scholarly journals Parental obesity programs pancreatic cancer development in offspring

2019 ◽  
Vol 26 (5) ◽  
pp. 511-523 ◽  
Author(s):  
Raquel Santana da Cruz ◽  
Johan Clarke ◽  
Ana Cristina P Curi ◽  
Aseel Al-Yawar ◽  
Lu Jin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Body Weight ◽  
Control Diet ◽  
Epidemiological Studies ◽  
Cancer Development ◽  
Separate Experiment ◽  
Metabolic Dysfunction ◽  
History Of ◽  
History Of Obesity ◽  
The Impact

Epidemiological studies suggest that timing of obesity onset – and underlying metabolic dysfunction – is important in determining pancreatic cancer rates: early and young adult abdominal overweight/obesity is more strongly associated with this cancer than obesity that develops later in life. Parental obesity and overweight are associated with metabolic dysfunction and obesity in their children. Here, we evaluated the impact of parental overweight on offspring’s susceptibility of pancreatic cancer using the P48Cre/+/KrasG12D/+ mouse model. Male mice were fed an obesity-inducing diet (OID) before conception and mated with females raised on a control diet (CO) to generate the offspring. In a separate experiment, pregnant dams were fed CO or OID throughout gestation. The resulting OID offspring from the maternal (OID-m) or paternal lineage (OID-p) were used to study body weight, metabolic parameters and pancreatic cancer development and for molecular analysis. Parental obesity increased offspring’s body weight at birth, weaning and in adulthood compared to CO, with gender- and genotype-specific differences. OID-p and OID-m offspring showed metabolic disorder and accelerated development of high-grade PanIN/PDAC. OID offspring also had higher rates of acinar-to-ductal reprogramming assessed by CPA1+/SOX9+-positive pancreatic cells. Levels of Tenascin C (TNC), an ECM glycoprotein shown to suppress apoptosis, were elevated in OID offspring, particularly females. In line with that, OID offspring displayed increased collagen content and decreased apoptosis in pancreatic lesions compared to CO. An ancestral history of obesity through either the paternal or maternal lineages increases offspring’s susceptibility to pancreatic cancer development.

Fluoxetine-induced changes in body weight and 5-HT1A receptor-mediated hormone secretion in rats on a tryptophan-deficient diet

2004 ◽  
Vol 286 (2) ◽  
pp. R390-R397 ◽  
Author(s):  
D. N. D'Souza ◽  
Y. Zhang ◽  
F. Garcia ◽  
G. Battaglia ◽  
L. D. Van de Kar
Keyword(s):  
Body Weight ◽  
Control Diet ◽  
Hormone Secretion ◽  
Significant Loss ◽  
Tryptophan Depletion ◽  
Deficient Diet ◽  
Hormone Responses ◽  
Plasma Hormones ◽  
Induced Changes ◽  
The Impact

Tryptophan depleting protocols are commonly used to study the role of serotonin in mood disorders. The present study examined the impact of a tryptophan-deficient diet and fluoxetine on the serotonergic regulation of neuroendocrine function and body weight. We hypothesized that the regulation of postsynaptic 5-HT1A receptors is dependent on the levels of 5-HT in the synapse. Rats on a control or a tryptophan-deficient diet received daily injections of saline or fluoxetine (5 or 10 mg·kg-1·day-1 ip) from day 7 to day 21. The tryptophan-deficient diet produced a 41% reduction in the level of 5-HT but no change in the density of [3H]paroxetine-labeled 5-HT transporters. Treatment with fluoxetine inhibited the gain in weight in rats maintained on the control diet. The tryptophan-deficient diet produced a significant loss in body weight that was not significantly altered by treatment with fluoxetine. Treatment with fluoxetine produced a dose-dependent desensitization of hormone responses to injection of the 5-HT1A receptor agonist (±)8-hydroxy-2-(di- n-propylamino)tetralin ((±)8-OH-DPAT). The tryptophan-deficient diet produced an increase in the basal levels of corticosterone but did not alter the basal levels of ACTH or oxytocin. Also, this diet inhibited the magnitude of 8-OH-DPAT-induced increase in plasma levels of ACTH and oxytocin but did not impair the ability of fluoxetine to desensitize the 5-HT1A receptor-mediated increase in plasma hormones. These data suggest that a reserve of 5-HT enables fluoxetine to desensitize postsynaptic 5-HT1A receptors in the hypothalamus. In conclusion, the profound physiological changes induced by tryptophan depletion may complicate the interpretation of studies using this experimental approach.

