BIOCHEMISTRY Publication Record Bazarbachi, A., M. El-Sabban, R. Nasr, F. Quignon, C. Awaraji,
J. Kersual, L. Dianoux, J. Haidar, O. Hermine, and H. De The. 1999. Arsenic
trioxide and interferon-alpha synergize to induce cell cycle arrest and
apoptosis in HTLV-I tranformed cells. Blood 93 (1):278–283. Bazarbachi, A., and O. Hermine. 2001. Treatment of adult T
cell leukemia/lymphoma: Current strategy and future perspectives. Virus
Research. Bazarbachi, A., R. Nasr, M. El-Sabban, A. Mahe, R. Mahieux, A. Gessain, N. Darwiche, G. Dbaibo, J. Kersual, Y. Zermati, L. Dianoux, M. Chelbi-Alix, H. De The, and O. Hermine. 2000. Evidence against a direct cytotoxic effect of alpha interferon and zidovudine in HTLV-I associated adult T cell leukemia/Lymphoma. Leukemia 14 (4):299–306. Bou-Moglabey, Y., R. Kircheisen, M. Seoud, N. El-Mogharbel, I.
Van den Veyyer, and R. Slim.
1999. Genetic mapping of a maternal locus responsible for familial
hydatidiform moles. Human Molecular Genetics 8 (4):667–671. Cilio, M. R., A. R. Bolanos, Z. Liu, R. Schmid, Y. Yang, C. E.
Stafstrom, M. A. Mikati, and G. L. Holmes. 2000. Anticonvulsant action and
long-term effects of gabapentin in the immature brain. Neuropharmacology
40 (1):139–147. Darwiche, N., M. El-Sabban, R. Bazzi, R. Nasr, S. Al Hashimi,
O. Hermine, H. De The, and A. Bazarbachi. 2001. Retinoic acid dramatically
enhances the arsenic trioxide induced cell cycle arrest and apoptosis in
retinoic acid receptor alpha-positive human T-cell lymphotropic virus type-I
transformed cells. The Hematology Journal. Darwiche, N., L. Freeman, and A. Strunnikov. 1999.
Characterization of the components of the putative mammalian sister chromatid
cohesion complex. Gene. DeAngelis, M. M., T. L. McGee, B. J. B. Keats, R. Slim, E. L.
Berson, and T. P. Dryja. 2001. Two families from New England with Usher
syndrome type 1C with distinct haplotypes. American Journal of Ophtalmology. El-Sabban, M., R. Nasr, G. Dbaibo, O. Hermine, N. Abboushi, F.
Quignon, J. C. Ameisen, F. Bex, H. De The, and A. Bazarbachi. 2000.
Arsenic/interferon-alpha triggered apoptosis in HTLV-I tranformed cells is
associated with tax downregulation and reversal of NF-kB activation. Blood
96 (8):2849–2855. Helwani, M. N., M. Seoud, L. Zahed, G. Zaatari, A. Khalil, and
R. Slim. 1999. Familial case of recurrent hydatidiform molar pregnancies with
biparental genomic contribution. Human Genetics 105 (1–2):112–115. Kreydiyyeh, S., J. Usta, and R. Copti. 2000. Effect of
cinnamon and clove and some of their constituents on the Na+/K+ ATPase
activity and alanine absorption in the rat jejunum. Food and Chemical
Toxicology 38 (9):755–762. Kreydiyyeh, S., J. Usta, I. Kaouk, and R. Al-Sadi. 2001. The
mechanism underlying the laxative properties of parsley extract. Phytomedicine. Marlin, S., S. Blanchard, R. Slim, D. Lacombe, F. Denoyelle,
J. L. Alessandri, E. Calzolari,
V. Droun-Garraud, F. G. Ferraz, A. Fourmaintraux, N. Philip, J. E. Toublanc, and C. Petit. 1999.
Townes-Brocks syndrome: Defection of a SALLI mutation hot spot and evidence
for a position effect in one patient. Human Mutation 14 (5):377–386. Matar, G., M. Fayad, and M. A. Mikati. 1999. A two-step protocol
for the identification of the etiology of bacterial meningitis in
cerebrospinal fluid by PCR-amplification of the 16S ribosomal RNA gene. Eastern
Journal of Medicine. Matar, G. M., M. Fayad, V. A. Khoudoud, and M. A. Mikati. 2000. Herpes simplex
encephalitis cases with variable or unusual clinical symptoms confirmed by
PCR-amplification of the DNA polymerase gene. Eastern Journal of Medicine. Megarbane, A., N. Waked, E. Chouery, Y. B. Moglabey, N.
