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1.  Comparison of Co-Temporal Modeling Algorithms on Sparse Experimental Time Series Data Sets 
Multiple approaches for reverse-engineering biological networks from time-series data have been proposed in the computational biology literature. These approaches can be classified by their underlying mathematical algorithms, such as Bayesian or algebraic techniques, as well as by their time paradigm, which includes next-state and co-temporal modeling. The types of biological relationships, such as parent-child or siblings, discovered by these algorithms are quite varied. It is important to understand the strengths and weaknesses of the various algorithms and time paradigms on actual experimental data. We assess how well the co-temporal implementations of three algorithms, continuous Bayesian, discrete Bayesian, and computational algebraic, can 1) identify two types of entity relationships, parent and sibling, between biological entities, 2) deal with experimental sparse time course data, and 3) handle experimental noise seen in replicate data sets. These algorithms are evaluated, using the shuffle index metric, for how well the resulting models match literature models in terms of siblings and parent relationships. Results indicate that all three co-temporal algorithms perform well, at a statistically significant level, at finding sibling relationships, but perform relatively poorly in finding parent relationships.
doi:10.1109/BIBE.2010.21
PMCID: PMC5096389  PMID: 27959971
Biological system modeling; reverse engineering; computational algebra modeling; Bayesian modeling
2.  Sphingosine 1-Phosphate Receptor 2 Regulates the Migration, Proliferation, and Differentiation of Mesenchymal Stem Cells 
Mesenchymal stem cells (MSCs) are a multipotent cell population acquired most prominently from bone marrow with the capacity to differentiate into osteoblasts, chondrocytes, adipocytes, and others. MSCs demonstrate the capacity to home to sites of injury and contribute to tissue repair. Sphingosine 1-phosphate (S1P) is a biologically active sphingolipid impacting proliferation, apoptosis, inflammation, and angiogenesis with changes in S1P concentration providing significant implications for various disease conditions including cancer, diabetes, and cardiac disease. These functions are primarily mediated by interactions with 5 G-protein coupled S1P receptors (S1PR1-5). In this paper, we demonstrate that inhibition of S1PR2 results in increased MSC clonogenicity, migration, and proliferation; features dependent on Erk phosphorylation. Furthermore, decreased S1PR2 expression decreases the differentiation of MSCs into adipocytes and mature osteoblasts that may be the result of increased expression of MSC pluripotency factors including Nanog, Sox-9, and Oct-4. Inhibition of S1PR1 and S1PR3 in contrast does not impact MSC migration or Erk activation although increased proliferation is observed. In the study, we describe the essential role of S1PR2 in MSC differentiation pathways through modification of pluripotency factors. We propose a MAPK dependent mechanism through S1PR2 inhibition that promotes equally multipotent MSC proliferation.
PMCID: PMC4888913  PMID: 27275017
Mesenchymal stem cells; Erk; S1PR2; Self renewal; Pluripotency factors
3.  Targeting (cellular) lysosomal acid ceramidase by B13: Design, synthesis and evaluation of novel DMG-B13 ester prodrugs 
Bioorganic & medicinal chemistry  2014;22(24):6933-6944.
Acid ceramidase (ACDase) is being recognized as a therapeutic target for cancer. B13 represents a moderate inhibitor of ACDase. The present study concentrates on the lysosomal targeting of B13 via its N, N-dimethylglycine (DMG) esters (DMG-B13 prodrugs). Novel analogs, the isomeric mono-DMG-B13, LCL522 (3-O-DMG-B13•HCl) and LCL596 (1-O-DMG-B13•HCl) and di-DMG-B13, LCL521 (1,3-O, O-DMG-B13•2HCl) conjugates, were designed and synthesized through N, N-dimethyl glycine (DMG) esterification of the hydroxyl groups of B13. In MCF7 cells, DMG-B13 prodrugs were efficiently metabolized to B13. The early inhibitory effect of DMG-B13 prodrugs on cellular ceramidases was ACDase specific by their lysosomal targeting. The corresponding dramatic decrease of cellular Sph (80-97% Control/1h) by DMG-B13 prodrugs was mainly from the inhibition of the lysosomal ACDase.
doi:10.1016/j.bmc.2014.10.025
PMCID: PMC4443482  PMID: 25456083
B13; DMG-B13 prodrugs; inhibitors; acid ceramidase; lysosomes; cancer
4.  Enterobacteria-secreted particles induce production of exosome-like S1P-containing particles by intestinal epithelium to drive Th17-mediated tumorigenesis 
Nature communications  2015;6:6956.
