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1.
Acad Radiol ; 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33504446

RESUMO

RATIONALE AND OBJECTIVES: To assess differences of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) parameters at different postcontrast time points (TPs), and to explore the predictive value of DCE-MRI parameters for axillary lymph node (ALN) metastasis of breast cancer. MATERIALS AND METHODS: A total of 107 breast cancer patients were included retrospectively, and 50 phases were collected on DCE-MRI for each patient. DCE-MRI parameters Ktrans, Kep, Ve, TTP, Peak, Washin, Washout, and AUC were extracted from the images at 67.8 seconds, 128.5 seconds, 189.2 seconds, 249.9 seconds, and 310.5 seconds (regard as TP1, 2, 3, 4, and 5). Wilcoxon signed rank test was used to compare DCE-MRI parameters at different postcontrast TPs. Logistic regression was performed to analyze the predictive value of DCE-MRI parameters for ALN metastasis of breast cancer, and receiver operating characteristic (ROC) curve was constructed to evaluate the predictive performance. RESULTS: The difference of DCE-MRI parameters between TP1, 2, 3, 4, and 5 was statistically significant (p < 0.01) in breast cancer. The TPs are considered as the optimal TPs when DCE-MRI parameters values reach the maximum. The optimal TPs of Ktrans, Kep, and Ve were respectively at TP2, TP2, and TP4 (Ktrans2, Kep2, and Ve4). The optimal TPs of TTP, Peak, and AUC were at TP5 (TTP5, Peak5, and AUC5). AUC5 showed the ability to predict ALN metastasis of breast cancer (area under ROC curve = 0.656, p < 0.05). CONCLUSIONS: DCE-MRI parameters values were different at different postcontrast TPs. AUC5 may be an independent predictor of ALN metastasis in breast cancer.

2.
ACS Appl Mater Interfaces ; 13(1): 2033-2043, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33378149

RESUMO

The effective activation and utilization of O2 have always been the focus of scientists because of its wide applications in catalysis, organic synthesis, life and medical science. Here, a novel method for activating O2 spontaneously via interfacial oxygen vacancies on carbon-coated TiO2-x to generate reactive oxygen species (ROS) with versatile applications is reported. The interfacial oxygen vacancies can be stabilized by the carbon layer and hold its intrinsic properties for spontaneous oxygen activation without light irradiation, while common surface oxygen vacancies on TiO2-x are always consumed by the capture of H2O to form the surface hydroxyls. Thus, O2 absorbed at the interface of carbon and TiO2-x can be directly activated into singlet oxygen (1O2) or superoxide radicals (·O2-), confirmed both experimentally and theoretically. These reactive oxygen species exhibit excellent performance in oxidation reactions and inhibition of MCF-7 cancer cells, providing new insight into the effective utilization of O2 via oxygen vacancies on metal oxides.

3.
Bioorg Chem ; 105: 104388, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33130343

RESUMO

A phytochemical investigation on the stems and leaves of Wikstroemia chuii resulted in the isolation of three new daphnane diterpenes, wikstroechuins A-C (1-3), together with eight known analogues (4-11). The structures of new daphnane diterpenes (1-3) were determined on the basis of extensive spectroscopic methods and the known daphnane diterpenes (4-11) were identified by comparing their observable spectroscopic data with those reported spectral data in the literature. The anti-inflammatory effects as well as anti-HIV activities in vitro of all isolated daphnane diterpenes 1-11 were assessed. As a consequence, daphnane diterpenes 1-11 displayed remarkable inhibitory activities on NO (nitric oxide) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells showing IC50 values in the range of 0.12 ± 0.03 to 10.58 ± 0.16 µM. Meanwhile, daphnane diterpenes 1-11 displayed significant anti-HIV-1 reverse transcriptase (RT) effects showing EC50 values ranging from 0.09509 to 8.62356 µM. These research results indicated that the discovery of these new daphnane diterpenes with remarkable anti-inflammatory and anti-HIV activities from W. chuii, especially these new ones, could be extremely meaningful to the discovery of new anti-inflammatory agents and anti-HIV drugs as well as their potential practical values in the health and pharmaceutical products.

