Stresses, Volume 1, Issue 1 (March 2021) – 5 articles

The survival rate of pancreatic ductal adenocarcinoma (PDAC) patients is short, and PDAC is a cancer type that ranks fourth in the statistics regarding death due to cancer. Mutation in the KRAS gene, which plays a role in pancreatic cancer development, activates the PI3K/AKT/mTOR signaling pathway. The activity of the AMPK as a cellular energy sensor is one of the fundamental mechanisms that can induce effective therapeutic responses against CDK4/6 inhibitors via adjusting the cellular and tumor microenvironment stress management. The phosphorylation of AMPKα at the different phosphorylation residues such as Thr172 and Ser 377 causes metabolic differentiation in the cells following CDK4/6 inhibitor treatment in accordance with an increased cell cycle arrest and senescence under the control of different cellular players. In this study, we examined the competencies of the CDK4/6 inhibitors LY2835219 and PD-0332991 on the mechanism of cell survival and death based on AMPK signaling. Both CDK4/6 inhibitors LY2835219 and PD-0332991 modulated different molecular players on the PI3K/AKT/mTOR and AMPK signaling axis in different ways to reduce cell survival in a cell type dependent manner. These drugs are potential inducers of apoptosis and senescence that can alter the therapeutic efficacy cells. Full article

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC. Full article

Stress, mood, and eating behavior play an important role in appetite and weight regulation. In particular, ghrelin, as the only known orexigenic hormone, has been suggested to be an influential mediator in food intake responses to stress. The exact role of ghrelin in the hypothalamic–pituitary–adrenal axis is still unknown and further challenged by the psychological aspects of stress and eating behavior. This study aimed to assess the effect of chronic stress and subjective concern about eating on acute stress-induced changes in acylated ghrelin. In a 2-day study, sixteen healthy male participants were confronted with a stressful situation as well as a control situation. Additional measurements of heart rate, subjective hunger ratings, and subjective mood ratings were made to assess successful acute stress induction. The linear mixed model approach revealed a significant effect of acute stress on acylated ghrelin for a study-day*chronic-stress interaction (p < 0.001). Concern about eating did not affect acylated ghrelin levels after acute stress exposure. The significant interaction showed that lower chronic stress exposure was associated with a stronger acylated ghrelin response after acute stress exposure versus control condition. At the same time, participants with higher chronic stress exposure showed a blunted acylated ghrelin response after acute stress exposure compared to the control situation. Our findings indicate that chronic stress exposure can influence acylated ghrelin response after acute stress encounters, possibly affecting subsequent food intake and explaining the often diverse outcome in measurements of acute stress responses. Full article

Disruption of the homeostasis of zinc (Zn) and copper (Cu) has been associated with nephrotoxicity of cadmium (Cd). Herein, we report the results of a cross sectional analysis of urinary excretion of Zn, Cu, Cd and lead (Pb) in 392 Thais (mean age 33.6) living in an area of low-level environmental exposure to Cd and Pb, reflected by the respective median Cd and Pb excretion rates of 0.44 and 1.75 μg/g creatinine. Evidence for dysregulation of Zn and Cu homeostasis has emerged together with gender differentiated responses. In men, excretion rates for Zn and Cu were increased concomitantly, and their urinary Zn-to-Cu ratios were maintained. In women, only Cu excretion rose, causing a reduction in urinary Zn-to-Cu ratios. Only in women, urinary Zn-to-Cu ratios were associated with worse kidney function, assessed by estimated glomerular filtration rate (eGFR) (β = −7.76, p = 0.015). Only in men, a positive association was seen between eGFR and body iron stores, reflected by serum ferritin (β = 5.32, p = 0.030). Thus, co-exposure to Cd and Pb may disrupt the homeostasis of Zn and Cu more severely in women than men, while urinary Zn-to-Cu ratios and body iron stores can serve as predictors of an adverse effect of co-exposure to Cd and Pb. Full article