Publications by authors named "Ke K Zhang"

28 Publications

  • Page 1 of 1

Maternal One-Carbon Supplement Reduced the Risk of Non-Alcoholic Fatty Liver Disease in Male Offspring.

Nutrients 2022 Jun 19;14(12). Epub 2022 Jun 19.

Department of Nutrition, Texas A&M University, College Station, TX 77840, USA.

Recent studies have suggested that prevention of obesity and non-alcoholic fatty liver disease (NAFLD) should start with maternal dietary management. We previously reported disrupted methionine cycle, associated with NAFLD, in male offspring liver due to maternal high-fat (HF) diet, thus we hypothesize that maternal one-carbon supplement may reduce the risk of NAFLD in offspring via the normalizing methionine cycle. To test it, female mice (F0) were exposed to either a maternal normal-fat diet (NF group) a maternal HF diet (HF group), or a maternal methyl donor supplement (H1S or H2S group) during gestation and lactation. The offspring male mice (F1) were exposed to a postweaning HF diet to promote NAFLD. While the HF offspring displayed obesity, glucose intolerance and hepatic steatosis, the H1S and H2S offspring avoided hepatic steatosis. This phenotype was associated with the normalization of the methionine cycle and the restoration of L-carnitine and AMPK activity. Furthermore, maternal HF diet induced epigenetic regulation of important genes involved in fatty acid oxidation and oxidative phosphorylation via DNA methylation modifications, which were recovered by maternal one-carbon supplementation. Our study provides evidence that maternal one-carbon supplement can reverse/block the adverse effects of maternal HF diet on promoting offspring NAFLD, suggesting a potential nutritional strategy that is administered to mothers to prevent NAFLD in the offspring.
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http://dx.doi.org/10.3390/nu14122545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9228996PMC
June 2022

Targeting the Tumor Microenvironment in Acute Myeloid Leukemia: The Future of Immunotherapy and Natural Products.

Biomedicines 2022 Jun 14;10(6). Epub 2022 Jun 14.

Department of Oncology/Hematology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA.

The tumor microenvironment (TME) plays an essential role in the development, proliferation, and survival of leukemic blasts in acute myeloid leukemia (AML). Within the bone marrow and peripheral blood, various phenotypically and functionally altered cells in the TME provide critical signals to suppress the anti-tumor immune response, allowing tumor cells to evade elimination. Thus, unraveling the complex interplay between AML and its microenvironment may have important clinical implications and are essential to directing the development of novel targeted therapies. This review summarizes recent advancements in our understanding of the AML TME and its ramifications on current immunotherapeutic strategies. We further review the role of natural products in modulating the TME to enhance response to immunotherapy.
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http://dx.doi.org/10.3390/biomedicines10061410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9219790PMC
June 2022

Disrupting Osr1 expression promoted hepatic steatosis and inflammation induced by high-fat diet in the mouse model.

PLoS One 2022 3;17(6):e0268344. Epub 2022 Jun 3.

Department of Nutrition, Texas A&M University, College Station, TX, United States of America.

NAFLD, regarded as the hepatic manifestation of metabolic syndrome, is the most common form of liver disease in the United States. The Odd-skipped related 1 (Osr1) gene was previously reported to play a critical role in embryonic development and as a cancer repressor gene, however its role in overnutrition induced fatty liver disease has never been explored. Induced by a high-fat diet (HFD) for 10-week, the development and the progression of NAFLD was evaluated in either Osr1 heterozygote (Osr1 group) or wildtype mice (WT group). The Osr1 mice, regardless of sex, exhibited more severe steatosis compared to WT. Upregulation of lipogenesis protein including Srebp1c was detected in the Osr1 group, together with impaired IRS2 expression and overactivated Akt/mTOR signaling. In addition, the Osr1 mice had decreased bile acid synthesis in the liver with depressed hepatic expression of Cyp7a1 and Cyp27a1. Furthermore, there was more macrophage infiltration with enhanced expression of Il-1β and TNF-α in the Osr1 liver, associated with overactivation of JNK and NF-κB signaling. In summary, our study showed that Osr1 plays an important role in regulating the lipid homeostasis and hepatic inflammation, whose disruption contributes to NAFLD progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0268344PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9165803PMC
June 2022

Targeting TKI-Activated NFKB2-MIF/CXCLs-CXCR2 Signaling Pathways in FLT3 Mutated Acute Myeloid Leukemia Reduced Blast Viability.

Biomedicines 2022 Apr 30;10(5). Epub 2022 Apr 30.

Division of Hematology and Oncology, Department of Medicine, Loma Linda University, Loma Linda, CA 92354, USA.