Gut-associated inflammation plays a crucial role in the progression of colon cancer. Here, we identify a novel pathogen-host interaction that promotes gut inflammation and the development of colon cancer. We find that enteropathogenic bacteria-secreted particles (ET-BSPs) stimulate intestinal epithelium to produce IDENs (intestinal mucosa-derived exosome-like nanoparticles) containing elevated levels of sphingosine-1-phosphate, CCL20 and prostaglandin E2 (PGE2). CCL20 and PGE2 are required for the recruitment and proliferation, respectively, of Th17 cells, and these processes also involve the MyD88-mediated pathway. By influencing the recruitment and proliferation of Th17 cells in the intestine, IDENs promote colon cancer. We demonstrate the biological effect of sphingosine-1-phosphate contained in IDENs on tumor growth in spontaneous and transplanted colon cancer mouse models. These findings provide deeper insights into how host-microbe relationships are mediated by particles secreted from both bacterial and host cells.
doi:10.1038/ncomms7956
PMCID: PMC4410277  PMID: 25907800
Intestinal mucus; exosomes; exosomal S1P; colon cancer; microbiota-secreted particles; PGE2; CCL20
5.  Origin of Light-Induced Spin-Correlated Radical Pairs in Cryptochrome 
The journal of physical chemistry. B  2010;114(45):14745-14754.
Blue-light excitation of cryptochromes and homologs uniformly triggers electron transfer (ET) from the protein surface to the flavin-adenine dinucleotide (FAD) cofactor. A cascade of three conserved tryptophan residues has been considered to be critically involved in this photoreaction. If the FAD is initially in its fully oxidized (diamagnetic) redox state, light-induced ET via the tryptophan triad generates a series of short-lived spin-correlated radical pairs comprising an FAD radical and a tryptophan radical. Coupled doublet-pair species of this type have been proposed as the basis, e.g., of a biological magnetic compass in migratory birds, and were found critical for some cryptochrome functions in vivo. In this contribution, a cryptochrome-like protein (CRYD) derived from Xenopus laevis has been examined as a representative system. The terminal radical-pair state FAD•⋯W324• of X. laevis CRYD has been characterized in detail by time-resolved electron-paramagnetic resonance (TREPR) at X-band microwave frequency (9.68 GHz) and magnetic fields around 345 mT, and at Q-band (34.08 GHz) at around 1215 mT. Different precursor states – singlet versus triplet – of radical-pair formation have been considered in spectral simulations of the experimental electron-spin polarized TREPR signals. Conclusively, we present evidence for a singlet-state precursor of FAD•⋯W324• radical-pair generation because at both magnetic fields, where radical pairs were studied by TREPR, net-zero electron-spin polarization has been detected. Neither a spin-polarized triplet precursor nor a triplet at thermal equilibrium can explain such an electron-spin polarization. It turns out that a two-microwave-frequency TREPR approach is essential to draw conclusions on the nature of the precursor electronic states in light-induced spin-correlated radical pair formations.
doi:10.1021/jp103401u
PMCID: PMC4329313  PMID: 20684534
cryptochrome; radical pairs; time-resolved electron-paramagnetic resonance; blue-light photoreception; flavin; tryptophan radical
6.  Autophagy is increased in prostate cancer cells over-expressing acid ceramidase and enhances resistance to C6-ceramide 
Acid ceramidase (AC) over-expression has been observed in prostate cancer cell lines and primary tumors, and contributes to resistance to chemotherapy and radiation. The consequence of AC over-expression is the ability to convert ceramide, which is often produced as a pro-apoptotic response to stress, to sphingosine, which can then be converted to the pro-survival molecule sphingosine-1-phosphate. In addition to their ability to metabolize ceramide produced in response to stress, we show here that prostate cancer cell lines over-expressing acid ceramidase also have increased lysosomal density and increased levels of autophagy. Furthermore, pre-treatment with 3-methyladenine restores sensitivity of these cells to treatment with C6-ceramide. We also observed increased expression of the lysosomal stabilizing protein KIF5B and increased sensitivity to the lysosomotropic agent LCL385. Thus, we conclude that acid ceramidase over-expression increases autophagy in prostate cancer cells, and that increased autophagy enhances resistance to ceramide.
