(E)-2-Methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a new (E)-2,4-bis(p-hydroxyphenyl)-2 - butenal derivative, reportedly has therapeutic effects such as anti-arthritic properties. ...Although previous studies showed that MMPP has anti-arthritic effects on rheumatoid arthritis (RA), the anti-inflammation mechanism of MMPP remains unclear. In this study, phorbol-12-myristate 13-acetate (PMA) was used as an inflammatory stimulus to evaluate the detailed mechanism of the MMPP-mediated anti-inflammatory effect in human monocytic THP-1 cells. We investigated the effects of MMPP on inflammation-related pathways including protein kinase Cδ (PKCδ), mitogen-activated protein kinase, and activator protein-1 (AP-1). PMA induced the translocation of PKCs from the cytosol to the membrane and phosphorylated JNK. MMPP inhibited PMA-induced membrane translocation of PKCδ, phosphorylation of JNK, and nuclear translocation of AP-1, resulting in downregulation of cyclooxygenase-2 and chemokine ligand 5 production. These findings indicate that MMPP inhibits inflammatory responses in THP-1 cells by mitigating PMA-induced activation of PKCδ and JNK and nuclear translocation of AP-1. Therefore, MMPP may be useful as an anti-inflammatory drug.
MMPP inhibits inflammatory responses in THP-1 cells by mitigating PMA-induced activation of PKCδ and JNK and nuclear translocation of AP-1. PMA induced the translocation of PKC from the cytosol to the membrane and phosphorylated JNK. MMPP inhibited PMA-induced membrane translocation of PKCδ, phosphorylation of JNK, and nuclear translocation of AP-1, resulting in downregulation of cyclooxygenase-2 and chemokine ligand 5 production. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
(E)-2-methoxy-4-3-(4-methoxyphenyl) prop-1-en-1-yl phenol (MMPP), a novel synthetic analog of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB), exerts anti-inflammatory and anticancer effects by ...downregulating the STAT3 pathway. It has also been recently reported that MMPP can act as a PPAR agonist which enhances glucose uptake and increases insulin sensitivity. However, it has not yet been elucidated whether MMPP can act as an antagonist of MD2 and inhibit MD2-dependent pathways. In this study, we evaluated the underlying modulatory effect of MMPP on inflammatory responses in LPS-stimulated THP-1 monocytes. MMPP inhibited the LPS-induced expression of inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, as well as the inflammatory mediator COX-2. MMPP also alleviated the IKKαβ/IκBα and JNK pathways and the nuclear translocation of NF-κB p50 and c-Jun in LPS-stimulated THP-1 monocytes. In addition, the molecular docking analyses and in vitro binding assay revealed that MMPP can directly bind to CD14 and MD2, which are expressed in the plasma membrane, to recognize LPS first. Collectively, MMPP was directly bound to CD14 and MD2 and inhibited the activation of the NF-κB and JNK/AP-1 pathways, which then exerted anti-inflammatory activity. Accordingly, MMPP may be a candidate MD2 inhibitor targeting TLR4, which exerts anti-inflammatory effects.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Neuroinflammation is implicated in dopaminergic neurodegeneration. We have previously demonstrated that (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a selective signal ...transducer and activator of transcription 3 (STAT3) inhibitor, has anti-inflammatory properties in several inflammatory disease models. We investigated whether MMPP could protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic cell loss and behavioral impairment. Imprinting control region (ICR) mice (8 weeks old, n = 10 per group) were administered MMPP (5 mg/kg) in drinking water for 1 month, and injected with MPTP (15 mg/kg, four times with 2 h intervals) during the last 7 days of treatment. MMPP decreased MPTP-induced behavioral impairments in rotarod, pole, and gait tests. We also showed that MMPP ameliorated dopamine depletion in the striatum and inflammatory marker elevation in primary cultured neurons by high-performance liquid chromatography and immunohistochemical analysis. Increased activation of STAT3, p38, and monoamine oxidase B (MAO-B) were observed in the substantia nigra and striatum after MPTP injection, effects that were attenuated by MMPP treatment. Furthermore, MMPP inhibited STAT3 activity and expression of neuroinflammatory proteins, including ionized calcium binding adaptor molecule 1 (Iba1), inducible nitric oxide synthase (iNOS), and glial fibrillary acidic protein (GFAP) in 1-methyl-4-phenylpyridinium (MPP
