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1.
Nat Nanotechnol ; 16(1): 104-113, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33437035

RESUMO

Tumour heterogeneity remains a major challenge in cancer therapy owing to the different susceptibility of cells to chemotherapy within a solid tumour. Cancer stem-like cells (CSCs), which reside in hypoxic tumour regions, are characterized by high tumourigenicity and chemoresistance and are often responsible for tumour progression and recurrence. Here we report a nanotherapeutic strategy to kill CSCs in tumours using nanoparticles that are co-loaded with the differentiation-inducing agent, all-trans retinoic acid, and the chemotherapeutic drug, camptothecin. All-trans retinoic acid is released under hypoxic conditions, leading to CSC differentiation in the hypoxic niche. In differentiating CSC, the reactive oxygen species levels increase, which then causes the release of camptothecin and subsequent cell death. This dual strategy enables controlled drug release in CSCs and reduces stemness-related drug resistance, enhancing the chemotherapeutic response. In breast tumour mouse models, treatment with the nanoparticles suppresses tumour growth and prevents post-surgical tumour relapse and metastasis.

2.
Chemosphere ; : 128637, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33097235

RESUMO

BACKGROUND: The adverse effects of TI exposure on pregnant women are still unclear, especially regarding the risk of gestational diabetes mellitus (GDM) Objective: We explored the association between maternal urinary Tl burden and the risk of GDM. METHODS: A subsample of 1789 pregnant women were enrolled who provided spot urine samples before the diagnostic 75-g oral glucose tolerance test. Urinary Tl concentration was measured using inductively coupled plasma mass spectrometry. Logistic regression and covariance analysis were carried out to estimate the association between Tl exposure and GDM risk. RESULTS: The median of urinary Tl concentration was 0.382 µg/L or 0.525 µg/g creatinine (CC-Tl). There were 437 (24.4%) participants who were diagnosed with GDM, and the urinary CC-Tl concentrations of pregnant women with GDM were higher than that of pregnant women without GDM [0.548 (0.402, 0.788) vs 0.518 (0.356, 0.724), p = 0.014]. After adjusting for the relevant covariates, an association between urinary Tl concentrations and GDM was found. In comparison to the pregnant women in the lowest quartile of urinary CC-Tl concentration, the pregnant women in the highest quartile had a higher risk of GDM [OR (95% CI) = 1.44 (1.03, 2.02), p-trend = 0.055]. If limited to the pregnant women without family history of diabetes, the results were still robust [OR (95% CI) = 1.59 (1.11, 2.30), p-trend = 0.012]. CONCLUSION: Urinary CC-Tl concentration was associated with GDM among Chinese pregnant women. Our findings provide evidence that moderately high Tl exposure may be a novel risk factor for pregnant women health.

3.
Sci Adv ; 6(41)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33036973

RESUMO

Pathological coagulation, a disorder of blood clotting regulation, induces a number of cardiovascular diseases. A safe and efficient system for the delivery of anticoagulants to mimic the physiological negative feedback mechanism by responding to the coagulation signal changes holds the promise and potential for anticoagulant therapy. Here, we exploit a "closed-loop" controlled release strategy for the delivery of recombinant hirudin, an anticoagulant agent that uses a self-regulated nanoscale polymeric gel. The cross-linked nanogel network increases the stability and bioavailability of hirudin and reduces its clearance in vivo. Equipped with the clot-targeted ligand, the engineered nanogels promote the accumulation of hirudin in the fibrous clots and adaptively release the encapsulated hirudin upon the thrombin variation during the pathological proceeding of thrombus for potentiating anticoagulant activity and alleviating adverse effects. We show that this formulation efficiently prevents and inhibits the clot formation on the mouse models of pulmonary embolism and thrombosis.

4.
J Cardiothorac Surg ; 15(1): 207, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738925

RESUMO

BACKGROUND: Although lobectomy with mediastinal lymph node dissection (MLND) is the first option for early-stage non-small cell lung cancer (NSCLC) patients, the time trends of MLND in stage IA NSCLC patients who undergo a lobectomy are not clear still. METHODS: We included stage IA NSCLC patients who underwent lobectomy or lobectomy with MLND between 2003 and 2013 in the SEER database. The time trend of MLND was compared among patients who underwent a lobectomy. RESULTS: For stage T1a patients, the lobectomy group and lobectomy with MLND group had no differences in postoperative overall survival (OS) (P = 0.34) or lung-cancer specific survival (LCSS) (P = 0.18) between 2003 and 2013. For stage T1b patients, the OS (P = 0.01) and LCSS (P = 0.01) were different between the lobectomy group and the lobectomy with MLND group in the period from 2003 to 2009; however, only OS (P = 0.04), not LCSS (P = 0.14), was different between the lobectomy group and the lobectomy with MLND group between 2009 and 2013. For T1c patients, the OS (P = 0.01) and LCSS (P = 0.02) were different between the two groups between 2003 and 2009 but not between 2009 and 2013 (P = 0.60; P = 0.39). From the Cox regression analysis, we found that the factors affecting OS/LCSS in T1b and T1c patients were age, sex, year of diagnosis, histology, and grade, in which year of diagnosis was the obvious factor (HR = 0.79, CI = 0.71-0.87; HR = 0.73, CI = 0.64-0.84). CONCLUSIONS: There was a time trend in prognosis differences between the lobectomy group and lobectomy with MLND group for T1b and T1c stage NSCLC patients.