doi:10.1038/pcan.2010.47
PMCID: PMC4203650  PMID: 21116286
autophagy; acid ceramidase; sphingolipids; ceramide; prostate cancer; apoptosis
7.  Interdiction of Sphingolipid Metabolism to Improve Standard Cancer Therapies 
Non-surgical therapies for human malignancies must negotiate complex cell signaling pathways to impede cancer cell growth, ideally promoting death of cancer cells while sparing healthy tissue. For most of the past half century, medical approaches for treating cancer have relied primarily on cytotoxic chemotherapeutics that interfere with DNA replication and cell division, susceptibilities of rapidly dividing cancer cells. As a consequence, these therapies exert considerable cell stress, promoting the generation of ceramide through de novo synthesis and recycling of complex glycosphingolipids and sphingomyelin into apoptotic ceramide. Radiotherapy of cancer exerts similar geno- and cytotoxic cell stresses, and generation of ceramide following ionizing radiation therapy is a well-described feature of radiation-induced cell death. Emerging evidence now describes sphingolipids as mediators of death in response to newer targeted therapies, cementing ceramide generation as a common mechanism of cell death in response to cancer therapy. Many studies have now shown that dysregulation of ceramide accumulation—whether by reduced generation or accelerated metabolism—is a common mechanism of resistance to standard cancer therapies. The aims of this chapter will be to discuss described mechanisms of cancer resistance to therapy related to dysregulation of sphingolipid metabolism and to explore clinical and preclinical approaches to interdict sphingolipid metabolism to improve outcomes of standard cancer therapies.
doi:10.1016/B978-0-12-394274-6.00001-7
PMCID: PMC4203652  PMID: 23290775
8.  Sliding Rocks on Racetrack Playa, Death Valley National Park: First Observation of Rocks in Motion 
PLoS ONE  2014;9(8):e105948.
The engraved trails of rocks on the nearly flat, dry mud surface of Racetrack Playa, Death Valley National Park, have excited speculation about the movement mechanism since the 1940s. Rock movement has been variously attributed to high winds, liquid water, ice, or ice flotation, but has not been previously observed in action. We recorded the first direct scientific observation of rock movements using GPS-instrumented rocks and photography, in conjunction with a weather station and time-lapse cameras. The largest observed rock movement involved >60 rocks on December 20, 2013 and some instrumented rocks moved up to 224 m between December 2013 and January 2014 in multiple move events. In contrast with previous hypotheses of powerful winds or thick ice floating rocks off the playa surface, the process of rock movement that we have observed occurs when the thin, 3 to 6 mm, “windowpane” ice sheet covering the playa pool begins to melt in late morning sun and breaks up under light winds of ∼4–5 m/s. Floating ice panels 10 s of meters in size push multiple rocks at low speeds of 2–5 m/min. along trajectories determined by the direction and velocity of the wind as well as that of the water flowing under the ice.
doi:10.1371/journal.pone.0105948
PMCID: PMC4146553  PMID: 25162535
9.  Meal replacement: calming the hot-state brain network of appetite 
There is a growing awareness in the field of neuroscience that the self-regulation of eating behavior is driven by complex networks within the brain. These networks may be vulnerable to “hot states” which people can move into and out of dynamically throughout the course of a day as a function of changes in affect or visceral cues. The goal of the current study was to identify and determine differences in the Hot-state Brain Network of Appetite (HBN-A) that exists after a brief period of food restraint followed either by the consumption of a meal replacement (MR) or water. Fourteen overweight/obese adults came to our laboratory on two different occasions. Both times they consumed a controlled breakfast meal and then were restricted from eating for 2.5 h prior to an MRI scan. On one visit, they consumed a meal replacement (MR) liquid meal after this period of food restriction; on the other visit they consumed an equal amount of water. After these manipulations, the participants underwent a resting fMRI scan. Our first study aim employed an exploratory, data-driven approach to identify hubs relevant to the HBN-A. Using data from the water condition, five regions were found to be the hubs or nodes of the HBN-A: insula, anterior cingulated cortex, the superior temporal pole, the amygdala, and the hippocampus. We then demonstrated that the consumption of a liquid MR dampened interconnectivity between the nodes of the HBN-A as compared to water. Importantly and consistent with these network data, the consumption of a MR beverage also lowered state cravings and hunger.
