Mogrol-mediated enhancement of radiotherapy sensitivity in non-small cell lung cancer: a mechanistic study.

This study investigated mogrol's impact on non-small cell lung cancer (NSCLC) radiosensitivity and underlying mechanisms, using various methods including assays, bioinformatics, and xenograft models. CCK-8, clonogenic, flow cytometry, TUNEL, and Western blot assays evaluated mogrol and radiation effects on NSCLC viability and apoptosis. Ubiquitin-specific protease 22 (USP22) expression in NSCLC patient tissues was determined by RT-qPCR and Western blot. A xenograft model validated mogrol's effects on tumor growth. Bioinformatics identified four ubiquitin-specific proteases, including USP22, in NSCLC. Kaplan-Meier analysis confirmed USP22's value in lung cancer survival. Human Protein Atlas (HPA) database analysis indicated higher USP22 expression in lung cancer tissues. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis implicated ERK1/2 in NSCLC progression, and molecular docking showed stability between mogrol and ERK1/2. Further in vivo and in vitro experiments have demonstrated that mogrol enhances the inhibitory effect of radiation on NSCLC cell viability and clonogenic capacity. Cell viability and clonogenic capacity are reduced by >50%, and an increase in cellular apoptosis is observed, with apoptotic levels reaching 10%. USP22 expression was significantly elevated in NSCLC tissues, particularly in radiotherapy-resistant patients. Mogrol downregulated USP22 expression by inhibiting the ERK/CREB pathway, lowering COX2 expression. Mogrol also enhanced radiation's inhibition of tumor growth in mice. Mogrol enhances NSCLC radiosensitivity by downregulating USP22 via the ERK/CREB pathway, leading to reduced COX2 expression.NEW & NOTEWORTHY Mogrol enhances non-small cell lung cancer (NSCLC) cell sensitivity to radiotherapy by downregulating USP22 through the ERK/CREB pathway, reducing COX2 expression. These findings highlight mogrol's potential as an adjunct to improve NSCLC radiotherapy and open avenues for further research and clinical applications.

Mogrol suppresses lung cancer cell growth by activating AMPK-dependent autophagic death and inducing p53-dependent cell cycle arrest and apoptosis.

Lung carcinoma is the leading cause of cancer-related death worldwide. Chemotherapy remains the cornerstone of lung cancer treatment. Unfortunately, most types of cancer will develop resistance to chemotherapies over the time. One of the efforts to prevent the chemotherapy resistance is to find alternative chemotherapy drugs. Mogrol has been found to have antitumor activity. However, little is known about the pharmacological mechanisms underlying the suppression of mogrol on lung cancers. In this study, we observed that mogrol exposure significantly reduced the tumor volume and weight in tumor-bearing nude mice without obvious effect on body weight and cardiac function. Mogrol also significantly inhibited the proliferation and migration of lung cancer cells, including non-small-cell lung carcinoma cells, A549, H1299, H1975 and SK-MES-1 cells, with no obvious effect on control human bronchial epithelial cells (HBE). Further studies revealed that mogrol stirred excessive autophagy and autophagic flux, and finally, autophagic cell death, in lung cancer cells, which could be attenuated by autophagy inhibitors, 3-MA and chloroquine. Furthermore, mogrol significantly activated AMPK to induce autophagy and autophagic cell death, which could be abrogated by Compound C, an AMPK inhibitor. In addition, mogrol induced a significant increase in p53 activity in lung cancer cells, accompanied with cell cycle arrest and apoptosis, which could be weakened by p53 silence. Our results indicated that mogrol effectively suppressed lung cancer cells in vivo and in vitro by inducing the excessive autophagy and autophagic cell death via activating AMPK signaling pathway, as well as cell cycle arrest and apoptosis via activating p53 pathway.

Design and synthesis of mogrol derivatives modified on a ring with anti-inflammatory and anti-proliferative activities.

A class of novel mogrol derivatives modified on A ring were synthesized. The screening result showed that indole-fused derivatives exhibited lower toxicity and better anti-inflammatory activity in LPS-induced RAW 264.7 cells model than mogrol and other compounds. Derivative B8 exerted superior inhibitory result of NO production (IC50 = 5.05 µM) and inhibitory ability of TNF-α and IL-6 secretion to mogrol through iNOS/NF-κB pathway. Besides, the CCK8 assay was performed to evaluate their anti-proliferative activity against non-small cell lung cancer including A549, NCI-H460, H1299 and H1975 cells. Compared with mogrol, compound B8 showed moderate anti-proliferative activities against A549 and H1975 cells, while derivatives bearing α, ß-unsaturated ketone scaffold displayed broad-spectrum growth inhibition against four cell lines. Among them, compound A9 showed 12-fold higher activity than mogrol against H1299 and H1975 cells. The suppressive effect on expression level of p-p65 might account for the compound A9-induced growth inhibition and cell cycle arrest at G1 phase.

