Oxidative stress and neuroinflammation is implicated in the pathogenesis and development of Alzheimer's disease (AD). Here, we investigated the suppressive possibility of ethanol extract of ...Nannochloropsis oceanica (N. oceanica) on memory deficiency along with the fundamental mechanisms in lipopolysaccharide (LPS)-treated mice model. Among several extracts of 32 marine microalgae, ethanol extract of N. oceanica showed the most significant inhibitory effect on nitric oxide (NO) generation, NF-κB activity and β-secretase activity in cultured BV-2 cells, neuronal cells and Raw 264.7 cells. Ethanol extract of N. oceanica (50, 100 mg/kg) also ameliorated LPS (250 μg/kg)-induced memory impairment. We also found that ethanol extract of N. oceanica inhibited the LPS-induced expression of iNOS and COX-2. Furthermore, the production of reactive oxygen species (ROS), malondialdehyde (MDA) level as well as glutathione (GSH) level was also decreased by treatment of ethanol extract of N.oceanica. The ethanol extract of N. oceanica also suppresses IκB degradation as well as p50 and p65 translocation into the nucleus in LPS-treated mice brain. Associated with the inhibitory effect on neuroinflammation and oxidative stress, ethanol extract of N. oceanica suppressed Aβ1-42 generation through down-regulation of APP and BACE1 expression in in vivo. These results suggest that ethanol extract of N. oceanica ameliorated memory impairment via anti-inflammatory, anti-oxidant and anti-amyloidogenic mechanisms.
Chitinase-3-like-1 (CHI3L1) is known to induce inflammation in the progression of allergic diseases. Previous our studies revealed that ...2-({3-2-(1-cyclohexen-1-yl)ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111; K284), the CHI3L1 inhibiting compound, has the anti-inflammatory effect on neuroinflammation. In this study, we investigated that K284 treatment could inhibit the development of atopic dermatitis (AD). To identify the effect of K284, we used phthalic anhydride (5% PA)-induced AD animal model and in vitro reconstructed human skin model. We analyzed the expression of AD-related cytokine mediators and NF-κB signaling by Western blotting, ELISA and quantitative real-time PCR. Histological analysis showed that K284 treatment suppressed PA-induced epidermal thickening and infiltration of mast cells. K284 treatment also reduced PA-induced release of inflammatory cytokines. In addition, K284 treatment inhibited the expression of NF-κB activity in PA-treated skin tissues and TNF-α and IFN-γ-treated HaCaT cells. Protein-association network analysis indicated that CHI3L1 is associated with lactoferrin (LTF). LTF was elevated in PA-treated skin tissues and TNF-α and IFN-γ-induced HaCaT cells. However, this expression was reduced by K284 treatment. Knockdown of LTF decreased the expression of inflammatory cytokines in TNF-α and IFN-γ-induced HaCaT cells. Moreover, anti-LTF antibody treatment alleviated AD development in PA-induced AD model. Our data demonstrate that CHI3L1 targeting K284 reduces AD-like skin inflammation and K284 could be a promising therapeutic agent for AD by inhibition of LTF expression.Chitinase-3-like-1 (CHI3L1) is known to induce inflammation in the progression of allergic diseases. Previous our studies revealed that 2-({3-2-(1-cyclohexen-1-yl)ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111; K284), the CHI3L1 inhibiting compound, has the anti-inflammatory effect on neuroinflammation. In this study, we investigated that K284 treatment could inhibit the development of atopic dermatitis (AD). To identify the effect of K284, we used phthalic anhydride (5% PA)-induced AD animal model and in vitro reconstructed human skin model. We analyzed the expression of AD-related cytokine mediators and NF-κB signaling by Western blotting, ELISA and quantitative real-time PCR. Histological analysis showed that K284 treatment suppressed PA-induced epidermal thickening and infiltration of mast cells. K284 treatment also reduced PA-induced release of inflammatory cytokines. In addition, K284 treatment inhibited the expression of NF-κB activity in PA-treated skin tissues and TNF-α and IFN-γ-treated HaCaT cells. Protein-association network analysis indicated that CHI3L1 is associated with lactoferrin (LTF). LTF was elevated in PA-treated skin tissues and TNF-α and IFN-γ-induced HaCaT cells. However, this expression was reduced by K284 treatment. Knockdown of LTF decreased the expression of inflammatory cytokines in TNF-α and IFN-γ-induced HaCaT cells. Moreover, anti-LTF antibody treatment alleviated AD development in PA-induced AD model. Our data demonstrate that CHI3L1 targeting K284 reduces AD-like skin inflammation and K284 could be a promising therapeutic agent for AD by inhibition of LTF expression.
