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Biomedical subjects

X P Lu

Publications and source records attributed to X P Lu.

At least 19 recordsLinked to original sources
PubMed2006

Down-regulation of prostate specific antigen in LNCaP cells by flavonoids from the pollen of Brassica napus L.

The pollen of Brassica napus L. has been used in China to treat benign prostatic hyperplasia (BPH) for over decades. In this study, the pollen of Brassica napus L. was extracted successively with chloroform, ethyl acetate and ethanol. The ethyl acetate extract showed strong activity in decreasing the secretion of prostate specific antigen (PSA) in LNCaP cells as compared to two other extracts, measured by ELISA with finasteride as positive control in the assay. Five flavonoids were subsequently isolated from the active extract using bioassay-guided fractionation. They were Naringenin (1); Luteolin (2); Kaempferol (3); Kaempferol 3-(3-E-p-coumaroyl-alpha-L-rhamnopyranoside) (4); and Kaempferol 3-(2,3-di-E-p-coumaroyl-alpha-L-rhamnopyranoside) (5). All these compounds inhibited PSA secretion significantly, with IC50 values in the range of 5-50 microM. Compounds 2, 4 and 5 showed moderate cytotoxicity to LNCaP cells within the active concentration range, while compounds 1 and 3 showed no cytotoxicity. Further studies on the mechanism action of these compounds were performed by evaluating their activation of estrogen receptor (ER) and antagonistic activities on androgen receptor (AR) in cell-based reporter gene assays. All compounds described here were first isolated from the pollen of Brassica napus L.

Brassica napus↗
PubMed1999

A selective retinoid with high activity against an androgen-resistant prostate cancer cell type.

Retinoic acid (RA) and its natural and synthetic analogs, the retinoids, regulate many biological processes, including development, differentiation, cell growth, morphogenesis, metabolism and homeostasis. Retinoid effects are mediated by specific nuclear receptors, the RARs and RXRs. Because of their ability to control cell growth and induce differentiation, retinoids are being examined for the prevention and treatment of several cancers. The majority of retinoids so far analyzed and available inhibit primarily cell proliferation and tumor progression but cannot eliminate cancer cells. In addition, the beneficial effects of the natural retinoids are undermined by undesirable side effects, possibly due to indiscriminate activation of all retinoid receptor subtypes and response pathways. Here, we show that a synthetic retinoid, CD-271, that activates selectively the RAR gamma subtype in a given context, shows increased anti-proliferative activity against certain carcinoma cells over all-trans-retinoic acid (tRA). CD-271 exhibits enhanced activity against DU-145 prostate adenocarcinoma cells through apoptosis-inducing activity, while tRA does not. The selective anti-cancer cell action appears to be receptor-mediated as an RAR antagonist reverses the inhibition. This profile was not seen with other selective retinoids, such as RAR alpha-selective agonists, anti-AP-1 compounds and a non-apoptosis inducing RAR gamma agonist. Our data point to a specific role for RAR gamma in controlling the growth of the prostate, consistent with previous RAR gamma gene knockout data. The identified retinoid represents a new class of compounds with potential for the treatment of prostate cancer.

Androgens↗
PubMed1998

Selective activation of an apoptotic retinoid precursor in macrophage cell lines.

Advances in the understanding of the retinoid signaling mechanism has allowed the discovery of highly selective retinoids that activate only one specific receptor class, subtype, or signaling pathway. These novel compounds lack certain of the common retinoid toxicities and therefore suggest promising new approaches for therapeutic applications. We describe here a new compound, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid methyl ester (MX84), that is selectively activated in macrophages, leading to killing of only macrophage monocyte type cells in vitro. We provide evidence that MX84 is an inactive precursor that is converted into an active apoptosis-inducing retinoid in macrophages. The macrophage activity is also secreted, and our data suggest that the secreted activity is a phospholipase D type activity. Our observation may lead to the development of molecules that are highly macrophage-selective apoptosis inducers in vivo and that could represent important novel therapeutics against diseases caused by excessive macrophage activity.

Apoptosis↗
PubMed1997

Novel retinoid-related molecules as apoptosis inducers and effective inhibitors of human lung cancer cells in vivo.

