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1.
Nat Prod Bioprospect ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32016770

RESUMO

A series of dearomatized isoprenylated acylphloroglucinols derivatives, hyperhenols A-E (1-5), as well as seven known analogues (6-12), were characterized from Hypericum henryi. Their structures were determined by combination of NMR, ECD spectroscopy, and X-ray diffraction analysis. Compounds 1 and 6-8 were tested to exhibit potential antitumor properties, of which 6 and 7 inhibited cell growth through inducing apoptosis and cell cycle arrest. In addition, these compounds could induce autophagy and PINK1/Parkin-mediated mitophagy in cancer cell lines, as well as suppress lung cancer A549 cells metastasis in vitro.

2.
J Ethnopharmacol ; : 112645, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32045684

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Coreopsis tinctoria Nutt. flower (CTF) has been used traditionally in China for treating hypertension and diabetes as well as reducing body weight and blood fat. However, the vascular protection effect of the CTF has not been studied to date. AIM OF THE STUDY: This study aimed to screen and identify bioactive fractions from the CTF with a diabetic endothelial protection effect and to clarify the underlying mechanism. MATERIALS AND METHODS: The vascular protection effect of Fraction A was studied in high-fat diet and streptozocin-induced diabetic models. The endothelial protection effect of Fraction A-2 was further studied in an in vitro vascular endothelial dysfunction model induced by high glucose. In a high glucose-induced human umbilical vein endothelial cell (HUVEC) model, Fractions A-2-2 and A-2-3 were screened, and their detailed mechanisms of endothelial protection were studied. Liquid chromatography mass spectrometry (LC-MS) was used to identify the main components in Fractions A-2-2 and A-2-3. RESULTS: Fraction A treatment significantly improved the endothelium-dependent vasodilation of the mesenteric artery induced by acetylcholine in diabetic rats. The maximum relaxation was 79.82 ±â€¯2.45% in the control group, 64.36 ±â€¯9.81% in the model group, and 91.87 ±â€¯7.38% in the Fraction A treatment group (P < 0.01). Fraction A treatment also decreased rat tail pressure compared with the model group at the 12th week. The systolic blood pressure was 152.7 5 ±â€¯16.99 mmHg in the control group, 188.50 ±â€¯5.94 mmHg in the model group, and 172.60 ±â€¯14.31 mmHg in the Fraction A treatment group (P < 0.05). The mean blood pressure was 128.50 ±â€¯13.79 mmHg in the control group, 157.00 ±â€¯6.06 mmHg in the model group, and 144.80 ±â€¯11.97 mmHg in the Fraction A treatment group (P < 0.05). In an in vitro vascular endothelium-dependent vasodilation dysfunction model induced by high glucose, Fraction A-2 improved the vasodilation of the mesenteric artery. The maximum relaxation was 82.15 ±â€¯16.24% in the control group, 73.29 ±â€¯14.25% in the model group, and 79.62 ±â€¯13.89% in the Fraction A-2 treatment group (P < 0.05). In a high glucose-induced HUVEC model, Fraction A-2-2 and Fraction A-2-3 upregulated the expression of IRS-1, Akt, and eNOS and increased the levels of p-IRS-1Ser307, p-Akt Ser473, and p-eNOSSer1177 and also decreased the expression of NOX4, TNF-α, IL-6, sVCAM, sICAM, and NF-κB (P < 0.01). With the intervention of AG490 and LY294002, the above effects of Fraction A-2-2 and Fraction A-2-3 were inhibited (P < 0.01). LC-MS data showed that in Fraction A-2-2 and Fraction A-2-3, there were 10 main components: flavanocorepsin; polyphenolic; flavanomarein; isochlorogenic acid A; dicaffeoylquinic acid; coreopsin; marein; coreopsin; luteolin-7-O-glucoside; and 3',5,5',7-tetrahydroxyflavanone-O-hexoside. CONCLUSION: The protective effect of the CTF on diabetic endothelial dysfunction may be due to its effect on the JAK2/IRS-1/PI3K/Akt/eNOS pathway and the related oxidative stress and inflammation. The results strongly suggested that Fraction A-2-2 and Fraction A-2-3 were the active fractions from the CTF, and the CTF might be a potential option for the prevention of vascular complications in diabetes.

