MOLECULAR MEDICINE
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2025
·Vol. 31
·期 1
·1-20
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IF 6.4
Peng Shuaijun,Su Pan,Liu Liming,Li Zibo,Liu Yuan,Tian Lei,Bai Ming,Xu Erping,Li Yucheng
Background The dysregulation of neuroinflammation triggered by imbalance of microglia M1/M2 polarization is a key pathogenic factor and closely associated with occurrence of depression. Formononetin (FMN), a natural non-steroidal isoflavonoid, has been confirmed to exhibit remarkable anti-inflammatory efficacy, but the impact of FMN on depression and the underlying antidepressant mechanisms are still not fully understood. This study aimed to investigate whether the antidepressant effect of FMN is involved in modulating microglia polarization, and if so, what are the underlying mechanisms.Methods Lipopolysaccharide (LPS)-induced depressive mice were used to study antidepressant mechanisms of FMN. Microglia cell line BV2 stimulated by LPS was employed to investigate pharmacological mechanisms of FMN. Effects of FMN on neuronal damage were detected by H&E, Nissl and Golgi staining. The efficacy of FMN were evaluated by immunostaining and western blots in vivo and vitro. In addition, molecular docking, luciferase reporter assay, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) were used to confirm the direct target of FMN.Results Our results showed that FMN significantly reverses depression-like behaviors, alleviates neuroinflammation and neuronal damage, rebalances M1/M2 polarization, inhibits NLRP3 inflammasome and enhances microglial autophagy level in prefrontal cortex of LPS-induced depressive mice. In vitro assays, results unraveled that autophagy inhibitor chloroquine (CQ) blocks effects of FMN on inhibiting NLRP3 inflammasome and rebalancing M1/M2 polarization. Moreover, PPARα is identified as a direct target of FMN and FMN can activate PPARα-mediated autophagy. Furtherly, combination PPARα agonist (WY14643) with FMN had no significant additive effects on inhibiting NLRP3 inflammasome and rebalancing M1/M2 polarization, whereas PPARα antagonist (GW6471) abrogated these pharmacologic effects of FMN in BV2. Importantly, GW6471 exhibited similar pharmacologic effects to abolish antidepressant effect of FMN in LPS-induced depressive mice.Conclusion Our study firstly demonstrated that FMN can rebalance microglia M1/M2 polarization and inhibit NLRP3 inflammasome, with the involvement of activating PPARα-mediated autophagy to ameliorate depression-like behaviors, which provides a novel view to elucidate antidepressant mechanisms of FMN and also offers a potential therapeutic target for depression.
研究领域:
神经科学
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药理学
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免疫学
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Hong Yu,Muyan Kong,Jinyi Chen,Jiyao Liu,Keyao Shan,Guiyu Zhang,Ruidi Jiang,Yinli Zheng,Qiulu Chen,Rong Zhang,Zhongqiu Liu,Jinjun Wu
Colorectal cancer (CRC), one of the primary causes of gastrointestinal malignancy-related mortality worldwide, encounters significant therapeutic challenges due to multidrug resistance. Multidrug resistance-associated protein 2 (MRP2), encoded by ABCC2, plays a crucial role in the development of drug resistance during clinical CRC treatment. This study elucidates a novel mechanism by which formononetin (FMNT), a bioactive isoflavone commonly found in food and medicinal-related plants, suppresses CRC via microRNA-490-3p (miR-490-3p)-mediated regulation of ABCC2 and synergizes with 5-fluorouracil (5-FU). HCT116 and SW480 cell lines as well as AOM/DSS-induced CRC models in wild-type and Mrp2 -/- mice were employed. The results demonstrated that FMNT markedly suppresses CRC proliferation in vitro and tumorigenesis in vivo . Transcriptomic profiling identified ABCC2 as the top target associated with FMNT’s efficacy. This finding was validated in clinical specimens, which revealed significant upregulation of MRP2 in human CRC tissues. FMNT markedly downregulated the MRP2 expression. Genetic ablation experiments further confirmed enhanced FMNT sensitivity in Mrp2 -/- mice and MRP2 silencing CRC cells. Mechanistically, FMNT upregulated tumor-suppressive miR-490-3p, which directly targets the ABCC2 3′UTR, thereby establishing a regulatory axis corroborated by gain/loss-of-function experiments. Notably, overexpression of miR-490-3p augmented FMNT’s antitumor effects, whereas inhibition of miR-490-3p diminished its efficacy. Therapeutic combination index analysis indicated robust synergy between FMNT and 5-FU, with combination therapy achieving superior tumor growth inhibition compared to monotherapies. Collectively, our findings uncover a novel miR-490-3p/ABCC2 regulatory mechanism underlying FMNT’s antitumor activity and highlight its potential for chemosensitization through ABCC2 inhibition, providing a strong rationale for flavonoid-based adjuvant therapy in CRC management.
