mogrol except that the C-11 a hydroxyl group is replaced by a carbonyl group, but the antifibrotic effect is unknown.…”

mentioning

confidence: 99%

Bryodulcosigenin attenuates bleomycin‐induced pulmonary fibrosis via inhibiting AMPK‐mediated mesenchymal epithelial transition and oxidative stress

Ding

Wang

Liu

et al. 2022

Phytotherapy Research

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Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in several organs, including the lungs. Bryodulcosigenin (BDG) is a cucurbitane‐type triterpene isolated from Siratia grosvenori and has clear‐cut anti‐inflammatory effects, yet its benefit of pulmonary fibrosis (PF) remains unclear. In this study, we investigated the protective effects of BDG (10 mg/kg/day, for 14 days) against TGF‐β1‐stimulated mouse alveolar epithelial MLE‐12 cells and bleomycin (BLM)‐induced PF mice. In vitro experiments showed that BDG could inhibit epithelial‐mesenchymal transition (EMT) and oxidative stress. In vivo experiments indicated that BDG could ameliorate BLM‐induced PF in mice as evidenced by characteristic structural changes in histopathology, increased collagen deposition and reduced survival and weight of mice. The abnormal increased expressions of TGF‐β1, p‐Smad2/3, α‐SMA, COL‐I, and NOX4 and decreased expressions for Sirt1 and p‐AMPK were improved in BDG treatment. But these beneficial effects could be eliminated by co‐treatment with Compound C (CC, a selective AMPK inhibitor). Molecular docking technology also revealed the potential of BDG to activate AMPK. In summary, AMPK activation modulated by BDG not only ameliorated TGF‐β1/Smad2/3 signaling pathways but also partially mediated the suppression effects on EMT and oxidative stress, thus mediating the anti‐fibrotic effects.

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Natural product mogrol attenuates bleomycin-induced pulmonary fibrosis development through promoting AMPK activation

Cited by 13 publications

References 28 publications

Construction and Optimization of the de novo Biosynthesis Pathway of Mogrol in Saccharomyces Cerevisiae

Construction and Optimization of the de novo Biosynthesis Pathway of Mogrol in Saccharomyces Cerevisiae

Pharmacological Activities of Mogrol: Potential Phytochemical against Different Diseases

Bryodulcosigenin attenuates bleomycin‐induced pulmonary fibrosis via inhibiting AMPK‐mediated mesenchymal epithelial transition and oxidative stress

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