4.
Eur J Med Chem ; : 113022, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33239261

RESUMO

Multitarget drugs have emerged as a promising treatment modality in modern anticancer therapy. Taking advantage of the synergy of NAMPT and EGFR inhibition, we have developed the first compounds that serve as dual inhibitors of NAMPT and EGFR. On the basis of CHS828 and erlotinib, a series of hybrid molecules were successfully designed and synthesized by merging of the pharmacophores. Among the compounds that were synthesized, compound 28 showed good NAMPT and EGFR inhibition, and excellent in vitro anti-proliferative activity. Compound 28, which is a new chemotype devoid of a Michael receptor, strongly inhibited the proliferation of several cancer cell lines, including H1975 non-small cell lung cancer cells harboring the EGFRL858R/T790M mutation. More importantly, it imparted significant in vivo antitumor efficacy in a human NSCLC (H1975) xenograft nude mouse model. This study provides promising leads for the development of novel antitumor agents and valuable pharmacological probes for the assessment of dual inhibition in NAMPT and EGFR pathway with a single inhibitor.

5.
J Agric Food Chem ; 68(44): 12326-12335, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33107299

RESUMO

Toona sinensis, popularly known as Chinese toon or Chinese mahogany, is a perennial deciduous arbor belonging to the genus Toona in the Meliaceae family, which is widely distributed and cultivated in eastern and southeastern Asia. Its fresh young leaves and buds have been consumed as a very popular nutritious vegetable in China and confirmed to display a wide variety of biological activities. To investigate the chemical constituents and their potential health benefits from the fresh young leaves and buds of T. sinensis, a phytochemical study on its fresh young leaves and buds was therefore undertaken. In our current investigation, 16 limonoids (1-16), including four new limonoids, toonasinenoids A-D (1-4), and a new naturally occurring limonoid, toonasinenoid E (5), were isolated and characterized from the fresh young leaves and buds of T. sinensis. The chemical structures and absolute configurations of limonoids 1-5 were elucidated by comprehensive spectroscopic data analyses. All known limonoids (6-16) were identified via comparing their experimental spectral data containing mass spectrometry data, 1H and 13C nuclear magnetic resonance data, and optical rotation values to the data reported in the literature. All known limonoids (6-16) were isolated from T. sinensis for the first time. Furthermore, the neuroprotective effects of all isolated limonoids 1-16 against 6-hydroxydopamine-induced cell death in human neuroblastoma SH-SY5Y cells were assessed in vitro. Limonoids 1-16 exhibited notable neuroprotective activities, with EC50 values in the range from 0.27 ± 0.03 to 17.28 ± 0.16 µM. These results suggest that regular consumption of the fresh young leaves and buds of T. sinensis might prevent the occurrence and development of Parkinson's disease (PD). Moreover, the isolation and characterization of these limonoids that exhibit notable neuroprotective activities from the fresh young leaves and buds of T. sinensis could be very significant for researching and developing new neuroprotective drugs used for the prevention and treatment of PD.

6.
J Immunother Cancer ; 8(2)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33037113

RESUMO

BACKGROUND: kalirin RhoGEF kinase (KALRN) is mutated in a wide range of cancers. Nevertheless, the association between KALRN mutations and the pathogenesis of cancer remains unexplored. Identification of biomarkers for cancer immunotherapy response is crucial because immunotherapies only show beneficial effects in a subset of patients with cancer. METHODS: We explored the correlation between KALRN mutations and antitumor immunity in 10 cancer cohorts from The Cancer Genome Atlas program by the bioinformatics approach. Moreover, we verified the findings from the bioinformatics analysis with in vitro and in vivo experiments. We explored the correlation between KALRN mutations and immunotherapy response in five cancer cohorts receiving immune checkpoint blockade therapy. RESULTS: Antitumor immune signatures were more enriched in KALRN-mutated than KALRN-wildtype cancers. Moreover, KALRN mutations displayed significant correlations with increased tumor mutation burden and the microsatellite instability or DNA damage repair deficiency genomic properties, which may explain the high antitumor immunity in KALRN-mutated cancers. Also, programmed cell death 1 ligand (PD-L1) expression was markedly upregulated in KALRN-mutated versus KALRN-wildtype cancers. The increased antitumor immune signatures and PD-L1 expression in KALRN-mutated cancers may favor the response to immune checkpoint blockade therapy in this cancer subtype, as evidenced in five cancer cohorts receiving antiprogrammed cell death protein 1 (PD-1)/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immunotherapy. Furthermore, the significant association between KALRN mutations and increased antitumor immunity was associated with the fact that KALRN mutations compromised the function of KALRN in targeting Rho GTPases for the regulation of DNA damage repair pathways. In vitro and in vivo experiments validated the association of KALRN deficiency with antitumor immunity and the response to immune checkpoint inhibitors. CONCLUSIONS: The KALRN mutation is a useful biomarker for predicting the response to immunotherapy in patients with cancer.

