bims-stacyt 2021-12-26 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2021–12–26
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Growth differentiation factor 15 is an early predictor for persistent organ failure and mortality in acute pancreatitis.
Multi-Omics Reveal the Immunological Role and the Theragnostic Value of miR-216a/GDF15 Axis in Human Colon Adenocarcinoma.
Transcription Factor ChREBP Mediates High Glucose-Evoked Increase in HIF-1α Content in Epithelial Cells of Renal Proximal Tubules.
TGFβ Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFβ Induced EMT in PDAC.
The Identification of a Novel Calcium-Dependent Link Between NAD+ and Glucose Deprivation-Induced Increases in Protein O-GlcNAcylation and ER Stress.
A ketogenic diet attenuates acute and chronic ischemic kidney injury and reduces markers of oxidative stress and inflammation.

Pancreatology. 2021 Dec 11. pii: S1424-3903(21)00648-7. [Epub ahead of print]

Growth differentiation factor 15 is an early predictor for persistent organ failure and mortality in acute pancreatitis.

Qingyuan Tan, Cheng Hu, Zhiyao Chen, Tao Jin, Lan Li, Ping Zhu, Yun Ma, Ziqi Lin, Weiwei Chen, Na Shi, Xiaoxin Zhang, Kun Jiang, Tingting Liu, Xiaonan Yang, Jia Guo, Wei Huang, Stephen J Pandol, Lihui Deng, Qing Xia.

   OBJECTIVES: Early prediction of persistent organ failure (POF) is crucial for patients with acute pancreatitis (AP). Growth differentiation factor 15 (GDF15), also known as macrophage inhibitory cytokine 1 (MIC-1), is associated with inflammatory responses. We investigated changes in plasma GDF15 and assessed its predictive value in AP.
METHODS: The study included 290 consecutive patients with AP admitted within 36 h after symptoms onset. Clinical data obtained during hospitalization were collected. Plasma GDF15 levels were determined using enzyme-linked immunosorbent assays. The predictive value of GDF15 for POF was analyzed.
RESULTS: There were 105 mild, 111 moderately severe, and 74 severe AP patients. Plasma GDF15 peak level were measured on admission, and significantly declined on the 3rd and 7th day. Admission GDF15 predicted POF and mortality with areas under the curve (AUC) of 0.847 (95% confidence interval [CI] 0.798-0.895) and 0.934 (95% CI 0.887-0.980), respectively. Admission GDF15, Bedside Index of Severity in Acute Pancreatitis, and hematocrit were independent factors for POF by univariate and multivariate logistic regression, and the nomogram built on these variables showed good performance (optimism-corrected c-statistic = 0.921). The combined predictive model increased the POF accuracy with an AUC 0.925 (95% CI 0.894-0.956), a net reclassification improvement of 0.3024 (95% CI: 0.1482-0.4565, P < 0.001), and an integrated discrimination index of 0.11 (95% CI 0.0497-0.1703; P < 0.001).
CONCLUSIONS: Plasma GDF15 measured within 48 h of symptom onset could help predict POF and mortality in AP patients.

Keywords:  Acute pancreatitis; Growth differentiation factor 15; Mortality; Persistent organ failure; Prediction

DOI:  https://doi.org/10.1016/j.pan.2021.12.001
Int J Mol Sci. 2021 Dec 20. pii: 13636. [Epub ahead of print]22(24):

Multi-Omics Reveal the Immunological Role and the Theragnostic Value of miR-216a/GDF15 Axis in Human Colon Adenocarcinoma.

Chun-Bin Tung, Chia-Ying Li, Hung-Yu Lin.

  Colon adenocarcinoma (COAD) is the most common type of gastrointestinal cancer and is still the third leading cause of cancer-related mortality worldwide. Accurate screening tools for early diagnosis and prediction of prognosis and precision treatment strategies are urgently required to accommodate the unmet medical needs of COAD management. We herein aimed to explore the significance of the microRNA (miR)-216a/growth differentiation factor 15 (GDF15) axis in terms of clinical value, tumor immunity, and potential mechanisms in COAD by using multi-omic analysis. The gene expression levels of miR-216a and GDF15 showed an increase in the COAD group compared to those of the normal group. The expression of miR-216a presented a negative correlation with GDF15 in COAD tumor tissue. The use of an in vitro luciferase reporter assay and bioinformatic prediction revealed that miR-216a-3p acted toward translational inhibition on GDF15 by targeting its 3'untranslated region (UTR) site. High miR-216a expression was associated with decreased overall survival (OS), while the high expression of GDF15 was associated with increased OS. Enriched type 1 T-helper (Th1), enriched regulatory T (Treg), enriched eosinophils, and decreased nature killer T-cells (NKTs) in COAD tumor tissue may play counteracting factors on the tumor-regulatory effects of miR-216a and GDF15. In addition, high GDF15 expression had associations with suppressed immunoinhibitory genes and negative correlations with the infiltration of macrophages and endothelial cells. The enrichment analysis revealed that GDF15 and its co-expression network may be implicated in mitochondrial organization, apoptosis signaling, and endoplasmic reticulum (ER) stress response. The Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) analysis identified that Gemcitabine acted as a precision treatment for COAD when GDF15 expression was low. This study supports the miR-216a/GDF15 axis as a diagnostic/prognostic panel for COAD, identifies Th1, Treg, eosinophils, and NKTs as counteracting factors, indicates potential relationships underlying immunomodulation, mitochondrial organization, apoptotic signaling, and ER stress and unveil Gemcitabine as a potential drug for the development of treatment strategy when combined with targeting GDF15.