Signal transducer and activator of transcription-3 (STAT3) plays a pivotal role in cancer biology. Many small-molecule inhibitors that target STAT3 have been developed as potential anticancer drugs. ...While designing small-molecule inhibitors that target the SH2 domain of STAT3 remains the leading focus for drug discovery, there has been a growing interest in targeting the DNA-binding domain (DBD) of the protein.
We demonstrated the potential antitumor activity of a novel, small-molecule (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol (MMPP) that directly binds to the DBD of STAT3, in patient-derived non-small cell lung cancer (NSCLC) xenograft model as well as in NCI-H460 cell xenograft model in nude mice.
MMPP effectively inhibited the phosphorylation of STAT3 and its DNA binding activity
and
. It induced G1-phase cell cycle arrest and apoptosis through the regulation of cell cycle- and apoptosis-regulating genes by directly binding to the hydroxyl residue of threonine 456 in the DBD of STAT3. Furthermore, MMPP showed a similar or better antitumor activity than that of docetaxel or cisplatin.
MMPP is suggested to be a potential candidate for further development as an anticancer drug that targets the DBD of STAT3.
Rheumatoid arthritis (RA) is a severely debilitating chronic autoimmune disease that leads to long-term joint damage. Signal transducer and activator of transcription 3 (STAT3)-targeted small ...molecules have shown promise as therapeutic drugs for treating RA. We previously identified (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB), a tyrosine-fructose Maillard reaction product, as a small molecule with potent anti-inflammatory and anti-arthritic properties, mediated through the inhibition of STAT3 activation. The aim of this study was to develop a novel BHPH derivative with improved anti-arthritic properties and drug-likeness. We designed and synthesised (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a novel synthetic BHPB analogue, and investigated its anti-inflammatory and anti-arthritic activities in experimentally-induced RA. We showed that MMPP strongly inhibited pro-inflammatory responses by inhibiting in vitro STAT3 activation and its downstream signalling in murine macrophages and human synoviocytes from patients with RA. Furthermore, we demonstrated that MMPP exhibited potent anti-arthritic activity in a collagen antibody-induced arthritis (CAIA) mouse model in vivo. Collectively, our results suggest that MMPP has great potential for use in the treatment of RA.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Neuroinflammation is implicated for dopaminergic neurodegeneration. Sulfur compounds extracted from garlic have been shown to have anti-inflammatory properties. Previously, we have investigated that ...thiacremonone, a sulfur compound isolated from garlic has anti-inflammatory effects on several inflammatory disease models. To investigate the protective effect of thiacremonone against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairment and dopaminergic neurodegeneration, 8 week old ICR mice were given thiacremonone (10 mg/kg) in drinking water for 1 month and received intraperitoneal injection of MPTP (15 mg/kg, four times with 2 h interval) during the last 7 days of treatment. Our data showed that thiacremonone decreased MPTP-induced behavioral impairments (Rotarod test, Pole test, and Gait test), dopamine depletion and microglia and astrocytes activations as well as neuroinflammation. Higher activation of p38 was found in the substantia nigra and striatum after MPTP injection, but p38 activation was reduced in thiacremonone treated group. In an in vitro study, thiacremonone (1, 2, and 5 μg/ml) effectively decreased MPP+ (0.5 mM)-induced glial activation, inflammatory mediators generation and dopaminergic neurodegeneration in cultured astrocytes and microglial BV-2 cells. Moreover, treatment of p38 MAPK inhibitor SB203580 (10 μM) further inhibited thiacremonone induced reduction of neurodegeneration and neuroinflammation. These results indicated that the anti-inflammatory compound, thiacremonone, inhibited neuroinflammation and dopaminergic neurodegeneration through inhibition of p38 activation.
Here we report that a novel synthesized compound (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol (MMPP) which exhibits better stability, drug-likeness and anti-cancer effect than ...(E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB) that we previously reported. Of all newly synthesized BHPB analogues, MMPP showed the most significant inhibitory effect on colon cancer cell growth. Thus, we evaluated the anti-cancer effects and possible mechanisms of MMPP
and
. MMPP treatment (0-15 μg/mL) induced apoptotic cell death and enhanced the expression of cleaved caspase-3 and cleaved caspase-8 in a concentration dependent manner. Notably, the expression of death receptor (DR)5 and DR6 was significantly increased by MMPP treatment. Moreover, DR5 siRNA or DR6 siRNA transfection partially abolished MMPP-induced cell growth inhibition. Pull down assay and docking experiment showed that MMPP bound directly to IkappaB kinase β (IKKβ). It was noteworthy that IKKβ mutant (C99S) partially abolished MMPP-induced cell growth inhibition and enhanced expression of DR5 and DR6. In addition, MMPP enhanced TRAIL-induced apoptosis, cell growth inhibition and expression of DRs. In xenograft mice model, MMPP (2.5-5 mg/kg) suppressed tumor growth in a dose dependent manner. Immunohistochemistry analysis showed that the expression levels of DR5 and DR6 and active caspase-3 were increased while the expression levels of PCNA and p-IKKβ were decreased in a dose dependent manner. Thus, MMPP may be a promising anti-cancer agent in colon cancer treatment.