Lung cancer causes more than 140,000 deaths annually in the United States alone, and the prognosis for non-small cell lung cancer (NSCLC) is particularly poor. Therapies using small molecules that preferentially kill lung tumor cells by inducing cellular suicide (apoptosis) would therefore be highly desirable. Retinoids have shown promise as cancer preventive and cancer therapeutic agents. Retinoid signals are mediated by two classes of nuclear receptors: the retinoic acid receptors (RAR alpha, beta, and gamma) and the retinoid X receptors (RXR alpha, beta and gamma). These receptors usually bind as heterodimers to specific DNA sequences and/or interact with other transcriptional regulators, such as AP-1 (ref. 10) to regulate gene transcription. Synthetic retinoids can be made that activate only specific portions of the complex retinoid response network and activate selective biological programs. To identify retinoids with novel biological activities, we used a high-throughput "biological activity fingerprint" screen on a large library of retinoids and retinoid-related molecules (RRMs). We identified new structures that are highly effective against lung cancer cells in vitro, inducing apoptosis. We show here for one of these compounds that it is very effective against a human NSCLC in vivo in an animal model. These new molecules show a distinct pattern of receptor signaling.

Animals↗
PubMed1996

Study of the prevalence of diabetes mellitus in adults in the Shougang Corporation in Beijing.

The aim was to determine the burden of diabetes mellitus (DM) in an urban area of China to aid us in planning preventive measures for those at risk of DM. A survey was conducted among the 29,859 subjects aged between 30 and 64 belonging to 32 units of the Shougang Corporation (a heavy industry enterprise) within the Beijing area. WHO study protocols and diagnostic criteria were used to determine the prevalence of DM and impaired glucose tolerance (IGT). The results showed that the age-adjusted prevalence of DM and impaired glucose tolerance (IGT) was 3.63% and 4.19%, respectively, both increasing with age. Peak prevalence for both occurred in the 60-64 age group. Prevalence showed no difference between the sexes in DM but was higher for females in IGT. Obesity, being overweight, a family history of diabetes mellitus and in women, a history of delivering babies with macrosomia, all correlated closely with the prevalence of DM and IGT. High protein intake was also associated with DM, Smoking had no effect on either DM or IGT. Intellectual workers had a higher incidence of IGT than manual workers. Seventy per cent DM was undiagnosed prior to the survey. This survey, done according to the recommendation of WHO, and including appropriate adjustments, reflects the growing prevalence of DM and IGT in this population. It can be compared with other studies for epidemiological analysis.

Adult↗
PubMed1996

Immunocytochemical expression of the 70 kD heat shock protein in ischaemic bowel disease.

Heat shock proteins (HSPs) are a family of polypeptides which are induced in response to diverse forms of cell injury including hyperthermia, anoxia, ethanol, heavy metals, and others, with a presumably protective function. Among several species of HSPs, the 70 kD protein (HSP70) is the most abundant and consistently induced in mammalian cells. Anti-HSP70 monoclonal antibody and a standard immunocytochemical method were used to study the expression of HSP70 in 28 surgical specimens of small and large intestines from patients with ischaemic bowel disease. Strong immunoreactivity was observed in viable, regenerating cells of both the crypt and surface epithelium within or adjacent to the necrotic foci in 86 per cent of the ischaemic bowel specimens. Staining was mostly cytoplasmic, but focally both cytoplasmic and nuclear. Smooth muscle cells of the muscularis mucosae in the ischaemic areas of some cases also showed immunoreactivity. On the other hand, HSP70 was not expressed in control specimens of small and large intestine or in colonic specimens of Crohn's disease, ulcerative colitis, and adenocarcinoma. These findings suggest a possible role of HSP70 in intestinal epithelial and smooth muscle cell response to ischaemic injury, especially in the recovery phase.

Aged↗
PubMed1994

A new class of retinoids with selective inhibition of AP-1 inhibits proliferation.

Retinoids regulate many biological processes, including differentiation, morphogenesis and cell proliferation. They are also important therapeutic agents, but their clinical usefulness is limited because of side effects. Retinoid activities are mediated by specific nuclear receptors, the RARs and RXRs, which can induce transcriptional activation through specific DNA sites or by inhibiting the transcription factor AP-1 (refs 12-15), which usually mediates cell proliferation signals. Because the two types of receptor actions are mechanistically distinct, we investigated whether conformationally restricted retinoids, selective for each type of receptor action, could be identified. Here we describe a new class of retinoids that selectively inhibits AP-1 activity but does not activate transcription. These retinoids do not induce differentiation in F9 cells but inhibit effectively the proliferation of several tumour cell lines, and could thus serve as candidates for new retinoid therapeutic agents with reduced side effects.