7.
Liver Int ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33025657

RESUMO

Liver plays a critical role in metabolism, nutrient storage and detoxification. Emergency signals or appropriate immune response leads to pathological inflammation and breaks the steady state when liver dysfunction appears, which makes body more susceptible to chronic liver infection, autoimmune diseases and tumour. Compelling proof has illustrated the non-redundant importance of C-C chemokine receptor type 2 (CCR2), one of G-protein-coupled receptors, in different diseases. Selectively expressed on the surface of cells, CCR2 is involved in various signalling pathways and regulates the migration of cells. Especially, a peculiar role of CCR2 has been identified within decades in the onset and progression of hepatic diseases, which led to particular focusing on CCR2 as a new therapeutic and diagnostic target for non-alcoholic fatty liver disease and hepatocellular carcinoma. In this review, we discuss the effect of CCR2 in monocytes/macrophages on liver diseases. The application and translation of the decades of discoveries into therapies promise novel approaches in the treatment of liver disease.

8.
Autophagy ; : 1-16, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32866426

RESUMO

Macroautophagy/autophagy is a cellular catabolic process that is implicated in several physiological and pathological processes. However, the role of epidermal autophagy in wound healing remains unknown. Here, using mice with genetic ablation of the essential Atg5 (autophagy related 5) or Atg7 (autophagy related 7) in their epidermis to inhibit autophagy, we show that keratinocyte autophagy regulates wound healing in mice. Wounding induces the expression of autophagy genes in mouse skin. Epidermis-specific autophagy deficiency inhibits wound closure, re-epithelialization, keratinocyte proliferation and differentiation, dermal granulation tissue formation, and infiltration of immune cells including macrophages, neutrophils, and mast cells, while it does not affect angiogenesis. Using cytokine array screening, we found that autophagy deficiency inhibits the transcription and production of the cytokine CCL2/MCP-1 by TNF. At the molecular level, TNF induces autophagic flux and the expression of autophagy genes through NFKB in epidermal keratinocytes. TNF promotes CCL2 transcription through the autophagy-AMPK-BRAF-MAPK1/3/ERK-activator protein 1 (AP1) pathway. Indeed, treating mice with recombinant CCL2 can reverse the effect of autophagy deficiency in keratinocytes. At the cellular level, we found that CCL2 induction via autophagy in keratinocytes is required not only for keratinocyte migration and proliferation but also for dermal fibroblast activation. Our findings demonstrate a critical role of epidermal autophagy in wound healing in vivo and elucidate a critical molecular machinery coordinating keratinocyte-fibroblast interaction in skin repair. Abbreviations: ACTA2/α-SMA: actin alpha 2, smooth muscle; ACTB: ß-actin; ADGRE1: adhesion G protein-coupled receptor E1; AMPK: AMP-activated protein kinase; AP1: activator protein 1; AP1-RE: AP1 response element; ATG: autophagy-related; ATG16L1: autophagy related 16 like 1; BECN1: beclin 1; BRAF: B-Raf proto-oncogene, serine/threonine kinase; C5: complement C5; CCL2/MCP-1: C-C motif chemokine ligand 2; CCL3: C-C motif chemokine ligand 3; CK: cytokeratin; cKO: conditional knockout; CRTC1: CREB-regulated transcription coactivator 1; CXCL1: C-X-C motif chemokine ligand 1; CXCL2: C-X-C motif chemokine ligand 2; ECM: extracellular matrix; EGF: epidermal growth factor; FGF7: fibroblast growth factor 7; GABARAPL2: GABA type A receptor associated protein like 2; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HBEGF: heparin binding EGF like growth factor; HPRT1: hypoxanthine phosphoribosyltransferase 1; IHC: immunohistochemical; IL1B: interleukin 1 beta; KRT10: keratin 10; KRT14: keratin 14; MAP1LC3B/LC3B-I/II: microtubule-associated protein 1 light chain 3 beta; MAPK1/3/ERK: mitogen-activated protein kinase 1/3; MKI67/Ki-67: marker of proliferation; MPO: myeloperoxidase; NFKB: NF-kappa B, nuclear factor kappa-light-chain-enhancer of activated B cells; NFKB-RE: NFKB response element; PDGF: platelet-derived growth factor; PECAM1: platelet and endothelial cell adhesion molecule 1; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; RELA/p65: RELA proto-oncogene, NFKB subunit; shCON: small hairpin negative control; siNC: negative control; siRNA: small interfering RNA; SP1: sp1 transcription factor; SQSTM1/p62: sequestosome 1; TGFA: transforming growth factor alpha; TGFB1: transforming growth factor beta 1; TIMP1: TIMP metallopeptidase inhibitor 1; TNF/TNF-alpha: tumor necrosis factor; TREM1: triggering receptor expressed on myeloid cells 1; WT: wild-type.