Disease relapse is a common cause of treatment failure in FMS-like tyrosine kinase 3 (FLT3) mutated acute myeloid leukemia (AML). In this study, to identify therapeutic targets responsible for the survival and proliferation of leukemic cells (blasts) with FLT3 mutations after gilteritinib (GILT, a 2nd generation tyrosine kinase inhibitor (TKI)) treatment, we performed proteomic screening of cytokine release and in vitro/ex vivo studies to investigate their associated signaling pathways and transcriptional regulation. Here, we report that macrophage migration inhibition factor (MIF) was significantly increased in the supernatant of GILT-treated blasts when compared to untreated controls. Additionally, the GILT-treated blasts that survived were found to exhibit higher expressions of the gene and protein, a common receptor for MIF and pro-inflammatory cytokines. The supplementation of exogenous MIF to GILT-treated blasts revealed a group of CD44High+ cells that might be responsible for the relapse. Furthermore, we identified the highly activated non-classical NFKB2 pathway after GILT-treatment. The siRNA transient knockdown of significantly reduced the gene expressions of , , and . Finally, treatments of AML patient samples ex vivo demonstrated that the combination of a pharmaceutical inhibitor of the NFKB family and GILT can effectively suppress primary blasts' secretion of tumor-promoting cytokines, such as CXCL1/5/8. In summary, we provide the first evidence that targeting treatment-activated compensatory pathways, such as the NFKB2-MIF/CXCLs-CXCR2 axis could be a novel therapeutic strategy to overcome TKI-resistance and effectively treat AML patients with FLT3 mutations.
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http://dx.doi.org/10.3390/biomedicines10051038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9138861PMC
April 2022

Maternal high-fat diet disrupted one-carbon metabolism in offspring, contributing to nonalcoholic fatty liver disease.

Liver Int 2021 06 16;41(6):1305-1319. Epub 2021 Feb 16.

Department of Nutrition, Texas A&M University, College Station, TX, USA.

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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http://dx.doi.org/10.1111/liv.14811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137550PMC
June 2021

Osr1 regulates hepatic inflammation and cell survival in the progression of non-alcoholic fatty liver disease.

Lab Invest 2021 04 1;101(4):477-489. Epub 2020 Oct 1.

Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.

Odd-skipped related 1 (Osr1) is a novel tumor suppressor gene in several cancer cell lines. Non-alcoholic steatohepatitis (NASH) is considered as a high-risk factor for hepatocellular carcinoma (HCC). This study is aimed to investigate the novel role of Osr1 in promoting the progression of hepatic steatosis to NASH. Following 12 weeks of diethylnitrosamine (DEN) and high-fat diet (HFD), wildtype (WT) and Osr1 heterozygous (Osr1) male mice were examined for liver injuries. Osr1 mice displayed worsen liver injury with higher serum alanine aminotransferase levels than the WT mice. The Osr1 mice also revealed early signs of collagen deposition with increased hepatic Tgfb and Fn1 expression. There was overactivation of both JNK and NF-κB signaling in the Osr1 liver, along with accumulation of F4/80+ cells and enhanced hepatic expression of Il-1b and Il-6. Moreover, the Osr1 liver displayed hyperphosphorylation of AKT/mTOR signaling, associated with overexpression of Bcl-2. In addition, Osr1 and WT mice displayed differences in the DNA methylome of the liver cells. Specifically, Osr1-responsible CpG islands of Ccl3 and Pcgf2, genes for inflammation and macrophage infiltration, were further identified. Taken together, Osr1 plays an important role in regulating cell inflammation and survival through multiple signaling pathways and DNA methylation modification for NAFLD progression.
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http://dx.doi.org/10.1038/s41374-020-00493-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987871PMC
April 2021

Pregestational diet transition to normal-fat diet avoids the deterioration of pancreatic β-cell function in male offspring induced by maternal high-fat diet.

J Nutr Biochem 2020 12 16;86:108495. Epub 2020 Sep 16.

Department of Nutrition, Texas A&M University, College Station, TX 77843, USA. Electronic address:

Novel progress has been made to understand the adverse pathophysiology in the pancreas of offspring exposed to overnutrition in utero. Our study is the first to evaluate whether the adverse effects of maternal overnutrition on offspring β-cell function are reversible or preventable through preconception maternal diet interventions. Herein, offspring mice were exposed in utero to one of the following: maternal normal-fat diet (NF group), maternal high-fat diet (HF group) or maternal diet transition from an HF to NF diet 9 weeks before pregnancy (H9N group). Offspring mice were subjected to postweaning HF diet for 12 weeks. HF offspring, but not H9N, displayed glucose intolerance and insulin resistance. HF male offspring had enlarged islet β-cells with reduced β-cell density, whereas, H9N male offspring did not show these changes. Co-immunofluorescent (Co-IF) staining of glucose transporter 2 (Glut2) and insulin (Ins) revealed significantly more Glut2Ins cells, indicative of insulin degranulation, in HF male offspring but not H9N. In addition, Co-IF of insulin and p-H3S10 indicated that β cells of HF male offspring, but not H9N, had proliferation defects likely due to inhibited protein kinase B (AKT) phosphorylation. In summary, our study demonstrates that maternal H9N diet effectively prevents functional deterioration of β cells seen in HF male offspring by avoiding β-cell proliferation defects and degranulation.
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http://dx.doi.org/10.1016/j.jnutbio.2020.108495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643480PMC
December 2020

In ovo hyperglycemia causes congenital limb defects in chicken embryos via disruption of cell proliferation and apoptosis.

Biochim Biophys Acta Mol Basis Dis 2020 12 30;1866(12):165955. Epub 2020 Aug 30.