; 0.5 mM)-treated primary cultured cells. However, mitogen-activated protein kinase (MAPK) inhibitors augmented the activity of MMPP. Collectively, our results suggest that MMPP may be an anti-inflammatory agent that attenuates dopaminergic neurodegeneration and neuroinflammation through MAO-B and MAPK pathway-dependent inhibition of STAT3 activation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
(E)-2-Methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol (MMPP), derived from butenal, is a recently synthesized Maillard reaction product. Owing to its novelty, little is known about the function ...of MMPP. In this study, we elucidated the effects of MMPP on apoptosis in cervical cancer by using the HeLa cervical cancer cell line, which is widely used in cancer research. We observed that MMPP was cytotoxic to HeLa cells and induced activation of caspase-3, -8, and -9, without affecting the expression of the viral oncogenes E6 and E7. In particular, the expression of the death receptors DR5 and FAS was significantly increased by MMPP treatment. There were no significant alterations of mitochondrial intrinsic factors. Taking all these results together, our findings show that MMPP primarily induces apoptosis in HeLa cervical cancer cells via the extrinsic apoptotic signaling pathway, accompanied by an enhanced expression of death receptors.
Abstract The increased proliferation of vascular smooth muscle cells (VSMCs) in the arterial wall is a critical pathogenic factor for vascular diseases such as atherosclerosis and restenosis after ...angioplasty. Clitocybin B was reported to have either a potent free radical scavenging effect or effects that were isolated from the culture broth of mushroom Clitocybe aurantiaca . The present study was designed to investigate the effects of clitocybin B on VSMC proliferation and its possible molecular mechanism. Clitocybin B significantly inhibited the proliferation and the DNA synthesis of PDGF-BB-stimulated VSMCs in a concentration-dependent manner. In agreement with these findings, clitocybin B suppressed the PDGF-BB-induced progression through G0/G1 to S phase of cell cycle. Clitocybin B also down-regulated the expressions of cell cycle-related proteins, including cyclin-dependent kinase (CDK)2, cyclin E, CDK4, cyclin D1, and proliferative cell nuclear antigen in PDGF-BB-stimulated VSMCs. Clitocybin B significantly inhibited the phosphorylation of Akt, extracellular signal-regulated kinase 1/2, and phospholipase C-γ1, in the PDGF-BB signaling pathway. Clitocybin B suppressed the PDGF-Rβ activation in PDGF-BB signaling cascade. These results suggested that the inhibitory effect of clitocybin B on the proliferation of VSMCs may be associated with suppressing PDGF-Rβ phosphorylation. Thus, clitocybin B may be an effective antiproliferative agent for the prevention of atherosclerosis and restenosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In cancer treatment, multi-target approach has paid attention to a reasonable strategy for the potential agents. We investigated whether (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol ...(MMPP) could exert an anticancer effect by dual-regulating VEGFR2 and PPARγ. MMPP showed modulating effects in TNBC type (MDA-MB-231 and MDA-MB-468) and luminal A type (MCF7) breast cancer cell lines. MMPP enhanced PPARγ transcriptional activity and inhibited VEGFR2 phosphorylation. MMPP-induced signaling by VEGFR2 and PPARγ ultimately triggered the downregulation of AKT activity. MMPP exhibited anticancer effects, as evidenced by growth inhibition, inducement of apoptosis, and suppression of migration and invasion. At the molecular level, MMPP activated pro-apoptotic proteins (caspase3, caspase8, caspase9, and bax), while inhibiting the anti-apoptotic proteins (bcl2). Additionally, MMPP inhibited the mRNA expressions of EMT-promoting transcription factors. Therefore, our findings showed molecular mechanisms of MMPP by regulating VEGFR2 and PPARγ, and suggested that MMPP has potential to treat breast cancer.