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 Adipose Tissue, Obesity and Adiponectin: Role in Endocrine Cancer Risk

2019 ◽  
Vol 20 (12) ◽  
pp. 2863 ◽  
Author(s):  
Andrea Tumminia ◽  
Federica Vinciguerra ◽  
Miriam Parisi ◽  
Marco Graziano ◽  
Laura Sciacca ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Protective Action ◽  
Endocrine System ◽  
Epidemiological Studies ◽  
Overweight And Obesity ◽  
Cancer Development ◽  
Multiple Factors ◽  
Prostate Cancers ◽  
The Impact ◽  
Complex Organ

Adipose tissue has been recognized as a complex organ with endocrine and metabolic roles. The excess of fat mass, as occurs during overweight and obesity states, alters the regulation of adipose tissue, contributing to the development of obesity-related disorders. In this regard, many epidemiological studies shown an association between obesity and numerous types of malignancies, comprising those linked to the endocrine system (e.g., breast, endometrial, ovarian, thyroid and prostate cancers). Multiple factors may contribute to this phenomenon, such as hyperinsulinemia, dyslipidemia, oxidative stress, inflammation, abnormal adipokines secretion and metabolism. Among adipokines, growing interest has been placed in recent years on adiponectin (APN) and on its role in carcinogenesis. APN is secreted by adipose tissue and exerts both anti-inflammatory and anti-proliferative actions. It has been demonstrated that APN is drastically decreased in obese individuals and that it can play a crucial role in tumor growth. Although literature data on the impact of APN on carcinogenesis are sometimes conflicting, the most accredited hypothesis is that it has a protective action, preventing cancer development and progression. The aim of the present review is to summarize the currently available evidence on the involvement of APN and its signaling in the etiology of cancer, focusing on endocrine malignancies.

Mild Traumatic Brain Injury and Postconcussive Symptom Endorsement: A Parallel Comparison Between Two Nonclinical Cohorts

2020 ◽  
Author(s):  
R Elisabeth Cornwell ◽  
Jorge I Arango ◽  
C B Eagye ◽  
Candace Hill-Pearson ◽  
Karen Schwab ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Epidemiological Studies ◽  
Emergency Department Visits ◽  
Survey Study ◽  
Military Health ◽  
History Of ◽  
The Military ◽  
The Impact

ABSTRACT Introduction The prevalence of mild traumatic brain injury (mTBI) is commonly estimated based on indirect metrics such as emergency department visits and self-reporting tools. The study of postconcussive symptoms faces similar challenges because of their unspecific character and indistinct causality. In this article, we compare two nonclinical, epidemiological studies that addressed these two elements and were performed within a relatively narrow period in the state of Colorado. Materials and Methods De-identified datasets were obtained from a random digit-dialed survey study conducted by the Craig Hospital and a study surveying soldiers returning from deployment by Defense and Veteran Traumatic Brain Injury Center. Information pertinent to participants’ demographics, a history of mTBI, and symptom endorsement was extracted and homogenized in order to establish a parallel comparison between the populations of the two studies. Results From the 1,558 (Warrior Strong, 679; Craig Hospital, 879) records selected for analysis, 43% reported a history of at least one mTBI. The prevalence was significantly higher among individuals from the Defense and Veteran Traumatic Brain Injury Center study independent of gender or race. Repetitive injuries were reported by 15% of the total combined cohort and were more prevalent among males. Symptom endorsement was significantly higher in individuals with a positive history of mTBI, but over 80% of those with a negative history of mTBI endorsed at least one of the symptoms interrogated. Significant differences were observed between the military and the civilian populations in terms of the types and frequencies of the symptoms endorsed. Conclusions The prevalence of mTBI and associated symptoms identified in the two study populations is higher than that of previously reported. This suggests that not all individuals sustaining concussion seek medical care and highlights the limitations of using clinical reports to assess such estimates. The lack of appropriate mechanisms to determine symptom presence and causality remains a challenge. However, the differences observed in symptom reporting between cohorts raise questions about the nature of the symptoms, the impact on the quality of life for different individuals, and the effects on military health and force readiness.