Department of Nutrition, Texas A&M University, College Station, TX, United States of America. Electronic address:

While the correlation between diabetes during pregnancy and birth defects is well-established, how hyperglycemia causes developmental abnormalities remains unclear. In this study, we developed a novel "hyperglycemic" chicken embryonic model by administrating various doses of glucose to fertilized eggs at embryonic stages HH16 or HH24. When the embryos were collected at HH35, the LD50 was 1.57 g/Kg under HH16 treatment and 0.93 g/Kg under HH24 treatment, indicating that "hyperglycemic" environments can be lethal for the embryos. When exposed to a dose equal to or higher than 1 g/Kg glucose at HH16 or HH24, more than 40% of the surviving chicken embryos displayed heart defects and/or limb defects. The limb defects were associated with proliferation defects of both the wing and leg buds indicated by reduced numbers of p-H3S10 labeled cells. These limb defects were also associated with ectopic apoptosis in the leg bud and expression changes of key apoptotic genes. Furthermore, glucose treatment induced decreased expression of genes involved in Shh-signaling, chondrogenesis, and digit patterning in the limb bud. In summary, our data demonstrated that a high-glucose environment induces congenital heart and limb defects associated with disrupted cell proliferation and apoptosis, possibly through depressed Shh-signaling.
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http://dx.doi.org/10.1016/j.bbadis.2020.165955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680440PMC
December 2020

Maternal diet intervention before pregnancy primes offspring lipid metabolism in liver.

Lab Invest 2020 04 20;100(4):553-569. Epub 2019 Nov 20.

Department of Nutrition and Food Sciences, Texas A&M University, College Station, TX, USA.

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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http://dx.doi.org/10.1038/s41374-019-0344-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102928PMC
April 2020

Tbx5 inhibits hedgehog signaling in determination of digit identity.

Hum Mol Genet 2020 06;29(9):1405-1416

Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58202, USA.

Dominant TBX5 mutation causes Holt-Oram syndrome (HOS), which is characterized by limb defects in humans, but the underlying mechanistic basis is unclear. We used a mouse model with Tbx5 conditional knockdown in Hh-receiving cells (marked by Gli1+) during E8 to E10.5, a previously established model to study atrial septum defects, which displayed polydactyly or hypodactyly. The results suggested that Tbx5 is required for digit identity in a subset of limb mesenchymal cells. Specifically, Tbx5 deletion in this cell population decreased cell apoptosis and increased the proliferation of handplate mesenchymal cells. Furthermore, Tbx5 was found to negatively regulate the Hh-signaling activity through transcriptional regulation of Ptch1, a known Hh-signaling repressor. Repression of Hh-signaling through Smo co-mutation in Tbx5 heterozygotes rescued the limb defects, thus placing Tbx5 upstream of Hh-signaling in limb defects. This work reveals an important missing component necessary for understanding not only limb development but also the molecular and genetic mechanisms underlying HOS.
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http://dx.doi.org/10.1093/hmg/ddz185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268785PMC
June 2020

A long-term maternal diet transition from high-fat diet to normal fat diet during pre-pregnancy avoids adipose tissue inflammation in next generation.

PLoS One 2018 18;13(12):e0209053. Epub 2018 Dec 18.

Department of Nutrition and Food Sciences, Texas A&M University, College Station, TX, United States of America.

Recent studies have suggested that maternal high-fat (HF) diet caused inflammation changes in adipose tissue; however, it remains unclear if maternal diet intervention before pregnancy rescues such effects in offspring. To address this question, female mice were continued on a normal-fat (NF group), or a HF diet (HF group) or transitioned from a HF diet to a NF diet at 1 (H1N group), 5 (H5N group) or 9 weeks (H9N group) prior to pregnancy. Among the three intervention groups, the H9N offspring displayed less and steady body weight gain, and maintained glucose tolerance, whereas the H1N and H5N offspring showed exacerbate these phenotypes. The H1N and H5N, but not the H9N offspring, displayed adipocyte hypertrophy associated with increased expression of genes involved in fat deposition. The H1N and H5N, but not the H9N adipose tissue, displayed increased macrophage infiltration with enhanced expression of inflammatory cytokine genes. In addition, overactivation of the NF-κB and the JNK signaling were observed in the H1N adipose tissue. Overall, our study showed that a long-term but not a short- or medium-term diet intervention before pregnancy released offspring adipose tissue inflammation induced by maternal HF diet, which adds details in our understanding how the maternal environment either promotes or discourages onset of disease in offspring. Clinically, this study is of great value for providing evidence in the design of clinical trials to evaluate the urgently required intervention strategies to minimize the intergenerational cycle of obesity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209053PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298692PMC
May 2019

The urothelial cell line UROtsa transformed by arsenite and cadmium display basal characteristics associated with muscle invasive urothelial cancers.

PLoS One 2018 14;13(12):e0207877. Epub 2018 Dec 14.

Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.

