**7. References**


Natural Flavonoids in StAR Gene Expression

Vol.143, No.5, pp. 1637-1642.

*Food Res,* Vol.52, No.11, pp. 1349-1357.

*Pharmacol,* Vol.63, No.3, pp. 512-523.

Vol.365, No.6449, pp. 855-859.

Vol.68, No.6, pp. 1089-1100.

26591-26598.

cells. *J Endocrinol,* Vol.192, No.3, pp. 527-537.

antioxidants. *Free Radic Biol Med,* Vol.9, No.1, pp. 19-21.

chrysin derivatives. *Pharmacol Res,* Vol.49, No.1, pp. 37-43.

557).

and Testosterone Biosynthesis in Leydig Cell Aging 197

Chen, H., Cangello, D., Benson, S., Folmer, J., Zhu, H., Trush, M.A., & Zirkin, B.R. (2001b).

Chen, H., Hardy, M.P., Huhtaniemi, I., & Zirkin, B.R. (1994). Age-related decreased Leydig

Chen, H., Hardy, M.P., & Zirkin, B.R. (2002). Age-related decreases in Leydig cell

Chen, H., Liu, J., Luo, L., & Zirkin, B.R. (2004). Dibutyryl cyclic adenosine monophosphate

characteristic of young cells. *Endocrinology,* Vol.145, No.10, pp. 4441-4446. Chen, H., Luo, L., Liu, J., & Zirkin, B.R. (2007b). Cyclooxygenases in rat Leydig cells: effects of luteinizing hormone and aging. *Endocrinology,* Vol.148, No.2, pp. 735-742. Chen, L.G., Hung, L.Y., Tsai, K.W., Pan, Y.S., Tsai, Y.D., Li, Y.Z., & Liu, Y.W. (2008).

Chen, Y.C., Nagpal, M.L., Stocco, D.M., & Lin, T. (2007c). Effects of genistein, resveratrol,

Chen, Y.T., Zheng, R.L., Jia, Z.J., & Ju, Y. (1990). Flavonoids as superoxide scavengers and

Cho, H., Yun, C.W., Park, W.K., Kong, J.Y., Kim, K.S., Park, Y., Lee, S., & Kim, B.K. (2004).

Cho, Y.H., Lee, C.H., & Kim, S.G. (2003). Potentiation of lipopolysaccharide-inducible

Choi, E.M., & Lee, Y.S. (2010). Luteolin suppresses IL-1beta-induced cytokines and MMPs

Chrivia, J.C., Kwok, R.P., Lamb, N., Hagiwara, M., Montminy, M.R., & Goodman, R.H.

Chun, K.S., & Surh, Y.J. (2004). Signal transduction pathways regulating cyclooxygenase-2

function? *Exp Gerontol,* Vol.36, No.8, pp. 1361-1373.

Age-related increase in mitochondrial superoxide generation in the testosteroneproducing cells of Brown Norway rat testes: relationship to reduced steroidogenic

cell testosterone production in the brown Norway rat. In *J Androl* (Vol. 15, pp. 551-

testosterone production are not restored by exposure to LH in vitro. *Endocrinology,* 

restores the ability of aged Leydig cells to produce testosterone at the high levels

Wogonin, a bioactive flavonoid in herbal tea, inhibits inflammatory cyclooxygenase-2 gene expression in human lung epithelial cancer cells. *Mol Nutr* 

and quercetin on steroidogenesis and proliferation of MA-10 mouse Leydig tumor

Modulation of the activity of pro-inflammatory enzymes, COX-2 and iNOS, by

cyclooxygenase 2 expression by C2-ceramide via c-Jun N-terminal kinase-mediated activation of CCAAT/enhancer binding protein beta in macrophages. *Mol* 

production via p38 MAPK, JNK, NF-kappaB and AP-1 activation in human synovial sarcoma cell line, SW982. *Food Chem Toxicol,* Vol.48, No.10, pp. 2607-2611. Christenson, L.K., Johnson, P.F., McAllister, J.M., & Strauss, J.F., 3rd. (1999).

CCAAT/enhancer-binding proteins regulate expression of the human steroidogenic acute regulatory protein (StAR) gene. *J Biol Chem,* Vol.274, No.37, pp.

(1993). Phosphorylated CREB binds specifically to the nuclear protein CBP. *Nature,* 

expression: potential molecular targets for chemoprevention. *Biochem Pharmacol,* 


Arun, P., Brown, M.S., Ehsanian, R., Chen, Z., & Van Waes, C. (2009). Nuclear NF-kappaB

Axelrod, J., Burch, R.M., & Jelsema, C.L. (1988). Receptor-mediated activation of

Bartke, A., Musto, N., Caldwell, B.V., & Behrman, H.R. (1973). Effects of a cholesterol

Belevych, A.E., Warrier, S., & Harvey, R.D. (2002). Genistein inhibits cardiac L-type Ca(2+)

Budnik, L.T., Jahner, D., & Mukhopadhyay, A.K. (1999). Inhibitory effects of TNF alpha on

Calkins, J.H., Guo, H., Sigel, M.M., & Lin, T. (1990). Differential effects of recombinant

Cano, F., Poderoso, C., Cornejo Maciel, F., Castilla, R., Maloberti, P., Castillo, F., Neuman, I.,

Cardenas, M., Marder, M., Blank, V.C., & Roguin, L.P. (2006). Antitumor activity of some

Carlone, D.L., & Richards, J.S. (1997). Functional interactions, phosphorylation, and levels of

Caron, K.M., Ikeda, Y., Soo, S.C., Stocco, D.M., Parker, K.L., & Clark, B.J. (1997b).

Chen, C.C., Sun, Y.T., Chen, J.J., & Chang, Y.J. (2001a). Tumor necrosis factor-alpha-induced

Chen, C.Y., Peng, W.H., Tsai, K.D., & Hsu, S.L. (2007a). Luteolin suppresses inflammation-

mouse alveolar macrophages. *Life Sci,* Vol.81, No.23-24, pp. 1602-1614.

aromatase in gonadal cells. *Mol Endocrinol,* Vol.11, No.3, pp. 292-304. Caron, K.M., Clark, B.J., Ikeda, Y., & Parker, K.L. (1997a). Steroidogenic factor 1 acts at all

levels of the reproductive axis. *Steroids,* Vol.62, No.1, pp. 53-56.

epithelial cells. *Mol Pharmacol,* Vol.59, No.3, pp. 493-500.

as second messengers. *Trends Neurosci,* Vol.11, No.3, pp. 117-123.

testosterone in mice. *Prostaglandins,* Vol.3, No.1, pp. 97-104.

*Mol Cell Endocrinol,* Vol.150, No.1-2, pp. 39-46.

cell lines. *Bioorg Med Chem,* Vol.14, No.9, pp. 2966-2971.

No.2, pp. 575-581.

Vol.62, No.3, pp. 554-565.

