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1.
J Clin Invest ; 130(1): 451-465, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31613799

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC. The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on the one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase 1 (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). In the current manuscript, we targeted this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-l-norleucine [DON]). Our results showed that DON decreased the self-renewal potential and metastatic ability of tumor cells. Further, treatment with DON decreased hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM and an increased infiltration of CD8+ T cells. Additionally, treatment with DON sensitized pancreatic tumors to anti-PD1 therapy, resulting in tumor regression and prolonged survival.

2.
Chemosphere ; 238: 124689, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31524624

RESUMO

Pharmaceutical effluents released from industries are accountable to deteriorate the aquatic and soil environment through indirect toxic effects. Microbes are adequately been used to biodegrade pharmaceutical industry wastewater and present study was envisaged to determine biodegradation of pharmaceutical effluent by Micrococcus yunnanensis. The strain showed 42.82% COD (Chemical oxygen demand) reduction before optimization. After applying Taguchi's L8 array as an optimization technique, the biodegradation rate was enhanced by 82.95% at optimum conditions (dextrose- 0.15%, peptone 0.1%, inoculum size 4% (wv-1), rpm 200, pH 8 at 25 °C) within 6 h. The confirmation of pharmaceuticals degradation was done by 1H NMR (Nuclear magnetic resonance) studies followed by elucidation of transformation pathways of probable drugs in the effluent through Q-Tof-MS (Quadrupole Time of Flight- Mass Spectrometry). The cytotoxicity evaluation of treated and untreated wastewater was analyzed on Human Embryonic Kidney (HEK 293) cells using Alamar Blue assay, which showed significant variance.


Assuntos
Biodegradação Ambiental , Resíduos Industriais/análise , Micrococcus/metabolismo , Preparações Farmacêuticas/análise , Águas Residuárias/química , Poluentes Químicos da Água/análise , Análise da Demanda Biológica de Oxigênio , Linhagem Celular , Indústria Farmacêutica , Células HEK293 , Humanos
3.
Oncogenesis ; 8(12): 68, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31740660

RESUMO

Presence of quiescent, therapy evasive population often described as cancer stem cells (CSC) or tumor initiating cells (TIC) is often attributed to extreme metastasis and tumor recurrence. This population is typically enriched in a tumor as a result of microenvironment or chemotherapy induced stress. The TIC population adapts to this stress by turning on cell cycle arrest programs that is a "fail-safe" mechanism to prevent expansion of malignant cells to prevent further injury. Upon removal of the "stress" conditions, these cells restart their cell cycle and regain their proliferative nature thereby resulting in tumor relapse. Growth Arrest Specific 5 (GAS5) is a long-non-coding RNA that plays a vital role in this process. In pancreatic cancer, CD133+ population is a typical representation of the TIC population that is responsible for tumor relapse. In this study, we show for the first time that emergence of CD133+ population coincides with upregulation of GAS5, that reprograms the cell cycle to slow proliferation by inhibiting GR mediated cell cycle control. The CD133+ population further routed metabolites like glucose to shunt pathways like pentose phosphate pathway, that were predominantly biosynthetic in spite of being quiescent in nature but did not use it immediately for nucleic acid synthesis. Upon inhibiting GAS5, these cells were released from their growth arrest and restarted the nucleic acid synthesis and proliferation. Our study thus showed that GAS5 acts as a molecular switch for regulating quiescence and growth arrest in CD133+ population, that is responsible for aggressive biology of pancreatic tumors.