研究领域:
肿瘤学
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分子生物学
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药理学
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癌症研究
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生物信息学
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EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2025
·
IF 4.7
Conglu Zhao,Liyuan Ji,Xiaoting Wang,Jia Zhang,Xiang Xu,Xiaoting Zhang,Yanjie Ding,Keran Li,Chaoyue Zheng,Kaijun Qiu,Jing Yan,Songtao Gu,Honggang Zhou,Cheng Yang,Hongli Li,Xiaoting Gu,Xiaoyu Ai
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung lesion, which is called a "tumor-like disease". Previous studies have confirmed that intratracheal instillation of formononetin-loaded porous microspheres (FMN-PLGA-MSs) can effectively improve bleomycin-induced pulmonary fibrosis. However, the poor lung retention of FMN-PLGA-MSs reduces the therapeutic efficacy of the FMN. Building on this foundation, this study prepared chitosan-coated formononetin porous microspheres (CS-FMN-PLGA-MSs) to enhance the FMN lung retention by leveraging the bioadhesive properties of chitosan. It is expected to prolong the action time of formononetin in lung tissues and enhance the therapeutic efficacy for pulmonary fibrosis. The study results showed that, compared to FMN-PLGA-MSs, CS-FMN-PLGA-MSs could be better taken up by MLG cells and NIH-3T3 cells. In vivo imaging demonstrated that CS-FMN-PLGA-MSs had a prolonged lung retention time, lasting up to 48 h. CS-FMN-PLGA-MSs exhibited a greater deposition in the regions of lung tissue compared to FMN-PLGA-MSs. The in vivo efficacy results in bleomycin-induced pulmonary fibrosis mice showed that, compared to FMN-PLGA-MSs, CS-FMN-PLGA-MSs had a higher anti-pulmonary fibrosis efficacy, significantly reducing hydroxyproline levels in fibrotic lung tissues, decreasing the extent of pulmonary fibrosis, and improving lung function. CS-FMN-PLGA-MSs provide a new reference for the treatment of pulmonary fibrosis.
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BIOCHEMICAL PHARMACOLOGY
·
2025
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IF 5.6
Yuan Liu,Jingjing Bu,Jiahui Wang,Yufang Zhao,Shuaijun Peng,Liming Liu,Pan Su,Ming Bai,Jiduo Shen,Erping Xu,Yucheng Li
Depression is frequently accompanied by myelin damage in the prefrontal cortex (PFC), and promoting remyelination may alleviate depressive symptoms. This study investigated the antidepressant mechanism of formononetin (FMN), a natural isoflavone phytoestrogen, in a corticosterone (CORT)-induced depression mouse model. FMN significantly improved depression-like behaviors and alleviated demyelination in the PFC. Proteomic analysis suggested the involvement of estrogen signaling in the antidepressant effects of FMN. Molecular docking, target capture, drug affinity responsive target stability (DARTS), and surface plasmon resonance (SPR) identified estrogen receptor alpha (ERα) as a direct target of FMN. FMN promoted ERα nuclear translocation and upregulated myelin basic protein (MBP). Edu assays indicated that FMN promoted oligodendrocyte precursor cells (OPCs) differentiation without affecting cell proliferation. Notably, its pro-differentiation effects were abolished by the ERα antagonist methylpiperidino pyrazole (MPP). Moreover, FMN did not induce proliferation or metastasis in breast cancer cells or promote tumor growth in vivo. These findings support FMN as a promising and safe therapeutic candidate for depression by targeting ERα to promote remyelination.
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Molecular Medicine Reports
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2021
·Vol. 24
·期 6
·1-9
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IF 2.952
Juanjuan Huang,Xianfeng Chen,Aihua Xie
Formononetin has proven to be anti‑inflammatory and able to alleviate symptoms of certain allergic diseases. The present study aimed to determine and elucidate the potential effects of formononetin in allergic rhinitis. JME/CF15 cells were pretreated with formononetin at different doses, followed by stimulation with IL‑13. Cell Counting Kit‑8 assay was performed to determine the cytotoxicity of formononetin. The expression levels of inflammation‑related proteins, histamine, IgE, TNF‑α, IL‑1β, IL‑6, granulocyte‑macrophage colony‑stimulating factor and eotaxin in IL‑13‑stimulated JME/CF15 cells were detected using ELISAs. The expression levels of phosphorylated‑NF‑κB p65, NF‑κB p65 and cyclooxygenase‑2 (Cox‑2) were analyzed using western blotting. Reverse transcription‑quantitative PCR, western blotting and immunofluorescence were performed to measure the levels of mucin 5AC oligomeric mucus/gel‑forming. Expression levels of sirtuin 1 (SIRT1) and nuclear erythroid factor 2‑related factor 2 (Nrf2) proteins were also measured using western blotting. The results of the present study revealed that formononetin exerted no cytotoxic effect on the viability of JME/CF15 cells. Following stimulation of JME/CF15 cells with IL‑13, formononetin suppressed the upregulated expression levels of proinflammatory cytokines. IL‑13‑induced formation of mucus was also attenuated by formononetin treatment. Furthermore, it was found that the SIRT1/Nrf2 signaling pathway was activated in formononetin‑treated JME/CF15 cells, whereas treatment with the SIRT1 inhibitor, EX527, reversed the effects of formononetin on IL‑13‑induced inflammation and mucus formation in JME/CF15 cells. In conclusion, the findings of the current study indicated that formononetin may activate the SIRT1/Nrf2 signaling pathway, thereby inhibiting IL‑13‑induced inflammation and mucus formation in JME/CF15 cells. These results suggested that formononetin may represent a promising agent for the treatment of allergic rhinitis.