3.
ChemSusChem ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31950602

RESUMO

The synthesis of NH-sulfoximines from sulfides has been first developed under mild conditions in an aqueous solution with surfactant TPGS-750-M as the catalyst at room temperature. In this newly developed process, a simple and convenient recycling strategy to regenerate the indispensable hypervalent iodine(III) is used. The resulting 1,2,3-trifluoro-5-iodobezene can be recovered almost quantitively from the mixture by liquid-liquid extraction and then oxidized to give the corresponding iodine(III) species. This optimized procedure is compatible with a broad range of functional groups and can be easily performed on a gram scale, providing a green protocol for the synthesis of sulfoximines.

4.
Acta Pharmacol Sin ; 41(1): 82-92, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31371781

RESUMO

Metastasis causes the main lethality in esophageal cancer patient. Garcinol, a natural compound extracted from Gambogic genera, is a histone acetyltransferase (HAT) inhibitor that has shown anticancer activities such as cell cycle arrest and apoptosis induction. In this study, we investigated the effects of garcinol on the metastasis of esophageal cancer in vitro and in vivo. We found that garcinol (5-15 µM) dose-dependently inhibited the migration and invasion of human esophageal cancer cell lines KYSE150 and KYSE450 in wound healing, transwell migration, and Matrigel invasion assays. Furthermore, garcinol treatment dose-dependently decreased the protein levels of p300/CBP (transcriptional cofactors and HATs) and p-Smad2/3 expression in the nucleus, thus impeding tumor cell proliferation and metastasis. Knockdown of p300 could inhibit cell metastasis, but CBP knockdown did not affect the cell mobility. It has been reported that TGF-ß1 stimulated the phosphorylation of Smad2/3, which directly interact with p300/CBP in the nucleus, and upregulating HAT activity of p300. We showed that garcinol treatment dose-dependently suppressed TGF-ß1-activated Smad and non-Smad pathway, inhibiting esophageal cancer cell metastasis. In a tail vein injection pulmonary metastasis mouse model, intraperitoneal administration of garcinol (20 mg/kg) or 5-FU (20 mg/kg) significantly decreased the number of lung tumor nodules and the expression levels of Ki-67, p300, and p-Smad2/3 in lung tissues. In conclusion, our study demonstrates that garcinol inhibits esophageal cancer metastasis in vitro and in vivo, which might be related to the suppression of p300 and TGF-ß1 signaling pathways, suggesting the therapeutic potential of Garcinol for metastatic tumors.

5.
PLoS Pathog ; 15(12): e1008174, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31830143

RESUMO

Primary effusion lymphoma (PEL) is an aggressive B-cell malignancy without effective treatment, and caused by the infection of Kaposi's sarcoma-associated herpesvirus (KSHV), predominantly in its latent form. Previously we showed that the SUMO2-interacting motif within the viral latency-associated nuclear antigen (LANASIM) is essential for establishment and maintenance of KSHV latency. Here, we developed a luciferase based live-cell reporter system to screen inhibitors selectively targeting the interaction between LANASIM and SUMO2. Cambogin, a bioactive natural product isolated from the Garcinia genus (a traditional herbal medicine used for cancer treatment), was obtained from the reporter system screening to efficiently inhibit the association of SUMO2 with LANASIM, in turn reducing the viral episome DNA copy number for establishment and maintenance of KSHV latent infection at a low concentration (nM). Importantly, Cambogin treatments not only specifically inhibited proliferation of KSHV-latently infected cells in vitro, but also induced regression of PEL tumors in a xenograft mouse model. This study has identified Cambogin as a novel therapeutic agent for treating PEL as well as eliminating persistent infection of oncogenic herpesvirus.

