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1.
Front Plant Sci ; 14: 1225897, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37767292

RESUMO

Watermelon (Citrullus lanatus) is susceptible to wilt disease caused by Fusarium oxysporum f. sp niveum (FON). AMF colonization alleviates watermelon wilt and regulates the composition of root exudates, but the effects of mycorrhizal watermelon root exudates on watermelon Fusarium wilt is not well understood. Root exudates of watermelon inoculated with AMF (Funeliformis mosseae or Glomus versiformme) were collected in this study. Then the root exudates of control plants and mycorrhizal plants were used to irrigate watermelon in continuous cropping soil, respectively. Meanwhile, the watermelon growth, antioxidant enzyme activity, rhizosphere soil enzyme activities and bacterial community composition, as well as the control effect on FON were analyzed. The results indicated that mycorrhizal watermelon root exudates promoted the growth of watermelon seedlings and increased soil enzyme activities, actinomyces, and the quantity of bacteria in rhizosphere soil. The proportion of Proteobacteria and Bacteroides was decreased, and the proportion of Actinobacteria, Firmicutes, and Chloroflexi in rhizosphere soil was increased when the seedlings were watered with high concentrations of mycorrhizal root exudates. The dominant bacterial genera in rhizosphere soil were Kaistobacter, Rhodanobacter, Thermomonas, Devosia, and Bacillus. The root exudates of mycorrhizal watermelon could reduce the disease index of Fusarium wilt by 6.7-30%, and five ml/L of watermelon root exudates inoculated with F. mosseae had the strongest inhibitory effect on watermelon Fusarium wilt. Our results suggest mycorrhizal watermelon root exudates changed the composition of bacteria and soil enzyme activities in rhizosphere soil, which increase the resistance of watermelon to Fusarium wilt and promoted the growth of plants in continuous cropping soil.

2.
Cancer Med ; 12(13): 13991-14003, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37211956

RESUMO

BACKGROUND: KRT80 is a human epithelial intermediate filament type II gene; its expression product is a component of intracellular intermediate filaments (IFs) and is involved in the assembly of the cytoskeleton. There is evidence that IFs form a dense network mainly in the perinuclear area, but they can also reach the cortex. They are essential for mechanical cushioning of cells, organelle positioning, cell apoptosis, migration, adhesion, and interactions with other cytoskeletal components. Humans possess 54 functional keratin genes, and KRT80 is one of the more unique genes. It is widely expressed in almost all epithelial cells, although it is structurally more similar to type II hair keratins than to type II epithelial keratins. AIM: In this review, we summarize the basic facts about the keratin family and KRT80, the essential role of KRT80 in neoplasms, and its potential as a therapeutic target. We hope that this review will inspire researchers to at least partially focus on this area. RESULT: In many neoplastic diseases, the high expression status of KRT80 and its role in regulating the biological functions of cancer cells have been well established. KRT80 can effectively enhance the proliferation, invasiveness and migration of cancer cells. However, the effects of KRT80 on prognosis and clinically relevant indices in patients with various cancers have not been extensively studied, and even opposite conclusions have been reached in different studies of the same cancer. Based on this, we should add more clinically relevant studies to clarify the prospect of clinical application of KRT80. Many researchers have made great progress in studying the mechanism of action of KRT80. However, their studies should be extended to more cancers to find common regulators and signaling pathways of KRT80 in different cancers. KRT80 may have far-reaching effects on the human body, and this marker may play a crucial role in the function of cancer cells and the prognosis of cancer patients, so it has a promising future in the field of neoplasms. CONCLUSION: In neoplastic diseases, KRT80 is overexpressed in many cancers and plays an essential role in promoting proliferation, migration, invasiveness and poor prognosis. The mechanisms of KRT80 functions in cancer have been partially elucidated, suggesting that KRT80 is a potentially useful cancer therapeutic target. However, more systematic, in-depth and comprehensive studies are still needed in this field.


