scholarly journals High Levels of Prebiotic Resistant Starch in Diet Modulate Gene Expression and Metabolomic Profile in Pancreatic Cancer Xenograft Mice

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 709 ◽  
Author(s):  
Concetta Panebianco ◽  
Annacandida Villani ◽  
Valerio Pazienza
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Resistant Starch ◽  
Control Diet ◽  
Metabolic Phenotype ◽  
Cancer Drug ◽  
Nutritional Interventions ◽  
Cancer Drug Resistance ◽  
Xenograft Mice ◽  
The Impact

Cancer initiation and protection mainly derives from a systemic metabolic environment regulated by dietary patterns. Less is known about the impact of nutritional interventions in people with a diagnosis of cancer. The aim of our study was to investigate the effect of a diet rich in resistant starch (RS) on cell pathways modulation and metabolomic phenotype in pancreatic cancer xenograft mice. RNA-Seq experiments on tumor tissue showed that 25 genes resulted in dysregulated pancreatic cancer in mice fed with an RS diet, as compared to those fed with control diet. Moreover, in these two different mice groups, six serum metabolites were deregulated as detected by LC–MS analysis. A bioinformatic prediction analysis showed the involvement of the differentially expressed genes on insulin receptor signaling, circadian rhythm signaling, and cancer drug resistance among the three top canonical pathways, whilst cell death and survival, gene expression, and neurological disease were among the three top disease and biological functions. These findings shed light on the genomic and metabolic phenotype, contributing to the knowledge of the mechanisms through which RS may act as a potential supportive approach for enhancing the efficacy of existing cancer treatments.

scholarly journals High Levels of Prebiotic Resistant Starch in Diet Modulate a Specific Pattern of miRNAs Expression Profile Associated to a Better Overall Survival in Pancreatic Cancer

Biomolecules ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 26
Author(s):  
Nadia Trivieri ◽  
Concetta Panebianco ◽  
Annacandida Villani ◽  
Riccardo Pracella ◽  
Tiziana Pia Latiano ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Overall Survival ◽  
Tumor Growth ◽  
Expression Profile ◽  
Resistant Starch ◽  
Target Genes ◽  
Human Pancreatic Cancer ◽  
Integrative Approach ◽  
The Impact

Dietary patterns are well known risk factors involved in cancer initiation, progression, and in cancer protection. Previous in vitro and in vivo studies underline the link between a diet rich in resistant starch (RS) and slowing of tumor growth and gene expression in pancreatic cancer xenograft mice. The aim of this study was to investigate the impact of a diet rich in resistant starch on miRNAs and miRNAs-target genes expression profile and on biological processes and pathways, that play a critical role in pancreatic tumors of xenografted mice. miRNA expression profiles on tumor tissues displayed 19 miRNAs as dysregulated in mice fed with RS diet as compared to those fed with control diet and differentially expressed miRNA-target genes were predicted by integrating (our data) with a public human pancreatic cancer gene expression dataset (GSE16515). Functional and pathway enrichment analyses unveiled that miRNAs involved in RS diet are critical regulators of genes that control tumor growth and cell migration and metastasis, inflammatory response, and, as expected, synthesis of carbohydrate and glucose metabolism disorder. Mostly, overall survival analysis with clinical data from TCGA (n = 175) displayed that almost four miRNAs (miRNA-375, miRNA-148a-3p, miRNA-125a-5p, and miRNA-200a-3p) upregulated in tumors from mice fed with RS were a predictor of good prognosis for pancreatic cancer patients. These findings contribute to the understanding of the potential mechanisms through which resistant starch may affect cancer progression, suggesting also a possible integrative approach for enhancing the efficacy of existing cancer treatments.

Abstract 1283: Targeting c-MYC and MAPK pathway to overcome pancreatic cancer drug resistance

2019 ◽  
Author(s):  
Erika Maria Parasido ◽  
George S. Avetian ◽  
Jonathan Brody ◽  
Jordan Winter ◽  
Eric Londin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Mapk Pathway ◽  
Cancer Drug ◽  
Cancer Drug Resistance

scholarly journals Impact of LMWH and Specific Factor Xa Inhibitors, Apixaban and Fondaparinux, on Cancer Cell Biology and Procoagulant Properties of Cancer Microenvironment

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2136-2136
Author(s):  
Huong Chi Mai Tran ◽  
Rania Amrane ◽  
Elisabeth Mbemba ◽  
Michele Sabbah ◽  
Ismail Elalamy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Biology ◽  
Thrombin Generation ◽  
Antithrombotic Agents ◽  
Pancreatic Cancer Cells ◽  
The Impact