6.
J Ginseng Res ; 43(4): 676-683, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31695571

RESUMO

Background: Korean Red Ginseng (KRG) is widely used for strengthening the immune system and fighting fatigue, especially in people with deficiency syndrome. However, there is concern that the long-term application or a high dose of KRG can cause "fireness" ( in Chinese) because of its "dryness" ( in Chinese). The aim of this study was to assess the safety and efficacy of a 4-week treatment with KRG in participants with deficiency syndrome. Methods: This was a 4-week, randomized, double-blind, placebo-controlled clinical trial. A total of 180 Chinese participants were randomly allocated to three groups: placebo control group, participants were given a placebo, 3.6 g/d; KRG 1.8 g and 3.6 g groups. The primary outcomes were the changes in fireness and safety evaluation (adverse events, laboratory tests, and electrocardiogram). The secondary outcomes were the efficacy of KRG on fatigue, which include the following: traditional Chinese medicine (TCM) symptom scale and fatigue self-assessment scale. Results: Of the 180 patients, 174 completed the full study. After 4 weeks of KRG treatment, the Fire-heat symptoms score including Excess fire-heat score and Deficient fire-heat score showed no significant change as compared with placebo treatment, and no clinically significant changes in any safety parameter were observed. Based on the TCM syndrome score and fatigue self-assessment score, TCM symptoms and fatigue were greatly improved after treatment with KRG, which showed a dose- and time-dependent effect. The total effective rate was also significantly increased in the KRG groups. Conclusion: Our study revealed that KRG has a potent antifatigue effect without significant adverse effects in people with deficiency syndrome. Although a larger sample size and longer treatment may be required for a more definite conclusion, this clinical trial is the first to disprove the common conception of "fireness" related to KRG.

7.
Front Pharmacol ; 10: 1281, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31736758

RESUMO

Introduction: Crocus sativus (saffron) is widely used in China, Iran, and India for dyeing and as a food additive and medicinal plant. Safranal, as one of the main constituents of saffron, is responsible for its aroma and has been reported to have anticancer, antioxidant, and anti-inflammation properties. Objective: In this study, we investigated the anti-inflammatory effects of Safranal in RAW264.7 cells, bone marrow-derived macrophages (BMDMs), and dextran sulfate sodium (DSS)-induced colitis mice. Methods: Safranal toxicity was determined using an MTT assay. We evaluated the inhibitory effect of nitric oxide (NO) and levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 cells and BMDMs. We assessed the inhibitory effect of pro-inflammatory cytokines, and the mRNA expressions of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), classical inflammatory pathways (MAPK and NF-κB), and the nuclear translocation factors AP-1 and NF-κB p65 were investigated. The in vivo anti-inflammatory effects of Safranal were assessed in a DSS-induced colitis model. DSS3.5% was used to induce colitis in mice with or without Safranal for 7 days; weight and disease activity index (DAI) were recorded daily. At the end of the experiment, the colon, mesenteric lymph nodes (MLNs), and spleen were collected for flow cytometry, ELISA, and Western blot analysis. Results: Safranal suppressed NO production, iNOS, and COX-2 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and BMDMs. Safranal decreased the production and mRNA expression of IL-6 and TNF-α in the RAW264.7 cell line and inhibited the phosphorylation and nuclear translocation of components of the MAPK and NF-κB pathways. Safranal alleviated clinical symptoms in the DSS-induced colitis model, and colon histology showed decreased severity of inflammation, depth of inflammatory involvement, and crypt damage. Immunohistochemical staining and flow cytometry showed reduced macrophage infiltration in colonic tissues and macrophage numbers in MLNs and the spleen. The levels of colonic IL-6 and TNF-α also decreased in Safranal-treated colitis mice. This study elucidates the anti-inflammation activity of Safranal, which may be a candidate for inflammatory bowel syndrome (IBD) therapy.

8.
Nat Prod Res ; : 1-8, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31512485

RESUMO

One new xanthone, (±) garciesculenxanthone C (1), two new biphenyls, garciesculenbiphenyls A (2) and B (3), together with two known compounds, doitungbiphenyl B (4) and morusignin D (5), were isolated from Garcinia esculenta. The structures of new compounds were elucidated by spectroscopic analysis, and the absolute configuration of (±) garciesculenxanthone C (1) was assigned by a modified Mosher's method. All isolates were evaluated for their antistaphylococcal activities against Staphylococcus aureus Newman, USA300 LAC, USA400 MW2, and Mu50 strains. Among these, (±) garciesculenxanthone C (1) showed the best antistaphylococcal activity, and its effect was determined to be bactericidal by time-kill experiment.