4.
Theranostics ; 9(12): 3410-3424, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281487

RESUMO

Pancreatic adenocarcinoma (PDAC) claims more than 90% of the patients diagnosed with the disease owing to its aggressive biology that is manifested by high rate of tumor recurrence. Aberrant upregulation in the transcriptional activity of proteins involved in self-renewal like Sox2, Oct4 and Nanog is instrumental in these recurrence phenomena. In cancer, Sox2 is aberrantly "turned-on" leading to activation of downstream genes those results in relapse of the tumor. Molecular mechanisms that regulate the activity of Sox2 in PDAC are not known. In the current study, we have studied the how glycosylation of Sox2 by O-GlcNAc transferase (OGT) can affect its transcriptional activity and thus regulate self-renewal in cancer. Methods: RNA-Seq analysis of CRISPR-OGTi PDAC cells indicated a deregulation of differentiation and self-renewal pathways in PDAC. Pancreatic tumor burden following inhibition of OGT in vivo was done by using small molecule inhibitor, OSMI, on subcutaneous implantation of PDAC cells. Sox2 activity assay was performed by Dual Luciferase Reporter Assay kit. Results: Our study shows for the first time that in PDAC, glycosylation of Sox2 by OGT stabilizes it in the nucleus. Site directed mutagenesis of this site (S246A) prevents this modification. We further show that inhibition of OGT delayed initiation of pancreatic tumors by inhibition of Sox2. We also show that targeting OGT in vivo with a small molecule-inhibitor OSMI, results in decreased tumor burden in PDAC. Conclusion: Understanding this mechanism of SOX2 regulation by its glycosylation is expected to pave the way for development of novel therapy that has the potential to eradicate the cells responsible for tumor-recurrence.

5.
Cell Death Dis ; 10(2): 132, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755605

RESUMO

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) signaling have been shown to be dysregulated in multiple cancer types. Glucose regulatory protein 78 (GRP78), the master regulator of the UPR, plays a role in proliferation, invasion, and metastasis in cancer. Cancer stem cells (CSCs) make up a crucial component of the tumor heterogeneity in pancreatic cancer, as well as other cancers. "Stemness" in pancreatic cancer defines a population of cells within the tumor that have increased therapeutic resistance as well as survival advantage. In the current study, we investigated how GRP78 was responsible for maintaining "stemness" in pancreatic cancer thereby contributing to its aggressive biology. We determined that GRP78 downregulation decreased clonogenicity and self-renewal properties in pancreatic cancer cell lines in vitro. In vivo studies resulted in delayed tumor initiation frequency, as well as smaller tumor volume in the shGRP78 groups. Additionally, downregulation of GRP78 resulted in dysregulated fatty acid metabolism in pancreatic tumors as well as the cells. Further, our results showed that shGRP78 dysregulates multiple transcriptomic and proteomic pathways that involve DNA damage, oxidative stress, and cell death, that were reversed upon treatment with a ROS inhibitor, N-acetylcysteine. This study thus demonstrates for the first time that the heightened UPR in pancreatic cancer may be responsible for maintenance of the "stemness" properties in these cells that are attributed to aggressive properties like chemoresistance and metastasis.

6.
J Photochem Photobiol B ; 190: 50-58, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30472614

RESUMO

The present study focuses on the catalytic, antibacterial and antibiofilm efficacy of silver nanoparticles (AgNPs) in an easy, rapid and eco-friendly pathway. Herein, we have synthesised AgNPs using an aqueous extract of P. juliflora leaf. The bioactive compounds present in the extract are responsible for the reduction of Ag+ to Ag0. The particle synthesis was first observed by visual color change and then characterized using UV-visible spectroscopy to confirm the formation of AgNPs. The synthesis conditions were then optimised using critical parameters such as reaction time, AgNO3 concentration, extract to AgNO3 ratio and temperature of the reaction. The hydrodynamic size of the AgNPs with Dynamic light scattering (DLS) was 55.24 nm, while, was in the range of 10-20 nm as determined through Transmission Electron Microscopy (TEM). Further, Fourier transform infrared spectroscopy (FTIR) studies were conducted to discern the functional groups or compounds responsible for the reduction of silver nitrate as well as the capping of silver nanoparticles. Later, X-ray diffraction (XRD) results showed crystalline nature of the biosynthesized AgNPs. To evaluate their antibacterial potential, AgNPs were assessed through disc-diffusion assay, which resulted in an appreciable dose-dependent activity. The antibacterial potential was investigated through disc-diffusion assay against E. coli and P. aeruginosa. The Congo red agar (CRA) plate assay successfully revealed the anti-biofilm activity against B. subtilis and P. aeruginosa. Further, the catalytic activity of synthesised AgNPs was assessed against azo dyes such a Methylene Blue (MB) and Congo Red (CR) that resulted in its effective degradation of toxic compounds in a short span of time. Further, AgNPs were assessed for their wound healing potential.


