Loma Linda University

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Marino De Leon, PhD
Director of Center, Ctr for Health Disp&Molec Med, Director of Center Ctr for Health Disp&Molec Med
School of Medicine
Professor, Basic Sciences
School of Medicine
Publications    Scholarly Journals--Published
  •  A Padilla, LK Almeyda, Magda Descorbeth, K Payne and M De Leon. Hyperglycemia magnifies palmitic acid-induced lipotoxicity in Schwann cells cultures.Brain Research.In press ( 11/2010 )
     
  • Basu A, Banerjee H, Rojas H, Martinez S, Roy S, Jia Z, De León, M, Lilly MB and Casiano CA. Peroxiredoxin expression in prostate cancer: consistent upregulation of PRDX3 and PRDX4. Prostate. In press  ( 8/2010 )
     
  • Beeson W. Larry, Batech Michael, Schultz Eloy, Salto Lorena, Firek Anthony, De León, M, Balcazar Hector, Cordero-MacIntyre Zaida. Comparison of Body Composition by Bioelectrical Impedance Analysis and Dual-Energy X-Ray Absorptiometry in Hispanic Diabetics,  International Journal of Body Composition Research, 8/ 45-50/ 2010. ( 6/2010 )
     
  • Kalla Singh S, Tan QW, Brito C, De León M, Garberoglio C, De León D. Differential insulin-like growth factor II (IGF-II) expression: A potential role for breast cancer survival disparity. Growth Hormone and IGF Research 20:162-70, 2010. ( 6/2010 )
     
  • Almaguel, FG., Liu, J-W., Pacheco, FJ., De León, D., Casiano, CA., De León, M. Lipotoxicity-mediated cell dysfunction and death involve lysosomal membrane permeabilization and cathepsin L activity. Brain Research 1318C:133-143, 2010. ( 6/2009 - 6/2010 )
     
  • Ojo, E., Beeson, L., Shulz, E., Firek, A., De León, M., Balcazar, H., and Cordero-McIntyre, Z. Effect of the “En Balance”, a cultural and language-sensitive diabetes education program, on dietary changes and plasma lipid profile in Hispanic diabetics. International Journal of Body Composition 8:S69-76, 2010. ( 6/2009 - 6/2010 )
  • Kalla Singh S, Tan QW, Brito C, De León M and De León D. Insulin-like growth factors I and II receptors in the breast cancer survival disparity among African-American women Growth Hormone & IGF Research 20:245-254, 2010. ( 6/2009 - 6/2010 )
     
  • Almaguel, FG., Liu, J-W., Pacheco, FJ., Casiano, CA., and De León, M. Activation and reversal of lipotoxicity in PC12 and rat cortical cells following exposure to palmitic acid. Journal of Neuroscience Research. 87:1207-1218, 2009.  ( 6/2009 - 6/2010 )
     
  • Khan, S., Aspe, JR., Asumen, MG., Almaguel, F., Odumosu, O., Acevedo-Martinez, S., De León, M., Langridge, WH., Wall, NR. Extracellular, cell-permeable surviving inhibits apoptosis while promoting proliferative and metastatic potential. Br J Cancer 100(7):1073-86, 2009. ( 6/2009 - 6/2010 )
     
  • Mediavilla-Varela, M., Pacheco, FJ., Almaguel, F., Perez, J., Sahakian, E., Daniels, TR., Wall, NR., Lilly, MB., De León, M., and Casiano. CA. Docetaxel-induced prostate cancer cell death involves concomitant activation of caspase and lysosomal pathways and is attenuated by LEDGF/p75. Molecular Cancer. 8:68,  2009 ( 6/2009 - 6/2010 )
     
  • Peterson1, RM., Beeson1, L., Shulz, E., Firek, A., De León, M, Balcazar, H., Tonstad, S., and Cordero-MacIntyre, ZR. Impacting obesity and glycemic control using a culturally-sensitive diabetes education program in Hispanic patients with type 2 diabetes. International Journal of Body Composition Research 8:87-96, 2010. ( 6/2009 - 6/2010 )
  • Beeson W. Larry, Batech Michael, Schultz Eloy, Salto Lorena, Firek Anthony, De Leon Marino, Balcazar Hector, Cordero-MacIntyre Zaida. Comparison of Body Composition by Bioelectrical Impedance Analysis and Dual-Energy X-Ray Absorptiometry in Hispanic Diabetics.  International Journal of Body Composition Research. April Vol. 8 No 2: 45-50. 2010. ( 4/2010 )
     
  • Metghalchi, S., Rivera, M., Beeson, L., Firek, A., De León, M., Balcazar, H., Cordero-Macintyere, ZR. Improved clinical outcomes using a culturally sensitive diabetes education program in a Hispanic population. The Diabetes Educ 34:698-706, 2008. ( 6/2008 - 6/2009 )
     
  • Liu, J-W., Almaguel, FG., Bu, L., De Leon, DD., and De León, M. Expression of E-FABP in PC12 cells increases neurite extension during differentiation: involvement of n-3 and n-6 fatty acids. Journal of Neurochemistry 1006(5):2015-2029, 2008. ( 6/2008 - 6/2009 )
     
  • Shiva M, Rivera M, Fukuda D, Beeson L, Libanati C, Firek, D, Balcazar H, De León, M, and Cordero-Macintyre, ZR. Impact of Spanish Diabetes Education Program on Plasma Glucosa, Insulin, HemoglobinA1c, Plasma Lipids and Body Composition in Hispanic Population. Diabetes Educator 34(4):698-706, 2008. ( 6/2008 - 6/2009 )
     
  • Singh KS., Moretta D., Almaguel F., De León, M., De Leon DD. Precursor Igf-II (Proigf-II) and Mature Igf-II (MIgf-II) Induce Bcl-2 And Bcl-x(l) Expression Through Different Signalling Pathways In Breast Cancer Cells. Growth Factors 26(2): 92-103, 2008. ( 6/2008 )
  • Sing, KS., Moretta, D., Almaguel, F., Wall, NR., De León, M, De Leon, DD. Differential effect of proIGF-II and IGF-II on resveratrol induced cell death by regulating surviving cellular localization and mitochondrial depolarization in breast cancer cells. Growth Factors 25(6): 363-372, 2008. ( 6/2008 )
     
  • Ulloth JE., Almaguel FG., Padilla A., Bu, L., Liu, J-W., De León, M. "Characterization of methyl-beta-cyclodextrin toxicity in NGF-differentiated PC12 cell death." Neurotoxicology 28:613-621, 2007. ( 5/2007 )
     
  • Chang Y, Edeen K, Lu X, De Leon M, Mason RJ. "Keratinocyte growth factor induces lipogenesis in alveolar type II cells through a sterol regulatory element binding protein-1c-dependent pathway." Am J Respir Cell Mol Biol 35.2 (2006): 268-274. ( 8/2006 ) Link...
  • Allen, GA., Denes, B., Fodor, I., De León, M. "Vacinia virus infection & gene transduction in cultured neurons." Journal of Microbes and Infection 7. (2005): 1087-1096. ( 1/2005 ) Link...
     