Chitinase-3-like-1 (CHI3L1) is known to induce inflammation in the progression of allergic diseases. Previous our studies revealed that ...2-({3-2-(1-cyclohexen-1-yl)ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111; K284), the CHI3L1 inhibiting compound, has the anti-inflammatory effect on neuroinflammation. In this study, we investigated that K284 treatment could inhibit the development of atopic dermatitis (AD). To identify the effect of K284, we used phthalic anhydride (5% PA)-induced AD animal model and in vitro reconstructed human skin model. We analyzed the expression of AD-related cytokine mediators and NF-κB signaling by Western blotting, ELISA and quantitative real-time PCR. Histological analysis showed that K284 treatment suppressed PA-induced epidermal thickening and infiltration of mast cells. K284 treatment also reduced PA-induced release of inflammatory cytokines. In addition, K284 treatment inhibited the expression of NF-κB activity in PA-treated skin tissues and TNF-α and IFN-γ-treated HaCaT cells. Protein-association network analysis indicated that CHI3L1 is associated with lactoferrin (LTF). LTF was elevated in PA-treated skin tissues and TNF-α and IFN-γ-induced HaCaT cells. However, this expression was reduced by K284 treatment. Knockdown of LTF decreased the expression of inflammatory cytokines in TNF-α and IFN-γ-induced HaCaT cells. Moreover, anti-LTF antibody treatment alleviated AD development in PA-induced AD model. Our data demonstrate that CHI3L1 targeting K284 reduces AD-like skin inflammation and K284 could be a promising therapeutic agent for AD by inhibition of LTF expression.
In the present study, we synthesized several non‐aldehyde analogues of (E)‐2,4‐bis(p‐hydroxyphenyl)‐2‐butenal which showed anti‐cancer effect. Interestingly, among the 16 compounds, we found that ...(E)‐2‐methoxy‐4‐(3‐(4‐methoxyphenyl)prop‐1‐en‐1‐yl)phenol (MMPP) showed the most significant anti‐proliferative effect on PA‐1 and SK‐OV‐3 ovarian epithelial cancer cells. MMPP treatment (0‐15 µg/mL) induced apoptotic cell death, enhanced the expression of cleaved caspase‐3, and cleaved caspase‐9 in a concentration dependent manner. Notably, DNA binding activity of STAT3, phosphorylation of extracellular signal‐regulated kinase (ERK) and p38 was significantly decreased by MMPP treatment. However, ERK siRNA augmented MMPP‐induced inhibitory effect on cell growth rather than p38 siRNA or JNK siRNA. Moreover, combination treatment of MMPP with ERK inhibitor U0126 (10 µM) augmented MMPP‐induced inhibitory effect on cell growth and DNA binding activity of STAT3, and enhanced expression of cleaved caspase‐3 and cleaved caspase‐9. In addition, STAT3 siRNA transfection augmented MMPP‐induced cell growth inhibition. In PA‐1 bearing xenograft mice model, MMPP (5 mg/kg) suppressed tumor growth significantly. Immunohistochemistry staining showed that the expression levels of p‐ERK, PCNA, p‐STAT3 were decreased while the expression level of caspase‐3 was increased by MMPP treatment. Thus, MMPP may be a promising anti‐cancer agent in ovarian epithelial cancer treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Alzheimer’s disease (AD) is pathologically characterized by an excessive accumulation of amyloid-beta (Aβ) fibrils within the brain. We tested the anti-inflammatory and anti-amyloidogenic effects of ...(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. We examined whether MMPP (5 mg/kg in drinking water for 1 month) prevents amyloidogenesis and cognitive impairment on AD model mice induced by intraperitoneal LPS (250 μg/kg daily 7 times) injections. Additionally, we investigated the anti-neuroinflammatory and anti-amyloidogenic effect of MMPP (1, 5, and 10 μg/mL) in LPS (1 μg/mL)-treated cultured astrocytes and microglial BV-2 cells. MMPP treatment reduced LPS-induced memory loss. This memory recovery effect was associated with the reduction of LPS-induced inflammatory proteins; cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as well as activation of microglial cells and astrocytes in the brain. Furthermore, MMPP reduced LPS-induced β-secretase and Aβ generation. In in vitro study, LPS-induced expression of inflammatory proteins and amyloidogenic proteins was decreased in microglial BV-2 cells and cultured astrocytes by MMPP treatment. Moreover, MMPP treatment suppressed DNA binding activities of the activation of STAT3 in in vivo and in vitro. These results indicated that MMPP inhibits LPS-induced amyloidogenesis and neuroinflammation via inhibition of STAT3.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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