Assuntos
Antibacterianos/síntese química , Biofilmes/efeitos dos fármacos , Nanopartículas Metálicas/química , Prosopis/química , Prata/química , Compostos Azo/química , Catálise , Extratos Vegetais/química , Cicatrização/efeitos dos fármacos
7.
Cancer Lett ; 439: 101-112, 2018 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-30290209

RESUMO

Metabolic rewiring is an integral part of tumor growth. Among metabolic pathways, the Mevalonic-Acid-Pathway (MVAP) plays a key role in maintaining membrane architecture through cholesterol synthesis, thereby affecting invasiveness. In the current study, we show for the first time that CD133Hi pancreatic tumor initiating cells (TIC) have increased expression of MVAP enzymes, cholesterol-content and Caveolin expression. Further, we show that CD133 in these cells is localized in the lipid-rafts (characterized by Cav-1-cholesterol association). Disruption of lipid-rafts by either depleting Cav-1 or by inhibiting MVAP by lovastatin decreased metastatic-potential and chemoresistance in CD133Hi cells while not affecting the CD133lo cells. Additionally, disruption of lipid-raft results in deregulation of FAK-signaling, decreasing invasiveness in pancreatic-TICs. Furthermore, this also inhibits ABC-transporter activity resulting in sensitizing TICs to standard chemotherapeutic agents. Repurposing existing drugs for new clinical applications is one of the safest and least resource intensive approaches to improve therapeutic options. In this context, our study is extremely timely as it shows that targeting lipid-rafts with statins can sensitize the normally resistant pancreatic TICHi-cells to standard chemotherapy and decrease metastasis, thereby defining a novel strategy for targeting the TICHi-PDAC.


Assuntos
Antígeno AC133/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Microdomínios da Membrana/metabolismo , Neoplasias Pancreáticas/genética , Antígeno AC133/metabolismo , Animais , Caveolina 1/genética , Caveolina 1/metabolismo , Linhagem Celular Tumoral , Colesterol/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lovastatina/farmacologia , Microdomínios da Membrana/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Nus , Metástase Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Paclitaxel/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
Public Health Nurs ; 35(6): 526-533, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29806745

RESUMO

BACKGROUND: The Indian national program stresses implementation of cervical cancer screening by health workers/nurses using VIA (Visual Inspection under Acetic acid). We demonstrate its feasibility and reliability in rural setting, assessing the role of smartphone-imaging for continuous training of nurses. DESIGN: A cross-sectional design to assess the reliability of the nurse-led VIA test. To assess feasibility, VIA positive patients were observed till confirmative diagnosis was made. SAMPLE: Hospital-based purposive sampling was used to recruit participants. MEASURES: A structured questionnaire for recording participants' details, VIA findings and follow-up information; and an observational checklist to record implementation parameters during each clinic. An expert assessed the nurse's judgment using smartphone-images of cervix. RESULTS: During October 2016-June 2017, 2758 patients attended the weekly clinic; 238 (8.6%) met the criteria, of those 180 (75.6%) tested after consent. Nurse reported 25 (13.8%) VIA-positive cases, but only 19 accessed the referral service. Kappa statistic: 0.45 (CI: 0.26-0.63) suggested moderate nurse-expert agreement. Image retrieval and quality affected expert's evaluation. Implementation challenges include low awareness among the population and referral link-up. CONCLUSION: Appropriately trained nurses can reliably conduct screening. Real-time expert feedback might improve reporting. Rigorous awareness activities and on-site treatment can reduce drop-outs. The medical institute's involvement and administrative will were instrumental.