Abstract Background Cancer patients with venous thromboembolism (VTE) or at risk of VTE are treated with antithrombotic agents. Cancer cells express procoagulant properties and induce hypercoagulability in the microenvironment, that could impact the efficiency of the antithrombotic agents. Aims In the present study, we investigated the interaction between antithrombotic agents with pancreatic cancer cells, as well as with their microenvironment. The impact of apixaban, fondaparinux, enoxaparin and tinzaparin on the procoagulant properties of pancreatic cancer cells BXPC3 was examinated. Reciprocally, we also investigated the impact of BXPC3 on the potency of these antithrombotic agents. Methods BXPC3 cells (400 cells/μl) were exposed for 48 hours to apixaban (2 µg/ml), fondaparinux (2 µg/ml), enoxaparin, tinzaparin (2 anti-Xa IU/ml) or NaCL (control). Then, conditioned media (CM) and BXPC3 cells were harvested, separated and put in contact with normal platelet-poor plasma (PPP). Subsequently, thrombin generation (TG) was assessed using Thrombogram-Thrombinoscope® assay (Diagnostica Stago). Cells' viability was also assessed with the MTT assay. Gene expression for Tissue Factor (TF), Vascular Endothelial Growth Factor (VEGF), Thrombospondin 1 (THSB1) was assessed with RT-qPCR at the cells exposed or not to the antithrombotic agents. Expression of TF protein and activity of cancer cells was assessed using ELISA method. Residual anti-Xa activity in CM was measured using specific amidolytic assays for each antithrombotic agent. Results Apixaban, fondaparinux, enoxaparin, and tinzaparin significantly reduced cell viability by 25%, 12%, 14%, and 11% respectively. In the control experiment non treated BXPC3 cells enhanced TG. Pre-treatment of BXPC3 with the antithrombotic agents did not significantly modify their capacity to trigger and enhance TG. Among the studied agents only apixaban resulted in significant decrease of TF mRNA expression. However, protein expression of TF was not significantly modified by any of the antithrombotic agents. VEGF's mRNA expression was significantly decreased by fondaparinux and enoxaparin. THBS1's mRNA expression was significantly increased by apixaban. The concentrations of the anti-Xa activity of fondaparinux, enoxaparin and tinzaparin in the CM obtained at 48h after exposure of cells were reduced by 27%, 48% and 26% respectively as compared to those initially added in the culture medium. In contrast, the concentration of apixaban in the CM did not significantly change. The CM obtained by cells exposed to apixaban, fondaparinux, enoxaparin and tinzaparin inhibited TG by 70%, 30%, 40% and 90% respectively. Conclusion. Antithrombotic agents reduced the viability of BXPC3 cells. Among the studied agents, apixaban had the most pronounced effect on cells' viability. The antithrombotic agents had a potential downregulating effect on the proangiogenetic properties of BXPC3 via the decrease of VEGF gene expression (fondaparinux and enoxaparin) and enhancement of THBS1 gene expression (apixaban). Nevertheless, preincubation of BXPC3 with the antithrombotic agents did not alter the expression of TF protein and their effect on thrombin generation. Moreover, BXPCE exerted a "degradation" effect on LMWH and fondaparinux. Apixaban appeared to escape from this effect of the cancer cells. A significant inhibitory effect on thrombin generation was exerted by the residual concentrations of the antithrombotic agents in the microenvironment of cancer cells. The ensemble of these data highlight for the first time that the presence of antithrombotic agents in cancer cell microenvironment alters the biology of cancer cells and offer a constant antithrombotic effect in the microenvironment. Disclosures No relevant conflicts of interest to declare.

scholarly journals MicroRNA and Alternative mRNA Splicing Events in Cancer Drug Response/Resistance: Potent Therapeutic Targets

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1818
Author(s):  
Rahaba Marima ◽  
Flavia Zita Francies ◽  
Rodney Hull ◽  
Thulo Molefi ◽  
Meryl Oyomno ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Alternative Splicing ◽  
Mirna Expression ◽  
Drug Targets ◽  
Mrna Splicing ◽  
Cancer Drug ◽  
Aberrant Splicing ◽  
Cancer Drug Resistance ◽  
Alternative Mrna Splicing