Muscle invasive urothelial carcinomas are divided into various molecular subtypes with basal and luminal subtypes being the prominent ones. The basal muscle-invasive urothelial carcinomas are generally more aggressive at presentation and significantly enriched with squamous features. Our laboratory has developed an in-vitro model of urothelial cancer by transforming the immortalized cell line UROtsa with arsenite (As3+) and cadmium (Cd2+). In this study, we characterized the tumors formed by these transformed cell lines as more basal-like based on their gene expression patterns with increased expression of KRT1, KRT5, KRT6, KRT14, KRT16, KRT17 and CD44. In addition, histological examination of these tumor transplants showed squamous features enriched in basal muscle invasive urothelial carcinomas. The expression of these genes increased in the transformed cell lines as well as in the urospheres, which are putative cancer initiating cells/stem cells derived from the cell lines. There was also increased expression of these genes in the urospheres derived from the parent UROtsa cell line. Thus, our data shows that the As3+ and Cd2+-transformed cell lines and their derived tumor transplants have gene expression profiles similar to the basal subtype of muscle invasive bladder carcinomas with tumors having enriched squamous features. The increased expression of basal markers in the urospheres suggests that stem cells may be involved in the development of squamous differentiation seen in some of the muscle invasive bladder carcinomas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207877PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294394PMC
May 2019

Sex-associated preventive effects of low-dose aspirin on obesity and non-alcoholic fatty liver disease in mouse offspring with over-nutrition in utero.

Lab Invest 2019 02 9;99(2):244-259. Epub 2018 Nov 9.

Department of Nutrition and Food Sciences, Texas A&M University, College Station, TX, 77843, USA.

Aspirin has been found to diminish hypertriglyceridemia and hyperglycemia in both obese rodents and patients with type 2 diabetes mellitus. We aimed to test whether low-dose aspirin can prevent obesity and the progression of non-alcoholic fatty liver disease (NAFLD) in high-risk subjects. We used offspring mice with maternal over-nutrition as a high-risk model of obesity and NAFLD. The offspring were given postnatal HF-diet and diethylnitrosamine (DEN) to induce obesity and NAFLD, and were treated with or without a low dose of aspirin for 12 weeks (ASP or CTL groups). Aspirin treatment reduced body weight gain, reversed glucose intolerance, and depressed hepatic lipid accumulation in female, but not in male mice. Female mice displayed re-sensitized insulin/Akt signaling and overactivated AMPK signaling, with enhanced level of hepatic PPAR-γ, Glut4, and Glut2, while male mice only enhanced hepatic PPAR-α and PPAR-γ levels. The female ASP mice had inhibited p44/42 MAPK activity and enhanced Pten expression, while male displayed activated p38 MAPK signaling. Furthermore, the female but not the male ASP mice reduced Wnt-signaling activity via both the epigenetic regulation of Apc expression and the post-transcriptional regulation of β-catenin degradation. In summary, our study demonstrates a sex-associated effect of low-dose aspirin on obesity and NAFLD prevention in female but not in male mice.
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http://dx.doi.org/10.1038/s41374-018-0144-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354253PMC
February 2019

A long-term maternal diet intervention is necessary to avoid the obesogenic effect of maternal high-fat diet in the offspring.

J Nutr Biochem 2018 12 22;62:210-220. Epub 2018 Sep 22.

Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58202; Department of Nutrition and Food Sciences, Texas A&M University, College Station, TX 77843. Electronic address:

Although a pre-pregnancy dietary intervention is believed to be able to prevent offspring obesity, research evidence is absent. We hypothesize that a long period of pre-pregnancy maternal diet transition from a high-fat (HF) diet to a normal-fat (NF) diet effectively prevents offspring obesity, and this preventive effect is independent of maternal body weight change. In our study, female mice were either continued on an NF diet (NF group) or an HF diet (HF group) until weaning, or switched from an HF to an NF for 1 week (H1N group), 5 weeks (H5N group) or 9 weeks (H9N group) before pregnancy. After weaning, the offspring were given the HF diet for 12 weeks to promote obesity. The mothers, regardless of which group, did not display maternal body weight change and glucose intolerance either before pregnancy or after weaning. Compared to the HF group, the H1N and H5N, but not the H9N, offspring developed glucose intolerance earlier, with more severely imbalanced glucose homeostasis. These offspring also displayed hepatocyte degeneration and significant adipocyte hypertrophy associated with higher expression of lipogenesis genes. The molecular mechanistic study showed blunted insulin signaling, overactivated adipocyte Akt signaling and hepatic AMPK signaling with enhanced lipogenesis genes in the H1N and H5N versus the NF offspring. However, maternal H9N diets normalized glucose and lipid metabolism of the offspring via resensitized insulin signaling and normalized Akt and AMPK signaling. In summary, we showed that a long-term maternal diet intervention effectively released the intergenerational obesogenic effect of maternal HF diet independent of maternal weight management.
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http://dx.doi.org/10.1016/j.jnutbio.2018.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263780PMC
December 2018

Sparse Representation in Awake Auditory Cortex: Cell-type Dependence, Synaptic Mechanisms, Developmental Emergence, and Modulation.