Assuntos
Detecção Precoce de Câncer/métodos , Educação em Enfermagem/métodos , Programas de Rastreamento/métodos , Smartphone , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/prevenção & controle , Adulto , Estudos Transversais , Feminino , Humanos , Índia/epidemiologia , Pessoa de Meia-Idade , Enfermeiras e Enfermeiros/estatística & dados numéricos , Enfermagem/métodos , Reprodutibilidade dos Testes , População Rural , Inquéritos e Questionários , Neoplasias do Colo do Útero/epidemiologia
9.
Mol Oncol ; 12(9): 1498-1512, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29738634

RESUMO

Chemoresistance is a major therapeutic challenge that plays a role in the poor statistical outcomes in pancreatic cancer. Unfolded protein response (UPR) is one of the homeostasis mechanisms in cancer cells that have been correlated with chemoresistance in a number of cancers including pancreatic cancer. In this study, we show that modulating glucose regulatory protein 78 (GRP78), the master regulator of the UPR, can have a profound effect on multiple pathways that mediate chemoresistance. Our study showed for the first time that silencing GRP78 can diminish efflux activity of ATP-binding cassette (ABC) transporters, and it can decrease the antioxidant response resulting in an accumulation of reactive oxygen species (ROS). We also show that these effects can be mediated by the activity of specificity protein 1 (SP1), a transcription factor overexpressed in pancreatic cancer. Thus, inhibition of SP1 negatively affects the UPR, deregulates the antioxidant response of NRF2, as well as ABC transporter activity by inhibiting GRP78-mediated ER homeostasis. Sp1 and NRF2 have been classified as nononcogene addiction genes and thus are imperative to understanding the molecular mechanism of resistance. These finding have huge clinical relevance as both Sp1 and GRP78 are overexpressed in pancreatic cancer patients and increased expression of these proteins is indicative of poor prognosis. Understanding how these proteins may regulate chemoresistance phenotype of this aggressive cancer may pave the way for development of efficacious therapy for this devastating disease.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Plicamicina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Animais , Antibióticos Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Progressão da Doença , Retículo Endoplasmático/metabolismo , Expressão Gênica , Inativação Gênica , Homeostase , Humanos , Camundongos , Camundongos Nus , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias Pancreáticas/patologia , Plicamicina/farmacologia , Fator de Transcrição Sp1/antagonistas & inibidores , Fator de Transcrição Sp1/metabolismo , Resposta a Proteínas não Dobradas
10.
Mol Cancer Res ; 16(1): 162-172, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28970361

RESUMO

Tumor-initiating cells (TIC) have been implicated in pancreatic tumor initiation, progression, and metastasis. Among different markers that define this cell population within the tumor, the CD133+ cancer stem cell (CSC) population has reliably been described in these processes. CD133 expression has also been shown to functionally promote metastasis through NF-κB activation in this population, but the mechanism is unclear. In the current study, overexpression of CD133 increased expression and secretion of IL1ß (IL1B), which activates an autocrine signaling loop that upregulates NF-κB signaling, epithelial-mesenchymal transition (EMT), and cellular invasion. This signaling pathway also induces CXCR4 expression, which in turn is instrumental in imparting an invasive phenotype to these cells. In addition to the autocrine signaling of the CD133 secreted IL1ß, the tumor-associated macrophages (TAM) also produced IL1ß, which further activated this pathway in TICs. The functional significance of the TIC marker CD133 has remained elusive for a very long time; the current study takes us one step closer to understanding how the downstream signaling pathways in these cells regulate the functional properties of TICs.Implications: This study demonstrates the important role of tumor- and macrophage-derived IL1ß stimulation in pancreatic cancer. IL1 signaling is increased in cells with CD133 expression, leading to increased NF-kB activity, EMT induction, and invasion. Increased invasiveness via IL1ß stimulation is mediated by the upregulation of CXCR4 expression. The study highlights the importance of IL1-mediated signaling in TICs. Mol Cancer Res; 16(1); 162-72. ©2017 AACR.


