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PubMed1999

Induction of nuclear translocation of NF-kappaB in epithelial cells by respirable mineral fibres.

A panel of mineral fibres has been studied for their ability to cause translocation of the transcription factor NF-kappaB to the nucleus in A549 lung epithelial cells. On the basis of inhalation studies, three fibres were designated as being carcinogenic-amosite asbestos, silicon carbide and refractory ceramic fibre 1 (RCF1)-or non-carcinogenic-man-made vitreous fibre (MMVF10), Code 100/475 glass fibre, and RCF4. The experiments were carried out at equal fibre number. It was hypothesized that carcinogenic fibres have greater free radical activity than non-carcinogenic fibres and that an oxidative stress produced in the lung after inhalation of fibres could cause translocation of the transcription factor NF-kappaB to the nucleus, where transcription of pro-inflammatory genes such as cytokines could occur. It was demonstrated that a simple oxidant, hydrogen peroxide, caused translocation in a time- and dose-dependent manner. The three carcinogenic fibres produced a significant dose-dependent translocation of NF-kappaB to the nucleus, whereas the non-carcinogenic fibres did not. Silicon carbide fibres were the most potent of the pathogenic fibres. MMVF10 was the most potent of the non-pathogenic fibres, causing significant nuclear translocation of NF-kappaB at high fibre number. Using three antioxidants, curcumin, pyrrolidine dithiocarbamate, and Nacystelin, translocation caused by carcinogenic fibres could be significantly reduced. The present study shows that a short-term in vitro assay can discriminate between pathogenic and non-pathogenic fibres in terms of a key pro-inflammatory event in epithelial cells. The mechanism of the activation of NF-kappaB by pathogenic fibres and its general applicability to other fibre types remain to be determined.

Antioxidants↗

PubMed2000

Methylglyoxal induces apoptosis in Jurkat leukemia T cells by activating c-Jun N-terminal kinase.

Methylglyoxal (MG) is a physiological metabolite, but it is known to be toxic, inducing stress in cells and causing apoptosis. This study examines molecular mechanisms in the MG-induced signal transduction leading to apoptosis, focusing particularly on the role of JNK activation. We first confirmed that MG caused apoptosis in Jurkat cells and that it was cell type dependent because it failed to induce apoptosis in MOLT-4, HeLa, or COS-7 cells. A caspase inhibitor, Z-DEVD-fmk, completely blocked MG-induced poly(ADP-ribose)polymerase (PARP) cleavage and apoptosis, showing the critical role of caspase activation. Inhibition of JNK activity by a JNK inhibitor, curcumin, remarkably reduced MG-induced caspase-3 activation, PARP cleavage, and apoptosis. Stable expression of the dominant negative mutant of JNK also protected cells against apoptosis notably, although not completely. Correspondingly, loss of the mitochondrial membrane potential induced by MG was decreased by the dominant negative JNK. These results confirmed a crucial role of JNK working upstream of caspases, as well as an involvement of JNK in affecting the mitochondrial membrane potential.

Animals↗

PubMed2000

Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection.

