18 research outputs found
Inhibitory effect of voluntary running wheel exercise on the growth of human pancreatic Panc-1 and prostate PC-3 xenograft tumors in immunodeficient mice
No full textIn the present study, we investigated the effect of voluntary exercise on the formation and growth of the human pancreas Panc-1 and prostate PC-3 tumors in immunodeficient mice.The present study demonstrated an inhibitory effect of voluntary exercise on the growth of pancreas and prostate tumors in a SCID mouse xenograft model.The present study was supported in part by grants from theNational Institutes of Health (CA 121391-01 and CA092268).The published version of this paper can be found at http://www.spandidos-publications.com/or/19/6/158
Ferramentas de identificação de espécies mais comuns de PANC no Estado do Rio de Janeiro
No full textAs Plantas Alimentícias não Convencionais (PANC) são aquelas que
possuem uma ou mais partes vegetativas e/ou reprodutivas com utilidade na
alimentação humana e capacidade de nutrição. O presente trabalho teve como
objetivo elaborar uma chave de identificação de 30 espécies de PANC mais
proeminentes encontradas no Estado do Rio de Janeiro. Acredita-se que uma
correta classificação permitirá a popularização das PANC e contribuirá para a
segurança e soberania alimentar. Dentre as famílias analisadas, as que
contaram com mais representantes foram: Asteraceae (4 espécies) e Fabaceae
(4 espécies), seguidas de Amaranthaceae (3 espécies) e Lamiaceae (2
espécies). O restante apresentou apenas uma espécie para cada família. Após
a triagem destas 30 espécies, foi feita a descrição morfológica de cada uma
(incluindo nome popular, nome científico, autor, família da planta, região de
endemismo). Em seguida foi feita a construção da chave de identificação
botânica e a construção de um glossário com ilustrações para complementar a
compreensão e identificação correta das plantas. Este estudo evidencia os
potenciais alimentícios das PANC e, em conjunto com o projeto de extensão
"Conhecendo outras plantas alimentícias (PANC-UFF)", funcionará como base
para a divulgação do conhecimento científico, dentro e fora da academia, e como
base para uma aplicativo de identificação destas plantas.Unconventional Food Plants (PANC) are those plants that have one or
more vegetative or reproductive parts with utility in human food and nutritional
capacity. The present work aimed to develop a botanical identification key for 30
most prominent PANC species found in the State of Rio de Janeiro. It is believed
that a correct classification will allow the popularization of PANC and also will
contribute to food security and sovereignty. Among the families analyzed, those
with the most representatives were: Asteraceae (4 species) and Fabaceae (4
species), followed by Amaranthaceae (3 species) and Lamiaceae (2 species).
The rest presented only one species for each family. After sorting, a
morphological description of each species was made (including popular name,
scientific name, author, plant family and region of endemism). Then, were made
the construction of the botanical identification key and the construction of a
glossary with illustrations to complement the understanding and correct
identification of the plants. This study, therefore, highlights the alimentary
potential of PANC and, together with the extension project "Conhecendo outras
plantas alimentícias (PANC-UFF)", will work as a basis for the dissemination of
scientific knowledge, inside and outside the academy, and as a basis for an
identification application of these plants.77 f
Oridonin nanosuspension was more effective than free oridonin on G2/M cell cycle arrest and apoptosis in the human pancreatic cancer PANC-1 cell line
No full textXiaoli Qi1, Dianrui Zhang2, Xia Xu1, Feifei Feng2, Guijie Ren1, Qianqian Chu1, Qiang Zhang3, Keli Tian11Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, 2Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan, 3State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of ChinaAbstract: Oridonin, a diterpenoid isolated from Rabdosia rubescencs, has been reported to have antitumor effects. However, low solubility has limited its clinical applications. Preparation of drugs in the form of nanosuspensions is an extensively utilized protocol. In this study, we investigated the anticancer activity of oridonin and oridonin nanosuspension on human pancreatic carcinoma PANC-1 cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to investigate the effect of oridonin on cell growth. Propidium iodide