Assuntos
Antígeno AC133/metabolismo , Interleucina-1/metabolismo , NF-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Comunicação Autócrina , Linhagem Celular Tumoral , Humanos , Camundongos , Invasividade Neoplásica , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/patologia , Comunicação Parácrina , Receptores de Interleucina-1/metabolismo , Transdução de Sinais
11.
J Bioenerg Biomembr ; 50(3): 205-211, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29204729

RESUMO

Whether embryonic, hematopoietic or cancer stem cells, this metabolic reprogramming is dependent on the nutrient-status and bioenergetic pathways that is influenced by the micro-environmental niches like hypoxia. Thus, the microenvironment plays a vital role in determining the stem cell fate by inducing metabolic reprogramming. Under the influence of the microenvironment, like hypoxia, the stem cells have increased glucose and glutamine uptake which result in activation of hexosamine biosynthesis pathway (HBP) and increased O-GlcNAc Transferase (OGT). The current review is focused on understanding how HBP, a nutrient-sensing pathway (that leads to increased OGT activity) is instrumental in regulating self-renewal not only in embryonic and hematopoietic stem cells (ESC/HSC) but also in cancer stem cells.


Assuntos
Vias Biossintéticas , Autorrenovação Celular , N-Acetilglucosaminiltransferases/metabolismo , Nutrientes/metabolismo , Animais , Metabolismo Energético , Hexosaminas/biossíntese , Humanos
12.
Artif Cells Nanomed Biotechnol ; 46(sup1): 188-197, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29265888

RESUMO

Cardiovascular diseases have been the major cause of mortality and morbidity all over the world accounting for more than 80% of the deaths from heart attacks and strokes. Hypercholesterolemia, an autosomal disorder of lipoprotein metabolism is one of the foremost causes of CVDs. An increased level of low-density lipoprotein cholesterol (LDL-C) in the plasma results in the rise of incidence rates in disease patients. Several conventional and combinational therapies have been proposed for lowering the LDL-C levels in the blood. These therapeutic agents are designed to target some crucial molecules that participates in the lipid metabolism such as apolipoprotein B, HMGCoA reductase, proprotein convertase subtilisin/kexin 9, etc. Although these therapies are effective but are associated with certain side effects. This article presents an overview on different conventional and nanotechnology-based approaches for the treatment and diagnosis of hypercholesterolemia. Numerous nanomaterial-based therapies including polymeric nanoparticles, cationic lipids, liposomes, dendrimers and inorganic nanoparticles have been discussed in lowering the cholesterol level along with recent advancement in diagnosis and imaging.


Assuntos
Hipercolesterolemia/diagnóstico , Hipercolesterolemia/terapia , Nanomedicina/métodos , Animais , Humanos
13.
Cancer Res ; 78(5): 1321-1333, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29259015

RESUMO

Resident fibroblasts that contact tumor epithelial cells (TEC) can become irreversibly activated as cancer-associated-fibroblasts (CAF) that stimulate oncogenic signaling in TEC. In this study, we evaluated the cross-talk between CAF and TEC isolated from tumors generated in a mouse model of KRAS/mut p53-induced pancreatic cancer (KPC mice). Transcriptomic profiling conducted after treatment with the anticancer compound Minnelide revealed deregulation of the TGFß signaling pathway in CAF, resulting in an apparent reversal of their activated state to a quiescent, nonproliferative state. TEC exposed to media conditioned by drug-treated CAFs exhibited a decrease in oncogenic signaling, as manifested by downregulation of the transcription factor Sp1. This inhibition was rescued by treating TEC with TGFß. Given promising early clinical studies with Minnelide, our findings suggest that approaches to inactivate CAF and prevent tumor-stroma cross-talk may offer a viable strategy to treat pancreatic cancer.Significance: In an established mouse model of pancreatic cancer, administration of the promising experimental drug Minnelide was found to actively deplete reactive stromal fibroblasts and to trigger tumor regression, with implications for stromal-based strategies to attack this disease. Cancer Res; 78(5); 1321-33. ©2018 AACR.