  • Ulloth JE., Casiano, CA., and De León, M. "Palmitic and Stearic Fatty Acids Induce Caspase Dependent and Independent Cell Death in Nerve Growth Factor Differentiated PC12 Cells.." Journal of Neurochem 84. (2003): 655-668. ( 1/2003 )
  • Allen GW., Liu, J-W., Kirby, MA., and De León, M. . "Induction and axonal localization of E-FABP in retinal Ganglion cells is associated with axonal growth and regeneration.." Journal of Neurosci Research 66. (2001): 396-400. ( 1/2001 )
     
  • Allen GW, Liu, J-W., and De León, M. "Depletion of a fatty acid-binding protein impairs neurite outgrowth in PC12 cells. " Molecular Brain Research 29. (2000): 315-324. ( 1/2000 )
  • Liu Y., Longo, LD., and De León, M. "In situ and immunocytochemical localization of E-FABP mRNA and protein during neuronal migration and differentiation in rat brain, ." Brain Research 852.1 (1999): 16-27. ( 1/1999 )
  • De León, M.: "Cloning: Dolly?s Mother is her sister?." Update: 14.2 (1998): 4-5. ( 1/1998 )
     
  • Patel, IP., Suter, U., Snipes, GJ., Welcher, AA., De León, M., Lupkski, JR., and EM Shooter. Peripheral Myelin Protein coding sequence and method. USA Patent number 005,599,920A. 1997. ( 2/1997 )
     