The Maillard Reaction Products (MRPs) are chemical compounds which have been known to be effective in chemoprevention. Death receptors (DR) play a central role in directing apoptosis in several ...cancer cells. In our previous study, we demonstrated that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal, a MRP product, inhibited human colon cancer cell growth by inducing apoptosis via nuclear factor-κB (NF-κB) inactivation and G2/M phase cell cycle arrest. In this study, (E)-2,4-bis(p-hydroxyphenyl)-2-butenal diacetate, a new (E)-2,4-bis(p-hydroxyphenyl)-2-butenal derivative, was synthesized to improve their solubility and stability in water and then evaluated against NCI-H460 and A549 human lung cancer cells. (E)-2,4-bis(p-hydroxyphenyl)-2-butenal diacetate reduced the viability in both cell lines in a time and dose-dependent manner. We also found that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal diacetate increased apoptotic cell death through the upregulation of the expression of death receptor (DR)-3 and DR6 in both lung cancer cell lines. In addition to this, the transfection of DR3 siRNA diminished the growth inhibitory and apoptosis inducing effect of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal diacetate on lung cancer cells, however these effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal diacetate was not changed by DR6 siRNA. These results indicated that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal diacetate inhibits human lung cancer cell growth via increasing apoptotic cell death by upregulation of the expression of DR3.
Many types of cancer are associated with excessive angiogenesis. Anti-angiogenic treatment is an effective strategy for treating solid cancers. This study aimed to demonstrate the inhibitory effects ...of (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP) in VEGFA-induced angiogenesis. The results indicated that MMPP effectively suppressed various angiogenic processes, such as cell migration, invasion, tube formation, and sprouting of new vessels in human umbilical vein endothelial cells (HUVECs) and mouse aortic ring. The inhibitory mechanism of MMPP on angiogenesis involves targeting VEGFR2. MMPP showed high binding affinity for the VEGFR2 ATP-binding domain. Additionally, MMPP improved VEGFR2 thermal stability and inhibited VEGFR2 kinase activity, suppressing the downstream VEGFR2/AKT/ERK pathway. MMPP attenuated the activation and nuclear translocation of NF-κB, and it down-regulated NF-κB target genes such as VEGFA, VEGFR2, MMP2, and MMP9. Furthermore, conditioned medium from MMPP-treated breast cancer cells effectively inhibited angiogenesis in endothelial cells. These results suggested that MMPP had great promise as a novel VEGFR2 inhibitor with potent anti-angiogenic properties for cancer treatment via VEGFR2/AKT/ERK/NF-κB signaling pathway. BMB Reports 2024; 57(5): 244-249
In cancer treatment, multi-target approach has paid attention to a reasonable strategy for the potential agents. We investigated whether (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol ...(MMPP) could exert an anticancer effect by dual-regulating VEGFR2 and PPARγ. MMPP showed modulating effects in TNBC type (MDA-MB-231 and MDA-MB-468) and luminal A type (MCF7) breast cancer cell lines. MMPP enhanced PPARγ transcriptional activity and inhibited VEGFR2 phosphorylation. MMPP-induced signaling by VEGFR2 and PPARγ ultimately triggered the downregulation of AKT activity. MMPP exhibited anticancer effects, as evidenced by growth inhibition, inducement of apoptosis, and suppression of migration and invasion. At the molecular level, MMPP activated pro-apoptotic proteins (caspase3, caspase8, caspase9, and bax), while inhibiting the anti-apoptotic proteins (bcl2). Additionally, MMPP inhibited the mRNA expressions of EMT-promoting transcription factors. Therefore, our findings showed molecular mechanisms of MMPP by regulating VEGFR2 and PPARγ, and suggested that MMPP has potential to treat breast cancer.
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