Assuntos
Fibroblastos Associados a Câncer/patologia , Carcinogênese , Carcinoma Ductal Pancreático/patologia , Modelos Animais de Doenças , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pancreáticas/patologia , Animais , Apoptose , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Proliferação de Células , Diterpenos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Organofosfatos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Fenantrenos/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética
14.
Sci Rep ; 7(1): 7872, 2017 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801636

RESUMO

Pancreatic tumors are renowned for their extremely hypoxic centers, resulting in upregulation of a number of hypoxia mediated signaling pathways including cell proliferation, metabolism and cell survival. Previous studies from our laboratory have shown that Minnelide, a water-soluble pro-drug of triptolide (anti-cancer compound), decreases viability of cancer cells in vitro as well as in vivo. However, its mechanism of action remain elusive. In the current study we evaluated the effect of Minnelide, on hypoxia mediated oncogenic signaling as well as stemness in pancreatic cancer. Minnelide has just completed Phase 1 trial against GI cancers and is currently awaiting Phase 2 trials. Our results showed that upon treatment with triptolide, HIF-1α protein accumulated in pancreatic cancer cells even though hypoxic response was decreased in them. Our studies showed even though HIF-1α is accumulated in the treated cells, there was no decrease in HIF-1 binding to hypoxia response elements. However, the HIF-1 transcriptional activity was significantly reduced owing to depletion of co-activator p300 upon treatment with triptolide. Further, treatment with triptolide resulted in a decreased activity of Sp1 and NF-kB the two major oncogenic signaling pathway in pancreatic cancer along with a decreased tumor initiating cell (TIC) population in pancreatic tumor.


Assuntos
Carcinogênese/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Organofosfatos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Fenantrenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Diterpenos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos SCID , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
15.
J Photochem Photobiol B ; 174: 90-96, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28756157

RESUMO

The work represents the potent catalytic activity of silver nanoparticles synthesized from Cicer arietinum (chickpea) leaf extract (CAL-AgNPs). Here, silver nano-catalysts were used against the anthropogenic pollutants mainly involving nitro-amines and azo dyes. These pollutants are extremely harmful to our environment and causes severe health issues. The CAL-AgNPs have the potential to degrade harmful toxins and their by-products, thereby decreasing the pollutants from the environment. The green synthesis of nano-catalyst includes a simple, cost effective and eco-friendly method using the leaf extract from the plant. A systematic study was conducted, including synthesis, optimization and characterization of the silver particles. The AgNPs were further assessed through DLS and TEM for size and morphological evaluation. The obtained particles have shown spherical morphology with the size range of 88.8nm. Further, FTIR were performed for compositional and functional group analysis of the particles. The antibacterial efficiency was also evaluated against E. coli and P. aeruginosa. For their catalytic evaluation, CAL-AgNPs were assessed for 4-nitrophenol, methylene blue and congo red. The results obtained through catalytic evaluation suggested that the CAL-AgNPs could be helpful to surmount the environmental pollution in a very effective manner.


Assuntos
Cicer/química , Corantes/química , Poluentes Ambientais/química , Nanopartículas Metálicas , Folhas de Planta/química , Prata/química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Catálise , Técnicas de Química Sintética , Corantes/isolamento & purificação , Poluentes Ambientais/isolamento & purificação , Escherichia coli/efeitos dos fármacos , Tamanho da Partícula , Extratos Vegetais/química , Pseudomonas aeruginosa/efeitos dos fármacos , Prata/farmacologia
16.
Sci Rep ; 7(1): 1564, 2017 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-28484232

RESUMO

Endoplasmic reticulum (ER) stress initiates an important mechanism for cell adaptation and survival, named the unfolded protein response (UPR). Severe or chronic/prolonged UPR can breach the threshold for survival and lead to cell death. There is a fundamental gap in knowledge on the molecular mechanism of how chronic ER stress is stimulated and leads to cell death in pancreatic ductal adenocarcinoma (PDAC). Our study shows that downregulating specificity protein 1 (Sp1), a transcription factor that is overexpressed in pancreatic cancer, activates UPR and results in chronic ER stress. In addition, downregulation of Sp1 results in its decreased binding to the ER stress response element present in the promoter region of Grp78, the master regulator of ER stress, thereby preventing homeostasis. We further show that inhibition of Sp1, as well as induction of ER stress, leads to lysosomal membrane permeabilization (LMP), a sustained accumulation of cytosolic calcium, and eventually cell death in pancreatic cancer.