Cancer is a multifaceted disease that involves several molecular mechanisms including changes in gene expression. Two important processes altered in cancer that lead to changes in gene expression include altered microRNA (miRNA) expression and aberrant splicing events. MiRNAs are short non-coding RNAs that play a central role in regulating RNA silencing and gene expression. Alternative splicing increases the diversity of the proteome by producing several different spliced mRNAs from a single gene for translation. MiRNA expression and alternative splicing events are rigorously regulated processes. Dysregulation of miRNA and splicing events promote carcinogenesis and drug resistance in cancers including breast, cervical, prostate, colorectal, ovarian and leukemia. Alternative splicing may change the target mRNA 3′UTR binding site. This alteration can affect the produced protein and may ultimately affect the drug affinity of target proteins, eventually leading to drug resistance. Drug resistance can be caused by intrinsic and extrinsic factors. The interplay between miRNA and alternative splicing is largely due to splicing resulting in altered 3′UTR targeted binding of miRNAs. This can result in the altered targeting of these isoforms and altered drug targets and drug resistance. Furthermore, the increasing prevalence of cancer drug resistance poses a substantial challenge in the management of the disease. Henceforth, molecular alterations have become highly attractive drug targets to reverse the aberrant effects of miRNAs and splicing events that promote malignancy and drug resistance. While the miRNA–mRNA splicing interplay in cancer drug resistance remains largely to be elucidated, this review focuses on miRNA and alternative mRNA splicing (AS) events in breast, cervical, prostate, colorectal and ovarian cancer, as well as leukemia, and the role these events play in drug resistance. MiRNA induced cancer drug resistance; alternative mRNA splicing (AS) in cancer drug resistance; the interplay between AS and miRNA in chemoresistance will be discussed. Despite this great potential, the interplay between aberrant splicing events and miRNA is understudied but holds great potential in deciphering miRNA-mediated drug resistance.

scholarly journals Adaptation of the Cecal Bacterial Microbiome of Growing Pigs in Response to Resistant Starch Type 4

2015 ◽  
Vol 81 (24) ◽  
pp. 8489-8499 ◽  
Author(s):  
Barbara U. Metzler-Zebeli ◽  
Stephan Schmitz-Esser ◽  
Evelyne Mann ◽  
Dietmar Grüll ◽  
Timea Molnar ◽  
...  
Keyword(s):  
Bacterial Community ◽  
Resistant Starch ◽  
Control Diet ◽  
Short Chain Fatty Acids ◽  
Growing Pigs ◽  
Short Chain ◽  
Rrna Gene ◽  
Content Type ◽  
Linear Discriminant ◽  
The Impact

ABSTRACTResistant starch (RS) exacerbates health benefits on the host via modulation of the gut bacterial community. By far, these effects have been less well explored for RS of type 4. This study aimed at gaining a community-wide insight into the impact of enzymatically modified starch (EMS) on the cecal microbiota and hindgut fermentation in growing pigs. Castrated male pigs (n= 12/diet; 29-kg body weight) were fed diets with either 70% EMS or control starch for 10 days. The bacterial profile of each cecal sample was determined by sequencing of the V345 region of the 16S rRNA gene using the Illumina MiSeq platform. EMS diet reduced short-chain fatty acid concentrations in cecum and proximal colon compared to the control diet. Linear discriminant analyses andKmeans clustering indicated diet-specific cecal community profiles, whereby diversity and species richness were not different among diets. Pigs showed host-specific variation in their most abundant phyla,Firmicutes(55%),Proteobacteria(35%), andBacteroidetes(10%). The EMS diet decreased abundance ofRuminococcus,Parasutterella,Bilophila,Enterococcus, andLactobacillusoperational taxonomic units (OTU), whereasMeniscusandActinobacillusOTU were increased compared to those with the control diet (P< 0.05). Quantitative PCR confirmed results for host effect onEnterobacteriaceaeand diet effect on members of theLactobacillusgroup. The presence of less cecal short-chain fatty acids and the imputed metabolic functions of the cecal microbiome suggested that EMS was less degradable for cecal bacteria than the control starch. The present EMS effects on the bacterial community profiles were different than the previously reported RS effects and can be linked to the chemical structure of EMS.

scholarly journals The pleiotropic effects of prebiotic galacto-oligosaccharides on the aging gut

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jason W. Arnold ◽  
Jeffery Roach ◽  
Salvador Fabela ◽  
Emily Moorfield ◽  
Shengli Ding ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intestinal Permeability ◽  
Control Diet ◽  
Receptor Interaction ◽  
Energetic Efficiency ◽  
Markers Of Inflammation ◽  
The Impact ◽  
Old Mice ◽  
Young Mice