Saliba, E. Mornet, J. L. Serre, and R. Slim. 2001. Micocephaly, cutis
verticis gyrata of the scalp, retinitis pigmentosa, cataracts, sensorineural
deafness, and mental retardation in two brothers. American Journal of
Medical Genetics 98 (3):244–249. Mikati, M. A., S. Tarif, L. Lteif, and M. A. Jawad. 2001. Time
sequence and types of memory deficits after experimental status epilepticus. Epilepsy
Research 43 (2):97–101. Mikati, M. A., S. Werner, A. Gatt, Z. Liu, A. Rahmeh, and R.
Rachid. 1999. Consequences of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid receptor blockade during status epilepticus in the developing brain. Developmental
Brain Research 113 (1–2):139–142. Ogretmen, B., D. Schady, J. Usta, R. Wood, J. Krakeva, C.
Luberto, H. Birbes, Y. Hannun, and L. Obeid. 2001. Role of ceramide in
mediating the inhibition of telomerase activity in A549 human lung
adenocarcinoma cells. Journal of Biological Chemistry 276
(27):24901–24910. Shamseddine, A., A. Taher, H. Jaafar, J. H. Haidar, R. Nasr,
V. Arzoumanian, Z. Salem, and A. Bazarbachi. 2000. Interferon alpha is an
effective therapy for congenital dyserythropoietic anaemia type I.
Euoropean Journal of Haematology 65 (3):207–209. Taher, A., I. Khalil, A. Shamseddine, F. El-Ahdab, and A.
Bazarbachi. 2001. High prevalence of factor V leiden mutation among healthy
individuals and patients with deep venous thrombosis in Lebanon: Is
Eastern Mediterranean region the primary focus of this mutation? Thrombosis
and Haemostasis 86 (2):723–724. Verpy, E., M. Leibovici, I. Zwaenepoel, X. Z. Liu, A. Gal, N. Salem, A. Mansour, S. Blanchard, I. Kobayashi, B. J. B. Keats, R. Slim, and C. Petit. 2000. Defect in harmonin, a PDZ domain-containing protein, expressed in the inner ear sensory hair cells, underlies Usher syndrome 1C. Nature Genetics 26 (1):51–55. Abstracts, Conferences, and Proceedings Abboushi, N., W. El-Assad, M. El-Sabban, A. Bazerbachi, J.
Usta, and G. Dbaibo. March 2001. Ceramide inhibits NF-kB dependent
interleukin-2 transcription. The American Society for Biochemistry and
Molecular Biology Meeting, Orlando, Florida, USA. Arnulf, B., J. Oddos, Y. Zermati, J. Kersual, A. Bazarbachi,
and O. Hermine. February 2000. Etude de la proteine virale TAX sur les
signaux de transduction du TGF-B. French Society of Hematology, Paris,
France. Basbous, J., H. Abi-Haidar, J. Nigmeh, R. Abou-Merhi, O.
Hermine, A. Bazarbachi, and M. El-Sabban. December 2000. Adhesion and
intercellular communication between HTLV-I-transformed cells and other
neoplastic T-cell lymphocytes and vascular endothelium. American Society of
Hematology, San Francisco, California, USA. Bazarbachi, A., M. Abdallah, T. Nasr, W. El-Assaad, M.
El-Sabban, and G. Dbaibo. December 1999. Involvement of the ceramide pathway
in the cytotoxicity of arsenic trioxide and interferon alpha in HTLV-I
transformed cells. American Society of Hematology, New Orleans, Louisiana,
USA. Bazzi, H., S. Al-Maalouf, E. Hatoum, H. Gali-Muhtasib, and N.
Darwiche. November 2000. Retinoic acid inhibits early vitamin A deficiency
induced by ultraviolet irradiation of primary mouse keratinocytes.
Proceedings of the 14th Science Meeting, Beirut, Lebanon. Bazzi, R., R. Nasr, M. El-Sabban, A. Bazarbachi, and N.