  • Liu Y, Molina CA, Welcher AA, Longo LD,  De León, M. "Expression of DA11, a neuronal-Injury induced fatty acid binding protein, coincides with axon growth and neuronal differentiation during central nervous system development.." Journal of Neuroscience Research 48. (1997): 551-562. ( 1/1997 )
  • De León, M., Welcher, AA., R.H Nahin, RL., Liu, Y., Ruda, MA, Shooter, EM. and Molina,CA. "Fatty Acid Binding Protein is induced in Neurons of the dorsal root ganglia after peripheral nerve injury.." Journal of Neuroscience Research 44. (1996): 283-292. ( 1/1996 )
  • De León, M. "Clinical insight in the cause and diagnosis of inherited human peripheral neuropathies: contribution from basic molecular neurobiology research.." The Bulletin (November): . (1995): 15-18. ( 11/1995 )
  • De León, M., Nahin, R.L., Molina, C., De León, D.D. and Ruda, M.A.. "Comparison of c-jun, jun B and jun D on RNA expression and protein in the rat dorsal root ganglia following sciatic nerve transection.." Journal of Neuroscience Research 42. (1995): 391-401. ( 1/1995 )
  • Ruda, M.A., Besse, D., Inagaki, S., De León, M. and Ren, K.. "Nitric oxide expression and regulation in the dorsal root ganglion and spinal cord.." Annuals New York Academy of Science 738. (1995): 181-190. ( 1/1995 )
  • Nahin, R.L., Ren, K., De León, M., and Ruda, M.A.. "A rat model of peripheral mononeuropathy identifies alterations in gene expression in primary sensory neurons in the rat.." Pain 58. (1994): 95-108. ( 1/1994 )
  • De León, M., Mendoza, M.E., Nahin, R.L., and Ruda, M.A.. " SR13/PMP-22 expression in rat nervous system, in PC12 cells and C6 gliomas cell lines.." J. Neuroscience Research 38. (1994): 167-181. ( 1/1994 )
  • Noguchi, K., Dubner, R., De León, M., Senba, E., and Ruda, M.A.. "Axotomy induces preprotachykinin gene expression in a subpopulation of dorsal root ganglion neurons.." J. Neuroscience Research 37. (1994): 569-603. ( 1/1994 )
  • Noguchi, K., De León, M., Nahin, R.L., Senba, E. and Ruda, M.A. . "Quantization of axotomy-induced alteration of neuropeptide mRNAs in dorsal root ganglion neurons with special reference to neuropeptide Y mRNA and the effects of neonatal capsaicin treatment.." Journal Neurosci Research 35. (1993): 54-66. ( 1/1993 )
  • Hammer, J.A., O''Shannessy, D.J., De León, M., Gould, B., Zank, D., Daune, G., and Quarles, R.H.. "Immunoreactivity of PMP-22, PO and mammals and fish with HNK1 and other related antibodies. ." Journal Neurosci Research 35. (1993): 546-558. ( 1/1993 )
  • Welcher, A.A., De León, M., Suter, U., Snipes, G.J., Meakin, S.O. and Shooter, E.M.. "Isolation of transcriptionally regulated sequences associated with neuronal and non-neuronal cell interactions.." Progress in Brain Research 94. (1992): 163-176. ( 1/1992 )
  • De León, M., Van Eldik, L.E. and Shooter, E.M.. "Differential regulation of S100B and mRNAs coding for S100-like proteins (42A and 42C) during development and after lesion of rat sciatic nerve.." Journal of Neuroscience Research 29. (1991): 155-162. ( 1/1991 )
  • De León, M., Welcher, A.A., Suter, U. and Shooter, E.M.. "Identification of transcriptionally regulated genes after sciatic nerve injury.." Journal of Neuroscience Research 29. (1991): 437-448. ( 1/1991 )
  • Welcher, A.A., Suter, U., De León, M., Snipes, G.J., and Shooter, E.M. . "A myelin protein is encoded by the homologue of a growth arrest-specific gene.." Proceedings National Academic of Sciences USA 88. (1991): 7195-7199. ( 1/1991 )
  • Welcher, A.A., Suter, U., De León, M., Bitler, C.M., and Shooter, E.M.. "Molecular approaches to nerve regeneration.." Philosophical Transactions of the Royal Society of London. 331.Series B (1991): 295-301. ( 1/1991 )
  • Richard Carlsen, De León, M., Tetzlaff, W., Swedberg, E., Parhad, I. and Bisby, M.A. . "Increase in protein and tubulin mRNA synthesis in frog sensory neurons treated with the adenylate cyclase activator, forskolin.." Restorative Neurology and Neuroscience 1. (1990): 225-232. ( 1/1990 )
  • Bisby, M.A., Redshaw, J.D., Tezlaff, W., De León, M. and Carlsen, R.C. . "Expression of Growth-Associated proteins (GAPs) in injured sensory axons acclimatized to 15oC is not sufficient to sustain regeneration.." Restorative Neurology and Neuroscience 1. (1989): 25-29. ( 1/1989 )
  • De León, M. and Carlsen, R.C.. "Comparison of the synthesis and axonal transport of fucosylated glycoproteins by intact and regenerating sensory neurons in the frog.." Restorative Neurology and Neuroscience 1. (1989): 65-75. ( 1/1989 )
  • Cox, D., Jackson, H., Vargas, V., Baez, A., Colon, J., Gonzales, B. and De León, M.. "Synthesis and biological activity of benzothiazolo and benzoxazolo [3,2a] quinolinium salts.." Journal of Medicinal Chemistry. 25. (1982): 1378-1381. ( 1/1982 )
  • De Motta, G.E., Cordova, F., De León, M. and del Castillo, J.. "Inhibitory action of high formamide concentrations on excitation-contraction coupling in skeletal muscle.." Journal of Neuroscience Research 7. (1982): 163-178. ( 1/1982 )
  • Cordoba F, del Castillo J, De León, M, Escalona de Motta G, Garcia-Salazar M, Jimenez C.. "Effects of high concentrations of formamide on muscle contraction.." Journal of Physiology (London) 291. (1979): 73-74. ( 1/1979 )
  • Figueroa J D, Cordero K, Serrano-Illan M, Almeyda A, Baldeosingh K, Almaguel F G, & De Leon M. (2013). METABOLOMICS UNCOVERS DIETARY OMEGA-3 FATTY ACID-DERIVED METABOLITES IMPLICATED IN ANTI-NOCICEPTIVE RESPONSES AFTER EXPERIMENTAL SPINAL CORD INJURY. Neuroscience, 255, 1-18. ( 12/2013 - Present ) Link...
    Chronic neuropathic pain is a frequent comorbidity following spinal cord injury (SCI) and often fails to respond to conventional pain management strategies. Preventive administration of docosahexaenoic acid (DHA) or the consumption of a diet rich in omega-3 polyunsaturated fatty acids (O3PUFAs) confers potent prophylaxis against SCI and improves functional recovery. The present study examines whether this novel dietary strategy provides significant antinociceptive benefits in rats experiencing SCI-induced pain. Rats were fed control chow or chow enriched with O3PUFAs for 8 weeks before being subjected to sham or cord contusion surgeries, continuing the same diets after surgery for another 8 more weeks. The paw sensitivity to noxious heat was quantified for at least 8 weeks post-SCI using the Hargreaves test. We found that SCI rats consuming the preventive O3PUFA-enriched diet exhibited a significant reduction in thermal hyperalgesia compared to those consuming the normal diet. Functional neurometabolomic profiling revealed a distinctive deregulation in the metabolism of endocannabinoids (eCB) and related N-acyl ethanolamines (NAEs) at 8 weeks post-SCI. We found that O3PUFAs consumption led to a robust accumulation of novel NAE precursors, including the glycerophospho-containing docosahexaenoyl ethanolamine (DHEA), docosapentaenoyl ethanolamine (DPEA), and eicosapentaenoyl ethanolamine (EPEA). The tissue levels of these metabolites were significantly correlated with the antihyperalgesic phenotype. In addition, rats consuming the O3PUFA-rich diet showed reduced sprouting of nociceptive fibers containing CGRP and dorsal horn neuron p38 mitogen-activated protein kinase (MAPK) expression, well-established biomarkers of pain. The spinal cord levels of inositols were positively correlated with thermal hyperalgesia, supporting their role as biomarkers of chronic neuropathic pain. Notably, the O3PUFA-rich dietary intervention reduced the levels of these metabolites. Collectively, these results demonstrate the prophylactic value of dietary O3PUFA against SCI-mediated chronic pain. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