Animals↗
PubMed1994

Primary rat hepatocytes express cyclin D1 messenger RNA during their growth cycle and during mitogenic transitions induced by transforming growth factor-alpha.

Cyclin D1 messenger RNA expression was investigated in differentiated proliferation-competent primary cultures of adult rat hepatocytes. Periodic expression was observed during the 12-day growth cycle (approximately two population doublings). Upon reaching a quiescent G(o)-state, 4-kb cyclin D1 mRNA levels were undetectable. When G(o) cultures were shifted into defined media without or with 0.2-0.8 nM TGF-alpha, conditions that reinitiate full proliferative transitions synchronously, cyclin D1 mRNA levels were elevated 1.2-4.6-fold, respectively. These findings support the hypothesis that hepatic mitogens stimulate periodic cyclin mRNA expression directly.

Animals↗
PubMed1994

An evolutionary conserved COUP-TF binding element in a neural-specific gene and COUP-TF expression patterns support a major role for COUP-TF in neural development.

The COUP transcription factors (COUP-TF and ARP-1) are the most highly conserved members of the nuclear receptor superfamily throughout evolution. Previous studies indicated that COUP orphan receptors may be involved in early neurogenesis in Drosophila and zebrafish. Here we identified a neural-specific gene, arrestin, whose transcription can be regulated by endogenous COUPs through a DR-7 element (direct repeat with a 7-base pair spacer) located upstream of the transcription start site. Importantly, the COUP binding site of the arrestin gene promoter is conserved among mouse, bovine, and human. However, the mouse element is also capable of responding to retinoic acid while the element in the human gene does not. Expression of COUP-TF correlates with the known expression sites of the arrestin gene in vivo, notably during the differentiation of the retina. We also show that COUP-TF is expressed in a spatio-temporally defined pattern in the murine central nervous system during embryogenesis. It appears that the expression pattern of COUP-TF is unique in certain regions of the developing brain, which would indicate a novel role for COUP-TF and/or ARP-1, distinct from their role in restricting other hormonal signaling pathways. Together our data suggest that COUPs play a crucial role in controlling a subset of neural-specific programs during development.

Animals↗
PubMed1993

Inactivation of plasmid reporter gene expression by one benzo(a)pyrene diol-epoxide DNA adduct in adult rat hepatocytes.

Polycyclic aromatic hydrocarbons such as benzo(a)pyrene diol-epoxide (BPDE-I) cause hepatocellular carcinoma. To identify short-term carcinogen effects, we studied hepatocytes transfected with nonreplicating plasmids, adducted covalently with BPDE-I, varying in promoter structure and encoded reporter gene (beta-galactosidase or luciferase). BPDE inactivated gene expression as a first-order function of BPDE concentration in adduction reactions. No evidence of cytotoxicity, diminished coprecipitation and availability, enhanced nicking of supercoiled forms and reduced cellular uptake, or instability of adducted plasmids was observed. At low BPDE:plasmid ratios, inactivation occurred with 1 adduct/plasmid within a target 23-27% of plasmid bases. Using nuclear extracts and BPDE-adducted G-free cassette-encoding plasmids, the fraction of full-length RNA polymerase II-initiated transcripts also declined as a first-order function of BPDE concentration when approximately 3 adducts were distributed among 48% of plasmid bases. These observations suggest that carcinogens such as BPDE block mRNA transcription along DNA templates by forming limited numbers of persistent adducts at coding or noncoding sites.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1993

DNA bending by retinoid X receptor-containing retinoid and thyroid hormone receptor complexes.

Retinoid X receptors (RXR) have been identified as common subunits in the regulation of multiple hormonal signaling pathways. Using circular permutation and phasing analysis of specific response elements, we present evidence that RXR-retinoic acid receptor and RXR-thyroid hormone receptor heterodimer or RXR-RXR homodimer complexes induce directed DNA bends when bound to their cognate response elements. The extent of DNA bending induced by the RXR alpha-containing complexes varied and depended on the structure of the DNA-binding sites and the RXR partners. The overall bending orientation for RXR-containing complexes is directed toward the major groove of the DNA helix at the center of hormone response elements. Our observation implicates DNA bending as a possible mechanism underlying transcriptional regulation of distinct retinoid and thyroid hormone responsive genes.