5.
Steroids ; 162: 108697, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32682814

RESUMO

An efficient and concise synthesis of 2-methoxyestradiol (4) from 17ß-estradiol (1) has been achieved in three synthetic steps with a 63.3% overall yield. The key step was the palladium-catalyzed direct C(sp2)-H methoxylation of 2-aryloxypyridines. Using 2-pyridyloxyl as the directing group, Pd(OAc)2 as the catalyst, PhI(OAc)2 as the oxidant and methanol as both the methoxylation reagent and solvent, the methoxy group could be handily installed at the 2-position of 3-(2-pyridoxy) estradiol (2). Subsequently, the pyridyl group could be easily removed by nucleophilic substitution with a methoxy anion after being oxidized to a pyridyl N-oxide by m-chloroperoxybenzoic acid, delivering the target product 2-methoxyestradiol (4) in quantitative yield. In contrast, when the pyridyl directing group was removed by the TfOMe-NaOMe/MeOH system as reported in the literature, TfOMe inevitably methylated the 17-OH of 2-methoxy-3-(2-pyridoxy) estradiol (3). In effect, we have fortuitously found a new method to cleave the pyridyl directing group, which is highly suitable for substrates bearing hydroxy groups.

6.
Mini Rev Med Chem ; 2020 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-32727325

RESUMO

In recent decades, much attention has been given to cyclopropyl scaffolds, which commonly exist in natural products and synthetic organic molecules. Clinical drug molecules with cyclopropyl rings are an area of focus in therapeutic research due to its interesting chemical properties and unique pharmacology activity. These molecular drugs against different targets are applicable in some therapeutic treatment fields including cancer, infection, respiratory disorder, cardiovascular and cerebrovascular diseases, dysphrenia, nervous system disorders, endocrine and metabolic disorders, skin disease, digestive disorders, urogenital diseases, otolaryngological and dental diseases, and eye diseases. This review is a guide for pharmacologists who are in search of valid preclinical/clinical drug compounds where the progress, from 1961 to the present day, of approved marketed drugs containing cyclopropyl scaffold is examined.

7.
Am J Hum Genet ; 107(1): 34-45, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32497488

RESUMO

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.


Assuntos
Artrogripose/genética , Mutação/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica/genética , Humanos , Ceratose/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Adulto Jovem
8.
Mol Immunol ; 123: 106-115, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32485469

RESUMO

Hepatocytes are the targets in autoimmune hepatitis (AIH) that results in T cell-dependent liver injury. However, hepatocytes may also affect the hepatic T cells in AIH, but the underlying mechanisms are not fully understood. Here we report that hepatocytes could secrete galectin-9 (Gal-9) to suppress the intrahepatic production of Th1 cytokine IFN-γ and restrict AIH development, but hepatocyte damage resulted in opposite effects due to release of TLR2/4 ligands that promoted the intrahepatic production of IL-1ß, IL-6, and IL-12. Through Tim-3, Gal-9 could efficiently suppress the intrahepatic T cell activation despite presence of TLR2/4 ligands, thus attenuating Th1 response in AIH. Intriguingly, intrahepatic IL-6/IL-12 suppressed the effect of TGF-ß on Treg cells. Therefore, in AIH, Gal-9 promoted Foxp3 expression and function of hepatic Treg cells through TL1A signaling, although Treg function was still impaired, compared with that in naive state. Due to its promoting effect on Treg function, together with its effect on T effector cells in a Tim-3-independent way, Gal-9 could attenuate intrahepatic IFN-γ production by hindering the increase of hepatic CD4+CD43+ T cells resulting from extrahepatic T cell activation. TLR2/4 ligands attenuated the effects of Gal-9 on Treg cells and CD4+CD43+ T cells by increasing intrahepatic IL-6 and IL-12. Blocking TLR2/4 ligands could efficiently suppress intrahepatic IFN-γ production, liver injury, and hepatic fibrosis. These findings suggest that hepatocytes paradoxically affect Th1 response in AIH due to Gal-9 expression and TLR2/4 ligands release, and that targeting TLR2/4 signaling may provide an important approach in the therapeutic strategy for AIH.