Cereb Cortex 2019 08;29(9):3796-3812

Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Sparse representation is considered an important coding strategy for cortical processing in various sensory modalities. It remains unclear how cortical sparseness arises and is being regulated. Here, unbiased recordings from primary auditory cortex of awake adult mice revealed salient sparseness in layer (L)2/3, with a majority of excitatory neurons exhibiting no increased spiking in response to each of sound types tested. Sparse representation was not observed in parvalbumin (PV) inhibitory neurons. The nonresponding neurons did receive auditory-evoked synaptic inputs, marked by weaker excitation and lower excitation/inhibition (E/I) ratios than responding cells. Sparse representation arises during development in an experience-dependent manner, accompanied by differential changes of excitatory input strength and a transition from unimodal to bimodal distribution of E/I ratios. Sparseness level could be reduced by suppressing PV or L1 inhibitory neurons. Thus, sparse representation may be dynamically regulated via modulating E/I balance, optimizing cortical representation of the external sensory world.
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http://dx.doi.org/10.1093/cercor/bhy260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686756PMC
August 2019

Cyclic GMP-AMP Ameliorates Diet-induced Metabolic Dysregulation and Regulates Proinflammatory Responses Distinctly from STING Activation.

Sci Rep 2017 07 25;7(1):6355. Epub 2017 Jul 25.

Department of Nutrition and Food Science, Texas A&M University, College Station, TX, 77843, USA.

Endogenous cyclic GMP-AMP (cGAMP) binds and activates STING to induce type I interferons. However, whether cGAMP plays any roles in regulating metabolic homeostasis remains unknown. Here we show that exogenous cGAMP ameliorates obesity-associated metabolic dysregulation and uniquely alters proinflammatory responses. In obese mice, treatment with cGAMP significantly decreases diet-induced proinflammatory responses in liver and adipose tissues and ameliorates metabolic dysregulation. Strikingly, cGAMP exerts cell-type-specific anti-inflammatory effects on macrophages, hepatocytes, and adipocytes, which is distinct from the effect of STING activation by DMXAA on enhancing proinflammatory responses. While enhancing insulin-stimulated Akt phosphorylation in hepatocytes and adipocytes, cGAMP weakens the effects of glucagon on stimulating hepatocyte gluconeogenic enzyme expression and glucose output and blunts palmitate-induced hepatocyte fat deposition in an Akt-dependent manner. Taken together, these results suggest an essential role for cGAMP in linking innate immunity and metabolic homeostasis, indicating potential applications of cGAMP in treating obesity-associated inflammatory and metabolic diseases.
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http://dx.doi.org/10.1038/s41598-017-05884-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526935PMC
July 2017

Determination of trans-resveratrol and its metabolites in rat serum using liquid chromatography with high-resolution time of flight mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2016 Dec 29;1039:35-43. Epub 2016 Oct 29.

Department of Chemistry, University of North Dakota, 151 Cornell Street, Grand Forks, ND 58202, USA. Electronic address:

In this study we developed a sensitive method using high performance liquid chromatography (HPLC) coupled to electrospray ionization (ESI) with high resolution time of flight (TOF) mass spectrometry (MS) for the determination of naturally occurring antioxidant trans-resveratrol (3,5,4'-trihydroxy-trans-stilbene, RES). This method enabled an investigation of a relationship between tumor growth in rats and concentration of RES and its primary metabolites, trans-resveratrol-3-O-sulfate-3-O-sulfate (R3S) and trans-resveratrol-3-O-β-d-glucuronide (R3G), in rat serum after RES exposure (5 or 25mg/kg/day). RES levels in rat serum were near the limit of detection, showing concentrations of 4±1 and 12±4ng/mL for low and high-dose exposure, respectively. Compared to RES, higher concentrations were found for its metabolites (R3G:4.8±0.3 and 6.8±0.3μg/mL; R3S:0.27±0.09 and 0.34±0.04μg/mL, respectively). Using TOF, for the first time, we measured the matrix affected limits of detection (LODs) in plasma (3.7, 82.4, and 4.7ng/mL for RES, R3G, and R3S, respectively), which were comparable to those reported in previous work using HPLC tandem mass spectrometry, but with a benefit of a full mass spectral profile. The ability to acquire data in full scan mode also revealed other isomers of R3S. The additional novelty of our study is in synthesis and application of deuterated recovery standards enabling accurate and precise quantification. In order to develop a robust method, the ESI conditions were optimized using a multilevel full factorial design of experiments.
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http://dx.doi.org/10.1016/j.jchromb.2016.10.028DOI Listing
December 2016

Gene network and familial analyses uncover a gene network involving Tbx5/Osr1/Pcsk6 interaction in the second heart field for atrial septation.

Hum Mol Genet 2016 Mar 6;25(6):1140-51. Epub 2016 Jan 6.