Synthesis and Antiproliferative Activity of Ester Derivatives of Mogrol through JAK2/STAT3 Pathway.

In attempt to enhance the antiproliferative activity of mogrol, two series of ester derivatives modified at C3 -OH and C11 -OH were designed and synthesized. The activity against human cancer cells including A549, NCI-H460 and CNE1 was screened by Cell Counting Kit-8 (CCK8) assay. According to the results, modifications of the mogrol core through introduction of different ester scaffolds drastically improved the cytotoxicity, and some of the derivatives exhibited even higher activity than the positive drug. Among them, compound M2h exhibited nearly 4 times more cytotoxic than 5-Fu against CNE1 cells, derivative M6c showed ten times higher activity with the IC50 value of 10.59 µM than mogrol against NCI-H460 cells, and compound M6a which contained one 1,2,3-triazole motif showed the strongest activity with an three folds lower IC50 value than mogrol. Furthermore, the most potent compound M2h could lead to cell cycle arrest at G2 phase on CNE1 cell lines and M6a induced G1 phase arrest on A549 cell lines. It was noteworthy that both M2h and M6a regulated signal transducer and activator of transcription 3 (STAT3) signal pathway through inhibiting phosphorylation of Janus Kinase 2 (JAK2) and STAT3, and simultaneously increasing the protein level of downstream cyclin p21.

Synthesis and anti-proliferation activity of mogrol derivatives bearing quinoline and triazole moieties.

A series of novel derivatives based on mogrol were designed and synthesized in attempt to improve anti-lung cancer activity. The cytotoxicity against human lung cancer cells including A549 and NCI-H460 were performed by Cell Counting Kit-8 (CCK8) assay in vitro. The screening result showed that compound 8f exhibited the strongest activity with an IC50 value of 4.47 µM against A549 cell, and could induce the cell apoptosis in a dose-dependent manner and arrest cell cycle at G0/G1 phase. Besides, compound 8f displayed anti-proliferation effect on A549 cell through inhibiting phosphorylation of signal transducer and activator of transcription 3 (STAT3). Furthermore, compared with morgol, compound 10a significantly improved the cytotoxicity against NCI-H460 with the IC50 value of 17.13 µM. The research stimulated the development of potential therapeutic agent for lung cancer from the natural mogrol.

Comparative In vitro metabolism of purified mogrosides derived from monk fruit extracts.

Mogrosides are the primary components responsible for the sweet taste of Monk fruit which is derived from Siraitia grosvenorii (Swingle), a herbaceous plant native to southern China. Many mogrosides have been identified from Monk fruit extract, but the major sweetness component of Monk fruit by mass is mogroside V, comprising up to 0.5% of the dried fruit weight. Recent pharmacokinetic studies indicate that the parent mogrosides undergo minimal systemic absorption following ingestion and hydrolysis by digestive enzymes and/or intestinal flora and are excreted as mogrol (i.e., the aglycone) and its mono- and diglucosides. The objective of this study was to demonstrate whether individual mogrosides, are metabolized to a common and terminal deglycosylated metabolite, mogrol. An in vitro assay was conducted with pooled human male and female intestinal fecal homogenates (HFH) using mogrosides IIIe, mogroside V, siamenoside I, and isomogroside V at two concentrations over a 48 h period. The results show that various mogrosides that differ in the linkages and number of glucose units attached to a common cucurbitane backbone, share a common metabolic fate, and are metabolized within 24 h to mogrol. Aside from an apparent difference in the initial rate of deglycosylation between mogrosides at higher concentrations, no apparent difference in the rate of deglycosylation was observed between the male and female HFH. Given the similar structures of these mogrosides and a shared metabolic fate to mogrol, the study provides support for a reasonably conservative approach to assess safety based on bridging safety data from an individual mogroside (i.e., Mogroside V) to other mogrosides, and the establishment of a group Acceptable Daily Intake (ADI), rather than individual ADI's for mogrosides.

Design, synthesis and biological evaluation of mogrol derivatives as a novel class of AMPKα2ß1γ1 activators.