Assuntos
Neoplasias , Humanos , Citoesqueleto/metabolismo , Células Epiteliais/metabolismo , Queratinas/genética , Queratinas/metabolismo , Neoplasias/genética , Neoplasias/metabolismo
3.
Journal of Clinical Hepatology ; (12): 2839-2844, 2023.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-1003274

RESUMO

ObjectiveTo investigate the value of combined determination of Model for End-Stage Liver Disease (MELD) score, albumin-bilirubin (ALBI) score, and β2-microglobulin in the diagnosis of liver cirrhosis with acute kidney injury (AKI). MethodsClinical data were collected from 258 patients with liver cirrhosis who attended The First Affiliated Hospital of Zhengzhou University from October 2019 to October 2022, and according to the presence or absence of AKI, they were divided into AKI group with 117 patients and non-AKI group with 141 patients. The changes in each index were compared between the two groups and between the patients with different stages of kidney injury. The independent samples t-test was used for comparison of normally distributed continuous data between two groups, and a one-way analysis of variance was used for comparison between multiple groups; the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups, and the Kruskal-Wallis H test was used for comparison between multiple groups; the chi-square test was used for comparison of categorical data between groups. The receiver operating characteristic (ROC) curve was plotted to evaluate the efficacy of each index in the diagnosis of liver cirrhosis with AKI. ResultsCompared with the non-AKI group, the AKI group had significantly higher age (t=2.307, P=0.022), proportion of patients with hepatic encephalopathy (χ2=18.064, P<0.001) or with spontaneous peritonitis (χ2=16.397, P<0.001), mortality rate (χ2=45.251, P<0.001), levels of creatinine (Z=-8.737, P<0.001) and β2-microglobulin (Z=-8.829, P<0.001), and scores of CTP (Z=-4.058, P<0.001), ALBI (t=2.563, P=0.011), and MELD (Z=-5.628, P<0.001), as well as a significantly shorter length of hospital stay (Z=-3.391, P=0.001). There were significant differences in creatinine, β2-microglobulin, MELD score, and ALBI score between the patients with stage 1, 2 or 3 AKI (P<0.05), while there was no significant difference in CTP score between these three groups (P>0.05). The combined determination of ALBI score, MELD score, and β2-microglobulin had an area under the ROC curve (AUC) of 0.837 (95% confidence interval [CI]: 0.782 — 0.892), with a sensitivity of 75.2% and a specificity of 90.8%; ALBI score combined with MELD score had an AUC of 0.700 (95%CI: 0.636 — 0.764), ALBI score combined with β2 microglobulin had an AUC of 0.823 (95%CI: 0.765 — 0.881), and MELD combined with and β2 microglobulin had an AUC of 0.835 (95%CI: 0.779 — 0.890), suggesting that combined determination of ALBI score, MELD score, and β2-microglobulin had a better diagnostic efficacy than ALBI score, MELD score, or β2-microglobulin used alone or in pairs, as well as a better diagnostic efficacy than creatinine. ConclusionCombined determination of ALBI score, MELD score, and β2-microglobulin has a relatively high value in the diagnosis of liver cirrhosis with AKI.

4.
China Tropical Medicine ; (12): 289-2023.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-979632

RESUMO

@#Abstract: Objective The purpose of this study is to find out the epidemiological and clinical characteristics of male patients with condyloma acuminatum (CA) in Liaocheng area, as well as to improve the understanding of human papillomavirus (HPV) infection and put forward targeted prevention and treatment measures. Methods The clinical data of 159 male CA patients who admitted to Liaocheng People's Hospital from January 2021 to January 2022 were collected, and the epidemiological characteristics, clinical manifestations, infection sites, HPV gene subtypes and other information were analyzed retrospectively. Results Most of the 159 CA patients (range from 15 to 77 years old) were 31-40 years old (31.45%, 50/159), more than half of them had smoking history, and more than 60% had low income (<5 000 yuan/month), multiple sexual partners (≥2) and no condom use habit, 70.44% of the patients had prepuce long combined with prepuce balanitis. 91 cases (57.23%) were single infection, 102 cases (64.15%) were simple low-risk HPV infection. The analysis of risk factors between mixed infection and simple low-risk infection found statistically significant differences in age≤ 40 years old, unmarried, or less affected by education duration of 15 years or less, engaged in the business or service industry, the number of sexual partners or 2, knew not to clean and not to use condoms, while differences in smoking history, alcohol history, monthly income level, and age at first sexual intercourse were not statistically significant. Low-risk HPV6 and/or HPV11 were detected in 139 cases (87.42%). Fifty-seven patients (35.85%) were infected with at least one high-risk HPV. 72.33% of the patients had multiple warts, and the most common sites were around the coronal sulcus and frenulum of the penis Conclusions The incidence of multiple infections and high-risk subtypes is high in male CA patients in Liaocheng area, and most of the patients have low income, low education level and multiple sexual partners. Strengthening the treatment and education follow-up of this population may contribute to the treatment and prognosis of male CA in this area.