Keywords:  Gemcitabine; colon adenocarcinoma; diagnostic biomarker; growth differentiation factor 15; immune infiltration; immunomodulation; miR-216a; precision treatment; prognostic biomarker

DOI:  https://doi.org/10.3390/ijms222413636
Int J Mol Sci. 2021 Dec 10. pii: 13299. [Epub ahead of print]22(24):

Transcription Factor ChREBP Mediates High Glucose-Evoked Increase in HIF-1α Content in Epithelial Cells of Renal Proximal Tubules.

Aleksandra Owczarek, Katarzyna B Gieczewska, Robert Jarzyna, Zuzanna Frydzinska, Katarzyna Winiarska.

  Hyperglycemia/diabetes appears to be accompanied by the state of hypoxia, which especially affects kidneys. The aim of the study was to elucidate the mechanism of high glucose action on HIF-1α expression in renal proximal tubule epithelial cells. The research hypotheses included: (1) the participation of transcription factor ChREBP; and (2) the involvement of the effects resulting from pseudohypoxia, i.e., lowered intracellular NAD+/NADH ratio. The experiments were performed on HK-2 cells and primary cells: D-RPTEC (Diseased Human Renal Proximal Tubule Epithelial Cells-Diabetes Type II) and RPTEC (Renal Proximal Tubule Epithelial Cells). Protein and mRNA contents were determined by Western blot and RT-qPCR, respectively. ChREBP binding to DNA was detected applying chromatin immunoprecipitation, followed by RT-qPCR. Gene knockdown was performed using siRNA. Sirtuin activity and NAD+/NADH ratio were measured with commercially available kits. It was found that high glucose in HK-2 cells incubated under normoxic conditions: (1) activated transcription of HIF-1 target genes, elevated HIF-1α and ChREBP content, and increased the efficacy of ChREBP binding to promoter region of HIF1A gene; and (2), although it lowered NAD+/NADH ratio, it affected neither sirtuin activity nor HIF-1α acetylation level. The stimulatory effect of high glucose on HIF-1α expression was not observed upon the knockdown of ChREBP encoding gene. Experiments on RPTEC and D-RPTEC cells demonstrated that HIF-1α content in diabetic proximal tubular cells was lower than that in normal ones but remained high glucose-sensitive, and the latter phenomenon was mediated by ChREBP. Thus, it is concluded that the mechanism of high glucose-evoked increase in HIF-1α content in renal proximal tubule endothelial cells involves activation of ChREBP, indirectly capable of HIF1A gene up-regulation.

Keywords:  NAD+/NADH ratio; carbohydrate response element binding protein (ChREBP); high glucose; hypoxia-inducible factor-1 (HIF-1); renal proximal tubules; sirtuin 1

DOI:  https://doi.org/10.3390/ijms222413299
Cancers (Basel). 2021 Dec 09. pii: 6204. [Epub ahead of print]13(24):

TGFβ Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFβ Induced EMT in PDAC.

Meena U Rajagopal, Shivani Bansal, Prabhjit Kaur, Shreyans K Jain, Tatiana Altadil, Charles P Hinzman, Yaoxiang Li, Joanna Moulton, Baldev Singh, Sunil Bansal, Siddheshwar Kisan Chauthe, Rajbir Singh, Partha P Banerjee, Mark Mapstone, Massimo S Fiandaca, Howard J Federoff, Keith Unger, Jill P Smith, Amrita K Cheema.

  Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFβ), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFβ-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFβ treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes.

Keywords:  9-cis retinoic acidPANC-1 cells; TGF beta; epithelial mesenchymal transition; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers13246204
Front Mol Biosci. 2021 ;8 780865

The Identification of a Novel Calcium-Dependent Link Between NAD+ and Glucose Deprivation-Induced Increases in Protein O-GlcNAcylation and ER Stress.