9.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(4): 469-474, 2020 Apr 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895123

RESUMO

OBJECTIVE: To evaluate the expression of thymidylate synthase (TS) in myoepithelial cells (MECs) of salivary adenoid tissues and explore its clinical significance. METHODS: Immunohistochemical staining EnVision method was used to detect the expression of TS, P63, Calponin, CK5/6 and S-100 in 32 salivary gland specimens, including 10 non-neoplastic and salivary inflammation specimens, 11 mixed tumor specimens, 5 basal cell carcinoma specimens and 6 adenoid cyst carcinoma specimens. The specificity and sensitivity of TS as a specific molecular marker of salivary muscle epithelial cells were evaluated in comparison with P63, Calponin, CK5/6 and S-100. RESULTS: The expression pattern of TS in all the salivary gland tissue specimens was identical with that of p63. TS and P63 both showed strong immunohistochemical expressions in MECs of salivary adenoid tissue specimens. Calponin, CK5/6, and S-100 showed cytoplasmic/membranous expressions in the MECs. In addition, TS exhibited weak or moderate cytoplasmic expression in a few salivary gland epithelial cells, cancer cells and scattered stromal cells, with negative expression in the cell nuclei. The expression of TS in the MECs of all the salivary adenoid specimens was highly consistent with those of P63, Calponin, CK5/6 and S-100 (P>0.05) Except for CK5/6 expression in Salivary inflammation and Salivary gland specimens. Kappa>0.75. The specificity and sensitivity of TS as a molecular marker of MECs were both 100%. CONCLUSIONS: TS is a new specific marker of MECs for differential diagnosis of salivary gland tumors.


Assuntos
Tonsila Faríngea , Células Epiteliais , Biomarcadores Tumorais , Carcinoma Adenoide Cístico , Humanos , Neoplasias das Glândulas Salivares , Timidilato Sintase
10.
Oncogene ; 39(45): 6893-6905, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32978517

RESUMO

Hypoxia is a key concern during the treatment of non-small cell lung cancer (NSCLC), and hypoxia-inducible factor 1 alpha (HIF-1α) has been associated with increased tumor resistance to therapeutic modalities such as cisplatin. Compensatory activation of nucleotide excision repair (NER) pathway is the major mechanism that accounts for cisplatin resistance. In the present study, we suggest a novel strategy to improve the treatment of NSCLC and overcome the hypoxia-induced cisplatin resistance by cotreatment with Oroxylin A, one of the main bioactive flavonoids of Scutellariae radix. Based on the preliminary screening, we found that xeroderma pigmentosum group C (XPC), an important DNA damage recognition protein involved in NER, dramatically increased in hypoxic condition and contributed to hypoxia-induced cisplatin resistance. Further data suggested that Oroxylin A significantly reversed the hypoxia-induced cisplatin resistance through directly binding to HIF-1α bHLH-PAS domain and blocking its binding to HRE3 transcription factor binding sites on XPC promoter which is important to hypoxia-induced XPC transcription. Taken together, our findings not only demonstrate a crucial role of XPC dependent NER in hypoxia-induced cisplatin resistance, but also suggest a previously unrecognized tumor suppressive mechanism of Oroxylin A in NSCLC which through sensitization of cisplatin-mediated growth inhibition and apoptosis under hypoxia.