Assuntos
Retículo Endoplasmático/metabolismo , Homeostase , Membranas Intracelulares/metabolismo , Lisossomos/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fator de Transcrição Sp1/metabolismo , Cálcio/metabolismo , Morte Celular , Linhagem Celular Tumoral , Citosol/metabolismo , Regulação para Baixo , Estresse do Retículo Endoplasmático , Humanos , Modelos Biológicos , Permeabilidade
17.
Vet Microbiol ; 189: 86-90, 2016 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-27259831

RESUMO

Porcine circovirus type 2 (PCV2), a small, single-stranded circular DNA virus and the causative agent of porcine circovirus associated disease (PCVAD), was first observed in the mid-1990s in pigs with a post-weaning wasting disease. In 2006 the number of PCVAD cases greatly increased, marking it as an important viral pathogen for the United States (US) swine industry. PCV2 vaccines were introduced to the US in 2006 in response to widespread outbreaks of PCVAD. These vaccines were effective in preventing disease, but did not eliminate virus from the animals. In 2006, prior to vaccine use, a study of PCV2 prevalence in pig herds across the US was performed in conjunction with the US National Animal Health Monitoring System. In 2012, 6 years after widespread PCV2 vaccination, this study was repeated. Since the introduction of PCV2 vaccines in 2006, viral presence and viral loads have greatly decreased, and a genotypic shift dominated by PCV2b has occurred. Antibody levels have decreased in the pig population, but approximately 95% of sites continue to be antibody-positive. Widespread vaccination has controlled PCVAD and decreased PCV2 prevalence to the point that viremia is not detected on many sites. Thus, continued vaccination may lead to PCV2 elimination in the national herd over time.


Assuntos
Infecções por Circoviridae/veterinária , Doenças dos Suínos/epidemiologia , Doenças dos Suínos/virologia , Vacinas Virais/normas , Animais , Anticorpos Antivirais/sangue , Infecções por Circoviridae/epidemiologia , Infecções por Circoviridae/prevenção & controle , Infecções por Circoviridae/virologia , Circovirus/genética , Erradicação de Doenças , Genótipo , Prevalência , Suínos , Doenças dos Suínos/prevenção & controle , Estados Unidos/epidemiologia , Vacinação/veterinária , Carga Viral
18.
J Virol ; 90(17): 7789-97, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27334590

RESUMO

UNLABELLED: Several innate sensing pathways contribute to the control of early cytomegalovirus (CMV) infection, leading to a multiphasic type I interferon (IFN-I) response that limits viral replication and promotes host defenses. Toll-like receptor (TLR)-dependent pathways induce IFN-I production in CMV-infected plasmacytoid dendritic cells; however, the initial burst of IFN-I that occurs within the first few hours in vivo is TLR independent and emanates from stromal cells. Here we show that primary human endothelial cells mount robust IFN-I responses to human CMV that are dependent upon cyclic GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3) signaling. Disruption of STING expression in endothelial cells by clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 revealed that it is essential for the induction of IFN-I and restriction of CMV replication. Consistently, STING was necessary to mount the first phase of IFN-I production and curb CMV replication in infected mice. Thus, DNA sensing through STING is critical for primary detection of both human and mouse CMV in nonhematopoietic cells and drives the initial wave of IFN-I that is key for controlling early viral replication in vivo. IMPORTANCE: Cytomegalovirus (CMV) is one of the most common viral pathogens, with the majority of people contracting the virus in their lifetime. Although acute infection is mostly asymptomatic in healthy persons, significant pathology is observed in immunocompromised individuals, and chronic CMV infection may exacerbate a myriad of inflammatory conditions. Here we show that primary human endothelial cells mount robust IFN-I responses against CMV via a cGAS/STING/IRF3 pathway. Disruption of STING expression by CRISPRs revealed an essential role in eliciting IFN-I responses and restricting CMV replication. Consistently, in mice, STING is necessary for the first phase of IFN-I production that limits early CMV replication. Our results demonstrate a pivotal role for the cGAS-STING pathway in the initial detection of CMV infection.


Assuntos
Infecções por Citomegalovirus/imunologia , Células Endoteliais/imunologia , Células Endoteliais/virologia , Imunidade Inata , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Transdução de Sinais , Animais , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , Humanos , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Camundongos Endogâmicos C57BL
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