Adenosine monophosphate-activated protein kinase (AMPK) has been considered as a promising drug target for its regulation in both glucose and lipid metabolism. Mogrol was originally identified from high throughput screening as a small molecule activator of AMPK subtype α2ß1γ1. In order to enhance its potency on AMPK and summarize the structure-activity relationships, a series of mogrol derivatives were designed, synthesized and evaluated in pharmacological AMPK activation assays. The results showed that the amine derivatives at the 24-position can improve the potency. Among them, compounds 3 and 4 exhibited the best potency (EC50: 0.15 and 0.14 µM) which was 20 times more potent than mogrol (EC50: 3.0 µM).

Separation, synthesis, and cytotoxicity of a series of mogrol derivatives.

Four metabolites of mogrol were separated, identified and characterized. Their antitumor activity was evaluated, and the results showed side chain modification would probably enhance the cytotoxicity. Therefore, three types of amines, alcohols and rigid planar derivatives were synthesized. Compounds 20 and 21 containing a tetrahydro-ß-carboline structure at the end of the side chain exhibited IC50 values around 2-9 µM against A549 and CNE1 cell comparing with 80-90 µM of mogrol. Structure analysis suggested that the perhydrocyclopentanophenanthrene moiety and the tetrahydro-ß-carboline moiety could probably enhance the activity through an intramolecular synergistic effect.[Formula: see text].

Mogrol attenuates lipopolysaccharide (LPS)-induced memory impairment and neuroinflammatory responses in mice.

This study aimed to evaluate whether mogrol, a main bioactive ingredient of Siraitia grosvenorii, could attenuate LPS-induced memory impairment in mice. The behavioral tests and immunohistochemical analysis and Western blot were performed. The present results showed that oral administration of mogrol (20, 40, 80 mg/kg) significantly improved LPS-induced memory impairment in mice. The results also indicated that mogrol treatment significantly reduced the number of Iba1-positive cells, the nuclear NF-κB p65 and levels of TNF-α, IL-1ß and IL-6 both in the hippocampus and frontal cortex of LPS-challenged mice. [Formula: see text].

Mogroside V and mogrol: unveiling the neuroprotective and metabolic regulatory roles of Siraitia grosvenorii in Parkinson's disease.

Introduction: Siraitia grosvenorii (Swingle) C. Jeffrey, is an edible and traditional medicine widely used in China. Mogroside V (MGV) and mogrol (MG) are its main active ingredients, which have been found to be effective in the treatment of neurodegenerative diseases recently. However, whether they can effectively treat Parkinson's disease (PD) and their underlying mechanisms have not been sufficiently explored. In this study, we investigated the neuroprotective and metabolic regulatory effects of MGV and MG on PD. Materials and methods: Using SH-SY5Y cell models and an MPTP-induced mouse model of PD, we evaluated the compounds' efficacy in mitigating MPP+-induced neurotoxicity and ameliorating motor deficits and dopaminergic neuron loss. Employing widely targeted metabolomics and bioinformatics analysis to investigate the Metabolic imbalance rectification caused by MGV and MG treatment. The vivo experimental protocol encompassed a 14-day drug administration regimen with mice randomly allocated into six groups (n = 9) receiving distinct compound dosages including a control group, a model group, MGV-H (30 mg/kg/day), MGV-L (10 mg/kg/day), MG-H (15 mg/kg/day), and MG-L (3 mg/kg/day). Results: Our findings revealed that pre-treatment with MGV and MG significantly enhanced cell viability in SH-SY5Y cells exposed to MPP+, demonstrating a potent protective effect against neurotoxicity. In the MPTP mouse model, MGV-H, MGV-L, and MG-H significantly enhanced motor coordination as assessed by the rotarod test (p < 0.05); MGV-L and MG-H evidently inhibited dopaminergic neuronal loss in the substantia nigra pars compacta (p < 0.05). Furthermore, metabolomic analysis of the substantia nigra highlighted the restoration of metabolic balance, with MGV-L and MG-H impacting 160 differential metabolites and modulating key pathways disrupted in PD, including sphingolipid metabolism, fatty acid metabolism, and amino acid metabolism. Notably, treatment with MGV-L and MG-H led to the regulation of 106 metabolites, showing a recovery trend towards normal levels, which constitutes approximately 17.5% of the identified metabolites. Key metabolites such as n-acetyl-l-glutamate, hexadecanoic acid, and 9-octadecenal were significantly altered (p < 0.05), underscoring their broad-spectrum metabolic regulatory capacity. Conclusion: This study underscores the potential of natural compounds in developing comprehensive treatment strategies for neurodegenerative diseases, paving the way for future clinical research to validate the therapeutic efficacy of mogrosides in PD.