11.
Autophagy ; : 1-22, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32432943

RESUMO

SCAP (SREBF chaperone) regulates SREBFs (sterol regulatory element binding transcription factors) processing and stability, and, thus, becomes an emerging drug target to treat dyslipidemia and fatty liver disease. However, the current known SCAP inhibitors, such as oxysterols, induce endoplasmic reticulum (ER) stress and NR1H3/LXRα (nuclear receptor subfamily 1 group H member 3)-SREBF1/SREBP-1 c-mediated hepatic steatosis, which severely limited the clinical application of this inhibitor. In this study, we identified a small molecule, lycorine, which binds to SCAP, which suppressed the SREBF pathway without inducing ER stress or activating NR1H3. Mechanistically, lycorine promotes SCAP lysosomal degradation in a macroautophagy/autophagy-independent pathway, a mechanism completely distinct from current SCAP inhibitors. Furthermore, we determined that SQSTM1 captured SCAP after its exit from the ER. The interaction of SCAP and SQSTM1 requires the WD40 domain of SCAP and the TB domain of SQSTM1. Interestingly, lycorine triggers the lysosome translocation of SCAP independent of autophagy. We termed this novel protein degradation pathway as the SQSTM1-mediated autophagy-independent lysosomal degradation (SMAILD) pathway. In vivo, lycorine ameliorates high-fat diet-induced hyperlipidemia, hepatic steatosis, and insulin resistance in mice. Our study demonstrated that the inhibition of SCAP through the SMAILD pathway could be employed as a useful therapeutic strategy for treating metabolic diseases. ABBREVIATION: 25-OHD: 25-hydroxyvitamin D; 3-MA: 3-methyladenine; ABCG5: ATP binding cassette subfamily G member 5; ABCG8: ATP binding cassette subfamily G member 8; ACACA: acetyl-CoA carboxylase alpha; AEBSF: 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride; AHI: anhydroicaritin; AKT/protein kinase B: AKT serine/threonine kinase; APOE: apolipoprotein E; ATF6: activating transcription factor 6; ATG: autophagy-related; BAT: brown adipose tissue; CD274/PD-L1: CD274 molecule; CETSA: cellular thermal shift assay; CMA: chaperone-mediated autophagy; COPII: cytoplasmic coat protein complex-II; CQ: chloroquine; DDIT3/CHOP: DNA damage inducible transcript 3; DNL: de novo lipogenesis; EE: energy expenditure; EGFR: epithelial growth factor receptor; eMI: endosomal microautophagy; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FADS2: fatty acid desaturase 2; FASN: fatty acid synthase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvate transaminase; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; HMGCS1: 3-hydroxy-3-methylglutaryl-CoA synthase 1; HSP90B1/GRP94: heat shock protein 90 beta family member 1; HSPA5/GRP78: heat hock protein family A (Hsp70) member 5; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; INSIG1: insulin induced gene 1; LAMP2A: lysosomal associated membrane protein 2A; LDLR: low density lipoprotein receptor; LyTACs: lysosome targeting chimeras; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MBTPS1: membrane bound transcription factor peptidase, site 1; MEF: mouse embryonic fibroblast; MST: microscale thermophoresis; MTOR: mechanistic target of rapamycin kinase; MVK: mevalonate kinase; PROTAC: proteolysis targeting chimera; RQ: respiratory quotient; SCAP: SREBF chaperone; SCD1: stearoyl-coenzemy A desaturase 1; SMAILD: sequestosome 1 mediated autophagy-independent lysosomal degradation; SQSTM1: sequestosome 1; SREBF: sterol regulatory element binding transcription factor; TNFRSF10B/DR5: TNF receptor superfamily member 10b; TRAF6: TNF receptor associated factor 6; UPR: unfolded protein response; WAT: white adipose tissue; XBP1: X-box binding protein 1.

12.
Sci Adv ; 6(10): eaaz0575, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32181355

RESUMO

Although photodynamic therapy (PDT) has been clinically applied tumor hypoxia still greatly restricts the performance of this oxygen-dependent oncological treatment. The delivery of oxygen donors to tumor may produce excessive reactive oxygen species (ROS) and damage the peripheral tissues. Herein, we developed a strategy to solve the hypoxia issue by enhancing the lethality of ROS. Before PDT, the ROS-defensing system of the cancer cells was obstructed by an inhibitor to MTH1, which is a key for the remediation of ROS-caused DNA damage. As a result, both nuclei and mitochondrial DNA damages were increased, remarkably promoting cellular apoptosis. The therapeutic results demonstrated that the performance of PDT can be improved by the MTH1 inhibitor, leading to efficient cancer cell killing effect in the hypoxic tumor. This strategy makes better use of the limited oxygen, holding the promise to achieve satisfactory therapeutic effect by PDT without generating redundant cytotoxic ROS.