Darwiche. November 1999. Retinoic acid receptor alpha status determines the
apoptotic response of HTLV-I transformed cells to the synergistic combination
of retinoic acid and arsenic trioxide treatment. Proceedings of the 13th
Science Meeting, Beirut, Lebanon. Darwiche, N., M. El-Sabban, R. Bazzi , R. Nasr, H. De The, and
A. Bazarbachi. January 2000. Retinoic acid dramatically enhances the arsenic
trioxide induced cell cycle arrest and apoptosis in retinoic acid receptor
alpha positive human T-cell leukemia virus type-I transformed cells. Cell and
Molecular Biology Keystone Symposium: Cancer, Cell Cycle and Therapeutics,
Steamboat Springs, Colorado, USA. Darwiche, N., E. Hatoum, J. Khoury, and M. El-Sabban. January
2001. Introduction of retinoic acid receptors alpha and gamma into epidermal
cell lines causes retinoic acid-induced growth arrest. Cell and Molecular
Biology Keystone Symposium, The Molecular Basis of Cancer: Signaling to
Cell Growth and Death, Taos, New Mexico, USA. Darwiche, N., M. Sabban, R. Bazzi, R. Nasr, O. Hermine, H. De
The, and A. Bazarbachi. December 2000. Retinoic acid and arsenic trioxide
combination induces cell cycle arrest and apoptosis and downregulates tax in
RAR alpha positive HTLV-I transformed cells. American Society of Hematology,
San Francisco, California, USA. El-Sabban, M., R. Nasr, G. Dbaibo, O. Hermine, N. Abboushi, F.
Bex, H. De The, and A. Bazarbachi. May 2000. Arsenic/interferon-alpha
triggered apoptosis in HTLV-I transformed cells is associated with Tax
downregulation and reversal of NF-kB activation. HTLV European Research
Network, Postdam, Germany. El-Sabban, M., R. Nasr, G. Dbaibo, O. Hermine, F. Bex, H. De
The, and A. Bazarbachi. December 1999. Arsenic trioxide and alpha interferon
combination downregulates Tax and targets the NF-kB pathway in HTLV-I
transformed cells. American Society of Hematology, New Orleans, Louisiana,
USA. Hatoum, E., J. Khoury, M. El-Sabban, and N. Darwiche. November
2000. Introduction of retinoic acid receptors alpha and gamma into epidermal
cell lines causes retinoic acid-induced growth arrest. Proceedings of the
14th Science Meeting, Beirut, Lebanon. Hermine, O., H. Dombret, J. Poupon, B. Arnulf, G. Damaj, F.
Lefrere, P. Rousselot, A. Tibbi, S. Solbes-Latourettes, J. P. Fermand, J. C.
Brouet, and A. Bazarbachi. December 2000. Phase II trial of arsenic trioxide
(As203) and combination of alpha interferon (INF) and As203 in patients with
relapsed/refractory adult T cell leukemia (ATL). American Society of
Hematology, San Francisco, California, USA. Mikati, M. October 1999. Channelopathies: Implications on the
pathophysiology, classification, and therapy of migraine and epilepsy. Syrian
Pediatric Society Annual Meeting, Damascus, Syria. ———. April 2001. Effects of status epilepticus on the
developing brain. The Annual Conference of Pediatrics Department, Cairo,
Eygpt. ———. April 2001. Pathophysiology of epilepsy. Annual Congress
of the Jordanian Neurology Society, Amman, Jordan. Mikati, M. A., A. Rahmeh, F. Farhat, G. Dbaibo, and W. Assad.
December 1999. Ceramide levels rise after status epilepticus in the
prepubescent and mature but not in the immature rat brain. American Epilepsy
Society, San Diego, California, USA. Mikati, M. A., A. Rahmeh, R. Kurdi, F. Farhat, E. Francis, G.
Geha, W. Maraashli, and R. Kaddoura-Daouk. December 1999. Creatine has
neuro-protective but not anti-seizure effects in the kainic acid seizure
model. American Epilepsy Society, San Diego, California, USA. Nakkash, H., K. Bajakian, S. Kreydiyyeh, and J. Usta. December
1999. The inhibitory effect of food spices on copper stimulated adenosine
triphosphatase activity. The Third Annual Meeting of the Association of
Colleges of Pharmacy in the Arab World, Tanta, Egypt. Nasr, R., N. Darwiche, H. De The, and A. Bazarbachi. December
2000. Retinoic acid increases retinoid X receptor DNA binding activity
despite the degradation of retinoid receptor proteins in HTLV-I transformed
cells. American Society of Hematology, San Francisco, California, USA. Nasr, R., M. El-Sabban, J. Basbous, R. Abou-Merhi, F. Bex, O.
Hermine, H. De The, and A. Bazarbachi. December 2000. Arsenic/interferon-alpha
triggered apoptosis in HTLV-I transformed cells is associated with proteasome
mediated tax degradation and reversal of NF-kB activation. American
Society of Hematology, San Francisco, California, USA. Usta, J., S. El-Bawab, Z. Szulc, Y. Hannun, and A. Bielawska.