  • Figueroa J D, Cordero K, Ilan M S, & De Leon M. (2013). Dietary Omega-3 Polyunsaturated Fatty Acids Improve the Neurolipidome and Restore the DHA Status while Promoting Functional Recovery after Experimental Spinal Cord Injury. Journal of Neurotrauma, 30(10), 853-868. ( 5/2013 - Present ) Link...
    Omega-3 polyunsaturated fatty acids (x-3 PUFAs) confer multiple health benefits and decrease the risk of neurological disorders. Studies are needed, however, to identify promising cellular targets and to assess their prophylactic value against neurodegeneration. The present study (1) examined the efficacy of a preventive diet enriched with x-3 PUFAs to reduce dysfunction in a well-established spinal cord injury (SCI) animal model and (2) used a novel metabolomics data analysis to identify potential neurolipidomic targets. Rats were fed with either control chow or chow enriched with x-3 PUFAs (750 mg/kg/day) for 8 weeks before being subjected to a sham or a contusion SCI operation. We report new evidence showing that rats subjected to SCI after being pre-treated with a diet enriched with x-3 PUFAs exhibit significantly better functional outcomes. Pre-treated animals exhibited lower sensory deficits, autonomic bladder recovery, and early improvements in locomotion that persisted for at least 8 weeks after trauma. We found that SCI triggers a robust alteration in the cord PUFA neurolipidome, which was characterized by a marked docosahexaenoic acid (DHA) deficiency. This DHA deficiency was associated with dysfunction and corrected with the x-3 PUFA-enriched diet. Multivariate data analyses revealed that the spinal cord of animals consuming the x-3 PUFA-enriched diet had a fundamentally distinct neurolipidome, particularly increasing the levels of essential and long chain x-3 fatty acids and lysolipids at the expense of x-6 fatty acids and its metabolites. Altogether, dietary x-3 PUFAs prophylaxis confers resiliency to SCI mediated, at least in part, by generating a neuroprotective and restorative neurolipidome.
  • Wheeler G, Montgomery S B, Beeson L, Bahjri K, Shulz E, . . . Cordero-MacIntyre Z. (2012). En Balance The Effects of Spanish Diabetes Education on Physical Activity Changes and Diabetes Control. Diabetes Educator, 38(5), 723-732. ( 9/2012 - Present ) Link...
    Purpose This study was designed to assess the feasibility of culturally and language-sensitive diabetes education as a way to increase physical activity and to improve health/diabetes management in a group of Spanish-speaking Hispanics in the Inland Empire region of Southern California. Methods En Balance is a culturally sensitive diabetes education program designed for Spanish-speaking Hispanic adults. The 3-month educational intervention assessed 16 males and 23 females living in Riverside and San Bernardino counties of Southern California. Baseline and 3-month evaluations of physical activity were assessed using the validated Arizona Activity Frequency Questionnaire. Results After 3 months on the En Balance program, there was a significant increase in moderate intensity physical activity energy expenditure (M = 368 +/- 894 kcal/day, P < 0.01) and high intensity physical activity energy expenditure (M = 405 +/- 2569 kcal/day, P = 0.05) compared to baseline and significant reductions in A1C (-0.90%, P = 0.01), total cholesterol (-13.44 mg/dl, P = 0.01), LDL cholesterol (-10.28 mg/dl, P = 0.03), and waist circumference (-1.52 cm, P = 0.04). Conclusion En Balance program resulted in significant mean increases in both moderate and high intensity physical activity energy expenditure among this group of Hispanic diabetic participants, indicating that despite a general pattern of low physical activity in this group, an intervention that stresses both nutrition and exercise in culturally sensitive ways can positively impact participant's physical activity levels as well as impact nutritional changes.
  • Basu A, Rojas H, Banerjee H, Cabrera I B, Perez K Y, De Leon M, & Casiano C A. (2012). Expression of the Stress Response Oncoprotein LEDGF/p75 in Human Cancer: A Study of 21 Tumor Types. Plos One, 7(1), . ( 1/2012 - Present ) Link...
    Oxidative stress-modulated signaling pathways have been implicated in carcinogenesis and therapy resistance. The lens epithelium derived growth factor p75 (LEDGF/p75) is a transcription co-activator that promotes resistance to stress-induced cell death. This protein has been implicated in inflammatory and autoimmune conditions, HIV-AIDS, and cancer. Although LEDGF/p75 is emerging as a stress survival oncoprotein, there is scarce information on its expression in human tumors. The present study was performed to evaluate its expression in a comprehensive panel of human cancers. Transcript expression was examined in the Oncomine cancer gene microarray database and in a TissueScan Cancer Survey Panel quantitative polymerase chain reaction (Q-PCR) array. Protein expression was assessed by immunohistochemistry (IHC) in cancer tissue microarrays (TMAs) containing 1735 tissues representing single or replicate cores from 1220 individual cases (985 tumor and 235 normal tissues). A total of 21 major cancer types were analyzed. Analysis of LEDGF/p75 transcript expression in Oncomine datasets revealed significant upregulation (tumor vs. normal) in 15 out of 17 tumor types. The TissueScan Cancer Q-PCR array revealed significantly elevated LEDGF/p75 transcript expression in prostate, colon, thyroid, and breast cancers. IHC analysis of TMAs revealed significant increased levels of LEDGF/p75 protein in prostate, colon, thyroid, liver and uterine tumors, relative to corresponding normal tissues. Elevated transcript or protein expression of LEDGF/p75 was observed in several tumor types. These results further establish LEDGF/p75 as a cancer-related protein, and provide a rationale for ongoing studies aimed at understanding the clinical significance of its expression in specific human cancers.
  • Chukwueke I, Firek A, Beeson L, Brute M, Shulz E, De Leon M, & Cordero-MacIntyre Z R. (2012). THE EN BALANCE SPANISH DIABETES EDUCATION PROGRAM IMPROVES APOLIPOPROTEINS, SERUM GLUCOSE AND BODY COMPOSITION IN HISPANIC DIABETICS. Ethnicity & Disease, 22(2), 215-220. ( 0/2012 - Present )
    Objective: We evaluated the changes in apolipoproteins, glycemic status, and body composition after 3 months using a culturally sensitive diabetes education program, En Balance, in diabetic Hispanics. Methods: Thirty-four (9 males, 25 females) Hispanic diabetics participated in the En Balance program over three months. Body composition was determined by dual energy X-ray absorptiometry (DXA.), fasting plasma glucose (FPG), A1c, and apolipoproteins (Apo) measured after 3 months participation. Differences were analyzed using paired t testing and relationships between changes in Apo, A1c, total cholesterol, body mass index and body composition by Spearman correlations. Results: Completion of En Balance resulted in a significant reduction in weight (80.31 +/- 1.97 kg vs 81.25 +/- 17.97 kg, P=.015), LTG (143.21 +/- 57.8 mg/dL vs 166.41 +/- 65.9 mg/dL P=.003), and A1c (7.08 +/- 1.6% vs 7.87 +/- 2.0%, P=<.001). DXA demonstrated reduction in total fat (29.54 +/- 10.0 kg vs 30.24 +/- 11.80 kg, P=<.001) and trunk fat (15.09 +/- 5.6 kg vs 16.87 +/- 5.4 kg, P=.001). High density lipoprotein significantly increased (48.85 +/- 11.4 vs 44.65 +/- 8.8, P=.002) and total serum cholesterol/high density lipoprotein ratio decreased (3.87 +/- .98 vs 4.35 +/- 1.0, P=.001). There were significant correlations at three months between changes in Apo A1 and A2 (r=.559, P<.001), Apo E and total cholesterol (r=.746, P<.001), between A1c and FPG (r=.563, P=.001) and BMI and body weight (r=.732, P<.00.1). Conclusions: The En Balance program improved body composition, A1c, FPG, total cholesterol/HDL ratio and HDL. If these trends can be sustained, En Balance may serve as a unique educational paradigm for improving type 2 diabetes in Hispanics. (Ethn Dis. 2012;22(2):215-220)