研究领域:
免疫学
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药理学
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细胞生物学
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过敏
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INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2018
·Vol. 42
·期 4
·2155-2162
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IF 2.784
Tao Song,Jingdong Zhao,Tongbai Jiang,Xing Jin,Yubin Li,Xinrong Liu
The present study investigated the effects of formononetin (FMN) against balloon injury‑induced neointima formation in vivo and platelet‑derived growth factor (PDGF)‑BB‑induced proliferation and migration of vascular smooth muscle cells (VSMCs) in vitro, and explored the underlying mechanisms. A rat model of carotid artery injury was established, in order to examine the effects of FMN on balloon injury‑induced neointima formation. Histological observation of the carotid artery tissues was conducted by hematoxylin and eosin staining. VSMC proliferation during neointima formation was observed by proliferating cell nuclear antigen staining. Subsequently, rat aortic VSMCs were isolated, and the effects of FMN on PDGF‑BB‑induced VSMC proliferation and migration were determined using Cell Counting Kit‑8 and Transwell/wound healing assays, respectively. Immunohistochemical and immunocytochemical staining was applied to measure the expression of transforming growth factor (TGF)‑β in carotid artery tissues and VSMCs, respectively. SMAD family member 3 (Smad3)/phosphorylated (p)‑Smad3 expression was examined by western blotting. FMN treatment significantly inhibited the abnormal proliferation of smooth muscle cells in neointima, and alterations to the vascular structure were attenuated. In addition, pretreatment with FMN effectively inhibited the proliferation of PDGF‑BB‑stimulated VSMCs (P<0.05). FMN also reduced the number of cells that migrated to the lower surface of the Transwell chamber and decreased wound‑healing percentage (P<0.05). The expression levels of TGF‑β were decreased by FMN treatment in vivo and in vitro, and Smad3/p‑Smad3 expression was also markedly inhibited. In conclusion, FMN significantly protected against balloon injury‑induced neointima formation in the carotid artery of a rat model; this effect may be associated with the regulation of VSMC proliferation and migration through altered TGF‑β1/Smad3 signaling.
研究领域:
药理学
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心血管疾病
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细胞生物学
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分子生物学
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Plants-Basel
·
2026
·Vol. 15
·期 17
·2654
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IF 4.7
Feiran Hu,Wenzhao Zhou,Nong Zhou,Lanlan Wan,Linyun Pu,Caiyun Fu,Hua Zhang,Junsheng Qi
Lycopus lucidusTurcz. var.hirtusRegel (L. lucidusvar.hirtus) is a medicinal herb traditionally used in Chinese folk medicine for the treatment of inflammatory disorders, joint pain, and rheumatoid arthritis (RA)-like symptoms. However, systematic research on the bioactive flavonoids of this herb in RA-related cellular models is limited. The aim of this study was to isolate the main flavonoid from this herb and evaluate its in vitro anti-inhibitory effects in TNF-α-induced human RA fibroblast-like synoviocytes (HFLS-RA). Flavonoids were extracted, purified, and isolated using chromatographic techniques. The structure was elucidated by spectroscopic analysis. The effects of the isolated compound were assessed in a TNF-α-induced HFLS-RA cell model by evaluating pro-inflammatory cytokine secretion and cell proliferation/metabolic activity. A main flavonoid was identified as formononetin. Formononetin exhibited antioxidant activity and inhibited TNF-α-provoked inflammatory responses in HFLS-RA cells under cell-safe concentrations, as evidenced by reduced secretion of IL-6, IL-8, and IL-1β and suppression of TNF-α-induced hyperproliferation. In conclusion, formononetin is a major flavonoid constituent ofL. lucidusvar.hirtus, and these findings provide preliminary in vitro cellular evidence that formononetin exerts in vitro anti-inflammatory inhibitory activity on TNF-α-activated human RA fibroblast-like synoviocytes. Further in vivo and mechanistic studies are required to explore its potential for anti-RA-related pharmacological application.
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