doi:10.3389/fpsyg.2014.00249
PMCID: PMC3971177  PMID: 24723901
meal replacement; craving; eating behavior; obesity; brain networks; graph-theory
10.  Continuous Cotemporal Probabilistic Modeling of Systems Biology Networks from Sparse Data 
Modeling of biological networks is a difficult endeavour, but exploration of this problem is essential for understanding the systems behaviour of biological processes. In this contribution, developed for sparse data, we present a new continuous Bayesian graphical learning algorithm to cotemporally model proteins in signaling networks and genes in transcriptional regulatory networks. In this continuous Bayesian algorithm the correlation matrix is singular because the number of time points is less than the number of biological entities (genes or proteins). A suitable restriction on the degree of the graph’s vertices is applied and a Metropolis-Hastings algorithm is guided by a BIC-based posterior probability score. Ten independent and diverse runs of the algorithm are conducted, so that the probability space is properly well-explored. Diagnostics to test the applicability of the algorithm to the specific data sets are developed; this is a major benefit of the methodology. This novel algorithm is applied to two time course experimental data sets: 1) protein modification data identifying a potential signaling network in chondrocytes; and 2) gene expression data identifying the transcriptional regulatory network underlying dendritic cell maturation. This method gives high estimated posterior probabilities to many of the proteins’ directed edges that are predicted by the literature; for the gene study, the method gives high posterior probabilities to many of the literature-predicted sibling edges. In simulations, the method gives substantially higher estimated posterior probabilities for true edges and true subnetworks than for their false counterparts.
doi:10.1109/TCBB.2010.95
PMCID: PMC3954570  PMID: 20855920
Biological system modeling; statistical computing; multivariate statistics; correlation and regression analysis; signal transduction networks; transcriptional regulatory networks; biological network modeling
11.  Inhibitory Activities of Omega-3 Fatty Acids and Traditional African Remedies on Keloid Fibroblasts 
Keloids develop when scar tissue responds to skin trauma with proliferative fibrous growths that extend beyond the boundaries of the original wound and progress for several months or years. Keloids most frequently occur in individuals of indigenous sub-Saharan African origin. The etiology for keloids is still unknown and treatment can be problematic as patients respond differently to various treatment modalities. Keloids have a high rate of recurrence following surgical excision. Some West African patients claim to have had successful outcomes with traditional African remedies—boa constrictor oil (BCO) and shea butter—leading the authors to investigate their effects on cultured fibroblasts. The effects of emulsions of BCO, fish oil, isolated omega-3 fatty acids, and shea butter were tested in comparison to triamcinolone regarding inhibition of cell growth in keloid and control fibroblast cultures. In a series of controlled studies, it was observed that fish oil and BCO were more effective than triamcinolone, and that cis-5, 8, 11, 14, 17-eicosapentaenoic acid was more effective than -linolenic acid. While cell counts in control cultures continuously decreased over a period of 5 days, cell counts in keloid cultures consistently declined between day 1 and day 3, and then increased between day 3 and day 5 for all tested reagents except for fish oil. These results suggest that oils rich in omega-3 fatty acids may be effective in reducing actively proliferating keloid fibroblasts. Additional studies are warranted to investigate whether oils rich in omega-3 fatty acids offer effective and affordable treatment for some keloid patients, especially in the developing world.
PMCID: PMC3905615  PMID: 24489452
12.  Acid Ceramidase Promotes Nuclear Export of PTEN through Sphingosine 1-Phosphate Mediated Akt Signaling 
PLoS ONE  2013;8(10):e76593.