Assuntos
Antineoplásicos/farmacologia , Enzimas Reparadoras do DNA/genética , DNA de Neoplasias/genética , Inibidores Enzimáticos/farmacologia , Melanoma Experimental/tratamento farmacológico , Monoéster Fosfórico Hidrolases/genética , Pirimidinas/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Enzimas Reparadoras do DNA/antagonistas & inibidores , Enzimas Reparadoras do DNA/metabolismo , DNA de Neoplasias/antagonistas & inibidores , DNA de Neoplasias/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Composição de Medicamentos/métodos , Inibidores Enzimáticos/química , Feminino , Expressão Gênica , Células HCT116 , Células HeLa , Humanos , Luz , Células MCF-7 , Melanoma Experimental/enzimologia , Melanoma Experimental/patologia , Camundongos Nus , Nanopartículas/administração & dosagem , Nanopartículas/química , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Monoéster Fosfórico Hidrolases/metabolismo , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Porfirinas/química , Porfirinas/farmacocinética , Pirimidinas/química , Espécies Reativas de Oxigênio/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Agric Food Chem ; 68(7): 2024-2030, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32037814

RESUMO

Artocarpus heterophyllus (jack tree) is an evergreen fruit tree belonging to the genus Artocarpus (Moraceae), which is widely distributed in subtropical and tropical regions of Asia. Its fruits (jackfruit), well-known as the world's largest tree-borne fruit, are being consumed in our daily diets as a very popular tropical fruit throughout the world and have been confirmed to hold various health benefits. In this study, five new prenylated chromones, artocarheterones A-E (1-5), as well as seven known prenylated chromones (6-12) were purified and isolated from the ripe fruits of A. heterophyllus (jackfruit). Their chemical structures were determined through comprehensive spectroscopic methods. This is the first report on prenylated chromones isolated from A. heterophyllus. The anti-HIV-1 effects of all isolated chromones were assessed in vitro. As a result, prenylated chromones (1-12) showed remarkable anti-HIV-1 effects with EC50 values ranging from 0.09 to 9.72 µM. These research results indicate that the isolation and characterization of these prenylated chromones with remarkable anti-HIV-1 activities from the ripe fruits of A. heterophyllus could be significant to the discovery and development of new anti-HIV-1 drugs.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Artocarpus/química , Cromonas/química , Cromonas/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Frutas/química , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Estrutura Molecular , Prenilação
14.
Int J Biol Macromol ; 149: 116-126, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-31987948

RESUMO

The development of ideal organic-inorganic composite scaffold with porous structure and favorable osteoinductive properties that mimics the extracellular matrix composition of bone, is essential for the guidance of new bone formation in orthopaedic practice. Nowadays, numerous efforts have been dedicated to constructing implantable biocomposite scaffolds with appropriate structure and bioactivity for repairing bone defects. In this study, we fabricated chitosan-alginate-gelatin (CAG)-based porous biocomposite scaffolds with calcium phosphate coating on the surface and dexamethasone (DEX)-loaded mesoporous silica nanoparticles within the scaffold, which allows sustained release of DEX for bone tissue engineering application. The inorganic components of calcium phosphate crystals formed on the wall of scaffolds were obtained through electrochemical deposition method. The hybrid mineralized scaffolds demonstrate significantly high mechanical strength and reduced swelling property compared with pristine CAG scaffolds. The in vitro proliferation and osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (BMSCs) cultured on biocomposite scaffolds were significantly enhanced. Furthermore, in vivo experiments revealed that biocomposite scaffolds with minerals deposition and DEX loading showed better new bone formation ability, as compared to pure CAG scaffold and single mineralized scaffold. Therefore, the developed biocomposite scaffolds may be highly promising as local implantable scaffolds for potential applications in bone tissue engineering.

15.
Nat Prod Res ; : 1-7, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31755785

RESUMO

A phytochemical study on the fruits of Artocarpus heterophyllus caused the isolation of a previously undescribed steroid, artoheterophoid (1), together with seven known analogues (2 - 8). The chemical structure of 1 was elucidated on the basis of comprehensive spectroscopic methods and the known compounds (2 - 8) were identified by comparing their spectroscopic data with those reported in the literatures. All known compounds (2-8) were separated from A. heterophyllus for the first time. All isolated compounds (1-8) were assessed for their anti-inflammatory activities in vitro by measuring the inhibitory effect against nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells. Compounds 1-8 displayed remarkable inhibitory effects against NO production with the IC50 values in the range of 0.72 ± 0.07 to 5.93 ± 0.12 µM.