5.
Exp Mol Med ; 54(12): 2135-2147, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36473936

RESUMO

PARPs play fundamental roles in multiple DNA damage recognition and repair pathways. Persistent nuclear PARP activation causes cellular NAD+ depletion and exacerbates cellular aging. However, very little is known about mitochondrial PARP (mtPARP) and poly ADP-ribosylation (PARylation). The existence of mtPARP is controversial, and the biological roles of mtPARP-induced mitochondrial PARylation are unclear. Here, we demonstrate the presence of PARP1 and PARylation in purified mitochondria. The addition of the PARP1 substrate NAD+ to isolated mitochondria induced PARylation, which was suppressed by treatment with the inhibitor olaparib. Mitochondrial PARylation was also evaluated by enzymatic labeling of terminal ADP-ribose (ELTA). To further confirm the presence of mtPARP1, we evaluated mitochondrial nucleoid PARylation by ADP ribose-chromatin affinity purification (ADPr-ChAP) and PARP1 chromatin immunoprecipitation (ChIP). We observed that NAD+ stimulated PARylation and TFAM occupancy on the mtDNA regulatory region D-loop, inducing mtDNA transcription. These findings suggest that PARP1 is integrally involved in mitochondrial PARylation and that NAD+-dependent mtPARP1 activity contributes to mtDNA transcriptional regulation.


Assuntos
NAD , Poli ADP Ribosilação , NAD/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases , Mitocôndrias/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo
6.
Cell Rep ; 41(4): 111529, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36288691

RESUMO

PARP13/ZAP (zinc-finger antiviral protein) acts against multiple viruses by promoting degradation of viral mRNA. PARP13 has four N-terminal zinc (Zn) fingers that bind CG-rich nucleotide sequences, a C-terminal ADP ribosyltransferase fold, and a central region with a fifth Zn finger and tandem WWE domains. The central PARP13 region, ZnF5-WWE1-WWE2, is implicated in binding poly(ADP-ribose); however, there are limited insights into its structure and function. We present crystal structures of ZnF5-WWE1-WWE2 from mouse PARP13 in complex with ADP-ribose and in complex with ATP. The crystal structures and binding studies demonstrate that WWE2 interacts with ADP-ribose and ATP, whereas WWE1 does not have a functional binding site. Binding studies with poly(ADP-ribose) ligands indicate that WWE2 serves as an anchor for preferential binding to the terminal end of poly(ADP-ribose) chains. The composite ZnF5-WWE1-WWE2 structure forms an extended surface to engage ADP-ribose chains, representing a distinctive mode of recognition that provides a framework for investigating the impact of poly(ADP-ribose) on PARP13 function.


Assuntos
Adenosina Difosfato Ribose , Poli Adenosina Difosfato Ribose , Camundongos , Animais , Adenosina Difosfato Ribose/metabolismo , Dedos de Zinco , ADP Ribose Transferases/metabolismo , RNA Mensageiro/genética , Antivirais , Zinco , Trifosfato de Adenosina
7.
IEEE Trans Netw Sci Eng ; 9(2): 467-480, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35582549

RESUMO

In comparison with individual testing, group testing is more efficient in reducing the number of tests and potentially leading to tremendous cost reduction. There are two key elements in a group testing technique: (i) the pooling matrix that directs samples to be pooled into groups, and (ii) the decoding algorithm that uses the group test results to reconstruct the status of each sample. In this paper, we propose a new family of pooling matrices from packing the pencil of lines (PPoL) in a finite projective plane. We compare their performance with various pooling matrices proposed in the literature, including 2D-pooling, P-BEST, and Tapestry, using the two-stage definite defectives (DD) decoding algorithm. By conducting extensive simulations for a range of prevalence rates up to 5%, our numerical results show that there is no pooling matrix with the lowest relative cost in the whole range of the prevalence rates. To optimize the performance, one should choose the right pooling matrix, depending on the prevalence rate. The family of PPoL matrices can dynamically adjust their construction parameters according to the prevalence rates and could be a better alternative than using a fixed pooling matrix.