Base Sequence↗
PubMed1993

Retinoic acid receptors and retinoid X receptor-alpha down-regulate the transforming growth factor-beta 1 promoter by antagonizing AP-1 activity.

Overexpression of the multifunctional growth factor transforming growth factor-beta 1 (TGF beta 1) has been connected to numerous diseases in human. TGF beta 1 expression is largely governed by three AP-1 binding sites located in two different promoters of this gene. We have examined the ability of retinoid receptors to inhibit the activity of the two promoters (especially the promoter 1) by cotransfection assays in the hepatocellular carcinoma cell line HepG2. When the TGF beta 1 promoter activity is induced by 12-O-tetradecanoyl phorbol13-acetate (an activator of AP-1-controlled gene transcription), this activity can be strongly repressed by retinoic acid receptor-alpha (RAR alpha), RAR beta, or retinoid X receptor-alpha (RXR alpha) as well as other members of the nuclear receptor family. Repression was hormone dependent and a function of receptor concentration. Heterodimerization of RAR alpha or RAR beta with RXR alpha did not modify the inhibition activities of these receptors, indicating that heterodimer formation is not required for antagonizing of AP-1 activity. On further examining the anti-AP-1 activity of RXR alpha we observed that three different AP-1-controlled promoters (TGF beta 1, collagenase, and cFos) can be inhibited. Using gel shift assays, we demonstrated that RXR alpha inhibits Jun and Fos DNA binding and that 9-cis RA enhances this inhibition, suggesting that a mechanism involving direct protein-protein interaction between RXR and AP-1 components mediates the inhibitory effect observed in vivo. Transfection analyses with RXR alpha point mutations revealed that residues L422, C432, and, to a lesser extent, residues L418 and L430, are involved in ligand-induced anti-AP1 activity of RXR alpha in vivo. Thus both types of retinoid receptors can inhibit AP-1-activated promoters, including the TGF beta 1 gene promoter, via a mechanism that involves protein-protein interaction.

Amino Acid Sequence↗
PubMed1992

Retinoids selective for retinoid X receptor response pathways.

Retinoids have a broad spectrum of biological activities and are useful therapeutic agents. Their physiological activities are mediated by two types of receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). RARs, as well as several related receptors, require heterodimerization with RXRs for effective DNA binding and function. However, in the presence of 9-cis-retinoic acid, a ligand for both RARs and RXRs, RXRs can also form homodimers. A series of retinoids is reported that selectively activates RXR homodimers but does not affect RAR-RXR heterodimers and thus demonstrates that both retinoid response pathways can be independently activated.

Animals↗
PubMed1992

Differential expression of the transfected liver-specific alpha 1-inhibitor III gene in normal hepatocytes and hepatoma cells in culture.

Normal and malignant hepatocytes were transfected during log phase culture with a nested series of DNA plasmids containing 5'-flanking regions of the rat liver-specific acute phase plasma proteinase alpha 1-inhibitor III (alpha 1 I3) gene. Under these conditions, luciferase reporter gene expression in primary adult rat and mouse hepatocytes was 10-fold higher than luciferase expression in hepatoma lines (human HepG2 and Hep3B; rat FAZA). Optimal expression in primary rat hepatocytes required regions stretching 2214 bp 5'-upstream of the transcription start site. Shorter 5'-flanking sequences were optimal for expression in hepatoma cells (-1025 and -186 bp for rat and human lines, respectively) and primary mouse hepatocytes (-225 bp). In contrast, regions from -186 to -225 bp drove luciferase expression in primary rat hepatocytes, but only 20-75% of optimal levels. Qualitative differences were unaccounted for by non-equivalent uptake of plasmid DNA, suggesting that tissue specific gene expression is regulated differently in normal and malignant cells, and with apparent species specificity.

Acute-Phase Proteins↗
PubMed1992

Induction of cyclin mRNA and cyclin-associated histone H1 kinase during liver regeneration.