Luyun Zou, Helen E Collins, Martin E Young, Jianhua Zhang, Adam R Wende, Victor M Darley-Usmar, John C Chatham.

  The modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) is associated with the regulation of numerous cellular processes. Despite the importance of O-GlcNAc in mediating cellular function our understanding of the mechanisms that regulate O-GlcNAc levels is limited. One factor known to regulate protein O-GlcNAc levels is nutrient availability; however, the fact that nutrient deficient states such as ischemia increase O-GlcNAc levels suggests that other factors also contribute to regulating O-GlcNAc levels. We have previously reported that in unstressed cardiomyocytes exogenous NAD+ resulted in a time and dose dependent decrease in O-GlcNAc levels. Therefore, we postulated that NAD+ and cellular O-GlcNAc levels may be coordinately regulated. Using glucose deprivation as a model system in an immortalized human ventricular cell line, we examined the influence of extracellular NAD+ on cellular O-GlcNAc levels and ER stress in the presence and absence of glucose. We found that NAD+ completely blocked the increase in O-GlcNAc induced by glucose deprivation and suppressed the activation of ER stress. The NAD+ metabolite cyclic ADP-ribose (cADPR) had similar effects on O-GlcNAc and ER stress suggesting a common underlying mechanism. cADPR is a ryanodine receptor (RyR) agonist and like caffeine, which also activates the RyR, both mimicked the effects of NAD+. SERCA inhibition, which also reduces ER/SR Ca2+ levels had similar effects to both NAD+ and cADPR on O-GlcNAc and ER stress responses to glucose deprivation. The observation that NAD+, cADPR, and caffeine all attenuated the increase in O-GlcNAc and ER stress in response to glucose deprivation, suggests a potential common mechanism, linked to ER/SR Ca2+ levels, underlying their activation. Moreover, we showed that TRPM2, a plasma membrane cation channel was necessary for the cellular responses to glucose deprivation. Collectively, these findings support a novel Ca2+-dependent mechanism underlying glucose deprivation induced increase in O-GlcNAc and ER stress.

Keywords:  ER stress; NAD+; O-GlcNAc; TRPM2 cation channel; calcium; glucose deprivation

DOI:  https://doi.org/10.3389/fmolb.2021.780865
Life Sci. 2021 Dec 16. pii: S0024-3205(21)01214-5. [Epub ahead of print]289 120227

A ketogenic diet attenuates acute and chronic ischemic kidney injury and reduces markers of oxidative stress and inflammation.

Pedro Rojas-Morales, Juan Carlos León-Contreras, Mónica Sánchez-Tapia, Alejandro Silva-Palacios, Agustina Cano-Martínez, Susana González-Reyes, Angélica Saraí Jiménez-Osorio, Rogelio Hernández-Pando, Horacio Osorio-Alonso, Laura Gabriela Sánchez-Lozada, Armando R Tovar, José Pedraza-Chaverri, Edilia Tapia.

   BACKGROUND: Ischemic kidney injury is a common clinical condition resulting from transient interruption of the kidney's normal blood flow, leading to oxidative stress, inflammation, and kidney dysfunction. The ketogenic diet (KD), a low-carbohydrate, high-fat diet that stimulates endogenous ketone body production, has potent antioxidant and anti-inflammatory effects in distinct tissues and might thus protect the kidney against ischemia and reperfusion (IR) injury.
MAIN METHODS: Male Wistar rats were fed a KD or a control diet (CD) for three days before analyzing metabolic parameters or testing nephroprotection. We used two different models of kidney IR injury and conducted biochemical, histological, and Western blot analyses at 24 h and two weeks after surgery.
KEY FINDINGS: Acute KD feeding caused protein acetylation, liver AMPK activation, and increased resistance to IR-induced kidney injury. At 24 h after IR, rats on KD presented reduced tubular damage and improved kidney functioning compared to rats fed with a CD. KD attenuated oxidative damage (protein nitration, 4-HNE adducts, and 8-OHdG), increased antioxidant defenses (GPx and SOD activity), and reduced inflammatory intermediates (IL6, TNFα, MCP1), p50 NF-κB expression, and cellular infiltration. Also, KD prevented interstitial fibrosis development at two weeks, up-regulation of HSP70, and chronic Klotho deficiency.
SIGNIFICANCE: Our findings demonstrate for the first time that short-term KD increases tolerance to experimental kidney ischemia, opening the opportunity for future therapeutic exploration of a dietary preconditioning strategy to convey kidney protection in the clinic.

Keywords:  Inflammation; Ketogenic diet; Ketosis; Kidney fibrosis; Kidney ischemia; Oxidative stress

DOI:  https://doi.org/10.1016/j.lfs.2021.120227