Assuntos
Galectinas/metabolismo , Hepatite Autoimune/metabolismo , Hepatócitos/fisiologia , Interferon gama/metabolismo , Fígado/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Células Cultivadas , Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Ligantes , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Células Th1/imunologia , Células Th1/metabolismo
9.
Sensors (Basel) ; 20(8)2020 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-32290518

RESUMO

A challenging rescue task for the underground disaster is to guide survivors in getting away from the dangerous area quickly. To address the issue, an escape guidance path developing method is proposed based on anisotropic underground wireless sensor networks under the condition of sparse anchor nodes. Firstly, a hybrid channel model was constructed to reflect the relationship between distance and receiving signal strength, which incorporates the underground complex communication characteristics, including the analytical ray wave guide model, the Shadowing effect, the tunnel size, and the penetration effect of obstacles. Secondly, a trustable anchor node selection algorithm with node movement detection is proposed, which solves the problem of high-precision node location in anisotropic networks with sparse anchor nodes after the disaster. Consequently, according to the node location and the obstacles, the optimal guidance path is developed by using the modified minimum spanning tree algorithm. Finally, the simulations in the 3D scene are conducted to verify the performance of the proposed method on the localization accuracy, guidance path effectiveness, and scalability.

10.
Biomater Sci ; 8(9): 2344-2365, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32254876

RESUMO

Nanomedicine has huge potential in cancer therapy due to its advantages of improving the solubility, increasing the bioavailability and reducing the side effects of anticancer drugs. However, the intratumoral accumulation of anticancer nanomedicine is still extremely low owing to multiple physiological barriers to drug delivery; thus, it is inefficient for cancer treatments. Inspired by the communication between natural cells and the body environment, living cell-based anticancer therapeutics have been developed as promising drug carriers or active drugs for cancer therapy. In this review, we will survey recent advances in living cell-based anticancer therapeutics by leveraging their physiological characteristics, from long circulating properties to tumor-homing capacity and anticancer immune responses. In addition, future prospects of this field will be discussed.

11.
Nano Lett ; 20(3): 1542-1551, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32039606

RESUMO

Neuroinflammation plays a pivotal part in the pathogenesis of stroke. Orphan nuclear receptor NR4A1 is involved in the inflammatory response of microglia and macrophages. In this study, we discovered an old drug, 9-aminoacridine (9-AA), as a novel NR4A1 activator from our in-house FDA-approved drug library, which exhibited anti-inflammatory activities through an NR4A1/IL-10/SOCS3 signaling pathway and modulated the microglia activation. To improve the druggability of 9-AA, different liposomal formulations were screened and investigated. 9-AA-loaded liposome (9-AA/L) was prepared to reduce the adverse effect of 9-AA. Furthermore, 9-AA-loaded PEG/cRGD dual-modified liposome (9-AA/L-PEG-cRGD) was obtained, which displayed prolonged circulation, improved biodistribution, and increased brain accumulation. In the transient middle cerebral artery occlusion (tMCAO) rat model, 9-AA/L-PEG-cRGD significantly reduced brain infarct area, ameliorated ischemic brain injury, and promoted long-term neurological function recovery. This "from drug discovery to drug delivery" methodology provides a potential therapeutic strategy using the liposomal 9-AA, the NR4A1 activator to suppress neuroinflammation for treatment of ischemic stroke.

12.
Nat Commun ; 11(1): 460, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974363

RESUMO

Recent interest in the control of bone metabolism has focused on a specialized subset of CD31hiendomucinhi vessels, which are reported to couple angiogenesis with osteogenesis. However, the underlying mechanisms that link these processes together remain largely undefined. Here we show that the zinc-finger transcription factor ZEB1 is predominantly expressed in CD31hiendomucinhi endothelium in human and mouse bone. Endothelial cell-specific deletion of ZEB1 in mice impairs CD31hiendomucinhi vessel formation in the bone, resulting in reduced osteogenesis. Mechanistically, ZEB1 deletion reduces histone acetylation on Dll4 and Notch1 promoters, thereby epigenetically suppressing Notch signaling, a critical pathway that controls bone angiogenesis and osteogenesis. ZEB1 expression in skeletal endothelium declines in osteoporotic mice and humans. Administration of Zeb1-packaged liposomes in osteoporotic mice restores impaired Notch activity in skeletal endothelium, thereby promoting angiogenesis-dependent osteogenesis and ameliorating bone loss. Pharmacological reversal of the low ZEB1/Notch signaling may exert therapeutic benefit in osteoporotic patients by promoting angiogenesis-dependent bone formation.


