Biomedical subjects

G P Collett

Publications and source records attributed to G P Collett.

6 recordsLinked to original sources

PubMed2001

Curcumin modifies Apc(min) apoptosis resistance and inhibits 2-amino 1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced tumour formation in Apc(min) mice.

Curcumin, the active ingredient of the rhizome of Curcuma longa, promotes apoptosis and may have chemopreventive properties. This study investigates the effects of curcumin on apoptosis and tumorigenesis in male Apc(min) mice treated with the human dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Intestinal epithelial apoptotic index in response to PhIP treatment was approximately twice as great in the wild-type C57BL/6 APC(+/+) strain than in Apc(min) mice (3.7% Apc(+/+) versus 1.9% Apc(min); P < 0.001). PhIP promoted tumour formation in Apc(min) proximal small intestine (4.6 tumours per mouse, PhIP treated versus 2.1 tumours per mouse, control untreated; P < 0.05). Curcumin enhanced PhIP-induced apoptosis (4.0% curcumin + PhIP versus 2.1% PhIP alone; P < 0.01) and inhibited PhIP-induced tumorigenesis in the proximal small intestine of Apc(min) mice (2.2 tumours per mouse, curcumin + PhIP versus 4.6 tumours per mouse PhIP alone; P < 0.05). This study shows that the Apc(min) genotype is associated with resistance to PhIP-induced apoptosis in intestinal epithelium. Curcumin attenuates Apc(min) resistance to PhIP-induced apoptosis and inhibits PhIP-induced tumorigenesis in proximal Apc(min) mouse small intestine.

Animals↗

PubMed2000

Peroxisome proliferator-activated receptor alpha is an androgen-responsive gene in human prostate and is highly expressed in prostatic adenocarcinoma.

Peroxisome proliferator-activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPARalpha is activated by peroxisome proliferators and fatty acids and has been shown to be involved in the transcriptional regulation of genes involved in fatty acid metabolism. In rodents, the PPARalpha-mediated change in such genes results in peroxisome proliferation and can lead to the induction of hepatocarcinogenesis. Using the mRNA differential display technique and Northern blot analysis, we have shown that chronic exposure of the prostate cancer epithelial cell line LNCaP to the synthetic androgen mibolerone results in the down-regulation of PPARalpha mRNA. Levels of PPARalpha mRNA are reduced to approximately 40% of control levels in LNCaP cells exposed to 10 nM mibolerone for 96 h. PPARalpha-responsive reporter plasmids derived from human ApoA-II and muscle carnitine palmitoyl-transferase I genes were stimulated by the PPARalpha-activating ligand Wy-14,643 in LNCaP cells. In situ hybridization and immunohistochemical analyses showed that PPARalpha expression in prostate is confined to epithelial cells. In benign prostatic tissue, PPARalpha mRNA was either absent or only weakly expressed in the basal epithelial cells. In 11 of 18 (61%) poorly differentiated (Gleason score, 8-10) prostatic carcinoma specimens, there was strong expression of PPARalpha compared with 4 of 12 Gleason score 7 tumors and 2 of 11 Gleason score 3-6 tumors (P < 0.01). These results suggest that PPARalpha is found and functional in human prostate and is down-regulated by androgens. The role of PPARalpha may be to integrate dietary fatty acid and steroid hormone signaling pathways, and its overexpression in advanced prostate cancer may indicate a role in tumor progression with the potential involvement of dietary factors.

Adenocarcinoma↗

PubMed1998

Paracrine regulation of talin mRNA expression by androgen in human prostate.

Androgens are essential for normal prostate physiology and are intimately associated with the growth and progression of prostate cancer. However, few androgen regulated genes in the prostate have been identified. Using the mRNA differential display technique a 164-bp cDNA fragment was identified as being androgen regulated in the human prostate. Nucleotide sequence analysis of this fragment revealed 84% homology with the gene encoding the cytoskeletal protein talin. Confirmation of the androgen regulation of this gene was carried out using Northern analysis. Primary prostatic stromal cells treated with conditioned medium (CM) from androgen-treated primary prostatic epithelial cells showed an approximate 2-fold reduction in talin mRNA levels compared with stromal cells treated with CM from epithelial cells not exposed to androgens. Expression of talin mRNA in human prostatic tissue was confirmed by in situ hybridisation. The highest levels of expression were present in the epithelial cells, with lower levels of expression in the stroma. Thus, androgen regulation of talin expression may play a role in normal and/or aberrant growth and development of the prostate.