Cyclins and cyclin-associated cdc kinases are key regulators of oocyte maturation (Maller, J. L. (1990) in The Biology and Medicine of Signal Transduction (Nishizuka, Y., Endo, M., and Tanaka, C., eds) pp. 323-328, Raven Press, New York), yeast cell cycles (Nurse, P. (1990) Nature 344, 503-508), DNA replication in cell-free systems (D'Urso, F., Marraccino, R. L., Marshak, R. R., and Roberts, J. M. (1990) Science 250, 786-791), and amphibian cell proliferative transitions (Hunt, T. (1991) Nature 350, 462-463). The extent to which these regulatory molecules participate in the growth control of differentiated epithelial cells like hepatocytes is unknown. Therefore, we investigated the expression of "G1" (E, C, and D) and "G2/M" (A, B1, and B2) cyclin mRNAs, the relative levels of cyclin A- and B1-associated histone H1-kinase activity, and the appearance of cyclin-associated kinases (p32/p33cdk2 and p33/p34cdc2) in regenerating rat liver and in control tissues from sham hepatectomized rats. To do this, we exploited a battery of human cyclin cDNAs and cyclin antisera that recognize rat molecules. The results suggest an apparent sequence of regeneration-specific changes: 1) elevated and induced expression of cyclins E (2.1 kilobases (kb)) and C (4 kb), and D mRNAs (4 kb), within 12 h, respectively; 2) induction of cyclins A (3.4 and 1.8 kb), B1 (2.5 and 1.8 kb), and B2 (1.9 kb) mRNAs at 24 h; 3) induction of cyclin A- and B1-associated nuclear histone H1 kinase at 24 h; and 4) enhanced levels of PSTAIRE-containing proteins of Mr approximately 32-33 and 33-34 kDa in nuclear extracts from 24-h regenerating liver that co-immunoprecipitate with cyclin A and B1 antisera, respectively. These observations provide an intellectual framework that unifies the biology of hepatocyte mitogenesis, proto-oncogene expression, and the machinery of the cell cycle.

Animals↗
PubMed1991

Induction of sodium pump beta 1-subunit mRNA expression during hepatocellular growth transitions in vitro and in vivo.

Previous suggestions (Hubert, J. J., Schenk, D. B., Skelly, H., and Leffert, H. L. (1986) Biochemistry 25, 4156-4163) of tissue-specific isoforms or nonexistence of hepatic Na,K-ATPase beta 1-subunits were reevaluated by quantifying beta 1-subunit mRNA levels in quiescent and proliferating liver. RNA was extracted from caudate liver lobes of sham or 67% hepatectomized adult rats and from primary cultures of adult rat hepatocytes that simulate developmental and regenerating growth transitions. Northern blot analysis with a 32P-labeled full-length Na,K-ATPase beta 1-cDNA probe (Mercer, R. W., Schneider, J. W., Savitz, A., Emmanuel, J., Benz, T.J., and Levenson, R. (1986) Mol. Cell. Biol. 6, 3884-3890) revealed four (approximately 2.7, 2.4, 1.7-1.8, and 1.5 kilobases) low abundance mRNA species in quiescent tissue, freshly isolated hepatocytes, and cultured hepatocytes derived from lag or late stationary phase (1-2 days or 11-12 days postplating, respectively). In contrast, proliferating liver from 4 h post-67% hepatectomized rats or cultured hepatocytes in logarithmic growth phase contained levels of beta 1-subunit mRNA which exceeded quiescent levels by 4-35-fold. Membrane Na,K-ATPase activity also increased 2-3-fold during liver regeneration 12-24 h after partial hepatectomy. When proliferation in vitro was augmented by transforming growth factor-alpha, a hepatocyte mitogen, or reinitiated in late stationary phase by a change to fresh culture medium containing rat serum, beta 1-subunit mRNA expression was restimulated 4-20-fold. Parallel measurements of alpha-tubulin mRNA induction showed relatively nonsynchronous or invariant changes during hepatocyte proliferative transitions; similar results were obtained after Northern blots with a sodium pump alpha I-subunit cDNA probe. No detectable hybridization signals were observed when either rat kidney or hepatocyte RNAs from freshly isolated and cultured cells or regenerating tissues were probed for the sodium pump 3.4-kilobase mRNA beta 2-isoform. These observations suggest that enhanced hepatic beta 1-subunit gene expression is linked specifically to growth-associated increases in Na,K-ATPase activity, hepatocyte proliferation, and mitogen activation.

Animals↗