and Hoechst 33342 staining were used to detect morphologic changes. The percentage of apoptosis and cell cycle progression was determined by flow cytometric method staining with propidium iodide. Annexin V-fluorescein isothiocyanate (FITC)/PI staining was used to evaluate cell apoptosis by flow cytometry. Caspase-3 activity was measured by spectrophotometry. The apoptotic and cell cycle protein expression were determined by Western blot analysis. Both oridonin and oridonin nanosuspension induced apoptosis and G2/M phase cell cycle arrest, and the latter had a more significant cytotoxic effect. The ratio of Bcl-2/Bax protein expression was decreased and caspase-3 activity was stimulated. The expression of cyclin B1 and p-cdc2 (T161) was suppressed. Our results showed that oridonin nanosuspension was more effective than free oridonin on G2/M cell cycle arrest and apoptosis in the human pancreatic cancer PANC-1 cell line.Keywords: cyclin B1, cdc2, caspase-3, Bcl-2, Ba
PANC Study (Pancreatitis: A National Cohort Study):national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK
No full textBackgroundAcute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment.MethodsAll patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals.ResultsA total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death.ConclusionMost patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions.</div
Borax pentahydrate as a promising boron-based angiogenesis inhibitor
No full textBackground: Boron, a trace element, is involved in various physiological and metabolic processes, and recent studies suggest that boron compounds may have potential in cancer prevention and treatment. In this study, the antiangiogenic effects of a boron compound, borax pentahydrate (BPH), were investigated. Angiogenesis is a tightly regulated biological process responsible for the formation of new blood vessels from existing vasculatures. This process plays a critical role in cancer progression, making it an important target for cancer therapy. Pancreatic and kidney cancers are difficult to treat because they are aggressive and resistant to chemotherapy. Methods: The antiproliferative activity was evaluated using the MTT assay, while antiangiogenic effects were tested through in vitro tube formation assays and in ovo chick chorioallantoic membrane (CAM) assay. The effect of BPH on VEGF levels was determined using Western blot analysis in HUVEC, ACHN, PANC-1 cells. The effect of BPH on tumor angiogenesis was investigated with an in vivo Ehrlich ascites carcinoma model (EAC). Results: BPH exhibited potent antiproliferative and antiangiogenic activities, inhibiting the proliferation of ACHN, PANC-1, and HUVECs, disrupting endothelial tube formation, and inhibiting vascular formation on the CAM surface in a dose-dependent manner. VEGF levels were significantly decreased in ACHN, PANC-1 and HUVECs. There was also a decrease in VEGF and TGF-beta 1 levels in BPH-treated tumor groups. In addition, BPH caused a decrease in tumor size. Conclusion: These findings suggest that BPH may be a new antiangiogenic and antitumoral agent. BPH may contribute to drug development studies targeting angiogenesis-related diseases as a promising new therapeutic agent.Ministry of National Education of the Republic of TurkeyThis study was funded by Ministry of National Education of the Republic of Turkey. (Since the responsible author works as a teacher at the Ministry of National Education of the Republic of Turkey, she was financially supported for the realization of this project without any contract)
Role of type I Interferons in the treatment of endocrine and non-endocrine cancers
No full textGli interferoni (IFNi) costituiscono una complessa famiglia di citochine, individuate inizialmente per la loro capacità di conferire uno stato anti-virale alle cellule. Successivamente, altri effetti biologici sono stati attribuiti agli IFNi, tra i quali una potente attività anti-tumorale. In relazione al tipo di recettore con cui interagiscono, gli IFNi sono stati classificati in due gruppi: IFNi di tipo I (IFN-, -, - and -) e IFNi di tipo II (IFN-).
L’attività di ricerca svolta dal candidato durante il corso di Dottorato ha avuto come obiettivo quello di valutare l’efficacia in vitro dell’IFN- e IFN- in linee cellulari umane di tumore neuroendocrino del pancreas (BON), adenocarcinoma del pancreas (BxPC-3, MiaPaCa-2, Panc-1) e carcinoma del surrene (SW-13, H-295), e di analizzare i meccanismi d’azione ed il ruolo delle relative subunità recettoriali.