  • Kalla Singh S, Brito C, Tan Q W, De Leon M, & De Leon D. (2011). Differential expression and signaling activation of insulin receptor isoforms A and B: A link between breast cancer and diabetes. Growth Factors, 29(6), 278-89. ( 12/2011 - Present ) Link...
    We showed that when insulin-like growth factor II (IGF-II) is highly expressed in breast tissues and cell lines, the IGF-I receptor signaling pathway is highly activated. Since IGF-II activates the insulin receptor (INSR), we propose that the INSR signaling is also activated in this system. We examined the expression of both INSR isoforms, insulin receptor A (INSR-A) and insulin receptor B (INSR-B), and the downstream signaling pathways in breast cancer (BC) cells and in paired (normal/tumor) breast tissues from 100 patients. Analysis was performed by real-time PCR, Western blot, immunohistochemistry, and phospho-ELISA techniques. Tumor tissues and cell lines from African-American patients expressed higher levels of INSR-A, but lower levels of INSR-B. Accordingly, insulin receptor substrate 1 and focal adhesion kinase activation were significantly increased in these women. We conclude that higher INSR-A and lower INSR-B contribute to higher proliferation and lower metabolic response. Thus, differential expression of INSR isoforms represents a potential biological link between BC and diabetes.
  • Figueroa J D, Cordero K, Baldeosingh K, Torrado A I, Walker R L, Miranda J D, & De Leon M. (2011). Docosahexaenoic Acid Pretreatment Confers Protection and Functional Improvements after Acute Spinal Cord Injury in Adult Rats. J Neurotrauma, , . ( 11/2011 - Present ) Link...
    Abstract Currently, few interventions have been shown to successfully limit the progression of secondary damage events associated with the acute phase of spinal cord injury (SCI). Docosahexaenoic acid (DHA, C22:6 n-3) is neuroprotective when administered following SCI, but its potential as a pretreatment modality has not been addressed. This study used a novel DHA pretreatment experimental paradigm that targets acute cellular and molecular events during the first week after SCI in rats. We found that DHA pretreatment reduced functional deficits during the acute phase of injury, as shown by significant improvements in Basso-Beattie-Bresnahan (BBB) locomotor scores, and the detection of transcranial magnetic motor evoked potentials (tcMMEPs) compared to vehicle-pretreated animals. We demonstrated that, at 7 days post-injury, DHA pretreatment significantly increased the percentage of white matter sparing, and resulted in axonal preservation, compared to the vehicle injections. We found a significant increase in the survival of NG2(+), APC(+), and NeuN(+) cells in the ventrolateral funiculus (VLF), dorsal corticospinal tract (dCST), and ventral horns, respectively. Interestingly, these DHA protective effects were observed despite the lack of inhibition of inflammatory markers for monocytes/macrophages and astrocytes, ED1/OX42 and GFAP, respectively. DHA pretreatment induced levels of Akt and cyclic AMP responsive element binding protein (CREB) mRNA and protein. This study shows for the first time that DHA pretreatment ameliorates functional deficits, and increases tissue sparing and precursor cell survival. Further, our data suggest that DHA-mediated activation of pro-survival/anti-apoptotic pathways may be independent of its anti-inflammatory effects.
  • Basu A, Drame A, Munoz R, Gijsbers R, Debyser Z, De Leon M, & Casiano C A. (2011). Pathway specific gene expression profiling reveals oxidative stress genes potentially regulated by transcription co-activator LEDGF/p75 in prostate cancer cells. Prostate, , . ( 7/2011 - Present ) Link...
    BACKGROUND: Lens epithelium-derived growth factor p75 (LEDGF/p75) is a stress survival transcription co-activator and autoantigen that is overexpressed in tumors, including prostate cancer (PCa). This oncoprotein promotes resistance to cell death induced by oxidative stress and chemotherapy by mechanisms that remain unclear. To get insights into these mechanisms we identified candidate target stress genes of LEDGF/p75 using pathway-specific gene expression profiling in PCa cells. METHODS: A "Human oxidative stress and antioxidant defense" qPCR array was used to identify genes exhibiting significant expression changes in response to knockdown or overexpression of LEDGF/p75 in PC-3 cells. Validation of array results was performed by additional qPCR and immunoblotting. RESULTS: Cytoglobin (CYGB), Phosphoinositide-binding protein PIP3-E/IPCEF-1, superoxidase dismutase 3 (SOD3), thyroid peroxidase (TPO), and albumin (ALB) exhibited significant transcript down- and up-regulation in response to LEDGF/p75 knockdown and overexpression, respectively. CYGB gene was selected for further validation based on its emerging role as a stress oncoprotein in human malignancies. In light of previous reports indicating that LEDGF/p75 regulates peroxiredoxin 6 (PRDX6), and that PRDXs exhibit differential expression in PCa, we also examined the relationship between these proteins in PCa cells. Our validation data revealed that changes in LEDGF/p75 transcript and protein expression in PCa cells closely paralleled those of CYGB, but not those of the PRDXs. CONCLUSIONS: Our study identifies CYGB and other genes as stress genes potentially regulated by LEDGF/p75 in PCa cells, and provides a rationale for investigating their role in PCa and in promoting resistance to chemotherapy- and oxidative stress-induced cell death. Prostate (c) 2011 Wiley-Liss, Inc.
  • Salto L M, Cordero-MacIntyre Z, Beeson L, Schulz E, Firek A, & De Leon M. (2011). En Balance Participants Decrease Dietary Fat and Cholesterol Intake as Part of a Culturally Sensitive Hispanic Diabetes Education Program. Diabetes Educator, 37(2), 239-253. ( 3/2011 - Present ) Link...
    Purpose The purpose of this study was to assess dietary intake habits of Mexican American Hispanic adults participating in the En Balance diabetes education program. Methods En Balance is a 3-month culturally sensitive diabetes education intervention for Spanish-speaking Hispanics. Of the 46 participants enrolled, 39 mainly Mexican American Hispanic adults with type 2 diabetes completed the En Balance program. Participants lived in the Riverside and San Bernardino counties of California, and all participants completed the program by June 2008. Dietary intake was assessed at baseline and at 3 months using the validated Southwest Food Frequency Questionnaire. Results Clinically important decreases in glycemic control and serum lipid levels were observed at the end of the 3-month program. The baseline diet was characterized by a high intake of energy (2478 +/- 1140 kcal), total fat (87 +/- 44 g/day), saturated fat (28 +/- 15 g/day), dietary cholesterol (338 +/- 217 mg/day), and sodium (4236 +/- 2055 mg/day). At 3 months, the En Balance group mean intake of dietary fat (P=.045) and dietary cholesterol (P=.033) decreased significantly. Low dietary intakes of docosahexaenoic acid, eicosapentaenoic acid, and vitamin E were also observed in these adults with type 2 diabetes. Conclusions The En Balance program improved glycemic control and lipid profiles in a group of Hispanic diabetic participants. En Balance also promoted decreases in dietary fat and dietary cholesterol intake.
