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1.
Curr Issues Mol Biol ; 45(5): 4035-4049, 2023 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-37232726

RESUMO

Patients with pediatric B-cell acute lymphoblastic leukemia (B-ALL) have a high survival rate, yet the prognosis of adults and patients with relapsed/refractory disease is relatively poor. Therefore, it is imperative to develop new therapeutic strategies. Here, we screened 100 plant extracts from South Korean Flora and investigated their anti-leukemic effect using CCRF-SB cells as a B-ALL model. The top cytotoxic extract identified in this screening was the Idesia polycarpa Maxim. branch (IMB), which efficiently inhibited the survival and proliferation of CCRF-SB cells, while having minimal to no impact on normal murine bone marrow cells. Mechanistically, the IMB-induced proapoptotic effect involves the increase of caspase 3/7 activity, which was shown to be associated with the disruption of the mitochondrial membrane potential (MMP) through the reduction in antiapoptotic Bcl-2 family expression. IMB also promoted the differentiation of CCRF-SB cells via the upregulation of the expression of differentiation-related genes, PAX5 and IKZF1. Given that resistance to glucocorticoid (GC) is often found in patients with relapsed/refractory ALL, we investigated whether IMB could restore GC sensitivity. IMB synergized GC to enhance apoptotic rate by increasing GC receptor expression and downmodulating mTOR and MAPK signals in CCRF-SB B-ALL cells. These results suggest that IMB has the potential to be a novel candidate for the treatment of B-ALL.

2.
Mar Drugs ; 20(12)2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36547926

RESUMO

Repetitive exposure to ultraviolet B (UVB) is one of the main causes of skin photoaging. We previously reported that dieckol isolated from Eisenia bicyclis extract has potential anti-photoaging effects in UVB-irradiated Hs68 cells. Here, we aimed to evaluate the anti-photoaging activity of dieckol in a UVB-irradiated hairless mouse model. In this study, hairless mice were exposed to UVB for eight weeks. At the same time, dieckol at two doses (5 or 10 mg/kg) was administered orally three times a week. We found that dieckol suppressed UVB-induced collagen degradation and matrix metalloproteinases (MMPs)-1, -3, and -9 expression by regulating transforming growth factor beta (TGF-ß)/Smad2/3 and mitogen-activated protein kinases (MAPKs)/activator protein-1 (AP-1) signaling. In addition, dieckol rescued the production of hyaluronic acid (HA) and effectively restored the mRNA expression of hyaluronan synthase (HAS)-1/-2 and hyaluronidase (HYAL)-1/-2 in UVB-irradiated hairless mice. We observed a significant reduction in transepidermal water loss (TEWL), epidermal/dermal thickness, and wrinkle formation in hairless mice administered dieckol. Based on these results, we suggest that dieckol, due to its anti-photoaging role, may be used as a nutricosmetic ingredient for improving skin health.


Assuntos
Benzofuranos , Proteínas Quinases Ativadas por Mitógeno , Envelhecimento da Pele , Proteínas Smad , Fator de Transcrição AP-1 , Fator de Crescimento Transformador beta , Animais , Camundongos , Camundongos Pelados , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Pele/efeitos dos fármacos , Pele/metabolismo , Envelhecimento da Pele/efeitos dos fármacos , Fator de Transcrição AP-1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Raios Ultravioleta/efeitos adversos , Benzofuranos/isolamento & purificação , Benzofuranos/farmacologia , Proteínas Smad/metabolismo
3.
Polymers (Basel) ; 16(9)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38732748

RESUMO

A polysaccharide fraction from Diospyros kaki (PLE0) leaves was previously reported to possess immunostimulatory, anti-osteoporotic, and TGF-ß1-induced epithelial-mesenchymal transition inhibitory activities. Although a few beneficial effects against colon cancer metastasis have been reported, we aimed to investigate the anti-metastatic activity of PLE0 and its underlying molecular mechanisms in HT-29 and HCT-116 human colon cancer cells. We conducted a wound-healing assay, invasion assay, qRT-PCR analysis, western blot analysis, gelatin zymography, luciferase assay, and small interfering RNA gene silencing in colon cancer cells. PLE0 concentration-dependently inhibited metastasis by suppressing cell migration and invasion. The suppression of N-cadherin and vimentin expression as well as upregulation of E-cadherin through the reduction of p-GSK3ß and ß-catenin levels resulted in the outcome of this effect. PLE0 also suppressed the expression and enzymatic activity of matrix metalloproteinases (MMP)-2 and MMP-9, while simultaneously increasing the protein and mRNA levels of the tissue inhibitor of metalloproteinases (TIMP-1). Furthermore, signaling data disclosed that PLE0 suppressed the transcriptional activity and phosphorylation of p65 (a subunit of NF-κB), as well as the phosphorylation of c-Jun and c-Fos (subunits of AP-1) pathway. PLE0 markedly suppressed JNK phosphorylation, and JNK knockdown significantly restored PLE0-regulated MMP-2/-9 and TIMP-1 expression. Collectively, our data indicate that PLE0 exerts an anti-metastatic effect in human colon cancer cells by inhibiting epithelial-mesenchymal transition and MMP-2/9 via downregulation of GSK3ß/ß-catenin and JNK signaling.