Gli effetti dell’IFN-2b e IFN-1a sulla proliferazione cellulare sono stati valutati tramite la quantificazione del DNA, rappresentativa del numero delle cellule, mediante determinazione fluorimetrica con il colorante fluorescente HoechstTM 33258. In tutte le linee cellulari che abbiamo testato, l’effetto inibitorio dell’IFN- risulta essere dose-dipendente e maggiore dell’IFN-. L’attività antitumorale dell’IFN- è prevalentemente dovuta all’arresto del ciclo cellulare, con accumulo delle cellule in fase S, evidenziato mediante lo studio dell’incorporazione di ioduro di propidio con la citometria a flusso (FACS). Mentre, l’IFN-, oltre ad indurre un ritardo di transizione delle cellule dalla fase S a G2M, ha un potente effetto stimolatorio sull’apoptosi in quasi tutte le linee cellulari esaminate. L’espressione dell’mRNA e delle proteine per le subunità recettoriali attive degli IFNi di tipo I (IFNAR-1 e IFNAR-2c) e’ stata identificata rispettivamente mediante RT-PCR quantitativa ed immunoistochimica in tutte le cellule esaminate. E’ interessante notare nelle linee cellulari di adenocarcinoma pancreatico le relazioni riscontrate tra la responsività alla terapia, l’espressione e la distribuzione delle due subunita’ recettoriali. L’analisi quantitativa alla RT-PCR dell’mRNA per IFNAR-1 e IFNAR-2c rivela una maggiore espressione nelle BxPC-3, la linea cellulare più sensibile agli IFNi di tipo I. L’immunoistochimica, oltre a confermare la superiore espressione del recettore nelle BxPC-3, evidenzia anche differenze nella localizzazione e distribuzione cellulare. Mentre nelle BxPC-3 le subunità IFNAR-1 e IFNAR-2c sono principalmente localizzate a livello della membrana cellulare, nelle Panc-1 (le cellule maggiormente resistenti alla terapia con IFN-/IFN-) il segnale è prevalentemente citoplasmatico, con una lieve positività membranosa. Pertanto, la maggiore sensibilità alla terapia con IFN nelle BxPC-3 potrebbe essere legata all’elevata espressione recettoriale, evidenziata prevalentemente a livello della membrana cellulare. L’IFN- sembra anche essere in grado di modulare l’espressione di importanti fattori di crescita tumorali. Infatti, nelle BON e H-295, cellule in grado di produrre grandi quantità di IGF-2, l’IFN- inibisce la trascrizione di tale fattore di crescita.
Infine, l’attività di ricerca è stata finalizzata all’identificazione di nuove strategie volte alla sensibilizzazione delle cellule tumorali all’azione dell’IFN-. L’IFN- a concentrazioni citostatiche aumenta l'espressione e la funzione del recettore per l'epidermal growth factor nelle cellule KB di carcinoma umano epidermoide, costituendo una risposta protettiva all'apoptosi indotta dall'IFN-. Abbiamo evidenziato che le cellule KB antagonizzano l'effetto antiproliferativo ed apoptotico dell'IFN- attraverso l'iperattivazione della cascata delle chinasi attivate da mitogeni (MAPK) dipendente da ras. Pertanto, il targeting selettivo di tale via metabolica potrebbe essere un valido strumento per eludere i meccanismi di resistenza all’IFN- attivati dalla cellula. Infatti, l’inibizione selettiva di ras, attraverso la trasfezione del dominante negativo di ras RASN17 nelle cellule KB, potenzia l'apoptosi indotta da IFN come determinato con analisi al FACS e tecnica TUNEL. Analogo potenziamento dell’attività apoptotica dell’IFN- è stato evidenziato dall’associazione con un inibitore selettivo di MEK-1 (PD 98059), a sua volta attivatore selettivo di ERK-1/2
Silencing of Astrocyte elevated gene-1 (AEG-1) inhibits proliferation, migration and invasion, and promotes apoptosis in pancreatic cancer cells
Get PDFTo investigate the role of Astrocyte elevated gene-1 (AEG-1) in the development and progress of pancreatic cancer, the short hairpin RNA (shRNA) was inserted into the RNA interference vector to knock down the endogenous AEG-1 in two pancreatic cancer cell lines, AsPC-1 and PANC-1. Our results showed that silencing of AEG-1 suppressed the proliferation, colony formation ability and cell stemness of AsPC-1 and PANC-1 cells, and inhibited their G1 to S phase transition. Results from apoptosis assay showed that knockdown of AEG-1 led to cell apoptosis. The expression of the anti-apoptotic Bcl-2 was downregulated and that of the pro-apoptotic Bax and cleaved Caspase-3 was upregulated in AEG-1-silenced pancreatic cancer cells. Further, the capability of AEG-1-silenced cells to migrate and to invade through the Matrigel-coated membrane was weaker, and the expression of matrix metallopeptidase 2 (MMP-2) and MMP-9 were decreased. Moreover, AKT/β-catenin signaling pathway was inhibited in these cells knockdown of AEG-1. In addition, the growth of xenograft tumors formed by AsPC-1 and PANC-1 cells was suppressed by AEG-1 shRNA. In conclusion, our study demonstrates that pancreatic cancer cells require AEG-1 to maintain their survival and metastasis, suggesting AEG-1 as a potential target for the treatment of pancreatic cancers.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author