Assuntos
Neovascularização Fisiológica/fisiologia , Osteogênese/fisiologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/farmacologia , Idoso , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/farmacologia , Células Endoteliais/metabolismo , Epigênese Genética , Feminino , Humanos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Neovascularização Fisiológica/genética , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Osteoporose/terapia , Ovariectomia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
13.
J Pediatr Hematol Oncol ; 42(8): 488-494, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31162296

RESUMO

BACKGROUND: Primary cardiac tumors in children are extremely rare. This study aimed to analyze clinical treatment and follow-up of pediatric primary cardiac tumors. PATIENTS AND METHODS: We performed a retrospective analysis by searching the medical records of 75 patients diagnosed with pediatric primary cardiac tumors from June 2005 to August 2017 in our institution. We followed operative patients every half year in the first postoperative year and then at least every year. If the patients had no serious symptoms or hemodynamic changes, they received nonoperative management and were followed regularly every year. RESULTS: Nineteen patients underwent surgery at our department for serious symptoms and critical hemodynamic changes. Four patients had postoperative complications. Two died of low cardiac output syndrome and arrhythmia after surgery. One patient with myxomas had tumor recurrence and one had been found of another rhabdomyoma after surgery. The other 14 patients recovered well. Fifty-six patients had nonoperative management. Four were lost in follow-up. Two patients with malignant tumors died of unknown causes after discharge. The remaining patients had no severe symptoms or tumor growth during follow-up. CONCLUSIONS: Clinical treatment of pediatric primary cardiac tumors should be performed individually. Most pediatric primary cardiac tumors are benign, and spontaneous regression is possible, especially for rhabdomyomas. The principle purpose of surgical treatment is to restore normal hemodynamics and protect important structures and cardiac tissue.

14.
Future Med Chem ; 11(22): 2919-2973, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31702389

RESUMO

Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure-activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.


Assuntos
Triazóis/química , Quimera/metabolismo , Proteólise , Relação Estrutura-Atividade , Ubiquitinação
15.
Theranostics ; 9(25): 7889-7905, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695806

RESUMO

Cancer immunotherapy aims to utilize the host immune system to kill cancer cells. Recent representative immunotherapies include T-cell transfer therapies, such as chimeric antigen receptor T cell therapy, antibody-based immunomodulator therapies, such as immune checkpoint blockade therapy, and cytokine therapies. Recently developed therapies leveraging engineered cells for immunotherapy against cancers have been reported to enhance antitumor efficacy while reducing side effects. Such therapies range from biologically, chemically and physically -engineered cells to bioinspired and biomimetic nanomedicines. In this review, advances of engineering cells for cancer immunotherapy are summarized, and prospects of this field are discussed.


Assuntos
Neoplasias/imunologia , Neoplasias/terapia , Animais , Anticorpos/imunologia , Biomimética/métodos , Humanos , Imunoterapia/métodos , Nanomedicina/métodos , Linfócitos T/imunologia
17.
Small ; 15(40): e1902998, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31441204

RESUMO

Nanocarrier-mediated codelivery of multiple anticancer drugs is a potential strategy for enhanced efficacy of combination cancer treatment by unifying differential pharmacokinetic properties and maintaining an optimal ratio of drug cargoes. However, a programmable codelivery system is highly desired to deliver different therapeutics to their specific sites of action to pursue maximized combinational effect. Herein a liposome-based nanoassembly (p53/C-rNC/L-FA) is developed for intracellular site-specific delivery of an apoptotic protein cytochrome c (CytoC) and a plasmid DNA encoding tumor-suppressing p53 protein (p53 DNA). p53/C-rNC/L-FA consists of an acid-activated fusogenic liposomal membrane shell modified with folic acid (L-FA) and a DNA/protein complex core assembled by the p53 DNA, protamine and CytoC-encapsulated redox-responsive nanocapsule (C-rNC). Intratumoral and intraendosomal acidities promote membrane fusion between liposome and biomembrane, resulting in release of the encapsulated p53/C-rNC complex into the cytoplasm. The cytoplasmic reduction causes degradation of C-rNC with release of CytoC that induces tumor cell apoptosis. The p53 DNA is transported into the nucleus by the aid of the cationic protamine and thus generates expression of the p53 protein that enhances apoptosis combined with CytoC. p53/C-rNC/L-FA is demonstrated to significantly induce tumor cell apoptosis and inhibit tumor growth in the orthotopic breast tumor mouse model.