Department of Basic Sciences, School of Medicine and Health Sciences and Department of Nutrition and Food Science, Texas A&M University, Cater-Mattil Hall Rm 217B, TAMU 2253, College Station, TX 77843, USA

Atrial septal defects (ASDs) are a common human congenital heart disease (CHD) that can be induced by genetic abnormalities. Our previous studies have demonstrated a genetic interaction between Tbx5 and Osr1 in the second heart field (SHF) for atrial septation. We hypothesized that Osr1 and Tbx5 share a common signaling networking and downstream targets for atrial septation. To identify this molecular networks, we acquired the RNA-Seq transcriptome data from the posterior SHF of wild-type, Tbx5(+/) (-), Osr1(+/-), Osr1(-/-) and Tbx5(+/-)/Osr1(+/-) mutant embryos. Gene set analysis was used to identify the Kyoto Encyclopedia of Genes and Genomes pathways that were affected by the doses of Tbx5 and Osr1. A gene network module involving Tbx5 and Osr1 was identified using a non-parametric distance metric, distance correlation. A subset of 10 core genes and gene-gene interactions in the network module were validated by gene expression alterations in posterior second heart field (pSHF) of Tbx5 and Osr1 transgenic mouse embryos, a time-course gene expression change during P19CL6 cell differentiation. Pcsk6 was one of the network module genes that were linked to Tbx5. We validated the direct regulation of Tbx5 on Pcsk6 using immunohistochemical staining of pSHF, ChIP-quantitative polymerase chain reaction and luciferase reporter assay. Importantly, we identified Pcsk6 as a novel gene associated with ASD via a human genotyping study of an ASD family. In summary, our study implicated a gene network involving Tbx5, Osr1 and Pcsk6 interaction in SHF for atrial septation, providing a molecular framework for understanding the role of Tbx5 in CHD ontogeny.
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http://dx.doi.org/10.1093/hmg/ddv636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764195PMC
March 2016

Comparison of RNA-seq and microarray-based models for clinical endpoint prediction.

Genome Biol 2015 Jun 25;16:133. Epub 2015 Jun 25.

Marshfield Clinic Research Foundation, Center of Human Genetics, 1000 N Oak Avenue, Marshfield, WI, 54449, USA.

Background: Gene expression profiling is being widely applied in cancer research to identify biomarkers for clinical endpoint prediction. Since RNA-seq provides a powerful tool for transcriptome-based applications beyond the limitations of microarrays, we sought to systematically evaluate the performance of RNA-seq-based and microarray-based classifiers in this MAQC-III/SEQC study for clinical endpoint prediction using neuroblastoma as a model.

Results: We generate gene expression profiles from 498 primary neuroblastomas using both RNA-seq and 44 k microarrays. Characterization of the neuroblastoma transcriptome by RNA-seq reveals that more than 48,000 genes and 200,000 transcripts are being expressed in this malignancy. We also find that RNA-seq provides much more detailed information on specific transcript expression patterns in clinico-genetic neuroblastoma subgroups than microarrays. To systematically compare the power of RNA-seq and microarray-based models in predicting clinical endpoints, we divide the cohort randomly into training and validation sets and develop 360 predictive models on six clinical endpoints of varying predictability. Evaluation of factors potentially affecting model performances reveals that prediction accuracies are most strongly influenced by the nature of the clinical endpoint, whereas technological platforms (RNA-seq vs. microarrays), RNA-seq data analysis pipelines, and feature levels (gene vs. transcript vs. exon-junction level) do not significantly affect performances of the models.

Conclusions: We demonstrate that RNA-seq outperforms microarrays in determining the transcriptomic characteristics of cancer, while RNA-seq and microarray-based models perform similarly in clinical endpoint prediction. Our findings may be valuable to guide future studies on the development of gene expression-based predictive models and their implementation in clinical practice.
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http://dx.doi.org/10.1186/s13059-015-0694-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506430PMC
June 2015

The concordance between RNA-seq and microarray data depends on chemical treatment and transcript abundance.

Nat Biotechnol 2014 Sep 24;32(9):926-32. Epub 2014 Aug 24.

Fondazione Bruno Kessler, Trento, Italy.

The concordance of RNA-sequencing (RNA-seq) with microarrays for genome-wide analysis of differential gene expression has not been rigorously assessed using a range of chemical treatment conditions. Here we use a comprehensive study design to generate Illumina RNA-seq and Affymetrix microarray data from the same liver samples of rats exposed in triplicate to varying degrees of perturbation by 27 chemicals representing multiple modes of action (MOAs). The cross-platform concordance in terms of differentially expressed genes (DEGs) or enriched pathways is linearly correlated with treatment effect size (R(2)0.8). Furthermore, the concordance is also affected by transcript abundance and biological complexity of the MOA. RNA-seq outperforms microarray (93% versus 75%) in DEG verification as assessed by quantitative PCR, with the gain mainly due to its improved accuracy for low-abundance transcripts. Nonetheless, classifiers to predict MOAs perform similarly when developed using data from either platform. Therefore, the endpoint studied and its biological complexity, transcript abundance and the genomic application are important factors in transcriptomic research and for clinical and regulatory decision making.
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http://dx.doi.org/10.1038/nbt.3001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243706PMC
September 2014

Polyunsaturated fatty acid content may be increased in the milk of women with pregnancy-associated breast cancer.

J Hum Lact 2014 Nov 17;30(4):420-4. Epub 2014 Jun 17.

Department of Surgery, University of Texas Health Sciences Center, Tyler, TX, USA

Background: Pregnancy-associated breast cancer (PABC) is aggressive and difficult to diagnose. High intake of most types of dietary fat is thought to increase breast cancer risk; however, results in humans supporting this premise remain equivocal. Fatty acid (FA) concentrations in the body comprise both dietary intake and endogenous FA production. Most assessments of FA levels have been performed on blood, with little information on the effect of FA levels in breast milk on PABC risk.