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Small-Molecule Modulators of Pancreatic Ductal Cells: Histone Methyltransferases and -Cell Transdifferentiation
No full textSmall molecules are important not only for treating human diseases but also for studying disease-related biological processes. This dissertation focuses on the effects of small molecules on pancreatic ductal adenocarcinoma cells. Here, I describe the discovery of two small-molecule tool compounds and their applications for interrogating the biological processes related to two distinct diseases in the human pancreas. First, BRD4770 was identified as a histone methyltransferase inhibitor through a target-based biochemical approach, and was used as a probe to study the function of methyltransferases in cancer cells. Second, BRD7552 was discovered as an inducer of Pdx1 using a cell-based phenotypic screening approach, and was used to induce the expression of Pdx1, a master regulatory transcription factor required for -cell transdifferentiation. This compound is particularly interesting for the study of type-1 diabetes (T1D). The histone methyltransferase G9a catalyzes methylation of lysine 9 on histone H3, a modification linked to aberrant silencing of tumor-suppressor genes. The second chapter describes the collaborative effort leading to the identification of BRD4770 as a probe to study the function of G9a in human pancreatic cancer cells. BRD4770 induces cellular senescence and inhibits both anchorage-dependent and -independent proliferation in PANC-1 cell line, presumably mediated through ATM-pathway activation. Chapter three describes the study of a natural product gossypol, which significantly enhances the BRD4770 cytotoxicity in p53-mutant cells through autophagic cell death. The up-regulation of BNIP3 might be responsible for the synergistic cell death, suggesting that G9a inhibition may help overcome drug resistance in certain cancer cells. Ectopic overexpression of Pdx1, Ngn3, and MafA can reprogram pancreatic exocrine cells to insulin-producing cells in mice, which sheds light on a new avenue for treating T1D. The fourth chapter focuses on a gene expression-based assay using quantitative real-time PCR technique to screen >60,000 compounds for induction of one or more of these three transcription factors. A novel compound BRD7552 which up-regulated Pdx1 mRNA and protein levels in PANC-1 cells was identified. BRD7552 induces changes of the epigenetic markers within the Pdx1 promoter region consistent with transcriptional activation. Furthermore, BRD7552 partially complements Pdx1 in cell culture, enhancing the expression of insulin induced by the introduction of the three genes in PANC-1 cells. In summary, the central theme of my dissertation is to identify novel bioactive small molecules using different screening approaches, as well as to explore their effects in pancreatic ductal cells.Chemistry and Chemical Biolog
Зависимая от гипоксии экспрессия белка adam8 в клеточных линиях рака поджелудочной железы человека
No full textOne of the most characteristic features of malignant tissue is the high level of intratumoral hypoxia, which is considered as a powerful factor for induction of tumor aggressiveness and malignant progression. Pancreatic cancer (PC) is a near fatal disease with very unfavorable clinical outcome despite the application of different treatment regimes. It was shown that PC is characterized by high level of hypoxia. Aim: To clarify the correlation between tumor hypoxia and ADAM8 protein expression. Materials and Methods: ASPC-1, Panc-1, BxPC-3, Capan-1, MiaPaCa-2, Colo-357, Su8686 and T3M4 cell lines were used in the study. Expression of mRNA ADAM8 was evaluated by real-time quantitative polymerase chain reaction method. Immunoblot analysis was used to evaluate the expression of ADAM8 protein. Results: Hypoxia induced a 2.5–5.9-fold increase of ADAM8 mRNA levels of in the examined pancreatic cancer cell lines except Panc-1 (p = 0.046). On the protein level, hypoxia induced a 1.2–5.9-fold increase of the ADAM8 prodomain removal form (90 kDa) in 5/8 pancreatic cancer cells. Moreover, hypoxia induced a 1.3–2.0-fold increase of the remnant form ADAM8 (60 kDa) in 4/8 pancreatic cancer cell lines: Aspc-1, Colo-357, Panc-1, T3M4. Conclusion: It was observed the clear tendency in the increase both of ADAM8 mRNA and ADAM8 protein levels in pancreatic cancer cell lines under hypoxia compared to normal conditions of oxygenation. A potential role of ADAM8 as a hypoxia-dependent protein in the pathogenesis and evolution of pancreatic cancer that is characterized by high level of intratumoral hypoxia can be suggested.Введение: известно, что характерной чертой злокачественных опухолей является внутриопухолевая гипоксия, положительно