Vol.167, No.2, pp. 548-553.

No.4-5, pp. 197-202.

138-147.

p65 phosphorylation at serine 276 by protein kinase A contributes to the malignant phenotype of head and neck cancer. *Clin Cancer Res,* Vol.15, No.19, pp. 5974-5984. Avallet, O., Vigier, M., Perrard-Sapori, M.H., & Saez, J.M. (1987). Transforming growth

factor beta inhibits Leydig cell functions. *Biochem Biophys Res Commun,* Vol.146,

phospholipase A2 via GTP-binding proteins: arachidonic acid and its metabolites

esterase inhibitor and of prostaglandin F2alpha on testis cholesterol and on plasma

channel activity by a tyrosine kinase-independent mechanism. *Mol Pharmacol,* 

mouse tumor Leydig cells: possible role of ceramide in the mechanism of action.

interleukin-1 alpha and beta on Leydig cell function. *Biochem Biophys Res Commun,* 

Paz, C., & Podesta, E.J. (2006). Protein tyrosine phosphatases regulate arachidonic acid release, StAR induction and steroidogenesis acting on a hormone-dependent arachidonic acid-preferring acyl-CoA synthetase. *J Steroid Biochem Mol Biol,* Vol.99,

natural flavonoids and synthetic derivatives on various human and murine cancer

3',5'-cyclic adenosine monophosphate-regulatory element binding protein and steroidogenic factor-1 mediate hormone-regulated and constitutive expression of

Characterization of the promoter region of the mouse gene encoding the steroidogenic acute regulatory protein. *Molecular Endocrinology,* Vol.11, No.2, pp.

cyclooxygenase-2 expression via sequential activation of ceramide-dependent mitogen-activated protein kinases, and IkappaB kinase 1/2 in human alveolar

associated gene expression by blocking NF-kappaB and AP-1 activation pathway in


Natural Flavonoids in StAR Gene Expression

288.

No.1, pp. 60-66.

4476-4485.

Vol.962, No.1-2, pp. 239-241.

and Testosterone Biosynthesis in Leydig Cell Aging 199

Du, Q., Xia, M., & Ito, Y. (2002). Purification of icariin from the extract of Epimedium

Feldman, H.A., Longcope, C., Derby, C.A., Johannes, C.B., Araujo, A.B., Coviello, A.D.,

Figueiroa, M.S., Cesar Vieira, J.S., Leite, D.S., Filho, R.C., Ferreira, F., Gouveia, P.S., Udrisar,

Frungieri, M.B., Gonzalez-Calvar, S.I., Parborell, F., Albrecht, M., Mayerhofer, A., &

Fuchs, A.R., & Chantharaksri, U. (1981). Prostaglandin F2alpha regulation of LH-stimulated testosterone production in rat testis. *Biol Reprod,* Vol.25, No.3, pp. 492-501. Gambelunghe, C., Rossi, R., Sommavilla, M., Ferranti, C., Rossi, R., Ciculi, C., Gizzi, S.,

Garcia-Lafuente, A., Guillamon, E., Villares, A., Rostagno, M.A., & Martinez, J.A. (2009).

Garcia-Mediavilla, V., Crespo, I., Collado, P.S., Esteller, A., Sanchez-Campos, S., Tunon,

Garcia-Saura, M.F., Galisteo, M., Villar, I.C., Bermejo, A., Zarzuelo, A., Vargas, F., & Duarte,

Gouras, G.K., Xu, H., Gross, R.S., Greenfield, J.P., Hai, B., Wang, R., & Greengard, P. (2000).

Guerrero, J.A., Lozano, M.L., Castillo, J., Benavente-Garcia, O., Vicente, V., & Rivera, J.

in Chang Liver cells. *Eur J Pharmacol,* Vol.557, No.2-3, pp. 221-229.

hypertension. *Mol Cell Biochem,* Vol.270, No.1-2, pp. 147-155.

human males. *J Med Food,* Vol.6, No.4, pp. 387-390.

disease. *Inflamm Res,* Vol.58, No.9, pp. 537-552.

*Natl Acad Sci U S A,* Vol.97, No.3, pp. 1202-1205.

receptor. *J Thromb Haemost,* Vol.3, No.2, pp. 369-376.

production in rat Leydig cells. *Asian J Androl,* Vol.11, No.3, pp. 362-370. Finkielstein, C., Maloberti, P., Mendez, C.F., Paz, C., Cornejo Maciel, F., Cymeryng, C.,

segittatum using high-speed counter-current chromatography. *J Chromatogr A,* 

Bremner, W.J., & McKinlay, J.B. (2002). Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. *J Clin Endocrinol Metab,* Vol.87, No.2, pp. 589-598. Ferrandiz, M.L., & Alcaraz, M.J. (1991). Anti-inflammatory activity and inhibition of

arachidonic acid metabolism by flavonoids. *Agents Actions,* Vol.32, No.3-4, pp. 283-

D.P., & Wanderley, M.I. (2009). Green tea polyphenols inhibit testosterone

Neuman, I., Dada, L., Mele, P.G., Solano, A., & Podesta, E.J. (1998). An adrenocorticotropin-regulated phosphoprotein intermediary in steroid synthesis is similar to an acyl-CoA thioesterase enzyme. *European journal of biochemistry* Vol.256,

Calandra, R.S. (2006). Cyclooxygenase-2 and prostaglandin F2 alpha in Syrian hamster Leydig cells: Inhibitory role on luteinizing hormone/human chorionic gonadotropin-stimulated testosterone production. *Endocrinology,* Vol.147, No.9, pp.

Micheletti, A., & Rufini, S. (2003). Effects of chrysin on urinary testosterone levels in

Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular

M.J., & Gonzalez-Gallego, J. (2007). The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway

J. (2005). Effects of chronic quercetin treatment in experimental renovascular

Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides. *Proc* 

(2005). Flavonoids inhibit platelet function through binding to the thromboxane A2


Chung, H.Y., Cesari, M., Anton, S., Marzetti, E., Giovannini, S., Seo, A.Y., Carter, C., Yu,

Chung, H.Y., Kim, H.J., Kim, J.W., & Yu, B.P. (2001). The inflammation hypothesis of aging:

Chung, H.Y., Sung, B., Jung, K.J., Zou, Y., & Yu, B.P. (2006). The molecular inflammatory

Clark, B.J., Wells, J., King, S.R., & Stocco, D.M. (1994). The purification, cloning, and

Cooke, B.A., Dix, C.J., Habberfield, A.D., & Sullivan, M.H. (1984). Control of steroidogenesis

Cornejo Maciel, F., Maloberti, P., Neuman, I., Cano, F., Castilla, R., Castillo, F., Paz, C., &

Crespo, I., Garcia-Mediavilla, M.V., Gutierrez, B., Sanchez-Campos, S., Tunon, M.J., &

Culty, M., Luo, L., Yao, Z.X., Chen, H., Papadopoulos, V., & Zirkin, B.R. (2002). Cholesterol

