bims-stacyt 2022-04-17 papers

Nutrients. 2022 Apr 01. pii: 1470. [Epub ahead of print]14(7):

Meals That Differ in Nutrient Composition and Inflammatory Potential Do Not Differentially Impact Postprandial Circulating Cytokines in Older Adults above a Healthy Weight.

Stephanie Cowan, Simone Gibson, Andrew J Sinclair, Helen Truby, Aimee L Dordevic.

In this exploratory study, mixed meals specifically formulated to differ in inflammatory potential were tested to determine whether they could differentially impact circulating levels of inflammatory markers in adults above a healthy weight. Complete data were analyzed from 11 adults (6 males and 5 females) aged 54-63 years with median BMI of 30.0 (27.1-31.6) kg/m². In a crossover study design, each participant consumed an isocaloric (2.2 MJ) meal with either a low (Anti-meal), moderate (Neutr-meal), or high (Pro-meal) inflammatory potential. Fasting and postprandial blood samples were analyzed for plasma levels of IL-6, IL-1β, TNF-α, IL-10, and metabolic makers. Postprandial plasma IL-6, IL-1β, TNF-α, and IL-10 incremental areas under the curve (iAUC) were not different between the three meals (p > 0.05). There was a trend of an increase in IL-6 with time in all three meals, but no changes were obvious for the other measured cytokines. The Pro-meal induced an increased postprandial iAUC for triglycerides compared to the Anti-meal and Neutr-meal (p = 0.004 and p = 0.012, respectively). Single meals, regardless of their theoretical inflammatory potential, did not substantially shift circulating inflammatory markers, suggesting that longer-term dietary patterns are important rather than single dietary exposures in the pathology of metabolic conditions.

Keywords: cardiovascular disease; cytokines; dietary inflammatory index; inflammation; obesity; postprandial

DOI: https://doi.org/10.3390/nu14071470

Mol Cell Oncol. 2022 ;9(1): 2039038

Immunogenic cell stress and injury versus immunogenic cell death: implications for improving cancer treatment with immune checkpoint blockade.

Ganapathy Sriram, Tiffany R Emmons, Lauren E Milling, Darrell J Irvine, Michael B Yaffe.

Inducing immunogenic tumor cell death to stimulate the response to immune checkpoint blockade has not yet been effectively translated into clinical practice. We recently discovered that stressed/injured but still viable tumor cells are critical for T-cell priming and substantially improve responses to systemic anti-PD1/CTLA4. Therapeutic tumor cell injury, rather than complete killing, in the tumor microenvironment may enhance efficacy of immunotherapy in various cancers.

Keywords: DNA damage; Immune checkpoint blockade; immunogenic cell stress, immunogenic cell injury; tumor immunotherapy

DOI: https://doi.org/10.1080/23723556.2022.2039038

Comp Med. 2022 Apr 11.

Effects of Exogenous ATP on Melanoma Growth and Tumor Metabolism in C57BL/6 Mice.

Yali Lei, Xu Zhou, Yang Zhao, Jianfa Zhang.

Altered energy metabolism (glucose, lipid, amino acid) is a hallmark of cancer growth that provides the theoretical basis for the development of metabolic therapies as cancer treatments. ATP is one of the major biochemical constituents of the tumor microenvironment. ATP promotes tumor progression or suppression depending on various factors, including concentration and tumor type. Here we evaluated the antitumor effect of extracellular ATP on melanoma and the potential underlying mechanisms. A subcutaneous tumor model in mice was used to investigate the antitumor effects of ATP. Major lymphocyte cell changes and intratumoral metabolic changes were assessed. Metabolomic analysis (1H nuclear magnetic resonance spectroscopy) was performed on tumor samples. We measured the activities of lactate dehydrogenase A (LDHA) and LDHB in the excised tumors and serum and found that ATP and its metabolites affected the proliferation of and LDHA activity in B16F10 cells, a murine melanoma cell line. In addition, treatment with ATP dose-dependently reduced tumor size in melanoma-bearing mice. Moreover, flow cytometry analysis demonstrated that the antitumor effect of ATP was not achieved through changes in T-cell or B-cell subsets. Metabolomics analysis revealed that ATP treatment simultaneously reduced multiple intratumoral metabolites related to energy metabolism as well as serum and tumor LDHA activities. Furthermore, both ATP and its metabolites significantly suppressed both tumor cell proliferation and LDHA activity in the melanoma cell line. Our results in vivo and in vitro indicate that exogenous ATP inhibits melanoma growth in association with altered intratumoral metabolism.

DOI: https://doi.org/10.30802/AALAS-CM-21-000099

J Cell Physiol. 2022 Apr 12.

HIF-1α plays an essential role in BMP9-mediated osteoblast differentiation through the induction of a glycolytic enzyme, PDK1.

Muhammad Subhan Amir, Norika Chiba, Chang Hwan Seong, Joji Kusuyama, Nahoko Eiraku, Tomokazu Ohnishi, Norifumi Nakamura, Tetsuya Matsuguchi.