Abstract Background Prebiotic galacto-oligosaccharides (GOS) have an extensively demonstrated beneficial impact on intestinal health. In this study, we determined the impact of GOS diets on hallmarks of gut aging: microbiome dysbiosis, inflammation, and intestinal barrier defects (“leaky gut”). We also evaluated if short-term GOS feeding influenced how the aging gut responded to antibiotic challenges in a mouse model of Clostridioides difficile infection. Finally, we assessed if colonic organoids could reproduce the GOS responder—non-responder phenotypes observed in vivo. Results Old animals had a distinct microbiome characterized by increased ratios of non-saccharolytic versus saccharolytic bacteria and, correspondingly, a lower abundance of β-galactosidases compared to young animals. GOS reduced the overall diversity, increased the abundance of specific saccharolytic bacteria (species of Bacteroides and Lactobacillus), increased the abundance of β-galactosidases in young and old animals, and increased the non-saccharolytic organisms; however, a robust, homogeneous bifidogenic effect was not observed. GOS reduced age-associated increased intestinal permeability and increased MUC2 expression and mucus thickness in old mice. Clyndamicin reduced the abundance Bifidobacterium while increasing Akkermansia, Clostridium, Coprococcus, Bacillus, Bacteroides, and Ruminococcus in old mice. The antibiotics were more impactful than GOS on modulating serum markers of inflammation. Higher serum levels of IL-17 and IL-6 were observed in control and GOS diets in the antibiotic groups, and within those groups, levels of IL-6 were higher in the GOS groups, regardless of age, and higher in the old compared to young animals in the control diet groups. RTqPCR revealed significantly increased gene expression of TNFα in distal colon tissue of old mice, which was decreased by the GOS diet. Colon transcriptomics analysis of mice fed GOS showed increased expression of genes involved in small-molecule metabolic processes and specifically the respirasome in old animals, which could indicate an increased oxidative metabolism and energetic efficiency. In young mice, GOS induced the expression of binding-related genes. The galectin gene Lgals1, a β-galactosyl-binding lectin that bridges molecules by their sugar moieties and is an important modulator of the immune response, and the PI3K-Akt and ECM-receptor interaction pathways were also induced in young mice. Stools from mice exhibiting variable bifidogenic response to GOS injected into colon organoids in the presence of prebiotics reproduced the response and non-response phenotypes observed in vivo suggesting that the composition and functionality of the microbiota are the main contributors to the phenotype. Conclusions Dietary GOS modulated homeostasis of the aging gut by promoting changes in microbiome composition and host gene expression, which was translated into decreased intestinal permeability and increased mucus production. Age was a determining factor on how prebiotics impacted the microbiome and expression of intestinal epithelial cells, especially apparent from the induction of galectin-1 in young but not old mice.

scholarly journals [6S]-5-Methyltetrahydrofolic Acid and Folic Acid Pregnancy Diets Differentially Program Metabolic Phenotype and Hypothalamic Gene Expression of Wistar Rat Dams Post-Birth

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 48
Author(s):  
Emanuela Pannia ◽  
Rola Hammoud ◽  
Rebecca Simonian ◽  
Erland Arning ◽  
Paula Ashcraft ◽  
...  
Keyword(s):  
Gene Expression ◽  
Folic Acid ◽  
Food Intake ◽  
Rna Sequencing ◽  
Control Diet ◽  
Wistar Rat ◽  
Metabolic Phenotype ◽  
Maternal Metabolism ◽  
Plasma Hormones ◽  
Plasma Leptin

[6S]-5-methyltetrahydrofolic acid (MTHF) is a proposed replacement for folic acid (FA) in diets and prenatal supplements. This study compared the effects of these two forms on maternal metabolism and hypothalamic gene expression. Pregnant Wistar rats received an AIN-93G diet with recommended FA (1X, 2 mg/kg, control), 5X-FA or equimolar levels of MTHF. During lactation they received the control diet and then a high fat diet for 19-weeks post-weaning. Body weight, adiposity, food intake, energy expenditure, plasma hormones, folate, and 1-carbon metabolites were measured. RNA-sequencing of the hypothalamus was conducted at parturition. Weight-loss from weaning to 1-week post-weaning was less in dams fed either form of the 5X vs. 1X folate diets, but final weight-gain was higher in 5X-MTHF vs. 5X-FA dams. Both doses of the MTHF diets led to 8% higher food intake and associated with lower plasma leptin at parturition, but higher leptin at 19-weeks and insulin resistance at 1-week post-weaning. RNA-sequencing revealed 279 differentially expressed genes in the hypothalamus in 5X-MTHF vs. 5X-FA dams. These findings indicate that MTHF and FA differ in their programing effects on maternal phenotype, and a potential adverse role of either form when given at the higher doses.