9.
Biochem Pharmacol ; 170: 113646, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31545974

RESUMO

Andrographolide (Andro), a well-known labdane diterpenoid of Andrographis paniculata, has been reported to have anti-inflammatory effects in various inflammatory disease models. Despite ongoing efforts to elucidate the anti-inflammatory mechanism of Andro, its specific mechanism is not entirely clear. In this study, we confirmed the inhibitory effect of Andro on inflammatory activity and studied its mechanism in depth to find potential anti-inflammatory targets of Andro using lipopolysaccharide (LPS)-induced macrophages in vitro and a dextran sulfate sodium (DSS)-induced mouse model of acute colitis in vivo. We found that Andro significantly reduced proinflammatory cytokines by suppressing nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and their upstream signaling pathways and activating the AMP activated protein kinase (AMPK) pathway in LPS-induced macrophages. Interestingly, Andro could not regulate the activation of the AMPK/NF-κB/MAPK pathway nor inhibit NF-κB and activator protein 1 (AP-1) nuclear translocation and nitric oxide (NO) production following knockdown of AMPKα2. Moreover, Andro attenuated DSS-induced intestinal barrier dysfunction and inflammation by suppressing the NF-κB and MAPK pathways in colon tissues while activating the AMPK pathway. In conclusion, our study demonstrates that Andro effectively inhibits LPS-induced inflammatory responses via AMPK activation in macrophages, whereby Andro can ameliorate DSS-induced acute colitis in mice.

10.
Org Lett ; 21(19): 8075-8079, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31550167

RESUMO

A bioinspired, Me2AlSEt-promoted domino Dieckmann cyclization via an 8-membered ring intermediate to construct bicyclo[3.3.1]nonanes was developed, and the divergent syntheses of nine complex polycyclic polyprenylated acylphloroglucinols were achieved. This novel domino cyclization tolerates a series of congested substrates, providing a very efficient way to construct diverse polycyclic structures. The selectivity and the advantages of the domino cyclization were studied. Moreover, the structure-activity relationship study leads to the identification of three simplified potent antitumor agents.

11.
Front Oncol ; 9: 586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428570

RESUMO

Non-small-cell lung cancer (NSCLC) is the predominant form of lung cancer, and it is regulated by a complex signal transduction network. Single-agent targeted therapy often results in acquired resistance, which leads to treatment failure. In this study, we demonstrated that a combination of the kinase inhibitors trametinib and bosutinib can synergistically suppress the growth of NSCLC by inhibiting both the mitogen-activated protein kinase (MAPK) and proto-oncogene tyrosine-protein kinase (SRC) pathways. The combination was profiled against a panel of 22 NSCLC cell lines, including one erlotinib-resistant cell line, and this combination was found to show synergistic effects against 16 cell lines. NSCLC cell lines (HCC827, HCC827-erlotinib-resistant, and H1650) were treated with trametinib, bosutinib, or a combination of these drugs. The drug combination inhibited colony formation and induced cell apoptosis. A mechanism study showed that the phosphorylation of multiple kinases in the epidermal growth factor receptor (EGFR) signaling pathway in NSCLC was down-regulated. In addition, the combination significantly attenuated tumor growth of HCC827 xenografts with low toxicity. Our findings provide a theoretical basis for further study of the combination of MAPK and SRC pathway inhibitors in NSCLC, especially in the treatment of erlotinib-resistant NSCLC.