  • Padilla A, Descorbeth M, Almeyda A L, Payne K, & De Leon M. (2011). Hyperglycemia magnifies Schwann cell dysfunction and cell death triggered by PA-induced lipotoxicity. Brain Research, 1370, 64-79. ( 1/2011 - Present ) Link...
    Lipid overload resulting in lipotoxicity is prominent in a number of chronic diseases and has been associated with cellular dysfunction and cell death. This study characterizes palmitic acid-induced lipotoxicity (PA-LTx) in Schwann cell cultures grown in normal and high glucose concentrations. The study shows for the first time that Schwann cell (SC) cultures exposed to elevated levels of PA exhibit a dose- and time-dependent loss in cell viability. Hoescht and Annexin V/7AAD staining confirmed cell death through apoptosis and the lipotoxic effect was more dramatic in SC cultures grown under high glucose conditions. The first indication of cellular dysfunction in treated SC cultures was a decrease in Ca(++) levels in the endoplasmic reticulum (ER, [Ca(++)](ER)) observed five minutes following the initial challenge with PA. This decrease in [Ca(++)](ER) was followed by a significant increase in the expression of ER stress signature genes CHOP, Xbp1 and GRP78. The early ER stress response induced by PA-LTx was followed by a strong mitochondrial membrane depolarization. Flow cytometry using 2', 7'-dichlorodihydrofluorescein diacetate (H(2)DCFDA) showed an increase in oxidative stress within three to six hours after PA treatment. Treatment of cultures undergoing PA-LTx with the calcium chelator BAPTA-AM and the anti-oxidant MCI-186 significantly reversed the lipotoxic effect by decreasing the generation of ROS and significantly increasing cell viability. We conclude that lipotoxicity in Schwann cells results in cellular dysfunction and cell death that involves a robust ER stress response, mitochondrial dysfunction and an augmented state of cellular oxidative stress (ASCOS). (C) 2010 Elsevier B.V. All rights reserved.
  • Bu Liming, Salto Lorena M, De Leon Kevin J, & De Leon Marino. (2011). Polymorphisms in fatty acid binding protein 5 show association with type 2 diabetes. Diabetes Research & Clinical Practice, 92(1), 82-91. ( 0/2011 - Present ) Link...
    Abstract: Genes for the fatty acid binding proteins (FABP) family encode small 14-15kDa cytosolic proteins and can be regulated during type 2 diabetes mellitus (T2DM) and obesity. This study compared association of single nucleotide polymorphisms (SNPs) in FABP1-5 with T2DM in different ethnic groups. Associations with T2DM of SNPs in these proteins were assessed in African American (AA), non-Hispanic White (NHW), and Hispanic American (HA) individuals. A total of 650 DNA samples were genotyped; control samples were obtained from Coriell''s North American Human Variation Panel Repository (NAHVP) of apparently healthy individuals and T2DM cases were taken from the American Diabetes Association GENNID Study. The rs454550 SNP of FABP5 showed a significant association with T2DM in NHW (OR: 9.03, 95% CI: 1.13-71.73, p =0.014). Our analysis also identified a new FABP5 SNP (nSNP) that showed a significant association with T2DM in NHW (OR: 0.44, 95% CI: 0.19-0.99, p =0.045) and AA (OR: 0.17, 95% CI: 0.03-0.80, p =0.016). The Ala54Thr FABP2 polymorphism was significantly associated with T2DM in HA individuals only (OR: 1.85, 95% CI: 1.05-3.27, p =0.032). All other FABP SNPs did not show association with T2DM. These findings suggest a potential distinct role(s) of SNPs in FABP5 and FABP2 genes in T2DM in different populations. [Copyright &y& Elsevier] Copyright of Diabetes Research & Clinical Practice is the property of Elsevier Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
  • Basu A, Banerjee H, Rojas H, Martinez S R, Roy S, . . . Casiano C A. (2010). Differential expression of peroxiredoxins in prostate cancer: Consistent upregulation of PRDX3 and PRDX4. Prostate, , . ( 10/2010 - Present ) Link...
    BACKGROUND: The peroxiredoxins (PRDXs) are emerging as regulators of antioxidant defense, apoptosis, and therapy resistance in cancer. Because their significance in prostate cancer (PCa) is unclear, we investigated their expression and clinical associations in PCa. METHODS: Transcript expression of PRDX1-6 in PCa was evaluated in cancer gene microarray datasets, whereas protein expression was evaluated by immunoblotting in prostate cell lines, and by immunohistochemistry (IHC) in prostate tissue microarrays (TMAs) containing tumor (n = 80) and control (n = 17) tissues. PRDX3 was also analyzed in TMAs containing PCa tissues from African-American and Caucasian patients (n = 150 per group). PRDX expression was correlated with patients' clinicopathologic characteristics. RESULTS: Analysis of PRDX expression in cancer microarray datasets revealed consistent upregulation (tumor vs. normal) of PRDX3 and 4. All PRDXs exhibited elevated protein expression in PCa cell lines, compared with non-tumor cells. IHC revealed significant overexpression of PRDX3 and 4 in PCa, associated with age, increased prostate specific antigen (PSA), tumor stage, or Gleason score. High PRDX3 staining was associated with early age and elevated Gleason score at time of radical prostatectomy in African-American but not in Caucasian patients with PCa. PSA recurrence free survival in patients with low PRDX3 tumor expression was significantly longer in Caucasians compared to African-Americans, but no difference was detected for high expression. CONCLUSIONS: PRDXs exhibit differential expression in prostate tumors, with PRDX3 and 4 consistently upregulated. Their role in PCa development, and their potential as biological determinants of PCa health disparities and novel therapeutic targets, deserve further investigation. Prostate (c) 2010 Wiley-Liss, Inc.
  • Kalla Singh S, Tan Q W, Brito C, De Leon M, & De Leon D. (2010). Insulin-like growth factors I and II receptors in the breast cancer survival disparity among African-American women. Growth Horm IGF Res, 20(3), 245-54. ( 6/2010 - Present ) Link...
    OBJECTIVE: African-American (AA) women with breast cancer are more likely to have advanced disease at diagnosis, higher risk of recurrence and poorer prognosis than Caucasian (CA) women. We have recently shown higher insulin-like growth factor II (IGF-II) expression in paired breast tissue samples from AA women as compared to CA women. IGF-II is a potent mitogen that induces cell proliferation and survival signals through activation of the IGF-I and Insulin receptors (IGF-IR, IR) while IGF-II circulating levels are regulated by cellular uptake through the IGF2 receptor. We hypothesize that differential expression of the IGF1R and IGF2R among AA and CA women potentiates IGF-II mitogenic effects, thus contributing to the health disparity observed between these ethnic groups. DESIGN: We examined IGF-IR and IGF2R mRNA, protein expression and IGF1R phosphorylation in paired breast tissue samples from AA and CA women by Real Time-PCR, Western blot analysis, immunohistochemistry and ELISA techniques. RESULTS: Our results showed significantly increased expression of IGF1R in AA normal tissues as compared to CA normal tissues. IGF1R expression was similar between AA normal and malignant tissues, while IGF1R, IRS-1 and Shc phosphorylation was significantly higher in AA tumor samples. Significantly higher levels of IGF2R were found in CA tumor samples as compared to AA tumor samples. CONCLUSIONS: We conclude that IGF1R and IGF2R differential expression may contribute to the increased risk of malignant transformation in young AA women and to the more aggressive breast cancer phenotype observed among AA breast cancer patients and represent, along with IGF-II, potential therapeutic targets in breast cancer.