Bone homeostasis is regulated by bone morphogenic proteins (BMPs), among which BMP9 is one of the most osteogenic. Here, we have found that BMP9 rapidly increases the protein expression of hypoxia-inducible factor-1α (HIF-1α) in osteoblasts under normoxic conditions more efficiently than BMP2 or BMP4. A combination of BMP9 and hypoxia further increased HIF-1α protein expression. HIF-1α protein induction by BMP9 is not accompanied by messenger RNA (mRNA) increase and is inhibited by the activation of prolyl hydroxylase domain (PHD)-containing protein, indicating that BMP9 induces HIF-1α protein expression by inhibiting PHD-mediated protein degradation. BMP9-induced HIF-1α protein increase was abrogated by inhibitors of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) kinase, indicating that it is mediated by PI3K-AKT signaling pathway. BMP9 increased mRNA expression of pyruvate dehydrogenase kinase 1 (PDK1), a glycolytic enzyme, and vascular endothelial growth factor-A (VEGF-A), an angiogenic factor, in osteoblasts. Notably, BMP9-induced mRNA expression of PDK1, but not that of VEGF-A, was significantly inhibited by small interference RNA-mediated knockdown of Hif-1α. BMP9-induced matrix mineralization and osteogenic marker gene expressions were significantly inhibited by chemical inhibition and gene knockdown of either Hif-1α or Pdk-1, respectively. Since increased glycolysis is an essential feature of differentiated osteoblasts, our findings indicate that HIF-1α expression is important in BMP9-mediated osteoblast differentiation through the induction of PDK1.

Keywords: bone morphogenetic protein 9 (BMP9); differentiation; glycolysis; hypoxia-inducible factor 1α (HIF-1α); osteoblast; pyruvate dehydrogenase kinase 1 (PDK1)

DOI: https://doi.org/10.1002/jcp.30752

Food Chem (Oxf). 2022 Jul 30. 4 100079

Sodium butyrate reduces endoplasmic reticulum stress by modulating CHOP and empowers favorable anti-inflammatory adipose tissue immune-metabolism in HFD fed mice model of obesity.

Vinita Kushwaha, Prashant Rai, Salil Varshney, Sanchita Gupta, Nilesh Khandelwal, Durgesh Kumar, Anil Nilkanth Gaikwad.

Over the past decade, the gut microbiome has been linked to several diseases including gastrointestinal diseases, cancer, immune disorder and metabolic syndrome. Shifts in the gut bacterial population affect the overall metabolic health status leading towards obesity and Type II diabetes mellitus. Secondary metabolites secreted by the gut microbiome interact with various host-sensing signalling pathways and are responsible for functional modulation of immune resident cells in metabolic tissues (Blüher, 2019). Of these, short- chain fatty acids (SCFAs) i.e., acetate, propionate and butyrate have been significantly correlated with the disposition of diabetes and metabolic disorder. The altered gut microbial population depletes the intestinal barrier causing entry of LPS into circulation and towards metabolic tissues triggering pro-inflammatory responses. As butyrate has been known to maintain intestinal integrity, we aimed to assess the apparent effect of externally given sodium butyrate [NaB] on immuno-metabolic profiling of adipose tissue, and its association with metabolic and inflammatory status of adipose tissue. To assess this, we put groups of C57BL/6 mice i.e., Control fed with a regular chow diet and another group that was fed on a high fat diet (HFD, 60%) for 8 weeks. Following this, the HFD group were further subdivided into two groups one fed with HFD and the other with HFD + NaB (5%w/w) for another 8 weeks. Body composition, weight gain, body adiposity and biochemical parameters were assessed. NaB fed group showed an improved metabolic profile compared to HFD fed group. Administration of NaB also improved glucose tolerance capacity and insulin sensitivity as determined by IPGTT and ITT profiles. Earlier reports have shown gut leakage and increased LPS in circulation is the primary cause of setting up inflammation at the tissue level. Our studies exhibited that, NaB increased the expression of tight junction proteins of intestinal linings and thereby enhanced intestinal barrier integrity. The FITC dextran permeability assay further confirmed this enhanced intestinal barrier integrity. We assessed the quantitative and relative population of different types of resident immune cells from a stromal vascular fraction of adipose tissue. Flow cytometry studies revealed significantly increased M2 (CD206+ ) macrophages and Tregs (CD25+ ) relative to the M1 macrophage population and CD4+ T cells respectively in NaB treated mice, suggesting its potential role in alleviating the inflammatory profile. In a nutshell, taken together better glucose tolerance, better gut health, reduced inflammatory adipose tissue immune cells, suggest potential beneficial role of sodium butyrate in alleviating overall inflammation and metabolic dysfunction associated with obesity.

Keywords: Adipose tissue; ER stress; Immune cell population; Obesity; SCFA

DOI: https://doi.org/10.1016/j.fochms.2022.100079