scholarly journals Effect of the Mediterranean diet with and without weight loss on surrogate markers of cholesterol homeostasis in men with the metabolic syndrome

2011 ◽  
Vol 107 (5) ◽  
pp. 705-711 ◽  
Author(s):  
Caroline Richard ◽  
Patrick Couture ◽  
Sophie Desroches ◽  
Suzanne Benjannet ◽  
Nabil G. Seidah ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Weight Loss ◽  
Body Weight ◽  
Control Diet ◽  
Cholesterol Absorption ◽  
Energy Restriction ◽  
Surrogate Markers ◽  
The Metabolic Syndrome ◽  
The Mediterranean ◽  
The Impact

The mechanisms implicated in the LDL-cholesterol (LDL-C)-lowering effects of the Mediterranean-type diet (MedDiet) are unknown. The present study assessed the impact of the MedDiet consumed under controlled feeding conditions, with and without weight loss, on surrogate markers of cholesterol absorption, synthesis and clearance using plasma phytosterols, lathosterol and proprotein convertase subtilisin/kexin-9 (PCSK9) concentrations, respectively, in men with the metabolic syndrome. The subjects' diet (n19, 24–62 years) was first standardised to a baseline North American control diet (5 weeks) followed by a MedDiet (5 weeks), both under weight-maintaining isoenergetic feeding conditions. The participants then underwent a 20-week free-living energy restriction period (10 (sd3) % reduction in body weight,P < 0·01), followed by the consumption of the MedDiet (5 weeks) under controlled isoenergetic feeding conditions. The LDL-C-lowering effect of the MedDiet in the absence of weight loss ( − 9·9 %) was accompanied by significant reductions in plasma PCSK9 concentrations ( − 11·7 %,P < 0·01) and in the phytosterol:cholesterol ratio ( − 9·7 %,P < 0·01) compared with the control diet. The addition of weight loss to the MedDiet had no further impact on plasma LDL-C concentrations and on these surrogate markers of LDL clearance and cholesterol absorption. The present results suggest that the MedDiet reduces plasma LDL-C concentrations primarily by increasing LDL clearance and reducing cholesterol absorption, with no synergistic effect of body weight loss in this process.

Pancreatic injury, genetic variation of PNPLA3, and risk of pancreatic cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 141-141
Author(s):  
Mohammed Aly ◽  
Ibrahim Halil Sahin ◽  
Donghui Li ◽  
Mohamed Fahd Khalil ◽  
Ping Chang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Liver Cancer ◽  
Fatty Liver ◽  
Genetic Susceptibility ◽  
Fatty Infiltration ◽  
A Genome ◽  
Increased Risk ◽  
History Of ◽  
History Of Obesity ◽  
Pancreatic Steatosis