Synthesis and anti-inflammatory activity of mogrol derivatives modified at C24 site.

Mogrol, the aglycone of well-known sweeter mogrosides, shows potent anti-inflammatory activity. In this study, forty-two mogrol derivatives bearing various pharmacophores with oxygen or nitrogen atoms were designed and synthesized via structural modification at C24 site, and their anti-inflammatory activity were screened against lipopolysaccharide (LPS)-induced RAW264.7 cells. Compared with mogrol, most of derivatives exhibited stronger inhibition of NO production without cytotoxicity. In particular, compound B5 that contained an indole motif effectively suppressed the secretion of inflammatory mediators including TNF-α and IL-6, and inhibited the expression levels of TLR4, p-p65 and iNOS proteins. Molecular docking showed that the active B5 interacted with amino acid residues of iNOS protein through π-π stacking and hydrophobic interactions with binding affinity value of -12.1 kcal/mol, which was much stronger than mogrol (-8.9 kcal/mol). These results suggest that derivative B5 is a promising anti-inflammatory molecule and the strategy of hybridizing indole skeleton on mogrol is worthy for further attention.

Efficient snailase-based production of mogrol from Luo Han Guo extract in an aqueous-organic system.

To solve the insufficient availability of mogrol, an 11α-hydroxy aglycone of mogrosides in Siraitia grosvenorii, snailase was employed as the enzyme to completely deglycosylate LHG extract containing 50% mogroside V. Other commonly used glycosidases performed less efficiently. Response surface methodology was conducted to optimize the productivity of mogrol, which peaked at 74.7% in an aqueous reaction. In view of the differences in water-solubility between mogrol and LHG extract, we employed an aqueous-organic system for the snailase-catalyzed reaction. Of five tested organic solvents, toluene performed best and was relatively well tolerated by snailase. After optimization, biphasic medium containing 30% toluene (v/v) could produce a high-quality mogrol (98.1% purity) at a 0.5 L scale with a production rate of 93.2% within 20 h. This toluene-aqueous biphasic system would not only provide sufficient mogrol to construct future synthetic biology systems for the preparation of mogrosides, but also facilitate the development of mogrol-based medicines.

Pharmacological Activities of Mogrol: Potential Phytochemical against Different Diseases.

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.

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

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.

Mogrol Attenuates Osteoclast Formation and Bone Resorption by Inhibiting the TRAF6/MAPK/NF-κB Signaling Pathway In vitro and Protects Against Osteoporosis in Postmenopausal Mice.

Osteoporosis is a serious public health problem that results in fragility fractures, especially in postmenopausal women. Because the current therapeutic strategy for osteoporosis has various side effects, a safer and more effective treatment is worth exploring. It is important to examine natural plant extracts during new drug design due to low toxicity. Mogrol is an aglycon of mogroside, which is the active component of Siraitia grosvenorii (Swingle) and exhibits anti-inflammatory, anticancer and neuroprotective effects. Here, we demonstrated that mogrol dose-dependently inhibited osteoclast formation and function. To confirm the mechanism, RNA sequencing (RNA-seq), real-time PCR (RT-PCR), immunofluorescence and Western blotting were performed. The RNA-seq data revealed that mogrol had an effect on genes involved in osteoclastogenesis. Furthermore, RT-PCR indicated that mogrol suppressed osteoclastogenesis-related gene expression, including CTSK, ACP5, MMP9 and DC-STAMP, in RANKL-induced bone marrow macrophages Western blotting demonstrated that mogrol suppressed osteoclast formation by blocking TNF receptor-associated factor 6 (TRAF6)-dependent activation of the mitogen-activated protein kinase nuclear factor-B (NF-κB) signaling pathway, which decreased two vital downstream transcription factors, the nuclear factor of activated T cells calcineurin-dependent 1 (NFATc1) and c-Fos proteins expression. Furthermore, mogrol dramatically reduced bone mass loss in postmenopausal mice. In conclusion, these data showed that mogrol may be a promising procedure for osteoporosis prevention or therapy.

Mogrol, an aglycone of mogrosides, attenuates ulcerative colitis by promoting AMPK activation.