12.
Eur J Med Chem ; 181: 111536, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376561

RESUMO

Nine new and unique xanthone derivatives, including one novel hybrid monoterpene-tetrahydroxanthone (1), three dihydro-xanthone derivatives (2-4), and five skeleton-rearranged xanthone derivatives (5-9), were obtained from a 95% EtOH extract of Garcinia oligantha leaves by a LC-MS-guided fractionation procedure. The structures of the new compounds were elucidated by analysis of their 1D and 2D NMR and MS data. The relative configurations of 2 and 8 were determined via X-ray crystallographic data analysis, while the absolute configurations of 1-2, 5-9 were assigned based on a comparison of calculated and experimental ECD and/or OR data. In SRB, PI-exclusion and Hoechst staining assays, 6 showed strong cytotoxic activities which could dose-dependently induce Taxol-insensitive quiescent LNCaP cell death. Additionally, a preliminary mechanism investigation using immunoblotting and Caspase-3 activity assay, indicated that 6 induced quiescent LNCaP cell death potentially through caspase-dependent mitochondrial apoptosis pathway.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Inibidores Enzimáticos/farmacologia , Garcinia/química , Folhas de Planta/química , Xantonas/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Xantonas/química , Xantonas/isolamento & purificação
13.
Front Oncol ; 9: 654, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31380287

RESUMO

The complexity and multi-target feature of natural compounds have made it difficult to elucidate their mechanism of action (MoA), which hindered the development of lead anticancer compounds to some extent. In this study, we applied RNA-Seq and GSEA transcriptome analysis to rapidly and efficiently evaluate the anticancer mechanisms of neobractatin (NBT), a caged prenylxanthone isolated from the Chinese herb Garcinia bracteata. We found that NBT exerted anti-proliferative effect on various cancer cells and caused both G1/S and G2/M arrest in synchronized cancer cells through its effects on the expression of E2F1 and GADD45α. The in vivo animal study further suggested that NBT could reduce tumor burden in HeLa xenograft model with no apparent toxicity. By demonstrating the biological effect of NBT, we provided evidences for further investigations of this novel natural compound with anticancer potential.

14.
Nat Commun ; 10(1): 3319, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346162

RESUMO

Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis. The JMJD6 gene at 17q21-ter activates gene transcription. Here we show that JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription. Knocking down JMJD6 reduces neuroblastoma cell proliferation and survival in vitro and tumor progression in mice, and high levels of JMJD6 expression in human neuroblastoma tissues independently predict poor patient prognosis. In addition, JMJD6 gene is associated with transcriptional super-enhancers. Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice, which are significantly reversed by forced JMJD6 over-expression. Our findings therefore identify JMJD6 as a neuroblastoma tumorigenesis factor, and the combination therapy as a treatment strategy.


Assuntos
Histona Desmetilases com o Domínio Jumonji/metabolismo , Neuroblastoma/tratamento farmacológico , Receptores de Superfície Celular/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinogênese , Proliferação de Células/efeitos dos fármacos , Fator de Transcrição E2F2/genética , Fator de Transcrição E2F2/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/fisiopatologia , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/genética
15.
Cell Death Dis ; 10(8): 554, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320607

RESUMO

Tumor metastasis is the predominant cause of lethality in cancer. We found that Neobractatin (NBT), a natural compound isolated from Garcinia bracteata, could efficiently inhibit breast and lung cancer cells metastasis. However, the mechanisms of NBT inhibiting cancer metastasis remain unclear. Based on the RNA-sequencing result and transcriptome analysis, Muscleblind-like 2 (MBNL2) was found to be significantly upregulated in the cells treated with NBT. The Cancer Genome Atlas (TCGA) database analysis indicated that the expression of MBNL2 in breast and lung carcinoma tumor tissues was significantly lower compared to normal tissues. We thus conducted to investigate the antimetastatic role of MBNL2. MBNL2 overexpression mimicked the effect of NBT on breast cancer and lung cancer cell motility and metastasis, in addition significantly enhanced the inhibition effect of NBT. MBNL2 knockdown furthermore partially eliminated the inhibitory effect of NBT on metastasis. Mechanistically, we demonstrated that NBT- and MBNL2-mediated antimetastasis regulation significantly correlated with the pAKT/epithelial-mesenchymal transition (EMT) pathway. Subsequent in vivo study showed the same metastasis inhibition effect in NBT and MBNL2 in MDA-MB-231 xenografts mouse model. This study suggest that NBT possesses significant antitumor activity in breast and lung cancer cells that is partly mediated through the MBNL2 expression and enhancement in metastasis via the pAKT/EMT signaling pathway.