16.
J Agric Food Chem ; 67(43): 11942-11947, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31622090

RESUMO

Manilkara zapota, usually known as Sapodilla, is a fairly slow-growing evergreen tropical tree which belongs to the genus Manilkara (Sapotaceae), indigenous to Central America, southern Mexico, and the Caribbean. The ripe fruits of M. zapota have been widely consumed as an uniquely flavored tropical fruit and verified to hold a variety of health benefits. In order to investigate the potential health-promoting chemical compositions from the fruits of M. zapota cultivated in Hainan Island of China, a systematic and in-depth phytochemical study on this fruit was accordingly implemented. In our current study, three new prenylated coumarins, manizapotins A-C (1-3), together with seven known prenylated coumarins (4-10), were separated from the fruits of M. zapota. The chemical structures of new prenylated coumarins 1-3 were unambiguously established by means of comprehensive spectroscopic analyses, and the known compounds 4-10 were determined by comparing their experimental spectral data with those described data in the literature. This is the first time to discover prenylated coumarins occurring in M. zapota. The potential anti-inflammatory effects and anti-HIV (human immunodeficiency virus) activities of all these separated prenylated coumarins were assessed. Prenylated coumarins 1-10 dispalyed remarkable inhibitory effects against nitric oxide production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells with the IC50 values equivalent to that of hydrocortisone in vitro. Meanwhile, prenylated coumarins 1-10 exhibited pronounced anti-HIV-1 reverse transcriptase activities with the EC50 values in range of 0.12-8.69 µM. These results suggest that appropriate and reasonable consumption of the fruits of M. zapota might assist people to prevent and reduce the occurrence of inflammatory diseases together with the infection of HIV. Furthermore, the discovery of these prenylated coumarins from the fruits of M. zapota holding pronounced anti-inflammatory effects along with anti-HIV activities could be of great significance to the research and development of new natural anti-inflammatory and anti-HIV agents.


Assuntos
Fármacos Anti-HIV/química , Anti-Inflamatórios/química , Cumarínicos/química , Manilkara/química , Extratos Vegetais/química , Animais , Fármacos Anti-HIV/isolamento & purificação , Fármacos Anti-HIV/farmacologia , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , China , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Frutas/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Estrutura Molecular , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Prenilação , Células RAW 264.7
17.
ACS Appl Mater Interfaces ; 11(43): 39513-39524, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31599562

RESUMO

Cancer immunotherapy can enhance the antitumor effect of drugs through a combinatorial approach in a synergistic manner. However, the effective targeted delivery of various drugs remains a challenge. We generated a peptide assembling tumor-targeted nanodelivery system based on a breast cancer homing and penetrating peptide for the codelivery of a programmed cell death ligand 1 (PD-L1) small interfering RNA (siRNA) (siPD-L1) and an indoleamine 2,3-dioxygenase inhibitor as a dual blockade of an immune checkpoint. The vector is capable of specifically accumulating in the breast cancer tumor site in a way that allows the siRNA to escape from endosomal vesicles after being endocytosed by tumor cells. The drug within these cells then acts to block tryptophan metabolism. The results showed that locally released siPD-L1 and 1-methyl-dl-tryptophan favor the survival and activation of cytotoxic T lymphocytes, resulting in apoptosis of breast cancer cells. Therefore, this study provides a potential approach for treating breast cancer by blocking immunological checkpoints through the assembly of micelles with functional peptides.


Assuntos
Peptídeos Penetradores de Células , Inibidores Enzimáticos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Nanopartículas , RNA Interferente Pequeno , Triptofano/análogos & derivados , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacocinética , Peptídeos Penetradores de Células/farmacologia , Peptídeos Penetradores de Células/uso terapêutico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacocinética , RNA Interferente Pequeno/farmacologia , Triptofano/química , Triptofano/farmacocinética , Triptofano/farmacologia
18.
Bioorg Chem ; 92: 103278, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31541802