8.
ACS Chem Biol ; 17(1): 17-23, 2022 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-34904435

RESUMO

Macrodomains are a class of conserved ADP-ribosylhydrolases expressed by viruses of pandemic concern, including coronaviruses and alphaviruses. Viral macrodomains are critical for replication and virus-induced pathogenesis; therefore, these enzymes are a promising target for antiviral therapy. However, no potent or selective viral macrodomain inhibitors currently exist, in part due to the lack of a high-throughput assay for this class of enzymes. Here we developed a high-throughput ADP-ribosylhydrolase assay using the SARS-CoV-2 macrodomain Mac1. We performed a pilot screen that identified dasatinib and dihydralazine as ADP-ribosylhydrolase inhibitors. Importantly, dasatinib inhibits SARS-CoV-2 and MERS-CoV Mac1 but not the closest human homologue, MacroD2. Our study demonstrates the feasibility of identifying selective inhibitors based on ADP-ribosylhydrolase activity, paving the way for the screening of large compound libraries to identify improved macrodomain inhibitors and to explore their potential as antiviral therapies for SARS-CoV-2 and future viral threats.


Assuntos
Antivirais/farmacologia , Ensaios de Triagem em Larga Escala/métodos , N-Glicosil Hidrolases/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , Dasatinibe/farmacologia , Domínios Proteicos , SARS-CoV-2/enzimologia
9.
Indian J Anaesth ; 65(2): 146-152, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33776090

RESUMO

BACKGROUND AND AIMS: Respiratory depression is a rare but serious complication during opioid administration. Therefore, early detection of signs of deterioration is paramount. The current standard of care of using manual intermittent respiratory rate (RR) measurement is labour intensive and inefficient. We evaluated a wireless sensor monitor, Aingeal (Renew Health Ltd, Ireland), to continuously monitor RR, heart rate (HR) and temperature compared to standard clinical measurements. METHODS: Patients who underwent major gynaecological operations and received postoperative opioid patient-controlled analgesia were recruited. Patients were connected to the sensor monitor via a central station software platform. The primary outcome was comparison of RR between sensor and nursing monitoring, with secondary outcomes being HR and temperature between two methods. Feedback from patients and healthcare providers was also collected. Bland-Altman analyses were used to compare the vital signs recorded in sensor against those in patient's electronic record. RESULTS: A total of 1121 hours of vital signs data were analysed. Bias for RR was -0.90 (95% confidence interval (CI): -9.39, 7.60) breaths/min between nursing and averaged sensor readings. Bias for heart rate was -1.12 (95% CI: -26.27, 24.03) and bias for temperature was 1.45 (95% CI: -5.67, 2.76) between the two methods. CONCLUSION: There is satisfactory agreement of RR measurements, as well as HR and temperature measurements, by the wireless sensor monitor with standard clinical intermittent monitoring with overall good user experience.

10.
Arch Microbiol ; 203(5): 2727-2733, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33646339

RESUMO

Nosema ceranae is the pathogen of nosemosis in the honey bee, which can bring great economic loss to apiculture. Chitin acts as a major component of the endospore of microsporidia and plays an essential role to form the bridges across the endospore. Here, Chitin Spore Coats (CSCs) of N. ceranae were successfully extracted by optimized hot alkaline treatment. SDS-PAGE and Calcofluor White Stain (CWS) staining indicated that the obtained CSCs were protein-free and the transmission electron microscopy analysis showed that CSCs performed the intact and loose chitin spore coats. Western blotting and indirect immunofluorescence analysis (IFA) demonstrated that CSCs could interact with three spore wall proteins (rNcSWP7, rNcSWP8, and rNcSWP12). Our method was effective to extract CSCs of N. ceranae and this could be very useful for screening spore wall proteins involved in endospore composition, which could be helpful to uncover the biological structure and pathogenesis of microsporidia.


Assuntos
Abelhas/microbiologia , Quitina/metabolismo , Proteínas Fúngicas/metabolismo , Nosema/metabolismo , Esporos Fúngicos/metabolismo , Animais , Parede Celular/química , Nosema/química
11.
RSC Adv ; 11(15): 8505-8515, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-35423368

RESUMO

The incidence of central nervous system (CNS) diseases is increasing with the aging population. However, it remains challenging to deliver drugs into the CNS because of the existence of a blood-brain barrier (BBB). Notably, rabies virus glycoprotein (RVG) peptides have been developed as delivery ligands for CNS diseases. So far, massive RVG peptide modified carriers have been reported, such as liposomes, micelles, polymers, exosomes, dendrimers, and proteins. Moreover, these drug delivery systems can encapsulate almost all small molecules and macromolecule drugs, including siRNA, microRNAs, DNA, proteins, and other nanoparticles, to treat various CNS diseases with efficient and safe drugs. In this review, targeted delivery systems with RVG peptide modified carriers possessing favorable biocompatibility and delivery efficiency are summarized.

