Browsing by Author "Zhou, Yi"

Now showing 1 - 5 of 5
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    Acid–base Homeostasis and Implications to the Phenotypic Behaviors of Cancer
    (Elsevier, 2023) Zhou, Yi; Chang, Wennan; Lu, Xiaoyu; Wang, Jin; Zhang, Chi; Xu, Ying; Medical and Molecular Genetics, School of Medicine
    Acid-base homeostasis is a fundamental property of living cells, and its persistent disruption in human cells can lead to a wide range of diseases. In this study, we conducted a computational modeling analysis of transcriptomic data of 4750 human tissue samples of 9 cancer types in The Cancer Genome Atlas (TCGA) database. Built on our previous study, we quantitatively estimated the average production rate of OH- by cytosolic Fenton reactions, which continuously disrupt the intracellular pH (pHi) homeostasis. Our predictions indicate that all or at least a subset of 43 reprogrammed metabolisms (RMs) are induced to produce net protons (H+) at comparable rates of Fenton reactions to keep the pHi stable. We then discovered that a number of well-known phenotypes of cancers, including increased growth rate, metastasis rate, and local immune cell composition, can be naturally explained in terms of the Fenton reaction level and the induced RMs. This study strongly suggests the possibility to have a unified framework for studies of cancer-inducing stressors, adaptive metabolic reprogramming, and cancerous behaviors. In addition, strong evidence is provided to demonstrate that a popular view that Na+/H+ exchangers along with lactic acid exporters and carbonic anhydrases are responsible for the intracellular alkalization and extracellular acidification in cancer may not be justified.
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    Co-expression based cancer staging and application
    (Nature Publishing group, 2020-06-30) Yu, Xiangchun; Cao, Sha; Zhou, Yi; Yu, Zhezhou; Xu, Ying; Biochemistry and Molecular Biology, School of Medicine
    A novel method is developed for predicting the stage of a cancer tissue based on the consistency level between the co-expression patterns in the given sample and samples in a specific stage. The basis for the prediction method is that cancer samples of the same stage share common functionalities as reflected by the co-expression patterns, which are distinct from samples in the other stages. Test results reveal that our prediction results are as good or potentially better than manually annotated stages by cancer pathologists. This new co-expression-based capability enables us to study how functionalities of cancer samples change as they evolve from early to the advanced stage. New and exciting results are discovered through such functional analyses, which offer new insights about what functions tend to be lost at what stage compared to the control tissues and similarly what new functions emerge as a cancer advances. To the best of our knowledge, this new capability represents the first computational method for accurately staging a cancer sample.
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    Maternal Diet Intervention Before Pregnancy Primes Offspring Lipid Metabolism in Liver
    (Springer Nature, 2020-04) Zhou, Yi; Peng, Hui; Xu, Huiting; Li, Jiangyuan; Golovko, Mikhail; Cheng, Henghui; Lynch, Ernest C.; Liu, Lin; McCauley, Naomi; Kennedy, Lindsey; Alpini, Gianfranco; Zhang, Ke K.; Xie, Linglin; Medicine, School of Medicine
    Nonalcoholic fatty liver disease (NAFLD) has a developmental origin and is influenced in utero. We aimed to evaluate if maternal diet intervention before pregnancy would be beneficial to reduce the risk of offspring NAFLD. In our study, female mice were either on a normal-fat diet (NF group), or a high-fat diet for 12 weeks and continued on this diet throughout pregnancy and lactation (HF group), or switched from HF-to-NF diet 1 week (H1N group), or 9 weeks (H9N group) before pregnancy. Compared with the NF offspring, the H1N and HF, but not the H9N offspring, displayed more severe hepatic steatosis and glucose intolerance. More specifically, an abnormal blood lipid panel was seen in the H1N offspring and abnormal hepatic free fatty acid composition was present in both the HF and H1N offspring, while the H9N offspring displayed both at normal levels. These physiological changes were associated with desensitized hepatic insulin/AKT signaling, increased expression of genes and proteins for de novo lipogenesis and cholesterol synthesis, decreased expression of genes and proteins for fatty acid oxidation, increased Pcsk9 expression, and hypoactivation of 5' AMP-activated protein kinase (AMPK) signaling in the HF and H1N offspring. However, these effects were completely or partially rescued in the H9N offspring. In summary, we found that early maternal diet intervention is effective in reducing the risk of offspring NAFLD caused by maternal HF diet. These findings provide significant support to develop effective diet intervention strategies and policies for prevention of obesity and NAFLD to promote optimal health outcomes for mothers and children.