scholarly journals Spatial structure impacts adaptive therapy by shaping intra-tumoral competition

2020 ◽  
Author(s):  
Maximilian A. R. Strobl ◽  
Jill Gallaher ◽  
Jeffrey West ◽  
Mark Robertson-Tessi ◽  
Philip K. Maini ◽  
...  
Keyword(s):  
Rational Design ◽  
Cancer Drug ◽  
Cell Turnover ◽  
Stepping Stones ◽  
Tumour Control ◽  
Cancer Drug Resistance ◽  
Initial Resistance ◽  
Selection Factors ◽  
The Impact ◽  
Adaptive Therapy

Abstract(1)BackgroundAdaptive therapy aims to tackle cancer drug resistance by leveraging intra-tumoural competition between drug-sensitive and resistant cells. Motivated by promising results in prostate cancer there is growing interest in extending this approach to other cancers. Here we present a theoretical study of intra-tumoural competition during adaptive therapy, to identify under which circumstances it will be superior to aggressive treatment, and how it can be improved through combination treatment;(2)MethodsWe study a 2-D, on-lattice, agent-based tumour model. We examine the impact of different micro-environmental factors on the comparison between continuous drug administration and the adaptive schedule pioneered in the first-in-human clinical trial.(3)ResultsWe show that the degree of crowding, the initial resistance fraction, the presence of possible resistance costs, and the rate of tumour cell turnover are key determinants of the benefit of adaptive therapy. Subsequently, we investigate whether combination with treatments which amplify proliferation or which target cell turnover can prolong tumour control. While the former increases competition, we find that only the latter can robustly improve time to progression;(4)ConclusionOur work helps to identify selection factors for adaptive therapy and provides stepping stones towards the rational design of multi-drug adaptive regimens.

scholarly journals Dysregulation of Hypothalamic Gene Expression and the Oxytocinergic System by Soybean Oil Diets in Male Mice

Endocrinology ◽  
2020 ◽  
Vol 161 (2) ◽  
Author(s):  
Poonamjot Deol ◽  
Elena Kozlova ◽  
Matthew Valdez ◽  
Catherine Ho ◽  
Ei-Wen Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Soybean Oil ◽  
Messenger Rna ◽  
Control Diet ◽  
Coconut Oil ◽  
Metabolic Phenotype ◽  
Sequencing Analysis ◽  
Male Mice ◽  
Metabolic Inflammation ◽  
Obesity And Diabetes

Abstract Soybean oil consumption has increased greatly in the past half-century and is linked to obesity and diabetes. To test the hypothesis that soybean oil diet alters hypothalamic gene expression in conjunction with metabolic phenotype, we performed RNA sequencing analysis using male mice fed isocaloric, high-fat diets based on conventional soybean oil (high in linoleic acid, LA), a genetically modified, low-LA soybean oil (Plenish), and coconut oil (high in saturated fat, containing no LA). The 2 soybean oil diets had similar but nonidentical effects on the hypothalamic transcriptome, whereas the coconut oil diet had a negligible effect compared to a low-fat control diet. Dysregulated genes were associated with inflammation, neuroendocrine, neurochemical, and insulin signaling. Oxt was the only gene with metabolic, inflammation, and neurological relevance upregulated by both soybean oil diets compared to both control diets. Oxytocin immunoreactivity in the supraoptic and paraventricular nuclei of the hypothalamus was reduced, whereas plasma oxytocin and hypothalamic Oxt were increased. These central and peripheral effects of soybean oil diets were correlated with glucose intolerance but not body weight. Alterations in hypothalamic Oxt and plasma oxytocin were not observed in the coconut oil diet enriched in stigmasterol, a phytosterol found in soybean oil. We postulate that neither stigmasterol nor LA is responsible for effects of soybean oil diets on oxytocin and that Oxt messenger RNA levels could be associated with the diabetic state. Given the ubiquitous presence of soybean oil in the American diet, its observed effects on hypothalamic gene expression could have important public health ramifications.

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