The tumor suppressor PTEN is now understood to regulate cellular processes at the cytoplasmic membrane, where it classically regulates PI3K signaling, as well as in the nucleus where multiple roles in controlling cell cycle and genome stability have been elucidated. Mechanisms that dictate nuclear import and, less extensively, nuclear export of PTEN have been described, however the relevance of these processes in disease states, particularly cancer, remain largely unknown. We investigated the impact of acid ceramidase on the nuclear-cytoplasmic trafficking of PTEN. Immunohistochemical analysis of a human prostate tissue microarray revealed that nuclear PTEN was lost in patients whose tumors had elevated acid ceramidase. We found that acid ceramidase promotes a reduction in nuclear PTEN that is dependent upon sphingosine 1-phosphate-mediated activation of Akt. We were further able to show that sphingosine 1-phosphate promotes formation of a complex between Crm1 and PTEN, and that leptomycin B prevents acid ceramidase and sphingosine 1-phosphate mediated loss of nuclear PTEN, suggesting an active exportin-mediated event. To investigate whether the tumor promoting aspects of acid ceramidase in prostate cancer depend upon its ability to export PTEN from the nucleus, we used enforced nuclear expression of PTEN to study docetaxel-induced apoptosis and cell killing, proliferation, and xenoengraftment. Interestingly, while acid ceramidase was able to protect cells expressing wild type PTEN from docetaxel, promote proliferation and xenoengraftment, acid ceramidase had no impact in cells expressing PTEN-NLS. These findings suggest that acid ceramidase, through sphingosine 1-phosphate, promotes nuclear export of PTEN as a means of promoting tumor formation, cell proliferation, and resistance to therapy.
doi:10.1371/journal.pone.0076593
PMCID: PMC3788144  PMID: 24098536
13.  Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse 
The Journal of Clinical Investigation  2013;123(10):4344-4358.
Escape of prostate cancer (PCa) cells from ionizing radiation–induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.
doi:10.1172/JCI64791
PMCID: PMC3784522  PMID: 24091326
14.  Power of Food ModeratesFood Craving, Perceived Control, and Brain Networks Following a Short-Term Post-Absorptive State in Older Adults 
Appetite  2012;58(3):806-813.
The Power of Food Scale (PFS) is a new measure that assesses the drive to consume highly palatable food in an obesogenic food environment. The data reported in this investigation evaluate whether the PFS moderates state cravings, control beliefs, and brain networks of older, obese adults following either a short-term post-absorptive state, in which participants were only allowed to consume water, or a short-term energy surfeit treatment condition, in which they consumed BOOST®. We found that the short-term post-absorptive condition,in which participants consumed water only, was associated withincreases in state cravings for desired food, a reduction in participants' confidence related to the control of eating behavior, and shifts in brain networks that parallel what is observed with other addictive behaviors. Furthermore, individuals who scored high on the PFSwere at an increased risk for experiencing these effects. Future research is needed to examine the eating behavior of persons who score high on the PFS and to develop interventions that directly target food cravings.
doi:10.1016/j.appet.2012.01.025
PMCID: PMC3340490  PMID: 22329987
aging; brain networks; food; cravings; self-efficacy
15.  Drive for consumption, craving, and connectivity in the visual cortex during the imagery of desired food 
There is considerable interest in understanding food cravings given the obesogenic environment of Western Society. In this paper we examine how the imagery of palatable foods affects cravings and functional connectivity in the visual cortex for people who differ on the power of food scale (PFS). Fourteen older, overweight/obese adults came to our laboratory on two different occasions. Both times they ate a controlled breakfast meal and then were restricted from eating for 2.5 h prior to scanning. On 1 day they consumed a BOOST® liquid meal after the period of food restriction, whereas on the other day they only consumed water (NO BOOST® condition). After these manipulations, they had an fMRI scan in which they were asked to image both neutral objects and their favorite snack foods; they also completed visual analog scales for craving, hunger, and the vividness of the imagery experiences. Irrespective of the BOOST® manipulation, we observed marked increases in food cravings when older, overweight/obese adults created images of favorite foods in their minds as opposed to creating an image of neutral objects; however, the increase in food craving following the imagery of desired food was more pronounced among those scoring high than low on the PFS. Furthermore, local efficiency within the visual cortex when imaging desired food was higher for those scoring high as compared to low on the PFS. The active imagery of desired foods seemed to have overpowered the BOOST® manipulation when evaluating connectivity in the visual cortex.
doi:10.3389/fnagi.2013.00077
PMCID: PMC3842155  PMID: 24348417
food craving; network science; visual cortex; power of food scale; older adults
16.  Specific isoforms of p73 control the induction of cell death induced by the viral proteins, E1A or apoptin 
Cell cycle (Georgetown, Tex.)  2007;7(2):205-215.