4.
Int Immunopharmacol ; 125(Pt A): 111083, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37871380

RESUMO

Hydrangenol, a dihydroisocoumarin, isolated from the leaves of Hydrangea serrata, possesses anti-inflammatory, anti-obesity, and anti-photoaging activities. In this study, we investigated the protective effects of hydrangenol (HG) against lipopolysaccharide (LPS)-induced endotoxemia and elucidated the underlying molecular mechanisms of action in C57BL/6 mice. Oral administration of HG (20 or 40 mg/kg) significantly restored the survival rate and population of macrophages, T helper cells (CD3+/CD4+), and Th17 cells (CD3+/CD4+/CCR6+) in the spleens of mice with LPS-induced endotoxemia. HG suppressed the expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1ß, and Interferon (IFN)-γ and the mRNA and protein expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in the intestine and lung of LPS-treated mice. Molecular data showed that HG ameliorated the activation of nuclear factor kappa B (NF-κB) p65, signal transducers and activators of transcription 3 (STAT3), and c-Fos and c-Jun (AP-1 subunits) via the myeloid differentiation primary response 88 (MyD88) dependent toll-like receptor 4 (TLR4) signaling pathway in the LPS-treated mouse intestines. HG treatment caused the recovery of LPS-induced impaired tight junction (occludin and claudin-2) protein and mRNA expressions. Furthermore, HG improved LPS-induced gut dysbiosis in mice. Taken together, our results suggest that HG protects against LPS-induced endotoxemia by restoring immune cells and the capacity of the intestinal barrier, reducing intestinal inflammation, and improving the composition of the gut microbiota.


Assuntos
Endotoxemia , Lipopolissacarídeos , Animais , Camundongos , Endotoxemia/induzido quimicamente , Endotoxemia/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Interleucina-6/metabolismo , RNA Mensageiro
5.
Eur J Med Chem ; 258: 115566, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37354740

RESUMO

New amide derivatives of the natural product 5,6,7-trimethoxyflavanone were designed as multifunctional antiproliferative molecules against blood cancer and the associated inflammatory conditions. The targeted compounds were synthesized efficiently in three linear steps employing known chalcone starting materials. Compounds 2h, 2i, 2l, 2t, 2v and 2x having bromo or nitro substituted-phenyl rings elicited potential inhibitory effects on macrophages production of nitric oxide, PGE2 and TNF-α which are proinflammatory mediators involved in tumorigenesis and progression of blood cancer. Additionally, evaluation of direct inhibitory effects on the growth of diverse blood cancers including leukemia, lymphoma, and myeloma cell lines unveiled compound 2v as the most potential molecules eliciting at least five-folds the potency of the standard imatinib drug over the used diverse blood cancers. Furthermore, compound 2v showed good selectivity to blood cancer cells rather than normal MRC5 cells. Moreover, compound 2v triggered death of HL60 leukemia cells via apoptosis induction. In conclusion, the natural product-derived compound 2v might serve as a multifunctional lead compound for further development of agents for treatment of blood cancers.


Assuntos
Antineoplásicos , Neoplasias Hematológicas , Leucemia , Neoplasias , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Anti-Inflamatórios/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Antineoplásicos/farmacologia , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais
6.
Food Funct ; 14(15): 6957-6968, 2023 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-37435675