March 2001. Structure-function relationship of ceramide analogues on rat
brain alkaline. Ceramidase Activity Faseb Meeting, Orlando, Florida, USA. Graduate Theses and Projects El-khoury, J. Kh. February 2000. Regulation of neoplastic
keratinocyte proliferation and cell cycle control by retinoic acid receptor
alpha. I. Durr and N. Darwiche. Hatoum, E. January 2001. Molecular mechanisms of cell cycle
control in retinoic acid receptor gamma-transduced neoplastic epidermal cell
lines. I. F. Durr and N. Darwiche. Research Projects The mechanism of action and development of novel
therapies for HTLV-I associated adult T-cell leukemia/lymphoma (ATL) ATL is a malignancy of activated T cells resistant to
chemotherapy. The viral transactivator protein, Tax, plays a critical
role in HTLV-I-induced transformation and apoptosis resistance by inducing
IkB-Kinase (IKK)-mediated IkB alpha phosphorylation and proteasomal
degradation, resulting in sustained activation of the NF-kB pathway. We
recently showed that As and IFN synergies induce cell cycle arrest and
apoptosis in ATL cells. We demonstrated that As/IFN induces the
degradation of Tax, associated with an upregulation of IkB-alpha, resulting
in cytoplasmic retention of the RelA subunit of NF-kB and a sharp
decrease in RelA DNA-binding NF-kB complexes. Due to the pivotal role
Tax plays in HTLV-I-induced transformation, its down-regulation by As/IFN may
account for cell death through inactivation of the NF-kB pathway. We also
showed that ATRA synergize with As to induce cell cycle arrest and apoptosis
RAR-alpha positive ATL cells. In this project, we aim to decipher the
mechanism of action of As/IFN and ATRA therapies in ATL derived cells.
Bazarbachi, A., M. El-Sabban, G. Dbaibo, and N. Darwiche. Molecular mechanisms of ceramide-mediated telomerase
inhinition in the A549 human lung adenocarcinoma cell line Submitted to Journal of Biological Chemistry. Besim, O.*, M. Jacqueline, J. Usta*, Y. Hannun*, and L. Obeid*. Supported by AUB and Medical University of South Carolina,
USA. The role of retinoic acid receptor alpha in the combined
retinoic acid and arsenic treatment of adult T-cell leukemic (ATL) cells Adult T-cell leukemia (ATL) is an aggressive malignancy of
mature activated T cells that is caused by human T-cell leukemia virus type I
(HTLV-I). Recently, we investigated the combined effects of retinoic
acid (RA) and arsenic (As) treatments on the growth of HTLV-I transformed
cells (HuT-102 and MT-2). We showed that, while both cell lines were
resistant to RA treatment, the combination RA/As induced a highly synergistic
effect only on HuT-102 cells. The combination treatment resulted in a
dramatic inhibition of cell proliferation and induction of massive apoptosis
in HuT-102 cells. Retinoid receptor protein analysis showed that both cell
lines express RXRalpha proteins, RARalpha protein levels are undetectable in
MT-2 cells but highly expressed in HuT-102 cells. We would like to test
our hypothesis linking the successful combination treatment of RA and As in
ATL to the presence of RARalpha using retroviral-mediated gene transfer
methods. Darwiche, N. (PL). Combined retinoic acid and arsenic treatment of adult
T-cell leukemic (ATL) cells: Effects on cell cycle control and
apoptosis regulation of neoplastic keratinocyte proliferation and cell
cycle control by retinoid receptors Adult T-cell leukemia (ATL) is an aggressive peripheral
T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-I).
Multiple chemotherapy combinations are used for the treatment of ATL
patients. Unfortunately, the results are disappointing with a mean
survival time of less than 8 months mainly due to acquired resistance.
We will investigate the effects of retinoic acid (RA) and arsenic (As) on
different cellular parameters, namely cytotoxicity, proliferation, cell cycle
analysis, and apoptosis. If RA and As combination treatment results in
the induction of apoptosis in ATL derived cells, we will also study the
induction of the different apoptotic pathways and their relationship to
retinoid receptor signaling. We will determine the retinoid receptor
profile in RA- and As-treated cells in an attempt to understand whether the
different treatments enhance retinoid responsiveness in these cells.