  • Almaguel F G, Liu J W, Pacheco F J, De Leon D, Casiano C A, & De Leon M. (2010). Lipotoxicity-mediated cell dysfunction and death involve lysosomal membrane permeabilization and cathepsin L activity. Brain Research, 1318, 133-143. ( 3/2010 - Present ) Link...
    Lipotoxicity, which is triggered when cells are exposed to elevated levels of free fatty acids, involves cell dysfunction and apoptosis and is emerging as an underlying factor contributing to various pathological conditions including disorders of the central nervous system and diabetes. We have shown that palmitic acid (PA)-induced lipotoxicity (PA-LTx) in nerve growth factor-differentiated PC12 (NGFDPC12) cells is linked to an augmented state of cellular oxidative stress (ASCOS) and apoptosis and that these events are inhibited by docosahexanoic acid (DHA). The mechanisms of PA-LTx in nerve cells are not well understood, but our previous findings indicate that it involves ROS generation, mitochondrial membrane permeabilization (MMP), and caspase activation. The present study used nerve growth factor differentiated PC12 cells (NGFDPC12 cells) and found that lysosomal membrane permeabilization (LMP) is an early event during PA-induced lipotoxicity that precedes MMP and apoptosis. Cathepsin L, but not cathepsin B, is an important contributor in this process since its pharmacological inhibition significantly attenuated LMP, MMP, and apoptosis. In addition, co-treatment of NGFDPC12 cells undergoing lipotoxicity with DHA significantly reduced LMP, suggesting that DHA acts by antagonizing upstream signals leading to lysosomal dysfunction. These results suggest that LMP is a key early mediator of lipotoxicity and underscore the value of interventions targeting upstream signals leading to LMP for the treatment of pathological conditions associated with lipotoxicity. (C) 2009 Elsevier B.V. All rights reserved.
  • Peterson R M, Beeson L, Shulz E, Firek A, De Leon M, . . . Cordero-Macintyre Z R. (2010). Impacting obesity and glycemic control using a culturally-sensitive diabetes education program in Hispanic patients with type 2 diabetes. Int J Body Compos Res, 8(3), 85-94. ( 0/2010 - Present ) Link...
    OBJECTIVES: Diabetes mellitus and obesity are prevalent in the Hispanic community. This group has not benefited greatly from diabetes interventions due to cultural, language and financial constraints. We designed a prospective cohort study to determine the clinical impact on adiposity and glycemic control in Hispanics with type 2 diabetes. RESEARCH DESIGN AND METHODS: The program conducted in Spanish by a multidisciplinary team of health care providers focused on improving glycemic control and complications through cultural lifestyle changes. Outcomes were changes in glycemic control by fasting insulin, glucose and HbA1c, body composition and selected adipokines, adiponectin, leptin and ghrelin. Body composition was measured by dual energy x-ray absorptiometry. Changes from baseline at three months were compared using paired t-tests and with Spearman's correlations. RESULTS: Glycemic control improved by HbA1c (7.9% +/- 2.0% vs 7.1% +/- 1.7%; P = <0.001), and fasting glucose (166.4 +/- 66.0 mg/dl vs 143.2 +/- 57.9 mg/dl; P = 0.003). Body weight (81.3 +/- 17.9 kg vs 80.3 +/- 18.0 kg; P = 0.002), waist circumference (101.6 +/- 13.4 cm vs 99.1 +/- 12.7 cm; P = 0.015), and truncal fat (16.5 +/- 5.7 kg vs 15.9 +/- 5.6 kg; P = 0.001) decreased. Only leptin (19.6 +/- 15.0 ng/ml vs 16.3 +/- 12.7 ng/ml; P = 0.002) was reduced and related to change in body weight (r = 0.392; P = 0.022). CONCLUSIONS: Our program significantly improved glycemic control and decreased obesity in diabetic Hispanic subjects. The early benefits on glycemic control may be related to reductions in leptin through loss of adipose tissue. Success in impacting diabetes and related complications can occur in a culturally focused and multidisciplinary context.
  • Ojo E, Beeson L, Shulz E, Firek A, De Leon M, Balcazar H, & Cordero-Macintyre Z. (2010). Effect of the EnBalance, a culturally and language-sensitive diabetes education program, on dietary changes and plasma lipid profile in Hispanic diabetics. Int J Body Compos Res, 8(Supp), S69-S76. ( 0/2010 - Present ) Link...
    OBJECTIVE: To assess the effects of a language-sensitive diabetes education program on dietary changes and plasma lipid profiles. METHOD: Hispanic participants (n=13 males and 18 females, mean age = 54.00 + 10.68 years) participated in a 3-month health education study. Spearman correlation coefficients were used to evaluate correlations between dietary intake and laboratory measurements. RESULTS: There were significant decreases in serum total cholesterol (-16.07 mg/dl, P= 0.035), HDL cholesterol (-3.23 mg/dl, P = 0.01), LDL cholesterol (-11.71 mg/dl, P = 0.013) and dietary cholesterol (-79.22 mg, P = 0.03). No significant mean change was observed in triglyceride and total cholesterol/HDL ratio. There was also a reduction in body mass index (BMI) (-0.15 kg/m(2), P = 0.40), fasting glucose (-3.90 mg/dl, P = 0.43) and dual energy X-ray absorptiometry (DXA) total fat (-0.50, P = 0.97). Although not statistically significant, saturated fatty acids (-4.90 g, P = 0.19), polyunsaturated fatty acids (-3.31g, P = 0.11), and carbohydrate (-44.82 g, P = 0.22), decreased after three months. CONCLUSION: There were significant improvements in dietary intake and serum lipids after a three-month culture-specific diabetes education program.
  • Peterson R M, Beeson L, Shulz E, Firek A, De Leon M, . . . Cordero-Macintyre Z R. (2010). Impacting obesity and glycemic control using a culturally-sensitive diabetes education program in Hispanic patients with type 2 diabetes. Int J Body Compos Res, 8(3), 85-94. ( 0/2010 - Present ) Link...
    OBJECTIVES: Diabetes mellitus and obesity are prevalent in the Hispanic community. This group has not benefited greatly from diabetes interventions due to cultural, language and financial constraints. We designed a prospective cohort study to determine the clinical impact on adiposity and glycemic control in Hispanics with type 2 diabetes. RESEARCH DESIGN AND METHODS: The program conducted in Spanish by a multidisciplinary team of health care providers focused on improving glycemic control and complications through cultural lifestyle changes. Outcomes were changes in glycemic control by fasting insulin, glucose and HbA1c, body composition and selected adipokines, adiponectin, leptin and ghrelin. Body composition was measured by dual energy x-ray absorptiometry. Changes from baseline at three months were compared using paired t-tests and with Spearman's correlations. RESULTS: Glycemic control improved by HbA1c (7.9% +/- 2.0% vs 7.1% +/- 1.7%; P = <0.001), and fasting glucose (166.4 +/- 66.0 mg/dl vs 143.2 +/- 57.9 mg/dl; P = 0.003). Body weight (81.3 +/- 17.9 kg vs 80.3 +/- 18.0 kg; P = 0.002), waist circumference (101.6 +/- 13.4 cm vs 99.1 +/- 12.7 cm; P = 0.015), and truncal fat (16.5 +/- 5.7 kg vs 15.9 +/- 5.6 kg; P = 0.001) decreased. Only leptin (19.6 +/- 15.0 ng/ml vs 16.3 +/- 12.7 ng/ml; P = 0.002) was reduced and related to change in body weight (r = 0.392; P = 0.022). CONCLUSIONS: Our program significantly improved glycemic control and decreased obesity in diabetic Hispanic subjects. The early benefits on glycemic control may be related to reductions in leptin through loss of adipose tissue. Success in impacting diabetes and related complications can occur in a culturally focused and multidisciplinary context.