Androgens↗

PubMed1996

Localization of endothelin receptors in human uterus throughout the menstrual cycle.

Quantitative autoradiography employing the ETA selective ligand [125I]PD 151242 and the ETB selective ligand [125I]BQ3020 was used to assess the localization of ETA and ETB receptors in human uterus throughout the menstrual cycle. ETA and ETB receptors were present in endometrium and myometrium across the menstrual cycle. In myometrium, neither ETA nor ETB receptor density showed any detectable change across the menstrual cycle. ETA receptors were expressed in stroma throughout the endometrium and showed an increase in density in proliferative endometrium compared with secretory and menstrual endometrium. Endometrial ETB receptors were expressed at low density in the proliferative phase. In the early secretory phase there was an increase in ETB receptor density in the glandular epithelium of the basal region of the endometrium but not in functional endometrium. In the late secretory phase ETB receptor expression was increased in glandular epithelium throughout the endometrium. The highest density of ETB receptors was seen in menstrual endometrium, where they were present in stromal as well as epithelial cells. These results suggest that ovarian steroid hormones may play a role in the control of expression of ETA and ETB receptors in endometrial stromal and epithelial cells respectively.

Autoradiography↗

PubMed1995

Endothelin expression in the uterus.

The endothelins (ETs) comprise a family of 21 amino acid peptides, ET-1, ET-2 and ET-3, first demonstrated as products of vascular endothelium. Subsequent work showed that they are also found in non-endothelial cells from a variety of tissues such as breast, parathyroid and adrenal gland. At first, the ETs were recognized for their pressor effects. However, ET administration in vivo initially caused hypotension at low concentrations by triggering the paracrine release of endothelial-derived vasodilators. The ETs exert powerful contractile actions on myometrium and other types of smooth muscle and are mitogenic, or co-mitogenic for fibroblasts, vascular smooth muscle and other cells. Demonstration of extravascular ET in endometrium has revealed a powerful vasoconstrictor which might act on the spiral arterioles to effect a powerful and sustained contraction of vascular smooth muscle. ETs might also contribute to the process of endometrial repair. In addition, the ETs appear to play a fundamental role in the control of uterine function in pregnancy. Effects on myometrial contractility have been implicated in the mechanisms governing the onset of normal and pre-term labour, and the peptides are likely to be key determinants of placental blood flow by binding to vascular smooth muscle receptors in the placenta.

Amino Acid Sequence↗

PubMedDate not supplied

Differential distribution of endothelin receptor subtypes in placentae from normal and growth-restricted pregnancies.

The endothelins (ETs) are potent vasoconstrictor peptides that bind to two distinct receptors, ETA and ETB. This study compares the localization of ETA and ETB receptors in placentae complicated by intrauterine growth retardation (IUGR) and abnormal umbilical Doppler waveform, gestationally matched controls, fetuses that were small for gestational age (SGA), and normal term placentae. Quantitative autoradiography was performed using ETA and ETB subtype-selective ligands. Both ETA and ETB receptors were expressed in the human placenta. Gestational and fetal size effects on the receptor density within stem villi were found, but no effect of abnormal placental blood flow could be demonstrated. A distinct spatial distribution of receptor subtypes within the placenta was observed. Smooth muscle cells expressed both receptors with ETA expression predominant in the proximal regions of the villous tree and ETB abundant in the periphery and decidua. Both receptors were also expressed at lower density on paravascular stromal cells in stem villi. Although these data do not demonstrate aberrant localization of ET receptors in IUGR and SGA placentae, the spatially distinct distribution of ET receptors in the human placenta suggests that ETs play a role in modulation of placental blood flow.

Adult↗