Assuntos
Apoptose , Citocromos c/uso terapêutico , Genes Supressores de Tumor , Neoplasias/terapia , Animais , Antineoplásicos/farmacologia , Sobrevivência Celular , DNA/metabolismo , Feminino , Fluorescência , Ácido Fólico/química , Humanos , Lipossomos , Células MCF-7 , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanocápsulas/química , Imagem Óptica , Tamanho da Partícula , Protaminas/química , Ratos Sprague-Dawley , Eletricidade Estática , Distribuição Tecidual , Proteína Supressora de Tumor p53/metabolismo
18.
Nat Nanotechnol ; 14(8): 799-809, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263194

RESUMO

A tumour microenvironment imposes barriers to the passive diffusion of molecules, which renders tumour penetration an unresolved obstacle to an effective anticancer drug delivery. Here, we present a γ-glutamyl transpeptidase-responsive camptothecin-polymer conjugate that actively infiltrates throughout the tumour tissue through transcytosis. When the conjugate passes on the luminal endothelial cells of the tumour blood vessels or extravasates into the tumour interstitium, the overexpressed γ-glutamyl transpeptidase on the cell membrane cleaves the γ-glutamyl moieties of the conjugate to generate positively charged primary amines. The resulting cationic conjugate undergoes caveolae-mediated endocytosis and transcytosis, which enables transendothelial and transcellular transport and a relatively uniform distribution throughout the tumour. The conjugate showed a potent antitumour activity in mouse models that led to the eradication of small solid tumours (~100 mm3) and regression of large established tumours with clinically relevant sizes (~500 mm3), and significantly extended the survival of orthotopic pancreatic tumour-bearing mice compared to that with the first-line chemotherapeutic drug gemcitabine.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , gama-Glutamiltransferase/metabolismo , Animais , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/metabolismo , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Portadores de Fármacos/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Neoplasias/metabolismo , Polímeros/metabolismo , Transcitose
19.
Steroids ; 146: 99-103, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30951759

RESUMO

A four-step route for the synthesis of 2-methoxyestradiol (5) starting from 17ß-estradiol (1) has been achieved with a 51% overall yield. The key step was the ruthenium-catalyzed ortho-C(sp2)-H bond hydroxylation of aryl carbamates. Using dimethyl carbamate as the directing group, [RuCl2(p-cymene)]2 as the catalyst, PhI(OAc)2 as the oxidant and trifluoroacetate/trifluoroacetic anhydride (1:1) as the co-solvent, the hydroxyl group could be singly installed at the 2-position of 3-dimethylcarbamoyloxyestradiol (2) with 65% yield. Subsequent methylation of hydroxy and removal of dimethyl carbamate afforded 2-methoxyestradiol (5).


Assuntos
2-Metoxiestradiol/química , 2-Metoxiestradiol/síntese química , Carbono/química , Estradiol/química , Hidrogênio/química , Técnicas de Química Sintética , Hidroxilação
20.
Mol Microbiol ; 111(1): 145-158, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30338872

RESUMO

Campylobacter jejuni is the leading cause of foodborne gastrointestinal illness worldwide, and chemotaxis plays an important role in its host colonization and pathogenesis. Although many studies on chemotaxis have focused on the physical organization and signaling mechanism of the system's protein complex, much less is known about the transcriptional regulation of its components. Here, we describe two novel regulators, CJJ81176_0275 and CJJ81176_0276 (designated as CheP and CheQ), which specifically activate the transcription of the chemotaxis core genes cheV, cheA and cheW in C. jejuni and they are also essential for chemotactic responses. CheP has a single HD-related output domain (HDOD) domain and can promote CheQ binding to the cheVAW operon promoter through a protein-protein interaction. Mutagenesis analyses identified key residues critical for CheP function and/or interaction with CheQ. Further structural characterization of CheQ revealed a novel fold with strong positive surface charges that allow for its DNA binding. These findings reveal the gene regulatory mechanism of the chemotaxis system in an important bacterial pathogen and provide potential anti-virulence targets for campylobacteriosis treatment. In addition, ChePQ is an example of how proteins with the widespread but functionally obscure HDOD can coordinate with a signal output DNA-binding protein/domain to regulate the expression of important signaling pathways.


Assuntos
Proteínas de Bactérias/metabolismo , Campylobacter jejuni/genética , Quimiotaxia , Regulação Bacteriana da Expressão Gênica , Genes Reguladores , Óperon , Proteínas de Bactérias/genética , Campylobacter jejuni/fisiologia , Análise Mutacional de DNA , Mapeamento de Interação de Proteínas
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