RESUMO

Ulcerative colitis (UC) is a chronic disease of the colon characterized by mucosal damage and relapsing gastrointestinal inflammation. Hydrangea serrata (Thunb.) Ser. and its bioactive compound, hydrangenol, are reported to have anti-inflammatory effects, but few studies have investigated the effects of hydrangenol in colitis. In the present study, we evaluated for the first time the anti-colitic effects and molecular mechanisms of hydrangenol in a dextran sodium sulfate (DSS)-induced mouse colitis model. To investigate the anti-colitic effects of hydrangenol, DSS-induced colitis mice, HT-29 colonic epithelial cells treated with supernatant from LPS-inflamed THP-1 macrophages, and LPS-induced RAW264.7 macrophages were used. In addition, to clarify the molecular mechanisms of this study, quantitative real time-PCR, western blot analysis, TUNEL assay, and annexin V-FITC/PI double staining analysis were conducted. Oral administration of hydrangenol (15 or 30 mg kg-1) significantly alleviated DSS-induced colitis by preventing DAI scores, shortening colon length, and colonic structural damage. F4/80+ macrophage numbers in mesenteric lymph nodes and macrophage infiltration in colonic tissues were significantly suppressed following hydrangenol treatment in DSS-exposed mice. Hydrangenol significantly attenuated DSS-induced destruction of the colonic epithelial cell layer through regulation of pro-caspase-3, occludin, and claudin-1 protein expression. Moreover, hydrangenol ameliorated abnormal tight junction protein expression and apoptosis in HT-29 colonic epithelial cells treated with supernatant from LPS-inflamed THP-1 macrophages. Hydrangenol suppressed the expression of pro-inflammatory mediators, such as iNOS, COX-2, TNF-α, IL-6, and IL-1ß through NF-κB, AP-1, and STAT1/3 inactivation in DSS-induced colon tissue and LPS-induced RAW264.7 macrophages. Taken together, our findings suggest that hydrangenol recovers the tight junction proteins and down-regulates the expression of the pro-inflammatory mediators by interfering with the macrophage infiltration in DSS-induced colitis. Our study provides compelling evidence that hydrangenol may be a candidate for inflammatory bowel disease therapy.


Assuntos
Colite Ulcerativa , Colite , Hydrangea , Animais , Camundongos , Sulfato de Dextrana/efeitos adversos , Lipopolissacarídeos/farmacologia , Transdução de Sinais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Colite Ulcerativa/induzido quimicamente , Colo/metabolismo , Macrófagos , NF-kappa B/genética , NF-kappa B/metabolismo , Mediadores da Inflamação/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
7.
Biomed Pharmacother ; 163: 114708, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37121153

RESUMO

Although drugs such as acetaminophen, opioids, and nonsteroidal anti-inflammatory drugs (NSAIDs), are commonly used for pain management, the side effects of these drugs such as hepatotoxicity, nephrotoxicity, nausea, and vomiting, can not be neglected. Therefore, combinations of analgesics with different mechanisms raise the possibility of developing novel analgesics. Therefore, the aim of the present study was to evaluate whether DW-1021, the ionic complex of pelubiprofen (NSAID) and tramadol (opioid), has synergic antinociceptive and anti-inflammatory effects in nociceptive as well as inflammation-induced nociceptive models compared to pelubiprofen- or tramadol-only administration. Strong synergistic antinociceptive efficacy of DW-1021 was observed in the mouse writhing test and von Frey paw withdrawal threshold test in the carrageenan-induced rats. The hot plate test in mice and the Randall-Selitto mechanical paw pressure test in carrageenan-induced rats revealed that DW-1021 had a preferable effect on relieving pain to pelubiprofen, but not as much as tramadol. In the carrageenan-induced rats, DW-1021 had a more potent effect on reducing paw inflammation (paw volume, width, and thickness) via the suppression of PGE2 production than tramadol, but less than that of pelubiprofen. Taken together, our results suggest that the administration of DW-1021, a combination of pelubiprofen and tramadol, exerted a potent effect and can be used as a potential therapeutic agent for relieving pain and inflammation.


Assuntos
Tramadol , Ratos , Camundongos , Animais , Tramadol/farmacologia , Tramadol/uso terapêutico , Roedores , Carragenina/uso terapêutico , Dor/tratamento farmacológico , Dor/induzido quimicamente , Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Analgésicos Opioides/uso terapêutico , Inflamação/tratamento farmacológico
8.
Sci Total Environ ; 847: 157482, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-35901873

RESUMO

Catalytic oxidation is a feasible method for remediating volatile organic compounds (VOCs), due to its lower energy consumption and mineralization of VOCs into H2O and CO2. Noble metal-based catalysts are preferred for the catalytic oxidation of VOCs because of their superior activity, but they are usually deactivated by thermal aging which sinters the metal particles. Here, we report that Pt-Pd/Al2O3 thermally aged at 700-900 °C in air showed enhanced catalytic activity for toluene oxidation in humid conditions. There were electronic and structural changes in the thermally aged Pt-Pd/Al2O3, as confirmed by numerous analyses. Both Pt and Pd existed in a metallic rather than oxidized state without additional reduction steps. The noble metal particles were assembled to form Pt-Pd alloy, in the form of isolated Pd atoms surrounded by Pt atoms. This specific alloy structure was found to be crucial to the observed enhancement in catalytic toluene oxidation at low temperature.


Assuntos
Tolueno , Compostos Orgânicos Voláteis , Ligas/química , Dióxido de Carbono , Catálise , Eletrônica , Metais , Oxirredução , Compostos Orgânicos Voláteis/química
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