Darwiche, N., (PL), A. Bazarbachi, and M. El-Sabban. Regulation of neoplastic keratinocyte proliferation and
cell cycle control by retinoid receptors Retinoids are essential for normal epidermal cell growth
and differentiation. They are widely used in the prevention, as well as
treatment of, several skin disorders and cancers in humans. Most of the
effects of retinoids are mediated by two families of nuclear retinoid
receptors, namely, RARs and RXRs, each consisting of the receptor types
alpha, beta, and gamma. Our studies indicate that retinoic acid
receptors, RARalpha and RARgamma, are lost during skin tumor
progression. Furthermore, during transformation, decreased expression
of RARalpha is closely linked to malignant conversion of skin tumors. Using
combined in vitro and in vivo strategies, we will explore the relationship
between RARs and neoplastic keratinocyte proliferation and cell cycle
regulation. This will include the use of RAR and RXR-selective ligands
and retroviral constructs harboring normal RARalpha, RARgamma, and RAR
dominant-negative mutants. Darwiche, N., (PL), and I. F. Durr. Overexpression of retinoic acid receptors, alpha and
gamma, in neoplastic epidermal cells causes retinoic acid-induced growth
arrest and apoptosis Retinoids are essential for normal epidermal
differentiation and are used for the prevention and treatment of numerous
skin disorders and cancers in humans. In previous studies, we have
shown that retinoic acid receptors (RARs), alpha and gamma, are
down-regulated during skin tumor progression. Our primary objective is
to investigate the roles that RARalpha and RARgamma play in keratinocyte
tumor cell proliferation. Through retroviral gene transduction, we
overexpressed RARalpha or RARgamma in neoplastic mouse epidermal cells.
Following retinoic acid (RA) treatment, RARalpha- and RARgamma-transduced
cell lines exhibit a progressive, dose-dependent growth inhibition relative
to the control LXSN cell lines. Chromatin condensation, PARP cleavage,
and a late upregulation and apparent cleavage of the squamous differentiation
marker PKCeta are observed in both RARalpha- and RARgamma-transduced
cells. These results suggest that RARalpha and RARgamma enhance growth
suppression and apoptosis of neoplastic epidermal keratinocytes. We
also showed that this growth inhibitory effect of both retinoid receptors in
neoplastic keratinocytes may be achieved through distinct as well as
overlapping mechanisms of cell cycle control. Submitted for publication.
Darwiche, N. (PL), E. Hatoum, M. El-Sabban, J. Khoury, and S. H. Yuspa. Molecular mechanisms of ceramide accumulation following
up-regulation of the tumor suppressor P53 Both the tumor suppressor, p53, and ceramide have been
implicated in the regulation of apoptosis. We recently showed that p53
functions "upstream" of ceramide in the genotoxic stress response
leading to apoptosis. We found that p53 up-regulation leads to the gradual
accumulation of cellular ceramide occurring over several hours. In this
proposal, we investigated the signaling pathways and the molecular events by
which p53 up-regulation results in ceramide accumulation. We also investigated
the order by which the different genes become induced, or their proteins
activated, in response to p53 and in relation to ceramide accumulation. In
on-going studies, we plan to determine the biochemical pathways that are
activated to generate ceramide. These studies will help us understand the
molecular mechanisms by which these two stress responses, namely, p53
up-regulation and ceramide accumulation, are linked and may help in the
discovery of future therapeutic targets in cancer and other diseases where
apoptosis plays a major role. Dbaibo, G. (PL). The role of ceramide in modulating the expression of the
growth factors Il-2, Il-15, and their receptors Interleukin (IL)-2 and IL-15 play a pivotal role in
initiating and potentiating the immune response. The receptors for IL-15 and
IL-2 consist of three subunits: a unique alpha chain and shared beta and
gamma chains. Expression of both receptors occurs via regulation of the
expression of their alpha chains. Both interleukins and their receptors have
been implicated in HTLV-1-associated adult T-cell leukemia and chronic
lymphoproliferative disorders, where they play a role in survival and
proliferation. In previous studies, we demonstrated that the sphingolipid
breakdown product, ceramide, blocks the production of IL-2 by Jurkat T-cell
leukemia cells with phorbol ester and PHA. We demonstrated that this
inhibition was at the IL-2 gene transcription level, and that it was likely
mediated by the inhibition of the transcription factor NF-kB. In this study,
we plan to examine whether our findings extend to the IL-2a receptor chain,
IL-15, and its receptor, all of which require NF-kB activation for proper
transcription. Dbaibo, G. (PL), A. Bazarbachi, and N. Abboushi. Mechanisms of programed cell death after status
epilepticus The goal of this study is to further investigate the
mechanisms of post-SE cellular injury and the role of ceramide in those
mechanisms. Mikati, M. Supported by URB Potential role of ceramide in status epilepticus related
brain injury The goal of this study is to investigate whether the demonstrated increases in ceramide are related to Status Epilepticus (SE)-associated neuronal injury. Mikati, M.