A member of the p53 family, p73, has several isoforms and differentially regulates transcription of genes involved in the control of the cell cycle and apoptosis. We have previously shown efficient and p53-independent, tumor-specific cell death induced by the viral proteins E1A and Apoptin. Here, we demonstrate that the induction of apoptosis by these viral proteins involves activation of TAp73. Both E1A and Apoptin induced expression of endogenous TAp73 and the p53/p73 BH3-only pro-apoptotic target, PUMA, independently of the p53 function. Furthermore, exogenous expression of TAp73 isoforms, particularly TAp73β, sensitized cells to killing by both E1A and Apoptin, while expression of ΔNp73α blocked this activity. Besides, knockout of the p73 regulator, c-Abl, attenuated E1A-induced apoptosis. In accordance with the role of p73 in apoptosis induced by these viral proteins, overexpression of TAp73β strongly induced apoptosis in p53-deficient cancer cells in vitro and in HNSCC xenografts. Using a doxycycline-inducible system, we provide evidence for target selectivity and significant differences in protein stability for specific p73 isoforms, suggesting a diverse and pivotal role for p73 in response to various genotoxic agents. Collectively, our data show that in the absence of the p53 function, viral proteins E1A and Apoptin utilize the p73 pathway to induce efficient tumor cell death.
PMCID: PMC3533136  PMID: 18256531
p73; E1A; Apoptin; apoptosis; PUMA
17.  Influence of Weight Loss, Body Composition, and Lifestyle Behaviors on Plasma Adipokines: A Randomized Weight Loss Trial in Older Men and Women with Symptomatic Knee Osteoarthritis 
Journal of Obesity  2012;2012:708505.
Objective. To investigate effects of weight loss on adipokines and health measures in obese older adults with symptomatic knee osteoarthritis. Methods. Participants were randomly assigned to either weight loss (WL) (men: 12, women: 14) or weight stable (WS) group (men: 12, women: 13). WL intervention included meal replacements and structured exercise training. Measurements of leptin, adiponectin, soluble leptin receptor, lifestyle behaviors, and body composition were collected at baseline and 6 months. Univariate analysis of covariance was performed on 6 month variables, and Spearman and partial correlations were made between variables. Results. Weight loss was 13.0% and 6.7% in WL for men and women, respectively. Women in WL had lower whole body and trunk fat than WS. The leptin : adiponectin ratio was lower for women in WL than WS at 6 months, with no group differences in adipokines for men. Leptin and free leptin index correlated with body fat in both genders at baseline. Interestingly, only women showed reductions in leptin (P < 0.100) and correlations between the percentage change leptin and trunk fat and the percentage changes in free leptin index with total fat and trunk fat. Partial correlations between 6 month adipokines after adjustments for covariates and group/time period show potential multivariate influences. Conclusions. In the presence of an effective weight loss intervention in older obese adults, there are significant relationships between weight and fat loss and leptin in women, but not men, suggesting gender-specific features of adipokine metabolism in this age group.
doi:10.1155/2012/708505
PMCID: PMC3541640  PMID: 23326650
18.  Molecular Targeting of Acid Ceramidase: Implications to Cancer Therapy 
Current Drug Targets  2008;9(8):653-661.
Increasingly recognized as bioactive molecules, sphingolipids have been studied in a variety of disease models. The impact of sphingolipids on cancer research facilitated the entry of sphingolipid analogues and enzyme modulators into clinical trials. Owing to its ability to regulate two bioactive sphingolipids, ceramide and sphingosine-1-phosphate, acid ceramidase (AC) emerges as an attractive target for drug development within the sphingolipid metabolic pathway. Indeed, there is extensive evidence supporting a pivotal role for AC in lipid metabolism and cancer biology. In this article, we review the current knowledge of the biochemical properties of AC, its relevance to tumor promotion, and its molecular targeting approaches.
PMCID: PMC3402562  PMID: 18691012
Ceramidase; sphingolipids; ceramide; sphingosine; cancer therapy
19.  Bayesian probabilistic network modeling from multiple independent replicates 
BMC Bioinformatics  2012;13(Suppl 9):S6.
Often protein (or gene) time-course data are collected for multiple replicates. Each replicate generally has sparse data with the number of time points being less than the number of proteins. Usually each replicate is modeled separately. However, here all the information in each of the replicates is used to make a composite inference about signal networks. The composite inference comes from combining well structured Bayesian probabilistic modeling with a multi-faceted Markov Chain Monte Carlo algorithm. Based on simulations which investigate many different types of network interactions and experimental variabilities, the composite examination uncovers many important relationships within the networks. In particular, when the edge's partial correlation between two proteins is at least moderate, then the composite's posterior probability is large.
doi:10.1186/1471-2105-13-S9-S6
PMCID: PMC3372452  PMID: 22901091
20.  Regulation of autophagy by ceramide-CD95-PERK signaling 
Autophagy  2008;4(7):929-931.