Dao, T.T., Chi, Y.S., Kim, J., Kim, H.P., Kim, S., & Park, H. (2004). Synthesis and inhibitory

Dhawan, K., Kumar, S., & Sharma, A. (2002). Beneficial effects of chrysin and benzoflavone on virility in 2-year-old male rats. *J Med Food,* Vol.5, No.1, pp. 43-48. Didolkar, A.K., & Sundaram, K. (1987). Arachidonic acid is involved in the regulation of hCG induced steroidogenesis in rat Leydig cells. *Life Sci,* Vol.41, No.4, pp. 471-477. Didolkar, A.K., & Sundaram, K. (1989). Mechanism of LHRH-stimulated steroidogenesis in

Dix, C.J., Habberfield, A.D., Sullivan, M.H., & Cooke, B.A. (1984). Inhibition of steroid

and age-related diseases. *Ageing Res Rev,* Vol.8, No.1, pp. 18-30.

process in aging. *Antioxid Redox Signal,* Vol.8, No.3-4, pp. 572-581.

No.1-3, pp. 465-471.

666.

action. *Ann N Y Acad Sci,* Vol.438, pp. 269-282.

endothelial cells. *Br J Nutr,* Vol.100, No.5, pp. 968-976.

*Bioorg Med Chem Lett,* Vol.14, No.5, pp. 1165-1167.

steroidogenesis. *Biochem J,* Vol.219, No.2, pp. 529-537.

cells. *J Androl,* Vol.23, No.3, pp. 439-447.

*Androl,* Vol.10, No.6, pp. 449-455.

B.P., & Leeuwenburgh, C. (2009). Molecular inflammation: underpinnings of aging

molecular modulation by calorie restriction. *Ann N Y Acad Sci,* Vol.928, pp. 327-335.

expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). *The Journal of biological chemistry,* Vol.269, No.45, pp. 28314-28322. Cooke, B.A., Dirami, G., Chaudry, L., Choi, M.S., Abayasekara, D.R., & Phipp, L. (1991).

Release of arachidonic acid and the effects of corticosteroids on steroidogenesis in rat testis Leydig cells. *The Journal of steroid biochemistry and molecular biology,* Vol.40,

in Leydig cells: roles of Ca2+ and lipoxygenase products in LH and LHRH agonist

Podesta, E.J. (2005). An arachidonic acid-preferring acyl-CoA synthetase is a hormone-dependent and obligatory protein in the signal transduction pathway of steroidogenic hormones. *Journal of Molecular Endocrinology,* Vol.34, No.3, pp. 655-

Gonzalez-Gallego, J. (2008). A comparison of the effects of kaempferol and quercetin on cytokine-induced pro-inflammatory status of cultured human

transport, peripheral benzodiazepine receptor, and steroidogenesis in aging Leydig

activity against COX-2 catalyzed prostaglandin production of chrysin derivatives.

rat Leydig cells: lipoxygenase products of arachidonic acid may not be involved. *J* 

production in Leydig cells by non-steroidal anti-inflammatory and related compounds: evidence for the involvement of lipoxygenase products in


Natural Flavonoids in StAR Gene Expression

Vol.197, No.2, pp. 315-323.

Vol.145, No.12, pp. 5629-5637.

No.1, pp. 92-98.

*Chem,* Vol.56, No.24, pp. 11571-11577.

and Testosterone Biosynthesis in Leydig Cell Aging 201

Jana, K., Yin, X., Schiffer, R.B., Chen, J.J., Pandey, A.K., Stocco, D.M., Grammas, P., & Wang,

Jiang, L., Fang, G., Zhang, Y., Cao, G., & Wang, S. (2008). Analysis of flavonoids in propolis

Jo, Y., & Stocco, D.M. (2004). Regulation of steroidogenesis and steroidogenic acute

Jung, J.C., Park, G.T., Kim, K.H., Woo, J.H., An, J.M., Kim, K.C., Chung, H.Y., Bae, Y.S., Park,

Kang, J., Cheng, H., Ji, J., Incardona, J., & Rampe, D. (2010). In vitro electrocardiographic and

Kassim, M., Achoui, M., Mustafa, M.R., Mohd, M.A., & Yusoff, K.M. (2010). Ellagic acid,

Kaufman, J.M., & Vermeulen, A. (2005). The decline of androgen levels in elderly men and its clinical and therapeutic implications. *Endocr Rev,* Vol.26, No.6, pp. 833-876. Kellis, J.T., Jr., & Vickery, L.E. (1984). Inhibition of human estrogen synthetase (aromatase)

Khaki, A., Fathiazad, F., Nouri, M., Maleki, N.A., Khamnei, H.J., & Ahmadi, P. (2010).

Khanna, D., Sethi, G., Ahn, K.S., Pandey, M.K., Kunnumakkara, A.B., Sung, B., Aggarwal,

Kim, H.P., Son, K.H., Chang, H.W., & Kang, S.S. (2004). Anti-inflammatory plant flavonoids and cellular action mechanisms. *J Pharmacol Sci,* Vol.96, No.3, pp. 229-245. Kim, J.S., & Jobin, C. (2005). The flavonoid luteolin prevents lipopolysaccharide-induced

Kim, S., Kim, S.H., Hur, S.M., Lee, S.K., Kim, W.W., Kim, J.S., Kim, J.H., Choe, J.H., Nam,

Kim, Y.P., Yamada, M., Lim, S.S., Lee, S.H., Ryu, N., Shin, K.H., & Ohuchi, K. (1999).

green tea. *J Pharmacol Exp Ther,* Vol.334, No.2, pp. 619-626.

by flavones. *Science,* Vol.225, No.4666, pp. 1032-1034.

*Curr Opin Pharmacol,* Vol.7, No.3, pp. 344-351.

*Ethnopharmacol,* Vol.126, No.2, pp. 252-257.

Vol.115, No.3, pp. 375-387.

anti-inflammatory activity. *Nutr Res,* Vol.30, No.9, pp. 650-659.

diabetic male rats. *Phytother Res,* Vol.24, No.9, pp. 1285-1291.

cytokine induction. *Endocrinology,* Vol.146, No.12, pp. 5100-5111.

1beta regulated by activation of c-Jun N-terminal kinase and cyclooxygenase-2 and

X. (2008). Chrysin, a natural flavonoid enhances steroidogenesis and steroidogenic acute regulatory protein gene expression in mouse Leydig cells. *J Endocrinol,* 

and Ginkgo biloba by micellar electrokinetic capillary chromatography. *J Agric Food* 

regulatory protein in R2C cells by DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene-1). *Endocrinology,* 

J.W., Kang, S.S., & Lee, Y.S. (2004). Differential expression of transforming growth factor-beta in the interstitial tissue of testis during aging. *J Cell Biochem,* Vol.92,

cardiac ion channel effects of (-)-epigallocatechin-3-gallate, the main catechin of

phenolic acids, and flavonoids in Malaysian honey extracts demonstrate in vitro

Beneficial effects of quercetin on sperm parameters in streptozotocin-induced

A., & Aggarwal, B.B. (2007). Natural products as a gold mine for arthritis treatment.