Completed or in progress at AUB The effect of experimental status epilepticus on
ceramide levels in the developing brain The goal of this study is to investigate whether Status
Epilepticus (SE) is followed by increases in ceramide levels, and whether
there are differences in ceramide levels after SE in developmental stages.
Mikati, M. Supported by URB and National Council for Scientific
Research
A copper-stimulated ATPase (Cu++-ATPase) activity was described in isolated rat liver mitochondria. Whether this protein is involved in regulating the copper level in the mitochondria remains to be established. Isolated mitochondria will be treated with different copper concentrations, the uptake of which will be estimated by inductively coupled plasma (ICP-MS). Copper uptake will be optimized according to time, concentration, temperature, and pH. Preliminary data have identified sodium azide and eugenol as inhibitors of the Cu++ ATPase stimulated activity. The effects of these inhibitors on copper transport will be determined as well. Usta, J., and N. Cortas.
Profile of sphingolipid metabolizing enzymes in the mitochondria. The discovery that cytochrome c, required for apoptosis,
and BcL-2, an anti-apoptotic, are mitochondrial has placed the mitochondria
at a central position in the study of apoptosis. Recent studies have shown
that the purification of a non-lysosomal mitochondria-associated
alkaline ceramidase from rat-brain, and partial purification of ceramide
synthase from Bovine liver mitochondrial-enriched fraction, suggesting that
the mitochondria is a possible site of sphingolipid metabolism. So far neither
the sphingolipid composition nor the profile of shingolipid metabolizing
enzymes in the mitochondria are known. Thus the objectives of this
study are first, to quantify the level of ceramide, diacylgycerol,
sphingosine, and sphingomyelin in the inner, outer mitochondrial membranes as
well as associated membranes, and second, to determine the profile of
sphingolipid metabolizing enzymes, both catabolic and anabolic, in the
mitochondria, such as alkaline and acid ceramidase, ceramide synthase,
glucocerebroside synthase, sphingomyelin synthase, and sphingomyelinase. Usta,
J., and Y. Hannun (Medical University of South Carolina, USA). Supported by AUB Medical Practice Plan Effects of eugenol and cinnamaldehyde on mitochondrial
functions We have recently reported inhibition of Na+/K+ATPase by
eugenol and cinnamaldehyde the main components of clove and cinnamaldehyde,
respectively. Contrary to their effect on Na+/K+ATPase, they stimulated
mitochondrial F0 F1 ATPase activity, the consequence of which is reduction of
the cellular energy level (ATP). We propose mitochondria as a potential
target for spices action. Hence, the objective of this study is 1) to
determine the effect of eugenol and cinnamaldehyde on complex-I and
complex-II, the main entry sites of NADH and FADH2 into the respiratory
chain, and 2) to identify whether the increase in the hydrolysis of ATP is
due to an effect on the mitochondrial membrane potential. Submitted to
Food and Chemical Toxicology. Usta, J., and S. Kreydiyyeh. Supported by AUB Medical Practice Plan and URB Direct effect of sphingosine and ceramide on the
mitochondrial functions It is well established that ceramide is an endogenous
regulator of apoptosis in many different cancer cells and in response to
many cytotoxic and chemotherapeutic agents. Preliminary experiments,
directing bSMase at different places in the cell were ineffective in the case
of nucleus and cytosol, but resulted in cell death when directed at
mitochondria. This suggests that generation of ceramide in the
mitochondria may trigger the apoptotic signal. This study attempts to
evaluate the mechanisms underlying the role of ceramide in induced
mitochondrial apoptosis. The direct effect of different chain length ceramide
(C2, C6, C12, C16) and sphingosine on mitochondrial functions will be
determined, including the integrity of the membrane potential and the
activity of NADH oxidase succinate dehydrogenase, cytochrome c reductase, and
cytochrome oxidase. Usta, J., and L. Obeid (Medical University of
South Carolina, USA). Supported by AUB Medical Practice Plan Inhibitors of mitochondrial ceramidase biochemistry
Supported by AUB and Medical University of South Carolina, USA. |