The manuscripts by Park et al.1 and Zhang et al.2 were initially planned as studies to understand the regulation of cell survival in transformed cells treated with sorafenib and vorinostat, and in primary hepatocytes treated with a bile acid+MEK1/2 inhibitor. In both cell systems we discovered that the toxicity of sorafenib and vorinostat or bile acid+MEK1/2 inhibitor exposure depended on the generation of ceramide and the ligand-independent activation of the CD95 death receptor, with subsequent activation of pro-caspase 8. We noted, however, in these systems that, in parallel with death receptor–induced activation of the extrinsic pathway, CD95 signaling also promoted increased phosphorylation of PKR-like endoplasmic reticulum kinase (PERK) and eIF2α, increased expression of ATG5, and increased processing of LC3 and vesicularization of a GFP-LC3 construct. The knockdown of ATG5 expression blocked GFP-LC3 vesicularization and enhanced cell killing. Thus ceramide-CD95 signaling promoted cell death via activation of pro-caspase 8 and cell survival via autophagy. PERK was shown to signal in a switch-hitting fashion; PERK promoted CD95-DISC formation and an eIF2α-dependent reduction in c-FLIP-s levels that were essential for cell killing to proceed, but in parallel it also promoted autophagy that was protective. The death receptor-induced apoptosis and autophagy occur proximal to the receptor rather than the mitochondrion, and the relative flow of death receptor signaling into either pathway may determine cell fate. Finally, death receptor induced apoptosis and autophagy could be potential targets for therapeutic intervention.
PMCID: PMC3292039  PMID: 18719356
Vorinostat; Sorafenib; bile acid; CD95; autophagy; ceramide; cell death; ASMase
21.  Genome Characterization of the Oleaginous Fungus Mortierella alpina 
PLoS ONE  2011;6(12):e28319.
Mortierella alpina is an oleaginous fungus which can produce lipids accounting for up to 50% of its dry weight in the form of triacylglycerols. It is used commercially for the production of arachidonic acid. Using a combination of high throughput sequencing and lipid profiling, we have assembled the M. alpina genome, mapped its lipogenesis pathway and determined its major lipid species. The 38.38 Mb M. alpina genome shows a high degree of gene duplications. Approximately 50% of its 12,796 gene models, and 60% of genes in the predicted lipogenesis pathway, belong to multigene families. Notably, M. alpina has 18 lipase genes, of which 11 contain the class 2 lipase domain and may share a similar function. M. alpina's fatty acid synthase is a single polypeptide containing all of the catalytic domains required for fatty acid synthesis from acetyl-CoA and malonyl-CoA, whereas in many fungi this enzyme is comprised of two polypeptides. Major lipids were profiled to confirm the products predicted in the lipogenesis pathway. M. alpina produces a complex mixture of glycerolipids, glycerophospholipids and sphingolipids. In contrast, only two major sterol lipids, desmosterol and 24(28)-methylene-cholesterol, were detected. Phylogenetic analysis based on genes involved in lipid metabolism suggests that oleaginous fungi may have acquired their lipogenic capacity during evolution after the divergence of Ascomycota, Basidiomycota, Chytridiomycota and Mucoromycota. Our study provides the first draft genome and comprehensive lipid profile for M. alpina, and lays the foundation for possible genetic engineering of M. alpina to produce higher levels and diverse contents of dietary lipids.