влияющая на злокачественную прогрессию. Рак поджелудочной железы (РПЖ) является очень агрессивной опухолью,
обладающей высокой способностью к инвазии в близлежащие ткани и органы, что обусловливает неудовлетворительные
результаты лечения. Показано при этом, что РПЖ относится к новообразованиям с высокой степенью гипоксии. Цель:
установление возможной зависимости экспрессии белка АДАМ8 и его мРНК от уровня оксигенации клеток. Материалы
и методы: использовали клеточные линии РПЖ человека. Экспрессию мРНК и белка ADAM8 определяли методами qRTPCR
и вестерн-блот-анализа соответственно. Результаты: установлено, что гипоксия индуцировала повышение уровня
мРНК АDAM8 в 2,5–5,9 раза в исследованных клеточных линиях РПЖ, за исключением клеток линии Panc-1. В клетках
линий BxPC-3, Capan-1 и Su8686 выявлено наиболее значительное возрастание уровня экспрессии мРНК ADAM8 при
гипоксии (p = 0,046). С помощью вестерн-блот-анализа показано, что экспрессия удаляемой формы продомена ADAM8
(90 kDa) усиливалась в несколько раз при гипоксии в 5 из 8 изученных клеточных линий РПЖ. Гипоксия индуцировала
повышение экспрессии остаточной формы ADAM8 (60 kDa) в 4 из 8 клеточных линий РПЖ: Aspc-1, Colo-357, Panc-1,
T3M4, хотя изменения оказались умеренно выраженными. Выводы: в клеточных линиях РПЖ человека отмечается четкая
тенденция к повышению при гипоксии уровня экспрессии, как мРНК, так и белка ADAM8, что позволяет предположить
зависимость экспрессии от уровня оксигенации и потенциальную роль ADAM8 в развитии и прогрессии РПЖ, который
отличается высокой степенью внутриопухолевой гипоксии.This work was supported by a program research
grant of the University of Heidelberg, where the study
was performed. The author gratefully acknowledges the
help and advisory of Dr. J. Kleeff and Dr. N. Giese
AI-driven discovery of synergistic drug combinations against pancreatic cancer
No full textTreatment regimens, especially in cancer, often include more than one medicine in order to achieve durable outcomes. Identifying the optimal combination of treatments has historically been done through clinical trial and error. And for many conditions, such as pancreatic cancer, an optimal treatment protocol has remained elusive, and the best available treatment combinations provide only modest benefit. Recent developments have led to the application of both experimental screening approaches and in silico modeling methods to identify synergistic drug combinations and expand the therapeutic options for multiple diseases. Here we conduct a study to compare different predictive approaches for identifying new treatment combinations for pancreatic cancer using cell line growth as an initial proxy for clinical utility. NCATS performed screening involving 496 pairwise combinations of 32 antineoplastic drugs, tested against the PANC-1 human pancreatic carcinoma cell line in duplicates using a 10 × 10 matrix format. This dataset served as the basis for generating and training advanced AI/ML models focused on pancreatic cancer. Next, three independent groups (NCATS, UNC and MIT), though in a collaborative manner, utilized three different workflows with AL/ML approaches to discover new perspective drug combinations against pancreatic cancer among over 1.5 million drug combinations. As a result of this collaboration, 88 proposed combinations were tested in a cell-based assay; 53 of them were synergistic (hit rate ~60%). While all machine learning approaches demonstrate advances in the direction of predicting synergistic drug combinations, graph convolutional networks resulted in the best performance with a hit rate ~83%, and Random Forest delivered the highest precision of 65%. Interestingly, all utilized AL/ML methods among the three groups proposed different drug combinations with a small overlap of only two combos from 90. This study demonstrates the potential of a collaborative modeling approach for prioritizing drug combinations in large-scale screening campaigns, particularly when focusing on maximizing the efficacy of drugs known to exhibit synergy