NF-kappaB signalling and gene expression by blocking IkappaB kinase activity in intestinal epithelial cells and bone-marrow derived dendritic cells. *Immunology,* 

S.J., Lee, J.E., & Yang, J.H. (2009). Silibinin prevents TPA-induced MMP-9 expression by down-regulation of COX-2 in human breast cancer cells. *J* 

Inhibition by tectorigenin and tectoridin of prostaglandin E2 production and


Guerrero, J.A., Navarro-Nunez, L., Lozano, M.L., Martinez, C., Vicente, V., Gibbins, J.M., &

Gutierrez-Venegas, G., Jimenez-Estrada, M., & Maldonado, S. (2007). The effect of

Ha, S.K., Lee, P., Park, J.A., Oh, H.R., Lee, S.Y., Park, J.H., Lee, E.H., Ryu, J.H., Lee, K.R., &

Ha, S.K., Moon, E., & Kim, S.Y. (2010). Chrysin suppresses LPS-stimulated proinflammatory

Hales, D.B. (1992). Interleukin-1 inhibits Leydig cell steroidogenesis primarily by decreasing

Haour, F., Kouznetzova, B., Dray, F., & Saez, J.M. (1979). hCG-induced prostaglandin E2 and

Hardy, R., & Cooper, M.S. (2010). Adrenal gland and bone. *Arch Biochem Biophys,* Vol.503,

Harman, S.M., Metter, E.J., Tobin, J.D., Pearson, J., & Blackman, M.R. (2001). Longitudinal

Harnly, J.M., Doherty, R.F., Beecher, G.R., Holden, J.M., Haytowitz, D.B., Bhagwat, S., &

Hogervorst, E., Williams, J., Budge, M., Barnetson, L., Combrinck, M., & Smith, A.D. (2001).

Hu, G.X., Zhao, B.H., Chu, Y.H., Zhou, H.Y., Akingbemi, B.T., Zheng, Z.Q., & Ge, R.S.

Huang, S.M., Wu, C.H., & Yen, G.C. (2006). Effects of flavonoids on the expression of the

Ishikawa, T., Hwang, K., Lazzarino, D., & Morris, P.L. (2005). Sertoli cell expression of

receptor for AGEs. *Mol Nutr Food Res,* Vol.50, No.12, pp. 1129-1139.

gingival fibroblasts. *Int Immunopharmacol,* Vol.7, No.9, pp. 1199-1210. Gutierrez-Venegas, G., Kawasaki-Cardenas, P., Arroyo-Cruz, S.R., & Maldonado-Frias, S.

ischemia mice model. *Neurochem Int,* Vol.52, No.4-5, pp. 878-886.

*Pharmacol,* Vol.64, No.2, pp. 133-144.

*Lett,* Vol.485, No.3, pp. 143-147.

Vol.131, No.5, pp. 2165-2172.

No.1, pp. 137-145.

724-731.

*Sci,* Vol.24, No.23, pp. 2151-2158.

*Food Chem,* Vol.54, No.26, pp. 9966-9977.

activities. *Asian J Androl,* Vol.12, No.4, pp. 519-526.

*Lett,* Vol.22, No.3, pp. 163-168.

*Eur J Pharmacol,* Vol.541, No.1-2, pp. 95-105.

Rivera, J. (2007). Flavonoids inhibit the platelet TxA(2) signalling pathway and antagonize TxA(2) receptors (TP) in platelets and smooth muscle cells. *Br J Clin* 

flavonoids on transduction mechanisms in lipopolysaccharide-treated human

(2006). Luteolin inhibits lipopolysaccharide actions on human gingival fibroblasts.

Kim, S.Y. (2008). Apigenin inhibits the production of NO and PGE2 in microglia and inhibits neuronal cell death in a middle cerebral artery occlusion-induced focal

responses by blocking NF-kappaB and JNK activations in microglia cells. *Neurosci* 

17 alpha-hydroxylase/C17-20 lyase cytochrome P450 expression. *Endocrinology,* 

F2 alpha release in adult rat testis: role in Leydig cell desensitization to hCG. *Life* 

effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. *J Clin Endocrinol Metab,* Vol.86, No.2, pp.

Gebhardt, S. (2006). Flavonoid content of U.S. fruits, vegetables, and nuts. *J Agric* 

Serum total testosterone is lower in men with Alzheimer's disease. *Neuro Endocrinol* 

(2010). Effects of genistein and equol on human and rat testicular 3betahydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase 3

pro-inflammatory response in human monocytes induced by ligation of the

steroidogenic acute regulatory protein-related lipid transfer 1 and 5 domaincontaining proteins and sterol regulatory element binding protein-1 are interleukin1beta regulated by activation of c-Jun N-terminal kinase and cyclooxygenase-2 and cytokine induction. *Endocrinology,* Vol.146, No.12, pp. 5100-5111.


Natural Flavonoids in StAR Gene Expression

pp. 1804-1814.

M76-99.

No.5, pp. 677-685.

3106-3112.

pp. 295-318.

*Neurology,* Vol.62, No.2, pp. 188-193.

and Testosterone Biosynthesis in Leydig Cell Aging 203

Maloberti, P., Maciel, F.C., Castillo, A.F., Castilla, R., Duarte, A., Toledo, M.F., Meuli, F.,

Manna, P.R., Eubank, D.W., Lalli, E., Sassone-Corsi, P., & Stocco, D.M. (2003).

Manna, P.R., Eubank, D.W., & Stocco, D.M. (2004). Assessment of the role of activator

Matsumoto, A.M. (2002). Andropause: clinical implications of the decline in serum

Matzkin, M.E., Gonzalez-Calvar, S.I., Mayerhofer, A., Calandra, R.S., & Frungieri, M.B.

Mayr, B., & Montminy, M. (2001). Transcriptional regulation by the phosphorylationdependent factor CREB. *Nat Rev Mol Cell Biol,* Vol.2, No.8, pp. 599-609. Mayr, B.M., Canettieri, G., & Montminy, M.R. (2001). Distinct effects of cAMP and mitogenic

Mele, P.G., Dada, L.A., Paz, C., Neuman, I., Cymeryng, C.B., Mendez, C.F., Finkielstein,

Meyer, T.E., & Habener, J.F. (1993). Cyclic adenosine 3',5'-monophosphate response element

Miean, K.H., & Mohamed, S. (2001). Flavonoid (myricetin, quercetin, kaempferol, luteolin,

Miller, W.L. (1988). Molecular biology of steroid hormone synthesis. *Endocr Rev,* Vol.9, No.3,

Moffat, S.D., Zonderman, A.B., Metter, E.J., Kawas, C., Blackman, M.R., Harman, S.M., &

synthesis in rat Leydig cells. *Endocr Res,* Vol.23, No.1-2, pp. 15-26.

binding proteins. *Endocr Rev,* Vol.14, No.3, pp. 269-290.

protein family. *Mol Endocrinol,* Vol.16, No.1, pp. 184-199.