16.
Pharmacol Res ; 147: 104328, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288080

RESUMO

A global transcriptional regulator, MgrA, was previously identified as a key determinant of virulence in Staphylococcus aureus. An 80% EtOH extract of Uncaria gambier was found to attenuate the virulence of S. aureus via its effects on MgrA. Using bioassay-guided fractionation, a polyphenolic polymer, uncariitannin, was found to be the main bioactive constituent of the extract, and its structure was characterized using spectral and chemical analysis. The molecular weight and polydispersity of uncariitannin were determined by gel permeation chromatography-refractive index-light scattering analysis. An electrophoretic mobility shift assay showed that uncariitannin could effectively inhibit the interaction of MgrA with DNA in a dose-dependent manner. Treatment with uncariitannin could decrease the mRNA and protein levels of Hla in both the S. aureus Newman and USA300 LAC strains. Further analysis of Hla expression levels in the Newman ΔmgrA and Newman ΔmgrA/pYJ335-mgrA strains indicated that uncariitannin altered Hla expression primarily in an MgrA-dependent manner. A mouse model of infection indicated that uncariitannin could attenuate MRSA virulence. In conclusion, uncariitannin may be a potential candidate for further development as an antivirulence agent for the treatment of S. aureus infection.

17.
Phytomedicine ; 58: 152874, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30889421

RESUMO

BACKGROUND: The fruits of Psoralea corylifolia L. (Fructus Psoraleae, FP) has a long history and a wide range of applications in the treatment of osteoporosis and leukoderma. Although it is well known that FP could cause hepatotoxicity and reproductive toxicity, less is known about its potential toxicity on multiple organs. PURPOSE: This study aims to determine the multiorgan toxicity of EtOH extract of FP (EEFP) and to investigate the underlying mechanisms through a systematic evaluation in Wistar rats. STUDY DESIGN AND METHODS: Wistar rats were orally administered with the EEFP at doses of 1.5, 1.0 and 0.5 g/kg for 28 days. Histopathologic and clinicopathologic analyses were performed, and the hormone levels in serum and the mRNA levels of enzymes related to the production of steroid hormones in adrenal glands were detected. The area of each band of adrenal glands and the steroid levels in the adrenal glands were also measured. RESULTS: After the treatment, both the histopathologic and clinicopathologic examination showed that EEFP caused liver, prostate, seminal vesicle and adrenal gland damage. Among the enzymes involved in the regulation of adrenal steroid hormone production, NET, VMAT2, and CYP11B1 were upregulated, while CYP17A1 was downregulated. Among the adrenal steroid hormones, COR and NE were upregulated, while levels of DHT and serum ACRH and CRH decreased. CONCLUSION: Our results indicated that adrenal gland, prostate, and seminal vesicles could also be the target organs of FP-induced toxicity. Abnormal enzyme and hormone production related to the hypothalamic pituitary adrenal (HPA) axis caused by the EEFP may be the potential toxic mechanism for changes in the adrenal gland and secondary sex organs of male rats.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Enzimas/metabolismo , Extratos Vegetais/toxicidade , Esteroides/metabolismo , Administração Oral , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Animais , Enzimas/genética , Etanol/química , Feminino , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Próstata/efeitos dos fármacos , Próstata/patologia , Ratos Wistar , Testes de Toxicidade/métodos
18.
J Virol ; 93(9)2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30814282