141 Background: Similar to primary liver cancer, obesity, diabetes mellitus and hepatitis B virus infection have been associated with increased risk of pancreatic cancer (PC) development. A genome-wide association study has reported that a polymorphic variant of the patatin-like phospholipase domain containing 3 (PNPLA3) gene was associated with a higher susceptibility to fatty liver and liver cancer. The relationship between this variation and PC has not been previously examined. We investigated the correlation in the degree of organ damage between the liver and the pancreas in patients with PC. In addition, we examined the effect of PNPLA3genetic variation (rs738409: C>G) on PC development. Methods: Using resources of our case-control study in MD Anderson Cancer Center, we analyzed 544 pathologically confirmed PC patients and 498 healthy controls. Cases and controls were frequency matched by age, gender, and race. Multivariate logistic regression analysis was performed to adjust for the confounding factors. Medical records of PC patients were reviewed for pancreatic and liver fatty changes. Results: We found that 18.8% of PC patients had evidence of pancreatic steatosis, fibrosis, or pancreatitis. Fatty liver was observed in 14.5% of PC patients which was frequently detected in patients with pancreatitis (p=0.002). A significant correlation between pancreatitis and cirrhosis was observed in PC patients with a prior history of obesity but not in patients without a history of obesity (p=0.001). On the other hand, we observed no significant association between PNPLA3 genotype and risk of PC. The adjusted odds ratio (OR) was 1.4 (95% confidence interval [CI], 0.7-2.7) for the homozygous variant GG genotype compared with the CC/CG genotypes. Conclusions: We concluded that despite the similarities between the liver and the pancreas, genetic susceptibility to fatty infiltration and its effect on cancer development may differ between the two organs. Evaluation and assessment of nonalcoholic fatty pancreatic disease (NAFPD) in PC patients and genetic susceptibility of NAFPD may be warranted in future research.

scholarly journals SUN-638 Perinatal DDE Exposure Disrupts Thermogenesis Early in Development

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Annalise vonderEmbse ◽  
Jason W Tong ◽  
Pamela J Lein ◽  
Michele La Merrill
Keyword(s):  
Body Weight ◽  
Area Under The Curve ◽  
Positive Association ◽  
Epidemiological Studies ◽  
Metabolic Phenotype ◽  
Infrared Analysis ◽  
Metabolic Dysfunction ◽  
Primary Metabolite ◽  
Brown Adipose ◽  
Cold Challenge

Abstract Numerous epidemiological studies have identified a positive association of exposure to the endocrine-disrupting pesticide dichlorodiphenyltrichloroethane (DDT) and its primary metabolite dichlorodiphenyldichloroethylene (DDE) with the risk of obesity. Of particular concern is the persistent metabolic dysfunction resulting from early life DDT and DDE exposures, evidenced as obesity, glucose intolerance, dyslipidemia, and impaired thermogenesis in adult rodents. However, little is known about the developmental timing and etiopathogenesis of this long-term DDT-related metabolic phenotype. This study aimed to address these knowledge gaps by evaluating endocrine phenotypes and thermogenic parameters at two postnatal (P) time points, P0 and P12, in C57BL/6J mice. Dams were orally gavaged with p,p’-DDT (1.7 mg/kg body weight [BW]), p,p’-DDE (1.31 mg/kg BW), or organic olive oil (vehicle) daily from gestational day (GD) 11.5-P0 or P5. Infrared analysis was then performed during a cold challenge. We further attempted to rescue the cold-challenged P12 mice by administering the β3-adrenergic receptor (AR)-agonist CL316,243 (CL), a direct stimulator of brown adipose (BAT) thermogenesis. At P0, area under the curve analysis revealed higher body temperatures in both males and females exposed to DDE compared to controls during the 9 min cold challenge. In addition, DDE-exposed females lost body heat at a significantly faster rate than sex-matched controls over the 9 min cold challenge. This occurred without any treatment-related differences in resting glucose, suprascapular BAT weight, or body weight for either sex at P0. To assess BAT-autonomous response to β3-AR stimulation during a cold challenge, P12 mice were exposed to the pharmacological β3-AR agonist, or PBS control in a 2x2 exposure design and suprascapular BAT temperature was evaluated via infrared analysis of the suprascapular surface at 10 min intervals. Blood glucose, BAT weight, and BW remained equivocal across all P12 treatment groups. However, BAT temperature was significantly decreased 10 min after cold- challenge in female P12 mice with perinatal DDE-exposure when compared to sex- and perinatal treatment-matched controls. This DDE effect among P12 female mice was rescued by CL. These data suggest that thermogenic dysfunction consequent to perinatal DDE exposure is detectable during postnatal development, well before the emergence of endocrine phenotypes. The CL rescue of the BAT thermogenic impairments observed after perinatal DDE exposure are consistent with DDE toxicities upstream in the β3-AR nerve circuitry. Additionally, the data highlight the emergence of an early postnatal sex divergence in DDE-related thermogenic dysfunction. We speculate that the effects of DDE on suprascapular BAT heat production result from prenatal alterations in sympathetic circuitry.