12.
IEEE Trans Netw Sci Eng ; 8(3): 2170-2182, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35783009

RESUMO

The group testing approach, which achieves significant cost reduction over the individual testing approach, has received a lot of interest lately for massive testing of COVID-19. Many studies simply assume samples mixed in a group are independent. However, this assumption may not be reasonable for a contagious disease like COVID-19. Specifically, people within a family tend to infect each other and thus are likely to be positively correlated. By exploiting positive correlation, we make the following two main contributions. One is to provide a rigorous proof that further cost reduction can be achieved by using the Dorfman two-stage method when samples within a group are positively correlated. The other is to propose a hierarchical agglomerative algorithm for pooled testing with a social graph, where an edge in the social graph connects frequent social contacts between two persons. Such an algorithm leads to notable cost reduction (roughly 20-35%) compared to random pooling when the Dorfman two-stage algorithm is applied.

13.
Cell Death Dis ; 11(12): 1046, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311481

RESUMO

B-cell translocation gene 3 (BTG3) is a member of the antiproliferative BTG gene family and is a downstream target of p53. Here, we show that senescence triggered by BTG3 depletion was accompanied by a secretome enriched with cytokines, growth factors, and matrix-remodeling enzymes, which could promote angiogenesis and cell scattering in vitro. We present evidence that at least part of these activities can be explained by elevated HIF-1α activity. Mechanistically, the BTG3 C-terminal domain competes with the coactivator p300 for binding the HIF-1α transactivation domain. The angiogenic promoting effect of BTG3 knockdown was largely diminished upon co-depletion of HIF-1α, indicating that HIF-1α is a major downstream target of BTG3 in the control of angiogenesis. In vivo, ectopic expression of BTG3 suppresses angiogenesis in xenograft tumors; and syngenic tumor growth and metastasis were enhanced in Btg3-null mice. Moreover, analysis of clinical datasets revealed that a higher BTG3/VEGFA expression ratio correlates with improved patient survival in a number of cancer types. Taken together, our findings highlight the non-autonomous regulation of tumor microenvironment by BTG3 while suppressing tumor progression.


Assuntos
Proteínas de Ciclo Celular/deficiência , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Microambiente Tumoral , Proteínas Supressoras de Tumor/deficiência , Animais , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Proliferação de Células/genética , Senescência Celular , Fibroblastos/metabolismo , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Neoplasias/irrigação sanguínea , Neoplasias/genética , Neoplasias/patologia , Neovascularização Fisiológica , Ligação Proteica , Análise de Sobrevida , Microambiente Tumoral/genética , Proteínas Supressoras de Tumor/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
IEEE Trans Netw Sci Eng ; 7(4): 3279-3294, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37981959

RESUMO

In this paper, we conduct mathematical and numerical analyses for COVID-19. To predict the trend of COVID-19, we propose a time-dependent SIR model that tracks the transmission and recovering rate at time [Formula: see text]. Using the data provided by China authority, we show our one-day prediction errors are almost less than [Formula: see text]. The turning point and the total number of confirmed cases in China are predicted under our model. To analyze the impact of the undetectable infections on the spread of disease, we extend our model by considering two types of infected persons: detectable and undetectable infected persons. Whether there is an outbreak is characterized by the spectral radius of a [Formula: see text] matrix. If [Formula: see text], then the spectral radius of that matrix is greater than 1, and there is an outbreak. We plot the phase transition diagram of an outbreak and show that there are several countries on the verge of COVID-19 outbreaks on Mar. 2, 2020. To illustrate the effectiveness of social distancing, we analyze the independent cascade model for disease propagation in a configuration random network. We show two approaches of social distancing that can lead to a reduction of the effective reproduction number [Formula: see text].