doi:10.1371/journal.pone.0028319
PMCID: PMC3234268  PMID: 22174787
23.  Role of CXC Chemokine Ligand 13 in Oral Squamous Cell Carcinoma Associated Osteolysis in Athymic Mice 
Oral squamous cell carcinomas (OSCC) are malignant tumors with a potent activity of local bone invasion; however the molecular mechanisms of tumor osteolysis are unclear. In this study, we identified high level expression of chemokine ligand, CXCL13 and RANK ligand (RANKL) in OSCC cells (SCC1, SCC12 and SCC14a). OSCC cell conditioned media (20%) induced osteoclast differentiation which was inhibited by OPG in peripheral blood monocyte cultures indicating that OSCC cells produce soluble RANKL. Recombinant hCXCL13 (10 ng/ml) significantly enhanced RANKL stimulated osteoclast differentiation in these cultures. Trans-well migration assay identified that CXCL13 induces chemotaxis of peripheral blood monocytes in vitro which was inhibited by addition of anti-CXCR5 receptor antibody. Zymogram analysis of conditioned media from OSCC cells revealed matrix metalloproteinase-9 (MMP-9) activity. Interestingly, CXCL13 treatment to OSCC cells induced CXCR5 and MMP-9 expression suggesting an autocrine regulatory function in OSCC cells. To examine the OSCC tumor cell bone invasion/osteolysis, we established an in vivo model for OSCC by subcutaneous injection of OSCC cells onto the surface of calvaria in NCr-nu/nu athymic mice, which developed tumors in 4–5 weeks. μCT analysis revealed numerous osteolytic lesions in calvaria from OSCC tumor-bearing mice. Histochemical staining of calvarial sections from these mice revealed a significant increase in the numbers of TRAP-positive osteoclasts at the tumor-bone interface. Immunohistochemical analysis confirmed CXCL13 and MMP-9 expression in tumor cells. Thus, our data implicate a functional role for CXCL13 in bone invasion and may be a potential therapeutic target to prevent osteolysis associated with OSCC tumors in vivo.
doi:10.1002/ijc.24920
PMCID: PMC2847058  PMID: 19816883
Oral squamous cell carcinoma (OSCC); Chemokine; MMP-9; Bone invasion; RANK ligand; Osteoclast; Mouse model
24.  Targeting sphingolipid metabolism in head and neck cancer: rational therapeutic potentials 
Importance of the field
Ceramide accumulation has been shown to be a conserved mechanism of apoptosis initiation in normal physiological processes as well as in response to cancer treatments such as radiation and chemotherapy. Therefore, it is unsurprising that many cancers develop aberrations of sphingolipid metabolism that prevent the accumulation of ceramide, whether by reduction of ceramide generation or by enhanced ceramide catabolism, particularly dangerous when catabolism leads to generation of pro-tumor sphingosine-1-phosphate and ceramide-1-phosphate. Numerous studies have now implicated dysregulation of sphingolipid metabolism in head and neck cancers.
What the reader will gain
The roles of sphingolipids and sphingolipid metabolism in cancer are reviewed and the reader will be brought up to date with discoveries in the field of sphingolipid metabolism in head and neck cancer.
Areas covered in this review
This review seeks to highlight the importance of sphingolipid metabolism and to bring sphingolipid metabolism to the forefront in the investigation of novel therapies for head and neck cancer. Further, it will review sphingolipid-centric therapies under investigation in preclinical and clinical trials of cancers of the head and neck.
Take home message
As treatments for head and neck cancers are currently limited, the potentials of targeting sphingolipid metabolism should be taken into consideration as we seek novel ways to combat this dangerous group of tumors.
doi:10.1517/14728221003752768
PMCID: PMC2861896  PMID: 20334489
Head and neck cancer; sphingolipids; ceramide; lipid metabolism; novel chemotherapeutic targets
25.  Acid Ceramidase Up-regulation in Prostate Cancer: Role in Tumor Development and Implications for Therapy 
Expert opinion on therapeutic targets  2009;13(12):1449-1458.
Bioactive sphingolipids, such as ceramide, sphingosine, and sphingosine-1-phosphate are known bio-effector molecules which play important roles in various aspects of cancer biology including cell proliferation, growth arrest, apoptosis, metastasis, senescence, and inflammation. Therefore, enzymes involved in ceramide metabolism are gaining recognition as being critical regulators of cancer cell growth and/or survival. We previously observed that the ceramide metabolizing enzyme, acid ceramidase (AC), is up-regulated in tumor tissues. Studies have now concluded that this creates a dysfunctional ceramide pathway which is responsible for tumor progression and resistance to chemotherapy and radiation. This suggests that development of small molecule drugs that inhibit AC enzyme activity is a promising approach for improving standard cancer therapy and patient’s clinical outcomes.
doi:10.1517/14728220903357512
PMCID: PMC2796572  PMID: 19874262
Prostate cancer; ceramide; acid ceramidase; tumor progression; therapeutic resistance; acid ceramidase inhibition; novel target

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