*Mol Endocrinol,* Vol.30, No.3, pp. 381-397.

*Reproduction,* Vol.138, No.1, pp. 163-175.

gene. *Mol Endocrinol,* Vol.18, No.3, pp. 558-573.

CoA synthetase 4 inhibits hormone-induced steroidogenesis. *Febs J,* Vol.272, No.7,

Mele, P., Paz, C., & Podesta, E.J. (2007). Enzymes involved in arachidonic acid release in adrenal and Leydig cells. *Mol Cell Endocrinol,* Vol.265-266, pp. 113-120. Manna, P.R., Dyson, M.T., Eubank, D.W., Clark, B.J., Lalli, E., Sassone-Corsi, P., Zeleznik,

A.J., & Stocco, D.M. (2002). Regulation of steroidogenesis and the steroidogenic acute regulatory protein by a member of the cAMP response-element binding

Transcriptional regulation of the mouse steroidogenic acute regulatory protein gene by the cAMP response-element binding protein and steroidogenic factor 1. *J* 

protein-1 on transcription of the mouse steroidogenic acute regulatory protein

testosterone levels with aging in men. *J Gerontol A Biol Sci Med Sci,* Vol.57, No.2, pp.

(2009). Testosterone induction of prostaglandin-endoperoxide synthase 2 expression and prostaglandin F(2alpha) production in hamster Leydig cells.

signals on CREB-binding protein recruitment impart specificity to target gene activation via CREB. *Proc Natl Acad Sci U S A,* Vol.98, No.19, pp. 10936-10941. McVey, M.J., Cooke, G.M., & Curran, I.H. (2004). Increased serum and testicular androgen

levels in F1 rats with lifetime exposure to soy isoflavones. *Reprod Toxicol,* Vol.18,

C.V., Cornejo Maciel, F., & Podesta, E.J. (1997). Involvement of arachidonic acid and the lipoxygenase pathway in mediating luteinizing hormone-induced testosterone

binding protein (CREB) and related transcription-activating deoxyribonucleic acid-

and apigenin) content of edible tropical plants. *J Agric Food Chem,* Vol.49, No.6, pp.

Resnick, S.M. (2004). Free testosterone and risk for Alzheimer disease in older men.

cyclooxygenase-2 induction in rat peritoneal macrophages. *Biochim Biophys Acta,*  Vol.1438, No.3, pp. 399-407.


Lee, K.M., Hwang, M.K., Lee, D.E., Lee, K.W., & Lee, H.J. (2010). Protective effect of

Leers-Sucheta, S., Stocco, D.M., & Azhar, S. (1999). Down-regulation of steroidogenic acute

Li, W., Pandey, A.K., Yin, X., Chen, J.J., Stocco, D.M., Grammas, P., & Wang, X.J. (2011).

Li, X., Huang, Q., Ong, C.N., Yang, X.F., & Shen, H.M. (2010). Chrysin sensitizes tumor

Liang, Y.C., Huang, Y.T., Tsai, S.H., Lin-Shiau, S.Y., Chen, C.F., & Lin, J.K. (1999).

Liew, R., Williams, J.K., Collins, P., & MacLeod, K.T. (2003). Soy-derived isoflavones exert

Lin, D., Sugawara, T., Strauss, J.F., 3rd, Clark, B.J., Stocco, D.M., Saenger, P., Rogol, A., &

Lin, T., Murono, E., Osterman, J., Allen, D.O., & Nankin, H.R. (1980). The aging Leydig cell:

Lin, T., Wang, T.L., Nagpal, M.L., Calkins, J.H., Chang, W.W., & Chi, R. (1991). Interleukin-1

Lopez, D., Nackley, A.C., Shea-Eaton, W., Xue, J., Schimmer, B.P., & McLean, M.P. (2001).

Luo, L., Chen, H., & Zirkin, B.R. (2001). Leydig cell aging: steroidogenic acute regulatory

Luo, L., Chen, H., & Zirkin, B.R. (2005). Temporal relationships among testosterone

Maloberti, P., Castilla, R., Castillo, F., Maciel, F.C., Mendez, C.F., Paz, C., & Podesta, E.J.

gonadal steroidogenesis. *Science,* Vol.267, No.5205, pp. 1828-1831.

cultures of Leydig cells. *Endocrinology,* Vol.129, No.3, pp. 1305-1311. Liu, Q., Merkler, K.A., Zhang, X., & McLean, M.P. (2007). Prostaglandin F2alpha suppresses

stimulation in rats. *Steroids,* Vol.35, No.6, pp. 653-663.

regulation. *Endocrine,* Vol.14, No.3, pp. 353-362.

epithelial cells. *J Agric Food Chem,* Vol.58, No.9, pp. 5815-5820.

Expression in Mouse Leydig Cells *J Nutritional Biochemistry*.

nuclear factor-kappaB. *Cancer Lett,* Vol.293, No.1, pp. 109-116.

Vol.1438, No.3, pp. 399-407.

No.10, pp. 1945-1952.

No.11, pp. 5209-5219.

pp. 149-156.

31.

Vol.304, No.3, pp. 985-993.

cyclooxygenase-2 induction in rat peritoneal macrophages. *Biochim Biophys Acta,* 

quercetin against arsenite-induced COX-2 expression by targeting PI3K in rat liver

regulatory (StAR) protein in rat Leydig cells: implications for regulation of testosterone production during aging. *Mech Ageing Dev,* Vol.107, No.2, pp. 197-203.

Effects of Apigenin on Steroidogenesis and Steroidogenic Acute Regulatory Gene

necrosis factor-alpha-induced apoptosis in human tumor cells via suppression of

Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. *Carcinogenesis,* Vol.20,

opposing actions on Guinea pig ventricular myocytes. *J Pharmacol Exp Ther,* 

Miller, W.L. (1995). Role of steroidogenic acute regulatory protein in adrenal and

1. Testosterone and adenosine 3',5'-monophosphate responses to gonadotropin

inhibits cholesterol side-chain cleavage cytochrome P450 expression in primary

rat steroidogenic acute regulatory protein expression via induction of Yin Yang 1 protein and recruitment of histone deacetylase 1 protein. *Endocrinology,* Vol.148,

Effects of mutating different steroidogenic factor-1 protein regions on gene

protein (StAR) and cholesterol side-chain cleavage enzyme. *J Androl,* Vol.22, No.1,

production, steroidogenic acute regulatory protein (StAR), and P450 side-chain cleavage enzyme (P450scc) during Leydig cell aging. *J Androl,* Vol.26, No.1, pp. 25-

(2005). Silencing the expression of mitochondrial acyl-CoA thioesterase I and acyl-

CoA synthetase 4 inhibits hormone-induced steroidogenesis. *Febs J,* Vol.272, No.7, pp. 1804-1814.