15.
Mol Cell ; 73(4): 845-856.e5, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30712989

RESUMO

ADP-ribosylation refers to the addition of one or more ADP-ribose groups onto proteins. The attached ADP-ribose monomers or polymers, commonly known as poly(ADP-ribose) (PAR), modulate the activities of the modified substrates or their binding affinities to other proteins. However, progress in this area is hindered by a lack of tools to investigate this protein modification. Here, we describe a new method named ELTA (enzymatic labeling of terminal ADP-ribose) for labeling free or protein-conjugated ADP-ribose monomers and polymers at their 2'-OH termini using the enzyme OAS1 and dATP. When coupled with various dATP analogs (e.g., radioactive, fluorescent, affinity tags), ELTA can be used to explore PAR biology with techniques routinely used to investigate DNA or RNA function. We demonstrate that ELTA enables the biophysical measurements of protein binding to PAR of a defined length, detection of PAR length from proteins and cells, and enrichment of sub-femtomole amounts of ADP-ribosylated peptides from cell lysates.


Assuntos
2',5'-Oligoadenilato Sintetase/metabolismo , ADP-Ribosilação , Adenosina Difosfato Ribose/metabolismo , Nucleotídeos de Desoxiadenina/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , 2',5'-Oligoadenilato Sintetase/genética , Animais , Células HeLa , Humanos , Ligação Proteica , Domínios Proteicos , Células Sf9 , Ubiquitina-Proteína Ligases/genética
16.
Bioorg Med Chem Lett ; 29(2): 216-219, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30503634

RESUMO

A131 (1) possesses a unique cancer cell selective dual mechanism of action where cancer cells are killed but normal cells only undergo growth arrest and are able to regrow after removal of 1. SAR studies of 1 indicate that only the specific structure of 1 elicits the full pharmacological effect. However, application of 1 in mouse models of cancer has been hampered by its low solubility and stability when given orally. In this work we describe the study of various prodrugs based on modification of the indole nitrogen. A range of acyl analogues were prepared as prodrugs which were shown to undergo degradation to the parent drug in plasma. A preferred prodrug fully elicited the pharmacological effects of 1 in cells and led to high aqueous solubility suitable for oral administration. In a mouse model of paclitaxel-resistant colon cancer, compound 10, as a TFA salt, showed 76% tumor growth inhibition when administered at an oral dose of 80 mg/kg twice a day.


Assuntos
Acrilonitrila/análogos & derivados , Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Indóis/farmacologia , Isoquinolinas/farmacologia , Pró-Fármacos/farmacologia , Acrilonitrila/administração & dosagem , Acrilonitrila/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/administração & dosagem , Isoquinolinas/administração & dosagem , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Paclitaxel/farmacologia , Pró-Fármacos/administração & dosagem , Solubilidade , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 156: 344-367, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30015072

RESUMO

Selective targeting of cancer cells over normal cells is a key objective of targeted therapy. However few approaches achieve true mechanistic selectivity resulting in debilitating side effects and dose limitation. In this work we describe the discovery of A131 (4a), a new agent with an unprecedented dual mechanism of action targeting both mitosis and autophagy. Compound 4a was first identified in a phenotypic screen in which HeLa cells treated with 4a manifested mitotic arrest along with formation of multiple vesicles. Further investigations showed that 4a causes an increase in mitotic marker pH3 and autophagy marker LC3. Importantly 4a induces cell death in cancer cells while sparing normal cells which regrow after 4a is removed. Dual activities against pH3 and LC3 markers are required for cancer cell selectivity. An extensive SAR investigation confirmed 4a as the optimal dual inhibitor with potency against a panel of 30 cancer cell lines (average antiproliferative GI50 1.5 µM). In a mouse model of paclitaxel-resistant colon cancer, 4a showed 74% tumor growth inhibition when administered at a dose of 20 mg/kg IP twice a day.


Assuntos
Acrilonitrila/análogos & derivados , Acrilonitrila/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Neoplasias/tratamento farmacológico , Acrilonitrila/farmacocinética , Acrilonitrila/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoquinolinas/farmacocinética , Isoquinolinas/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitose/efeitos dos fármacos , Neoplasias/metabolismo , Neoplasias/patologia , Ratos
18.
Proc Natl Acad Sci U S A ; 114(7): 1666-1671, 2017 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-28143925