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    Maternal High-Fat Diet Disrupted One-Carbon Metabolism in Offspring, contributing to Nonalcoholic Fatty Liver Disease
    (Wiley, 2021) Peng, Hui; Xu, Huiting; Wu, Jie; Li, Jiangyuan; Zhou, Yi; Ding, Zehuan; Siwko, Stefan K.; Yuan, Xianglin; Schalinske, Kevin L.; Alpini, Gianfranco; Zhang, Ke K.; Xie, Linglin; Medicine, School of Medicine
    Background & aims: Pregnant women may transmit their metabolic phenotypes to their offspring, enhancing the risk for nonalcoholic fatty liver disease (NAFLD); however, the molecular mechanisms remain unclear. Methods: Prior to pregnancy female mice were fed either a maternal normal-fat diet (NF-group, "no effectors"), or a maternal high-fat diet (HF-group, "persistent effectors"), or were transitioned from a HF to a NF diet before pregnancy (H9N-group, "effectors removal"), followed by pregnancy and lactation, and then offspring were fed high-fat diets after weaning. Offspring livers were analysed by functional studies, as well as next-generation sequencing for gene expression profiles and DNA methylation changes. Results: The HF, but not the H9N offspring, displayed glucose intolerance and hepatic steatosis. The HF offspring also displayed a disruption of lipid homeostasis associated with an altered methionine cycle and abnormal one-carbon metabolism that caused DNA hypermethylation and L-carnitine depletion associated with deactivated AMPK signalling and decreased expression of PPAR-α and genes for fatty acid oxidation. These changes were not present in H9N offspring. In addition, we identified maternal HF diet-induced genes involved in one-carbon metabolism that were associated with DNA methylation modifications in HF offspring. Importantly, the DNA methylation modifications and their associated gene expression changes were reversed in H9N offspring livers. Conclusions: Our results demonstrate for the first time that maternal HF diet disrupted the methionine cycle and one-carbon metabolism in offspring livers which further altered lipid homeostasis. CpG islands of specific genes involved in one-carbon metabolism modified by different maternal diets were identified.
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    STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation
    (Nature Publishing Group, 2014-12) Sheng, Wanqiang; Yang, Fan; Zhou, Yi; Yang, Henry; Low, Pey Yng; Kemeny, David Michael; Tan, Patrick; Moh, Akira; Kaplan, Mark H.; Zhang, Yongliang; Fu, Xin-Yuan; Department of Pediatrics, IU School of Medicine
    T helper (TH)-cell subsets, such as TH1 and TH17, mediate inflammation in both peripheral tissues and central nervous system. Here we show that STAT5 is required for T helper-cell pathogenicity in autoimmune neuroinflammation but not in experimental colitis. Although STAT5 promotes regulatory T cell generation and immune suppression, loss of STAT5 in CD4+ T cells resulted in diminished development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Our results showed that loss of encephalitogenic activity of STAT5-deficient autoreactive CD4+ T cells was independent of IFN-γ or interleukin 17 (IL-17) production, but was due to the impaired expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), a crucial mediator of T-cell pathogenicity. We further showed that IL-7-activated STAT5 promotes the generation of GM-CSF-producing CD4+ T cells, which were preferentially able to induce more severe EAE than TH17 or TH1 cells. Consistent with GM-CSF-producing cells being a distinct subset of TH cells, the differentiation program of these cells was distinct from that of TH17 or TH1 cells. We further found that IL-3 was secreted in a similar pattern as GM-CSF in this subset of TH cells. In conclusion, the IL-7-STAT5 axis promotes the generation of GM-CSF/IL-3-producing TH cells. These cells display a distinct transcriptional profile and may represent a novel subset of T helper cells which we designate as TH-GM.