Natural Flavonoids in StAR Gene Expression

*Food Chem,* Vol.57, No.19, pp. 8873-8883.

*Endocrinol Invest,* Vol.18, No.3, pp. 186-193.

*Endocrinology,* Vol.139, No.12, pp. 4820-4831.

Vol.47, No.5, pp. 345-352.

factor DAX-1. *Endocrine,* Vol.10, No.1, pp. 83-91.

mediators. *Circulation,* Vol.105, No.23, pp. 2760-2765.

Vol.131, No.4 Suppl, pp. 1362S-1375S.

Vol.87, No.4, pp. 1052-1055.

No.5, pp. 729-741.

and Testosterone Biosynthesis in Leydig Cell Aging 205

Piomelli, D., & Greengard, P. (1991). Bidirectional control of phospholipase A2 activity by

and casein kinase II. *Proc Natl Acad Sci U S A,* Vol.88, No.15, pp. 6770-6774. Puangpraphant, S., & de Mejia, E.G. (2009). Saponins in yerba mate tea ( Ilex paraguariensis

Ramsden, M., Nyborg, A.C., Murphy, M.P., Chang, L., Stanczyk, F.Z., Golde, T.E., & Pike,

Reinhart, A.J., Williams, S.C., Clark, B.J., & Stocco, D.M. (1999a). SF-1 (steroidogenic factor-

Reinhart, A.J., Williams, S.C., & Stocco, D.M. (1999b). Transcriptional regulation of the StAR

Romanelli, F., Valenca, M., Conte, D., Isidori, A., & Negro-Vilar, A. (1995). Arachidonic acid

Romier, B., Van De Walle, J., During, A., Larondelle, Y., & Schneider, Y.J. (2008). Modulation

Ronco, A.M., Moraga, P.F., & Llanos, M.N. (2002). Arachidonic acid release from rat Leydig

Rosario, E.R., & Pike, C.J. (2008). Androgen regulation of beta-amyloid protein and the risk

Saksena, S.K., el-Safoury, S., & Bartke, A. (1973). Prostaglandins E2 and F2 decrease plasma testosterone levels in male rats. *Prostaglandins,* Vol.4, No.2, pp. 235-242. Sandhoff, T.W., Hales, D.B., Hales, K.H., & McLean, M.P. (1998). Transcriptional regulation

Sandhoff, T.W., & McLean, M.P. (1999). Repression of the rat steroidogenic acute regulatory

Sawada, T., Asada, M., & Mori, J. (1994). Effects of single and repeated administration of

Schroer, K., Zhu, Y., Saunders, M.A., Deng, W.G., Xu, X.M., Meyer-Kirchrath, J., & Wu, K.K.

Setchell, K.D., Brown, N.M., Desai, P., Zimmer-Nechemias, L., Wolfe, B.E., Brashear, W.T.,

gene. *Molecular Cellular Endocrinology,* Vol.151, No.1-2, pp. 161-169.

intestinal Caco-2 cells. *Br J Nutr,* Vol.100, No.3, pp. 542-551.

production. *Journal of Endocrinology,* Vol.172, No.1, pp. 95-104.

of Alzheimer's disease. *Brain Res Rev,* Vol.57, No.2, pp. 444-453.

Ca2+/calmodulin-dependent protein kinase II, cAMP-dependent protein kinase,

A. St.-Hil) and quercetin synergistically inhibit iNOS and COX-2 in lipopolysaccharide-induced macrophages through NFkappaB pathways. *J Agric* 

C.J. (2003). Androgens modulate beta-amyloid levels in male rat brain. *J Neurochem,* 

1) and C/EBP beta (CCAAT/enhancer binding protein-beta) cooperate to regulate the murine StAR (steroidogenic acute regulatory) promoter. *Mol Endocrinol,* Vol.13,

and its metabolites effects on testosterone production by rat Leydig cells. *J* 

of signalling nuclear factor-kappaB activation pathway by polyphenols in human

cells: the involvement of G protein, phospholipase A2 and regulation of cAMP

of the rat steroidogenic acute regulatory protein gene by steroidogenic factor 1.

(StAR) protein gene by PGF2alpha is modulated by the negative transcription

prostaglandin F2 alpha on secretion of testosterone by male rats. *Prostaglandins,* 

(2002). Obligatory role of cyclic adenosine monophosphate response element in cyclooxygenase-2 promoter induction and feedback regulation by inflammatory

Kirschner, A.S., Cassidy, A., & Heubi, J.E. (2001). Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. *J Nutr,* 


Montminy, M.R., Sevarino, K.A., Wagner, J.A., Mandel, G., & Goodman, R.H. (1986).

Morley, J.E., & Baumgartner, R.N. (2004). Cytokine-related aging process. *J Gerontol A Biol* 

Nackley, A.C., Shea-Eaton, W., Lopez, D., & McLean, M.P. (2002). Repression of the

Navarro-Nunez, L., Castillo, J., Lozano, M.L., Martinez, C., Benavente-Garcia, O., Vicente,

Nielsen, S.E., Young, J.F., Daneshvar, B., Lauridsen, S.T., Knuthsen, P., Sandstrom, B., &

Ogilvie, K.M., Held Hales, K., Roberts, M.E., Hales, D.B., & Rivier, C. (1999). The inhibitory

Overman, A., Chuang, C.C., & McIntosh, M. (2011). Quercetin attenuates inflammation in

Pandey, A.K., Li, W., Yin, X., Stocco, D.M., Grammas, P., & Wang, X. (2010). Blocking L-type

Pandey, A.K., Yin, X., Schiffer, R.B., Hutson, J.C., Stocco, D.M., Grammas, P., & Wang, X.

Papasozomenos, S., & Shanavas, A. (2002). Testosterone prevents the heat shock-induced

Paz, C., Dada, L.A., Cornejo Maciel, M.F., Mele, P.G., Cymeryng, C.B., Neuman, I., Mendez,

*Proc Natl Acad Sci U S A,* Vol.83, No.18, pp. 6682-6686.

Yang 1. *Endocrinology,* Vol.143, No.3, pp. 1085-1096.

in human subjects. *Br J Nutr,* Vol.81, No.6, pp. 447-455.

*Endocrinology,* Vol.150, No.7, pp. 3267-3273.

*Sci U S A,* Vol.99, No.3, pp. 1140-1145.

adrenal gland. *Eur J Biochem,* Vol.224, No.2, pp. 709-716.

*Sci Med Sci,* Vol.59, No.9, pp. M924-929.

pp. 2970-2976.

Vol.60, No.2, pp. 527-533.

*Int J Obes (Lond)*.

No.1, pp. 67-74.