RESUMO

Chikungunya virus (CHIKV), an Old World alphavirus, is transmitted to humans by infected mosquitoes and causes acute rash and arthritis, occasionally complicated by neurologic disease and chronic arthritis. One determinant of alphavirus virulence is nonstructural protein 3 (nsP3) that contains a highly conserved MacroD-type macrodomain at the N terminus, but the roles of nsP3 and the macrodomain in virulence have not been defined. Macrodomain is a conserved protein fold found in several plus-strand RNA viruses that binds to the small molecule ADP-ribose. Prototype MacroD-type macrodomains also hydrolyze derivative linkages on the distal ribose ring. Here, we demonstrated that the CHIKV nsP3 macrodomain is able to hydrolyze ADP-ribose groups from mono(ADP-ribosyl)ated proteins. Using mass spectrometry, we unambiguously defined its substrate specificity as mono(ADP-ribosyl)ated aspartate and glutamate but not lysine residues. Mutant viruses lacking hydrolase activity were unable to replicate in mammalian BHK-21 cells or mosquito Aedes albopictus cells and rapidly reverted catalytically inactivating mutations. Mutants with reduced enzymatic activity had slower replication in mammalian neuronal cells and reduced virulence in 2-day-old mice. Therefore, nsP3 mono(ADP-ribosyl)hydrolase activity is critical for CHIKV replication in both vertebrate hosts and insect vectors, and for virulence in mice.


Assuntos
Adenosina Difosfato Ribose/metabolismo , Vírus Chikungunya/metabolismo , N-Glicosil Hidrolases/metabolismo , Proteínas não Estruturais Virais/metabolismo , Aedes/virologia , Sequência de Aminoácidos , Animais , Animais Recém-Nascidos , Sítios de Ligação/genética , Linhagem Celular , Febre de Chikungunya/virologia , Vírus Chikungunya/genética , Vírus Chikungunya/patogenicidade , Chlorocebus aethiops , Insetos Vetores/virologia , N-Glicosil Hidrolases/genética , Homologia de Sequência de Aminoácidos , Especificidade por Substrato , Células Vero , Proteínas não Estruturais Virais/genética , Virulência/genética , Replicação Viral/genética
19.
PLoS One ; 11(2): e0147549, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26840596

RESUMO

To clarify the mechanisms of Nosema ceranae parasitism, we deep-sequenced both honey bee host and parasite mRNAs throughout a complete 6-day infection cycle. By time-series analysis, 1122 parasite genes were significantly differently expressed during the reproduction cycle, clustering into 4 expression patterns. We found reactive mitochondrial oxygen species modulator 1 of the host to be significantly down regulated during the entire infection period. Our data support the hypothesis that apoptosis of honey bee cells was suppressed during infection. We further analyzed genome-wide genetic diversity of this parasite by comparing samples collected from the same site in 2007 and 2013. The number of SNP positions per gene and the proportion of non-synonymous substitutions per gene were significantly reduced over this time period, suggesting purifying selection on the parasite genome and supporting the hypothesis that a subset of N. ceranae strains might be dominating infection.


Assuntos
Abelhas/microbiologia , Interações Hospedeiro-Patógeno , Microsporídios , Animais , Apoptose , Abelhas/genética , Perfilação da Expressão Gênica , Regulação Fúngica da Expressão Gênica , Genoma Fúngico , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imunidade/genética , Microsporídios/genética , Microsporídios/imunologia , Polimorfismo de Nucleotídeo Único , Interferência de RNA , Virulência/genética
20.
Int J Mol Sci ; 15(7): 11665-77, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24987951

RESUMO

Protein tyrosine kinase 7 (PTK7) has been studied in various tumors, but its role in prostate cancer remains unknown. This study is aimed to investigate the prognostic and predictive significance of PTK7 in patients with prostate cancer. PTK7 expression was evaluated by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis in 20 pairs of benign prostatic hyperplasia specimens and prostate cancer specimens. Then, we examined the immunohistochemical expression of PTK7 in 180 prostate cancer specimens and evaluated its clinical significances. Elevated PTK7 expression was significantly associated with lymph node metastases, seminal vesicle invasion, prostate cancer stage, the higher preoperative prostate-specific antigen, the higher Gleason score, angiolymphatic invasion, and biochemical recurrence. The results revealed that the overexpression of PTK7 in prostate cancer was an independent prognostic factor for poor overall survival and biochemical recurrence-free survival. The present data provide evidence that PTK7 predicts lymph node metastasis and poor overall survival and biochemical recurrence-free survival, highlighting its potential function as a therapeutic target for prostate cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Moléculas de Adesão Celular/metabolismo , Neoplasias da Próstata/diagnóstico , Receptores Proteína Tirosina Quinases/metabolismo , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Moléculas de Adesão Celular/genética , Humanos , Metástase Linfática/diagnóstico , Masculino , Receptores Proteína Tirosina Quinases/genética
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