  • Mediavilla-Varela M, Pacheco F J, Almaguel F, Perez J, Sahakian E, . . . Casiano C A. (2009). Docetaxel-induced prostate cancer cell death involves concomitant activation of caspase and lysosomal pathways and is attenuated by LEDGF/p75. Molecular Cancer, 8, . ( 8/2009 - Present ) Link...
    Background: Hormone-refractory prostate cancer (HRPC) is characterized by poor response to chemotherapy and high mortality, particularly among African American men when compared to other racial/ethnic groups. It is generally accepted that docetaxel, the standard of care for chemotherapy of HRPC, primarily exerts tumor cell death by inducing mitotic catastrophe and caspase-dependent apoptosis following inhibition of microtubule depolymerization. However, there is a gap in our knowledge of mechanistic events underlying docetaxel-induced caspase-independent cell death, and the genes that antagonize this process. This knowledge is important for circumventing HRPC chemoresistance and reducing disparities in prostate cancer mortality. Results: We investigated mechanistic events associated with docetaxel-induced death in HRPC cell lines using various approaches that distinguish caspase-dependent from caspase-independent cell death. Docetaxel induced both mitotic catastrophe and caspase-dependent apoptosis at various concentrations. However, caspase activity was not essential for docetaxel-induced cytotoxicity since cell death associated with lysosomal membrane permeabilization still occurred in the presence of caspase inhibitors. Partial inhibition of docetaxel-induced cytotoxicity was observed after inhibition of cathepsin B, but not inhibition of cathepsins D and L, suggesting that docetaxel induces caspase-independent, lysosomal cell death. Simultaneous inhibition of caspases and cathepsin B dramatically reduced docetaxel-induced cell death. Ectopic expression of lens epithelium-derived growth factor p75 (LEDGF/p75), a stress survival autoantigen and transcription co-activator, attenuated docetaxel-induced lysosomal destabilization and cell death. Interestingly, LEDGF/p75 overexpression did not protect cells against DTX-induced mitotic catastrophe, and against apoptosis induced by tumor necrosis factor related apoptosis inducing ligand (TRAIL), suggesting selectivity in its pro-survival activity. Conclusion: These results underscore the ability of docetaxel to induce concomitantly caspase-dependent and independent death pathways in prostate cancer cells. The results also point to LEDGF/p75 as a potential contributor to cellular resistance to docetaxel-induced lysosomal destabilization and cell death, and an attractive candidate for molecular targeting in HRPC.
  • Almaguel F G, Liu J W, Pacheco F J, Casiano C A, & De Leon M. (2009). Activation and Reversal of Lipotoxicity in PC12 and Rat Cortical Cells Following Exposure to Palmitic Acid. Journal of Neuroscience Research, 87(5), 1207-1218. ( 4/2009 - Present ) Link...
    Lipotoxicity involves a series of pathological cellular responses after exposure to elevated levels of fatty acids. This process may be detrimental to normal cellular homeostasis and cell viability. The present study shows that nerve growth factor-differentiated PC12 cells (NGFDPC12) and rat cortical cells (RCC) exposed to high levels of palmitic acid (PA) exhibit significant lipotoxicity and death linked to an "augmented state of cellular oxidative stress" (ASCOS). The ASCOS response includes generation of reactive oxygen species (ROS), alterations in the mitochondrial transmembrane potential, and increase in the mRNA levels of key cell death/survival regulatory genes. The observed cell death was apoptotic based on nuclear morphology, caspase-3 activation, and cleavage of lamin B and PARR Quantitative real-time PCR measurements showed that cells undergoing lipotoxicity exhibited an increase in the expression of the mRNAs encoding the cell death-associated proteins BNIP3 and FAS receptor. Cotreatment of NGFDPC12 and RCC cells undergoing lipotoxicity with docosahexaenoic acid (DHA) and bovine serum albumin (BSA) significantly reduced cell death within the first 2 hr following the initial exposure to PA. The data suggest that lipotoxicity in NGFDPC12 and cortical neurons triggers a strong cell death apoptotic response. Results with NGFDPC12 cells suggest a linkage between induction of ASCOS and the apoptotic process and exhibit a temporal window that is sensitive to DHA and BSA interventions. (C) 2008 Wiley-Liss, Inc.
  • Khan S, Aspe J R, Asumen M G, Almaguel F, Odumosu O, . . . Wall N R. (2009). Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential. British Journal of Cancer, 100(7), 1073-1086. ( 3/2009 - Present ) Link...
    The tumour microenvironment is believed to be involved in development, growth, metastasis, and therapy resistance of many cancers. Here we show survivin, a member of the inhibitor of apoptosis protein (IAP) family, implicated in apoptosis inhibition and the regulation of mitosis in cancer cells, exists in a novel extracellular pool in tumour cells. Furthermore, we have constructed stable cell lines that provide the extracellular pool with either wild-type survivin (Surv-WT) or the previously described dominant-negative mutant survivin (Surv-T34A), which has proven pro-apoptotic effects in cancer cells but not in normal proliferating cells. Cancer cells grown in conditioned medium (CM) taken from Surv-WT cells absorbed survivin and experienced enhanced protection against genotoxic stresses. These cells also exhibited an increased replicative and metastatic potential, suggesting that survivin in the tumour microenvironment may be directly associated with malignant progression, further supporting survivin's function in tumourigenesis. Alternatively, cancer cells grown in CM taken from the Surv-T34A cells began to apoptose through a caspase-2- and caspase-9-dependent pathway that was further enhanced by the addition of other chemo- and radiotherapeutic modalities. Together our findings suggest a novel microenvironmental function for survivin in the control of cancer aggressiveness and spread, and should result in the genesis of additional cancer treatment modalities.
  Abstract
  • Al Abdrabalnabi A A, Marghalani A A, Beeson L, Firek A, Schulz E, . . . Cordero-MacIntyre Z R. (2013). Impact of "En Balance" Culturally Sensitive Educational Program on Lifestyle Changes among Hispanics with Type-2 Diabetes. FASEB Journal, 27, 1. ( 4/2013 - Present )
  • Descorbeth M, Figueroa K F, Serrano-Illan M, & De Leon M. (2013). Protective effect of Docosahexaenoic acid (DHA) on lipotoxicity -induced cell death: implication of PI3K/AKT and MAPK pathways. FASEB Journal, 27, 1. ( 4/2013 - Present )
  • Mendivil F, Beeson L, Schulz E, Firek A, Balcazar H, De Leon M, & Cordero-MacIntyre Z R. (2011). Increments in Physical Activity in the "En Balance" Diabetes Education Program in Type 2 Hispanic Diabetics. Faseb Journal, 25, . ( 4/2011 - Present )
  • Wheeler G, Beeson L, Montgomery S, Bhajri K, Schulz E, . . . Cordero-MacIntyre Z. (2011). The effects of the "En Balance" diabetes education program on physical activity and diabetes control. Faseb Journal, 25, . ( 4/2011 - Present )
  • Mendler M H, Schulz E, Salto L M, Beeson L, Firek A, De Leon M, & Cordero-MacIntyre Z. (2009). THE "EN BALANCE" 3-MONTH DIABETES EDUCATION PROGRAM FOR HISPANICS LEADS TO SIGNIFICANT IMPROVEMENTS IN NONALCOHOLIC FATTY LIVER DISEASE. Hepatology, 50(4), 765A-765A. ( 10/2009 - Present )
  • Figueroa J D, Liming B, Miranda J D, & De L M. (2009). NOVEL ROLES OF FATTY ACID BINDING PROTEIN 5 IN SPINAL CORD INJURY. Journal of Neurochemistry, 108, 104-104. ( 3/2009 - Present )