BACKGROUND: Ulcerative colitis (UC) is a non-specific chronic inflammatory disease. The incidence of UC in China has been increasing in recent years. Mogrol is an aglycone of mogrosides. Studies have shown that mogrosides have anti-oxygenation, anti-inflammatory, and laxative effects as well as other biological activities. PURPOSE: To investigate the beneficial effects of mogrol on UC and identify its underlying mechanisms. STUDY DESIGN: We used the dextran sodium sulphate (DSS)-induced UC model in mice, TNF-α-damaged NCM460 colonic epithelial cells, macrophage cells THP-M stimulated with lipopolysaccharide (LPS) / adenosine triphosphate (ATP) and compound C (an AMPK inhibitor) to confirm the key role of AMPK (AMP-activated protein kinase) activation. METHODS: Histological evaluation, immunohistochemical staining, Western blot analysis, immunofluorescence assay and quantitative real time-PCR were used in the study. RESULTS: Oral administration of mogrol (5 mg/kg/daily) in vivo significantly attenuated pathological colonic damage, inhibited inflammatory infiltration and improved the abnormal expression of NLRP3 inflammasome in colonic mucosa via the AMPK and NF-κB signaling pathways. In vitro, mogrol protected against intestinal epithelial barrier dysfunction by activating AMPK in TNF-α-treated NCM460 cells and inhibited the production of inflammatory mediator in LPS-stimulated THP-M cells. Furthermore, mogrol's effects were reversed by compound C intervention in DSS-induced UC model. CONCLUSION: Mogrol exerts protective effects in experimental UC and inhibits production of inflammatory mediators through activation of AMPK-mediated signaling pathways.

Highly sweet compounds of plant origin: From ethnobotanical observations to wide utilization.

ETHNOPHARMACOLOGICAL RELEVANCE: Ethnobotanical studies have been of very great importance in recognizing plants that contain substances that modulate the heterodimer T1R2-T1R3 sweet taste receptor, inclusive of Stevia rebaudiana (Asteraceae) and Siraitia grosvenorii (Cucurbitaceae). AIM OF THE REVIEW: In addition to reviewing relevant ethnobotanical literature, inclusive of original field work conducted, the authors have provided a progress report on the ultimate regulatory acceptance of highly sweet ent-kaurane (steviol) diterpene glycosides from S. rebaudiana leaves ("stevia") and cucurbitane triterpene glycosides (mogrosides) from the fruits of S. grosvenorii (popularly known as "monk fruit"). Despite their relatively high prices relative to that of sucrose, the steviol glycosides and mogrosides are of current great interest for further more extensive utilization on the market as sweet-tasting non-caloric food additives, due to increases in the rates of obesity and diabetes all over the world. Recent phytochemical work on the sweet principles of these two species is highlighted, including the important "next-generation" sweetener, rebaudioside M, from S. rebaudiana. RESULTS: Initial observations on the ethnobotany of both S. rebaudiana and S. grosvenorii have proved crucial to indicating the presence of their sweet-tasting principles to the wider scientific community. CONCLUSIONS: Ethnobotanical observations have been pivotal in enabling the discovery of many sweet-tasting plant constituents, with those of S. rebaudiana and S. grosvenorii both being examples. Extractives prepared from these species are now commercially used widely in the U.S. as additives for the sweetening of foods and beverages.

Neuroprotective effect of mogrol against Aß1-42 -induced memory impairment neuroinflammation and apoptosis in mice.

OBJECTIVES: Cognitive impairment is the main character of Alzheimer's disease (AD). This study mainly focused on whether mogrol, a tetracyclic triterpenoids compound of Siraitia grosvenorii Swingle, can ameliorate the memory impairment induced by Aß1-42 . METHODS: Memory impairment mice model was made by stereotactic intra-hippocampal microinjection of Aß1-42 (410 pm/mouse). Mogrol (20, 40, 80 mg/kg) was given to mice by intragastric administration at 3 days after Aß1-42 injection for totally 3 weeks. Morris water maze test and Y-maze test were operated to evaluate the therapeutic effect of morgrol on Aß1-42 -induced memory impairments. Immunohistochemical analyses and Hoechst 33258 assay were used to evaluate effect of morgrol on Aß1-42 -induced microglia overactivation and apoptotic response in hippocampus of mice. Western blotting assay was used to evaluate effect of mogrol on the Aß1-42 -activated NF-κB signaling. KEY FINDINGS: Mogrol could significantly alleviate Aß1-42 -induced memory impairments, inhibit Aß1-42 -induced microglia overactivation and prevent Aß1-42 -triggered apoptotic response in the hippocampus. Mogrol also could suppress Aß1-42 -activated NF-κB signaling, reduce the production of proinflammatory cytokines. CONCLUSIONS: This study suggested that mogrol would ameliorate the memory impairment induced by Aß1-42 , which is involved in anti-inflammation and anti-apoptosis in the brain.