RESUMO

Enterovirus 71 (EV-A71) is a human pathogen that causes hand, foot, and mouth disease (HFMD) and fatal neurological diseases, and no effective treatment is available. Characterization of key host factors is important for understanding its pathogenesis and developing antiviral drugs. Here we report that Hsp27 is one of the most upregulated proteins in response to EV-A71 infection, as revealed by two-dimensional gel electrophoresis-based proteomics studies. Depletion of Hsp27 by small interfering RNA or CRISPR/Cas9-mediated knockout significantly inhibited viral replication, protein expression, and reproduction, while restoration of Hsp27 restored such virus activities. Furthermore, we show that Hsp27 plays a crucial role in regulating viral internal ribosome entry site (IRES) activities by two different mechanisms. Hsp27 markedly promoted 2Apro-mediated eukaryotic initiation factor 4G cleavage, an important process for selecting and initiating IRES-mediated translation. hnRNP A1 is a key IRES trans-acting factor (ITAF) for enhancing IRES-mediated translation. Surprisingly, knockout of Hsp27 differentially blocked hnRNP A1 but not FBP1 translocation from the nucleus to the cytoplasm and therefore abolished the hnRNP A1 interaction with IRES. Most importantly, the Hsp27 inhibitor 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran [7,6-b] xanthone (TDP), a compound isolated from a traditional Chinese herb, significantly protected against cytopathic effects and inhibited EV-A71 infection. Collectively, our results demonstrate new functions of Hsp27 in facilitating virus infection and provide novel options for combating EV-A71 infection by targeting Hsp27.IMPORTANCE Outbreaks of infections with EV-A71, which causes hand, foot, and mouth disease, severe neurological disorders, and even death, have been repeatedly reported worldwide in recent decades and are a great public health problem for which no approved treatments are available. We show that Hsp27, a heat shock protein, supports EV-A71 infection in two distinct ways to promote viral IRES-dependent translation. A small-molecule Hsp27 inhibitor isolated from a traditional Chinese medicinal herb effectively reduces virus yields. Together, our findings demonstrate that Hsp27 plays an important role in EV-A71 infection and may serve as an antiviral target.


Assuntos
Enterovirus Humano A/fisiologia , Infecções por Enterovirus/metabolismo , Regulação Viral da Expressão Gênica , Proteínas de Choque Térmico/metabolismo , Sítios Internos de Entrada Ribossomal , Chaperonas Moleculares/metabolismo , Biossíntese de Proteínas , Proteínas Virais/biossíntese , Replicação Viral/fisiologia , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/virologia , Citoplasma/genética , Citoplasma/metabolismo , Citoplasma/virologia , Fator de Iniciação 4G em Eucariotos/genética , Fator de Iniciação 4G em Eucariotos/metabolismo , Frutose-Bifosfatase/genética , Frutose-Bifosfatase/metabolismo , Técnicas de Inativação de Genes , Proteínas de Choque Térmico/genética , Ribonucleoproteína Nuclear Heterogênea A1/genética , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Humanos , Chaperonas Moleculares/genética , Proteínas Virais/genética
19.
Org Lett ; 21(5): 1534-1537, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30775925

RESUMO

Garsubelone A (1), the first dimeric polycyclic polyprenylated acylphloroglucinols type metabolite featuring a complicated 6/6/6/6/6/6/6 heptacyclic architecture containing 10 stereogenic centers, was isolated from Garcinia subelliptica. Biogenetically, this compound was constructed by the plausible monomeric precursor, garsubelone B (2) and secohyperforin, via a key Diels-Alder cycloaddition to form an unique 2-oxabicyclo[3.3.1]nonane core. Their structures and absolute configurations were determined by comprehensive spectroscopic and X-ray diffraction techniques. The cytotoxic activities of these isolates were also evaluated.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Garcinia/química , Floroglucinol/análogos & derivados , Compostos Policíclicos/química , Compostos Policíclicos/metabolismo , Terpenos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Floroglucinol/química , Compostos Policíclicos/isolamento & purificação , Difração de Raios X
20.
Planta Med ; 85(6): 444-452, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30650454

RESUMO

Six new prenylated xanthones (1: -6: ) and seventeen known xanthones were isolated from extracts of Garcinia bracteata leaves. Their structures were determined by extensive NMR and MS spectroscopic data analysis. The inhibitory activities of the isolates were assayed on HeLa, A549, PC-3, HT-29, and WPMY-1 cell lines. Compounds 1: and 15: -17: showed moderate inhibitory effects on tumor cell growth, with IC50s ranging from 3.7 to 14.7 µM.


Assuntos
Citotoxinas/isolamento & purificação , Garcinia/química , Folhas de Planta/química , Xantonas/isolamento & purificação , Linhagem Celular Tumoral/efeitos dos fármacos , Citotoxinas/farmacologia , Células HeLa/efeitos dos fármacos , Humanos , Células PC-3/efeitos dos fármacos , Relação Estrutura-Atividade , Xantonas/farmacologia
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