RESUMO

Clausena lansium (Lour.) Skeels is an evergreen small tree or shrub with great economic value, which belongs to the genus Clausena of the Rutaceae family. C. lansium is indigenous to Southern China, while currently widely cultivated in subtropical and tropical regions not only for the nutritional value and pharmacological uses of its fruits but also as a medicinal and ornamental plant. In this study, a systematic phytochemical study on the stems and leaves of C. lansium caused the separation and identification of two new geranylated carbazole alkaloids, clauselansiumines A (1) and B (2), as well as 10 known geranylated carbazole alkaloids (3-12). The chemical structures of these isolated geranylated carbazole alkaloids (1-12) were unambiguously determined based on comprehensive spectral data analyses. All these isolated geranylated carbazole alkaloids were tested for their neuroprotective effects against 6-hydroxydopamine induced cell death in human neuroblastoma SH-SY5Y cells in vitro. Compounds 1-12 displayed remarkable neuroprotective effects holding the EC50 values ranging from 0.48 ±â€¯0.04 to 12.36 ±â€¯0.16 µM. These research results disclosed that the separation and purification of these geranylated carbazole alkaloids possessing remarkable neuroprotective effects separated from C. lansium could be extremely important to the discovery of new agents for the treatment and prevention for Parkinson's disease.


Assuntos
Alcaloides/farmacologia , Carbazóis/farmacologia , Clausena/química , Fármacos Neuroprotetores/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Carbazóis/química , Carbazóis/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Folhas de Planta/química , Caules de Planta/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
19.
J Nanobiotechnology ; 17(1): 93, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481080

RESUMO

Exosomes (Exo) hold great promise as endogenous nanocarriers that can deliver biological information between cells. However, Exo are limited in terms of their abilities to target specific recipient cell types. We developed a strategy to isolate Exo exhibiting increased binding to integrin αvß3. Binding occurred through a modified version of a disintegrin and metalloproteinase 15 (A15) expressed on exosomal membranes (A15-Exo), which facilitated co-delivery of therapeutic quantities of doxorubicin (Dox) and cholesterol-modified miRNA 159 (Cho-miR159) to triple-negative breast cancer (TNBC) cells, both in vitro and in vivo. The targeted A15-Exo were derived from continuous protein kinase C activation in monocyte-derived macrophages. These cell-derived Exo displayed targeting properties and had a 2.97-fold higher production yield. In vitro, A15-Exo co-loaded with Dox and Cho-miR159 induced synergistic therapeutic effects in MDA-MB-231 cells. In vivo, miR159 and Dox delivery in a vesicular system effectively silenced the TCF-7 gene and exhibited improved anticancer effects, without adverse effects. Therefore, our data demonstrate the synergistic efficacy of co-delivering miR159 and Dox by targeted Exo for TNBC therapy.


Assuntos
Doxorrubicina/administração & dosagem , Doxorrubicina/química , Exossomos/química , MicroRNAs/administração & dosagem , MicroRNAs/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Camundongos , Células THP-1
20.
Bioorg Chem ; 91: 103107, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31344516

RESUMO

Twelve prenylated carbazole alkaloids, containing a novel prenylated carbazole alkaloid, named as clausevestine (1), and 11 known prenylated carbazole alkaloids (2-12), were isolated and identified from the stems and leaves of Clausena vestita, which is a Chinese endemic plant. The chemical structure of 1 was established by means of comprehensive spectroscopic data analyses and the known compounds were determined via comparing their NMR and MS data as well as optical rotation values with those reported in literature. Especially, clausevestine (1) is an unusual prenylated carbazole alkaloid possessing an unprecedented carbon skeleton holding 20 carbon atoms. The anti-inflammatory effects and antiproliferative activities of those isolated prenylated carbazole alkaloids were tested. Prenylated carbazole alkaloids 1-12 displayed remarkable inhibitory effects on NO (nitric oxide) production with IC50 values equivalent to that of the positive control (hydrocortisone). Meanwhile, prenylated carbazole alkaloids 1-12 exhibited remarkable antiproliferative activities against diverse human cancer cell lines in vitro holding the IC50 values ranging from 0.32 ±â€¯0.04 to 18.76 ±â€¯0.18 µM. These findings indicate that these prenylated carbazole alkaloids possessing remarkable anti-inflammatory effects and antiproliferative activities could be meaningful to the discovery of new anti-inflammatory and anti-tumor candidate drugs.


Assuntos
Alcaloides/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Carbazóis/farmacologia , Clausena/química , Óxido Nítrico/antagonistas & inibidores , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Carbazóis/química , Carbazóis/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Folhas de Planta/química , Células RAW 264.7 , Relação Estrutura-Atividade
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