Effect and mechanism of mogrol on lipopolysaccharide-induced acute lung injury / 中华急诊医学杂志

Objective:To explore the targeted regulation of the inflammatory pathway and its mechanism after AMPK phosphorylation induced by lipopolysaccharide (LPS) in mice and human monocytes induced by THP-1, so as to provide evidence for the clinical application of Mogrol (MO) in the clinical treatment of acute lung injury.Methods:Twenty-four clean C57BL/6 male mice aged 6-8 weeks were randomly (random number) divided into the control group, MO group, LPS group and LPS+ MO group with 6 mice in each group. Mice in the control group were intraperitoneally injected with normal saline (30 mL/kg), mice in the MO group were intraperitoneally injected with MO (30 mg/kg), mice in the lipopolysaccharide group were intraperitoneally injected with lipopolysaccharide (10 mg/kg), mice in the lipopolysaccharide + MO group were intraperitoneally injected with MO (30 mg/kg), and the other side was injected with lipopolysaccharide (10 mg/kg) 30 min later. After 12 h, the mice were sacrificed for sampling and pathology and molecular biological tests were carried out. Cell experiment: THP-1 cells in good condition were cultured in RPMI 1640 medium containing 10% fetal bovine serum for 24 h, and then induced to differentiate into macrophages with 100 ng/mL PMA. The control group, MO group, LPS group and LPS + MO group were established. After drug stimulation, the cell suspension of each group was collected, and the cells and culture medium supernatants were used for subsequent detectionResults:Compared with the control group, the injury degree of the lipopolysaccharide group was obvious, the alveolar cavity structure was destroyed, the inflammatory cell infiltration was increased, and the alveolar septum was obviously thickened in the tissue sections. After MO intervention, the injury degree of lung tissue injury was greatly improved, and MPO and the lung wet/dry weight ratio were also significantly decreased. The mRNA levels of the inflammatory cytokines IL-1β, IL-6 and TNF- α in lung tissues were also significantly decreased under MO intervention [(2.96±0.10) vs. (5.53±0.14), (8.62±0.17) vs. (12.31±0.09), (3.01±0.09) vs. (4.85±0.36)]. The expression levels of NLRP3, caspase-1 p20, GSDMD-N and ASC in the lung tissues of mice in the lipopolysaccharide group were significantly higher than those in the control group, while the phosphorylation level of AMPK in the lipopolysaccharide + MO group was increased, and the expression of scorched death-related proteins was effectively inhibited [(0.58±0.09) vs. (0.89±0.15), (0.19±0.08) vs. (0.93±0.16), (0.65±0.09) vs. (0.86±0.14), (0.30±0.12) vs. (0.47±0.10), all P<0.05]. At the same time, the secretion of the inflammatory factors IL-1β and IL-18, the main markers of scorch death in the tissue measured by ELISA, could also be alleviated by MO. In the cell experiment, MO also promoted the phosphorylation of AMPK, inhibited the expression of proteins related to NLRP3 inflammatory bodies, and significantly improved cell viability. Conclusions:MO attenuates LPS-induced acute lung injury by inhibiting NLRP3-mediated cell pyrogenesis by promoting the phosphorylation of AMPK.

Mogrol represents a novel leukemia therapeutic, via ERK and STAT3 inhibition.

Unlike solid tumors, the primary strategy for leukemia treatment is chemotherapy. However, leukemia chemotherapy is associated with adverse drug effects and drug resistance. Therefore, it is imperative to identify novel agents that effectively treat leukemia while minimizing adverse effects. The Raf/MEK/extracellular regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) pathways have been implicated in leukemia carcinogenesis, and provide novel molecular targets for therapeutic intervention in cancer. Mogrol, a biometabolite of mogrosides found in Siraitia grosvenorii, has exhibited anti-cancer activities; however, the underlying mechanism of this effect remains unclear. To clarify its anti-cancer activity and mechanism of action, we treated K562 leukemia cells with mogrol. Mogrol suppressed leukemia cell growth via inhibition of the ERK1/2 and STAT3 pathways, in particular, through the suppression of p-ERK1/2 and p-STAT3. Inhibition of these pathways suppressed Bcl-2 expression, thereby inducing K562 cell apoptosis. Furthermore, mogrol enhanced p21 expression, resulting in G0/G1 cell cycle arrest. The findings provide new perspectives regarding the role of mogrol in leukemia treatment.