Objective: This study aimed to determine if FA concentrations in the milk from women diagnosed with breast cancer while nursing were different in the cancer-containing breast and opposite breast.

Methods: We quantified 16 long-chain FA and soluble FA synthase (sFAS) enzyme levels from 4 women diagnosed with PABC, comparing results from the cancer-containing breast to those from the normal breast.

Results: Fatty acid concentrations consistently exceeded and trended higher (P < .10) in each cancer-containing breast for 20:4n-6 (arachidonic acid [AA]), 20:5n-3 (eicosapentaenoic acid [EPA]), and 22:5n-6 (docosapentaenoic acid [DPA]). Soluble FA synthase levels were similar in the cancer-containing and normal breasts.

Conclusion: Breast milk concentrations of AA, EPA, and DPA increased in the cancer-containing breast of women with PABC. This increase was not associated with higher sFAS levels.
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http://dx.doi.org/10.1177/0890334414539576DOI Listing
November 2014

Overexpression of IL-10 in C2D macrophages promotes a macrophage phenotypic switch in adipose tissue environments.

PLoS One 2014 21;9(1):e86541. Epub 2014 Jan 21.

Division of Biology, Kansas State University, Manhattan, Kansas, United States of America.

Adipose tissue macrophages are a heterogeneous collection of classically activated (M1) and alternatively activated (M2) macrophages. Interleukin 10 (IL-10) is an anti-inflammatory cytokine, secreted by a variety of cell types including M2 macrophages. We generated a macrophage cell line stably overexpressing IL-10 (C2D-IL10) and analyzed the C2D-IL10 cells for several macrophage markers after exposure to adipocytes compared to C2D cells transfected with an empty vector (C2D-vector). C2D-IL10 macrophage cells expressed more CD206 when co-cultured with adipocytes than C2D-vector cells; while the co-cultured cell mixture also expressed higher levels of Il4, Il10, Il1β and Tnf. Since regular C2D cells traffic to adipose tissue after adoptive transfer, we explored the impact of constitutive IL-10 expression on C2D-IL10 macrophages in adipose tissue in vivo. Adipose tissue-isolated C2D-IL10 cells increased the percentage of CD206(+), CD301(+), CD11c(-)CD206(+) (M2) and CD11c(+)CD206(+) (M1b) on their cell surface, compared to isolated C2D-vector cells. These data suggest that the expression of IL-10 remains stable, alters the C2D-IL10 macrophage cell surface phenotype and may play a role in regulating macrophage interactions with the adipose tissue.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086541PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897709PMC
September 2014

Prediction of the number of activated genes in multiple independent Cd(+2)- and As(+3)-induced malignant transformations of human urothelial cells (UROtsa).

PLoS One 2014 22;9(1):e85614. Epub 2014 Jan 22.

Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.

Background: Many toxic environmental agents such as cadmium and arsenic are found to be epidemiologically linked to increasing rates of cancers. In vitro studies show that these toxic agents induced malignant transformation in human cells. It is not clear whether such malignant transformation induced by a single toxic agent is driven by a common set of genes. Although the advancement of high-throughput technology has facilitated the profiling of global gene expression, it remains a question whether the sample size is sufficient to identify this common driver gene set.

Results: We have developed a statistical method, SOFLR, to predict the number of common activated genes using a limited number of microarray samples. We conducted two case studies, cadmium and arsenic transformed human urothelial cells. Our method is able to precisely predict the number of stably induced and repressed genes and the number of samples to identify the common activated genes. The number of independent transformed isolates required for identifying the common activated genes is also estimated. The simulation study further validated our method and identified the important parameters in this analysis.

Conclusions: Our method predicts the degree of similarity and diversity during cell malignant transformation by a single toxic agent. The results of our case studies imply the existence of common driver and passenger gene sets in toxin-induced transformation. Using a pilot study with small sample size, this method also helps microarray experimental design by determining the number of samples required to identify the common activated gene set.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085614PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899011PMC
December 2014

Interaural level difference-dependent gain control and synaptic scaling underlying binaural computation.

Neuron 2013 Aug;79(4):738-53

Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

Binaural integration in the central nucleus of inferior colliculus (ICC) plays a critical role in sound localization. However, its arithmetic nature and underlying synaptic mechanisms remain unclear. Here, we showed in mouse ICC neurons that the contralateral dominance is created by a "push-pull"-like mechanism, with contralaterally dominant excitation and more bilaterally balanced inhibition. Importantly, binaural spiking response is generated apparently from an ipsilaterally mediated scaling of contralateral response, leaving frequency tuning unchanged. This scaling effect is attributed to a divisive attenuation of contralaterally evoked synaptic excitation onto ICC neurons with their inhibition largely unaffected. Thus, a gain control mediates the linear transformation from monaural to binaural spike responses. The gain value is modulated by interaural level difference (ILD) primarily through scaling excitation to different levels. The ILD-dependent synaptic scaling and gain adjustment allow ICC neurons to dynamically encode interaural sound localization cues while maintaining an invariant representation of other independent sound attributes.
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http://dx.doi.org/10.1016/j.neuron.2013.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755964PMC
August 2013

Slit/Robo signaling mediates spatial positioning of spiral ganglion neurons during development of cochlear innervation.