Identification of a cyclic-AMP-responsive element within the rat somatostatin gene.

steroidogenic acute regulatory gene by the multifunctional transcription factor Yin

V., & Rivera, J. (2009). Thromboxane A2 receptor antagonism by flavonoids: structure-activity relationships. *J Agric Food Chem,* Vol.57, No.4, pp. 1589-1594. Navarro-Nunez, L., Lozano, M.L., Palomo, M., Martinez, C., Vicente, V., Castillo, J.,

Benavente-Garcia, O., Diaz-Ricart, M., Escolar, G., & Rivera, J. (2008). Apigenin inhibits platelet adhesion and thrombus formation and synergizes with aspirin in the suppression of the arachidonic acid pathway. *J Agric Food Chem,* Vol.56, No.9,

Dragsted, L.O. (1999). Effect of parsley (Petroselinum crispum) intake on urinary apigenin excretion, blood antioxidant enzymes and biomarkers for oxidative stress

effect of intracerebroventricularly injected interleukin 1beta on testosterone secretion in the rat: role of steroidogenic acute regulatory protein. *Biol Reprod,* 

human macrophages and adipocytes exposed to macrophage-conditioned media.

calcium channels reduced the threshold of cAMP-induced steroidogenic acute regulatory gene expression in MA-10 mouse Leydig cells. *J Endocrinol,* Vol.204,

(2009). Involvement of the thromboxane A2 receptor in the regulation of steroidogenic acute regulatory gene expression in murine Leydig cells.

overactivation of glycogen synthase kinase-3 beta but not of cyclin-dependent kinase 5 and c-Jun NH2-terminal kinase and concomitantly abolishes hyperphosphorylation of tau: implications for Alzheimer's disease. *Proc Natl Acad* 

C.F., Finkielstein, C.V., Solano, A.R., Park, M., & et al. (1994). Purification of a novel 43-kDa protein (p43) intermediary in the activation of steroidogenesis from rat


Natural Flavonoids in StAR Gene Expression

Vol.143, No.10, pp. 3935-3945.

Vol.143, No.9, pp. 3276-3283.

No.2, pp. 851-857.

3375.

Vermeulen, A. (2000). Andropause. *Maturitas,* Vol.34, No.1, pp. 5-15.

*Endocrinology,* Vol.146, No.10, pp. 4202-4208.

expression. *J Endocrinol,* Vol.190, No.3, pp. 871-878.

*Cellular Endocrinology,* Vol.188, No.1-2, pp. 55-63.

*Molecular Cellular Endocrinology,* Vol.158, No.1-2, pp. 7-12.

and Testosterone Biosynthesis in Leydig Cell Aging 207

Tong, X., Van Dross, R.T., Abu-Yousif, A., Morrison, A.R., & Pelling, J.C. (2007). Apigenin

Tremblay, J.J., Hamel, F., & Viger, R.S. (2002). Protein kinase A-dependent cooperation

Tsatsanis, C., Androulidaki, A., Venihaki, M., & Margioris, A.N. (2006). Signalling networks regulating cyclooxygenase-2. *Int J Biochem Cell Biol,* Vol.38, No.10, pp. 1654-1661.

Walch, L., & Morris, P.L. (2002). Cyclooxygenase 2 pathway mediates IL-1beta regulation of

Wang, X., Shen, C.L., Dyson, M.T., Eimerl, S., Orly, J., Hutson, J.C., & Stocco, D.M. (2005).

Wang, X., Shen, C.L., Dyson, M.T., Yin, X., Schiffer, R.B., Grammas, P., & Stocco, D.M.

Wang, X., & Stocco, D.M. (2005). The decline in testosterone biosynthesis during male aging: a consequence of multiple alterations. *Mol Cell Endocrinol,* Vol.238, No.1-2, pp. 1-7. Wang, X., Yin, X., Schiffer, R.B., King, S.R., Stocco, D.M., & Grammas, P. (2008). Inhibition of

Wang, X.J., Dyson, M.T., Jo, Y., Eubank, D.W., & Stocco, D.M. (2003a). Involvement of 5-

Wang, X.J., Dyson, M.T., Mondillo, C., Patrignani, Z., Pignataro, O., & Stocco, D.M. (2002).

Wang, X.J., Liu, Z., Eimerl, S., Timberg, R., Weiss, A.M., Orly, J., & Stocco, D.M. (1998). Effect

Wang, X.J., & Stocco, D.M. (1999). Cyclic AMP and arachidonic acid: a tale of two pathways.

Wang, X.J., Walsh, L.P., Reinhart, A.J., & Stocco, D.M. (2000). The role of arachidonic acid in

and translational inhibition. *Mol Cell Biol,* Vol.27, No.1, pp. 283-296.

prevents UVB-induced cyclooxygenase 2 expression: coupled mRNA stabilization

between GATA and CCAAT/enhancer-binding protein transcription factors regulates steroidogenic acute regulatory protein promoter activity. *Endocrinology,* 

IL-1alpha, -1beta, and IL-6 mRNA levels in Leydig cell progenitors. *Endocrinology,* 

Cyclooxygenase-2 regulation of the age-related decline in testosterone biosynthesis.

(2006). The involvement of epoxygenase metabolites of arachidonic acid in cAMPstimulated steroidogenesis and steroidogenic acute regulatory protein gene

thromboxane a synthase activity enhances steroidogenesis and steroidogenic acute regulatory gene expression in MA-10 mouse Leydig cells. *Endocrinology,* Vol.149,

lipoxygenase metabolites of arachidonic acid in cyclic AMP-stimulated steroidogenesis and steroidogenic acute regulatory protein gene expression. *The Journal of Steroid Biochemistry and Molecular Biology,* Vol.85, No.2-5, pp. 159-166. Wang, X.J., Dyson, M.T., Jo, Y., & Stocco, D.M. (2003b). Inhibition of cyclooxygenase-2

activity enhances steroidogenesis and steroidogenic acute regulatory gene expression in MA-10 mouse Leydig cells. *Endocrinology,* Vol.144, No.8, pp. 3368-

Interaction between arachidonic acid and cAMP signaling pathways enhances steroidogenesis and StAR gene expression in MA-10 Leydig tumor cells. *Molecular* 

of truncated forms of the steroidogenic acute regulatory protein on intramitochondrial cholesterol transfer. *Endocrinology,* Vol.139, No.9, pp. 3903-3912.

steroidogenesis and steroidogenic acute regulatory (StAR) gene and protein expression. *The Journal of Biological Chemistry.,* Vol.275, No.26, pp. 20204-20209.


Setchell, K.D., Brown, N.M., Zimmer-Nechemias, L., Brashear, W.T., Wolfe, B.E., Kirschner,

Shea-Eaton, W., Sandhoff, T.W., Lopez, D., Hales, D.B., & McLean, M.P. (2002).