scholarly journals Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma

2021 ◽  
Vol 22 (19) ◽  
pp. 10219
Author(s):  
Shirin Hafezi ◽  
Maha Saber-Ayad ◽  
Wael M. Abdel-Rahman
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Human Cancer ◽  
Ductal Adenocarcinoma ◽  
Ras Gene ◽  
Kras Mutations ◽  
Oncogenic Mutations ◽  
History Of ◽  
Novel Therapeutic Strategies ◽  
The Impact

The most frequent mutated oncogene family in the history of human cancer is the RAS gene family, including NRAS, HRAS, and, most importantly, KRAS. A hallmark of pancreatic cancer, recalcitrant cancer with a very low survival rate, is the prevalence of oncogenic mutations in the KRAS gene. Due to this fact, studying the function of KRAS and the impact of its mutations on the tumor microenvironment (TME) is a priority for understanding pancreatic cancer progression and designing novel therapeutic strategies for the treatment of the dismal disease. Despite some recent enlightening studies, there is still a wide gap in our knowledge regarding the impact of KRAS mutations on different components of the pancreatic TME. In this review, we will present an updated summary of mutant KRAS role in the initiation, progression, and modulation of the TME of pancreatic ductal adenocarcinoma (PDAC). This review will highlight the intriguing link between diabetes mellitus and PDAC, as well as vitamin D as an adjuvant effective therapy via TME modulation of PDAC. We will also discuss different ongoing clinical trials that use KRAS oncogene signaling network as therapeutic targets.

scholarly journals Pancreatic Macrophages: Critical Players in Obesity-Promoted Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1946
Author(s):  
Yaroslav Teper ◽  
Guido Eibl
Keyword(s):  
Pancreatic Cancer ◽  
Immune Cells ◽  
Current Knowledge ◽  
Review Article ◽  
Cancer Development ◽  
Detailed Knowledge ◽  
Inflammatory Macrophages ◽  
Pancreatic Neoplasia ◽  
The Impact

Obesity is a known risk factor for the development of pancreatic cancer, one of the deadliest types of malignancies. In recent years it has become clear that the pancreatic microenvironment is critically involved and a contributing factor in accelerating pancreatic neoplasia. In this context obesity-associated chronic inflammation plays an important role. Among several immune cells, macrophages have been shown to contribute to obesity-induced tissue inflammation. This review article summarizes the current knowledge about the role of pancreatic macrophages in early pancreatic cancer development. It describes the heterogenous origin and mixture of pancreatic macrophages, their role in pancreatic endocrine and exocrine pathology, and the impact of obesity on islet and stromal macrophages. A model is postulated, by which during obesity monocytes are recruited into the pancreas, where they are polarized into pro-inflammatory macrophages that drive early pancreatic neoplasia. This occurs in the presence of local inflammatory, metabolic, and endocrine signals. A stronger appreciation and more detailed knowledge about the role of macrophages in early pancreatic cancer development will lead to innovative preventive or interceptive strategies.

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