J Neurosci 2013 Jul;33(30):12242-54

Zilkha Neurogenetic Institute, Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.

During the development of periphery auditory circuits, spiral ganglion neurons (SGNs) extend their neurites to innervate cochlear hair cells (HCs) with their soma aggregated into a cluster spatially segregated from the cochlear sensory epithelium. The molecular mechanisms underlying this spatial patterning remain unclear. In this study, in situ hybridization in the mouse cochlea suggests that Slit2 and its receptor, Robo1/2, exhibit apparently complementary expression patterns in the spiral ganglion and its nearby region, the spiral limbus. In Slit2 and Robo1/2 mutants, the spatial restriction of SGNs was disrupted. Mispositioned SGNs were found to scatter in the space between the cochlear epithelium and the main body of spiral ganglion, and the neurites of mispositioned SGNs were misrouted and failed to innervate HCs. Furthermore, in Robo1/2 mutants, SGNs were displaced toward the cochlear epithelium as an entirety. Examination of different embryonic stages in the mutants revealed that the mispositioning of SGNs was due to a progressive displacement to ectopic locations after their initial normal settlement at an earlier stage. Our results suggest that Slit/Robo signaling imposes a restriction force on SGNs to ensure their precise positioning for correct SGN-HC innervations.
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http://dx.doi.org/10.1523/JNEUROSCI.5736-12.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721837PMC
July 2013

Short and long term gene expression variation and networking in human proximal tubule cells when exposed to cadmium.

BMC Med Genomics 2013 23;6 Suppl 1:S2. Epub 2013 Jan 23.

Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA.

Cadmium (Cd²⁺) is a known nephrotoxin causing tubular necrosis during acute exposure and potentially contributing to renal failure in chronic long-term exposure. To investigate changes in global gene expression elicited by cadmium, an in-vitro exposure system was developed from cultures of human renal epithelial cells derived from cortical tissue obtained from nephrectomies. These cultures exhibit many of the qualities of proximal tubule cells. Using these cells, a study was performed to determine the cadmium-induced global gene expression changes after short-term (1 day, 9, 27, and 45 μM) and long-term cadmium exposure (13 days, 4.5, 9, and 27 μM). These studies revealed fundamental differences in the types of genes expressed during each of these time points. The obtained data was further analyzed using regression to identify cadmium toxicity responsive genes. Regression analysis showed 403 genes were induced and 522 genes were repressed by Cd²⁺ within 1 day, and 366 and 517 genes were induced and repressed, respectively, after 13 days. We developed a gene set enrichment analysis method to identify the cadmium induced pathways that are unique in comparison to traditional approaches. The perturbation of global gene expression by various Cd²⁺ concentrations and multiple time points enabled us to study the transcriptional dynamics and gene interaction using a mutual information-based network model. The most prominent network module consisted of INHBA, KIF20A, DNAJA4, AKAP12, ZFAND2A, AKR1B10, SCL7A11, and AKR1C1.
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http://dx.doi.org/10.1186/1755-8794-6-S1-S2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552673PMC
August 2013

The current trend of genomics research for human diseases.

BMC Med Genomics 2013 23;6 Suppl 1:S1. Epub 2013 Jan 23.

Department of Pathology, Bioinformatics Core, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58201, USA.

This is an introduction to the supplement to BMC Medical Genomics that includes 16 papers selected from the 2011 World Congress in Computer Science, Computer Engineering, Applied Computing as well as other sources with a focus on genomics studies with a focus on human diseases.
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http://dx.doi.org/10.1186/1755-8794-6-S1-S1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552669PMC
August 2013

Comparative analysis of de novo transcriptome assembly.

Sci China Life Sci 2013 Feb 8;56(2):156-62. Epub 2013 Feb 8.

Bioinformatics Core, Department of Pathology, University of North Dakota, Grand Forks, ND 58202, USA.

The fast development of next-generation sequencing technology presents a major computational challenge for data processing and analysis. A fast algorithm, de Bruijn graph has been successfully used for genome DNA de novo assembly; nevertheless, its performance for transcriptome assembly is unclear. In this study, we used both simulated and real RNA-Seq data, from either artificial RNA templates or human transcripts, to evaluate five de novo assemblers, ABySS, Mira, Trinity, Velvet and Oases. Of these assemblers, ABySS, Trinity, Velvet and Oases are all based on de Bruijn graph, and Mira uses an overlap graph algorithm. Various numbers of RNA short reads were selected from the External RNA Control Consortium (ERCC) data and human chromosome 22. A number of statistics were then calculated for the resulting contigs from each assembler. Each experiment was repeated multiple times to obtain the mean statistics and standard error estimate. Trinity had relative good performance for both ERCC and human data, but it may not consistently generate full length transcripts. ABySS was the fastest method but its assembly quality was low. Mira gave a good rate for mapping its contigs onto human chromosome 22, but its computational speed is not satisfactory. Our results suggest that transcript assembly remains a challenge problem for bioinformatics society. Therefore, a novel assembler is in need for assembling transcriptome data generated by next generation sequencing technique.
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http://dx.doi.org/10.1007/s11427-013-4444-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778448PMC
February 2013
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