Shea-Eaton, W.K., Trinidad, M.J., Lopez, D., Nackley, A., & McLean, M.P. (2001). Sterol

Shukla, S., & Gupta, S. (2004). Suppression of constitutive and tumor necrosis factor alpha-

Silverman, E., Yivgi-Ohana, N., Sher, N., Bell, M., Eimerl, S., & Orly, J. (2006).

Slimestad, R., Fossen, T., & Vagen, I.M. (2007). Onions: a source of unique dietary

Stocco, D.M., & Clark, B.J. (1996). Regulation of the acute production of steroids in

Sugawara, T., Holt, J.A., Kiriakidou, M., & Strauss, J.F., 3rd. (1996). Steroidogenic factor 1-

Sugawara, T., Kiriakidou, M., McAllister, J.M., Holt, J.A., Arakane, F., & Strauss, J.F., 3rd.

Sullivan, M.H., & Cooke, B.A. (1985). Effects of calmodulin and lipoxygenase inhibitors on

Syntin, P., Chen, H., Zirkin, B.R., & Robaire, B. (2001). Gene expression in Brown Norway

flavonoids. *J Agric Food Chem,* Vol.55, No.25, pp. 10067-10080.

steroidogenic cells. *Endocrine Review,* Vol.17, No.3, pp. 221-244.

(StAR) gene. *Biochemistry,* Vol.35, No.28, pp. 9052-9059.

*Endocrinology,* Vol.141, No.8, pp. 2895-2903.

Vol.142, No.12, pp. 5277-5285.

Leydig cells. *Biochem J,* Vol.232, No.1, pp. 55-59.

regulatory protein gene. *Endocrinology,* Vol.142, No.4, pp. 1525-1533. Sheu, J.R., Hsiao, G., Chou, P.H., Shen, M.Y., & Chou, D.S. (2004). Mechanisms involved in

bioavailability. *Am J Clin Nutr,* Vol.76, No.2, pp. 447-453.

platelets. *J Agric Food Chem,* Vol.52, No.14, pp. 4414-4418.

Vol.274, No.25, pp. 17987-17996.

*Endocrinol,* Vol.252, No.1-2, pp. 92-101.

161-170.

A.S., & Heubi, J.E. (2002). Evidence for lack of absorption of soy isoflavone glycosides in humans, supporting the crucial role of intestinal metabolism for

Transcriptional repression of the rat steroidogenic acute regulatory (StAR) protein gene by the AP-1 family member c-Fos. *Mol Cell Endocrinol,* Vol.188, No.1-2, pp.

regulatory element binding protein-1a regulation of the steroidogenic acute

the antiplatelet activity of rutin, a glycoside of the flavonol quercetin, in human

induced nuclear factor (NF)-kappaB activation and induction of apoptosis by apigenin in human prostate carcinoma PC-3 cells: correlation with down-regulation of NF-kappaB-responsive genes. *Clin Cancer Res,* Vol.10, No.9, pp. 3169-3178. Silverman, E., Eimerl, S., & Orly, J. (1999). CCAAT enhancer-binding protein beta and

GATA-4 binding regions within the promoter of the steroidogenic acute regulatory protein (StAR) gene are required for transcription in rat ovarian cells. *J Biol Chem,* 

Transcriptional activation of the steroidogenic acute regulatory protein (StAR) gene: GATA-4 and CCAAT/enhancer-binding protein beta confer synergistic responsiveness in hormone-treated rat granulosa and HEK293 cell models. *Mol Cell* 

dependent promoter activity of the human steroidogenic acute regulatory protein

(1997). Regulation of expression of the steroidogenic acute regulatory protein (StAR) gene: a central role for steroidogenic factor 1. *Steroids,* Vol.62, No.1, pp. 5-9. Sugawara, T., Saito, M., & Fujimoto, S. (2000). Sp1 and SF-1 interact and cooperate in the

regulation of human steroidogenic acute regulatory protein gene expression.

LH (lutropin)- and LHRH (luliberin)-agonist-stimulated steroidogenesis in rat

rat Leydig cells: effects of age and of age-related germ cell loss. *Endocrinology,* 


**10** 

*Germany* 

**Role of Central Insulin-Like Growth Factor-1** 

Insulin-like growth factors (IGFs) are, besides other mechanisms, controlled by growth hormone (GH) secretion and there are at least two different IGFs: IGF-1 and IGF-2. IGFs regulate various cellular processes e.g. survival, differentiation and proliferation (McMorris

Growth hormone, which induces IGF-1 secretion from the liver, is generated in the anterior pituitary and regulated by the hypothalamus via growth hormone releasing hormone (GHRH) and growth hormone inhibiting hormone (GHIH) (Jansson et al., 1985; Carlsson & Jansson 1990). IGFs in the brain are synthesised de novo or transported across the blood brain barrier (BBB) and seem to induce a variety of effects on the central nervous system (CNS). So far, the exact transport mechanisms of IGFs into the brain are not fully

In the rodent brain, IGF-1 is mainly expressed in neuron-dense regions like the hippocampus, striatum, thalamus, hypothalamus and olfactory bulb (Rotwein et al. 1988; Bondy et al. 1990; Garcia-Segura et al. 1991). Accordingly, the insulin-like growth factor-1 receptors (IGF-1Rs) are mainly found in the olfactory bulb, cerebellar cortex and granule cell layer of the dentate gyrus (Rotwein et al. 1988; Bondy et al. 1990; Bondy and Lee 1993; Werther et al. 1990). However, the function of IGF-1R mediated signals in the central

After binding of IGF-1 to the IGF-1R, a signalling cascade is activated which leads to recruitment and subsequently phosphorylation of intracellular adaptor proteins, the so called insulin receptor substrates (IRS) (Jacobs et al. 1983; Rubin et al., 1983; Sun et al. 1991; Lavan et al. 1997; Lavan et al., 1997). Via these adaptor proteins, the MAP kinase (MAPK, mitogen activated protein kinase) cascade, as well as the phosphatidylinositide(PI)3-kinase signalling pathway, is turned on leading to protein kinase B (PKB/AKT) activation, which phosphorylates forkhead box O transcription factors (FoxO) causing their nuclear export (Stokoe et al. 1997; Alessi et al. 1996; Partridge & Bruning 2008). FoxO mediated transcription is involved in cell proliferation, differentiation and oxidative stress defence (Clark et al. 1993; Brunet et al. 1999; Dijkers et al. 2000; Dijkers, Medema, Pals et al. 2000; Medema et al. 2000) suggesting a function of FoxO during development and cellular stress

et al. 1986; McMorris & Dubois-Dalcq 1988; Mozell & McMorris 1991).

understood (Duffy, Pardridge, and Rosenfeld 1988).

nervous system (CNS) is still under investigation.

**1. Introduction** 

response.

**Receptor Signalling in Ageing and** 

Lorna Moll, Johanna Zemva and Markus Schubert *Center of Endocrinology, Diabetes and Preventive Medicine* 

**Endocrine Regulation** 