A large variety of natural products have been described as anti-HIV agents, and for a portion thereof the target of interaction has been identified. Cyanovirin-N, a 11-kDa protein from Cyanobacterium (blue-green alga) irreversibly inactivates HIV and also aborts cell-to-cell fusion and transmission of HIV, due to its high-affinity interaction with gp120. Various sulfated polysaccharides extracted from seaweeds (i.e., Nothogenia fastigiata, Aghardhiella tenera) inhibit the virus adsorption process. Ingenol derivatives may inhibit virus adsorption at least in part through down-regulation of CD4 molecules on the host cells. Inhibition of virus adsorption by flavanoids such as (-)epicatechin and its 3-O-gallate has been attributed to an irreversible interaction with gp120 (although these compounds are also known as reverse transcriptase inhibitors). For the triterpene glycyrrhizin (extracted from the licorice root Glycyrrhiza radix) the mode of anti-HIV action may at least in part be attributed to interference with virus-cell binding. The mannose-specific plant lectins from Galanthus, Hippeastrum, Narcissus, Epipac tis helleborine, and Listera ovata, and the N-acetylgl ucosamine-specific lectin from Urtica dioica would primarily be targeted at the virus-cell fusion process. Various other natural products seem to qualify as HIV-cell fusion inhibitors: the siamycins [siamycin I (BMY-29304), siamycin II (RP 71955, BMY 29303), and NP-06 (FR901724)] which are tricyclic 21-amino-acid peptides isolated from Streptomyces spp that differ from one another only at position 4 or 17 (valine or isoleucine in each case); the betulinic acid derivative RPR 103611, and the peptides tachyplesin and polyphemusin which are highly abundant in hemocyte debris of the horseshoe crabs Tachypleus tridentatus and Limulus polyphemus, i.e., the 18-amino-acid peptide T22 from which T134 has been derived. Both T22 and T134 have been shown to block T-tropic X4 HIV-1 strains through a specific antagonism with the HIV corecept or CXCR4. A number of natural products have been reported to interact with the reverse transcriptase, i.e., baicalin, avarol, avarone, psychotrine, phloroglucinol derivatives, and, in particular, calanolides (from the tropical rainforest tree, Calophyllum lanigerum) and inophyllums (from the Malaysian tree, Calophyllum inophyllum). The natural marine substance illimaquinone would be targeted at the RNase H function of the reverse transcriptase. Curcumin (diferuloylmethane, from turmeric, the roots/rhizomes of Curcuma spp), dicaffeoylquinic and dicaffeoylt artaric acids, L-chicoric acid, and a number of fungal metabolites (equisetin, phomasetin, oteromycin, and integric acid) have all been proposed as HIV-1 integrase inhibitors. Yet, we have recently shown that L-c hicoric acid owes its anti-HIV activity to a specific interaction with the viral envelope gp120 rather than integrase. A number of compounds would be able to inhibit HIV-1 gene expression at the transcription level: the flavonoid chrysin (through inhibition of casein kinase II, the antibacter ial peptides melittin (from bee venom) and cecropin, and EM2487, a novel substance produced by Streptomyces. (ABSTRACT TRUNCATED)

Amino Acid Sequence↗

PubMed2002

Protective activities of some phenolic 1,3-diketones against lipid peroxidation: possible involvement of the 1,3-diketone moiety.

The protective activities of four ginger-derived phenolic 1,3-diketones (1-4) and curcumin (5) against lipid peroxidation was studied by using different biologically relevant model systems and pulse radiolysis. The extraordinary activity of 5 vis-à-vis 1-4 against Fe(2+)-mediated peroxidation may be attributed to the additional phenolic hydroxy group in the former, which lends it better iron-chelating and radical-scavenging properties. In iron-independent peroxidation, however, the ginger constituent [6]-dehydrogingerdione (1) showed activity comparable to that of 5; this indicates its higher affinity for the lipid peroxide radical (LOO(.)), due to its higher hydrophobicity. A very high rate constant for the reaction between 1 and Cl(3)COO(.), measured by pulse radiolysis, not only confirmed this, but also established the superior antioxidant efficacy of 1 in comparison to vitamins E and C. This was also evident from the results obtained from a liposomal peroxidation study with 1 and vitamin C. This study also established a synergistic effect of the latter on the antioxidant activity of 1. HPLC analysis of the products of the reaction between 1 and Cl(3)COO(.) revealed the formation of higher concentrations of ferulic acid (7), along with vanillin (6). The presence of ascorbate affected the generation of 7 more than it did that of 6. On this basis, a mechanism for the antioxidant action of 1 has been proposed, which suggests the contribution of the phenolic group as well as the active methylene group of the 1,3-diketones.

Animals↗

PubMed2005

Herbal medicines for treating HIV infection and AIDS.

BACKGROUND: HIV-infected people and AIDS patients often seek complementary therapies including herbal medicines due to reasons such as unsatisfactory effects, high cost, non-availability, or adverse effects of conventional medicines. OBJECTIVES: To assess beneficial effects and risks of herbal medicines in patients with HIV infection and AIDS. SEARCH STRATEGY: Electronic searches included the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, LILACS, Science Citation Index, the Chinese Biomedical Database, TCMLARS; plus CISCOM, AMED, and NAPRALERT; combined with manual searches. The search ended in December 2004. SELECTION CRITERIA: Randomized clinical trials on herbal medicines compared with no intervention, placebo, or antiretroviral drugs in patients with HIV infection, HIV-related disease, or AIDS. The outcomes included mortality, HIV disease progression, new AIDS-defining event, CD4 cell counts, viral load, psychological status, quality of life, and adverse effects. DATA COLLECTION AND ANALYSIS: Two authors extracted data independently and assessed the methodological quality of trials according to randomization, allocation concealment, double blinding, and drop-out. MAIN RESULTS: Nine randomized placebo-controlled trials involving 499 individuals with HIV infection and AIDS met the inclusion criteria. Methodological quality of trials was assessed as adequate in five full publications and unclear in other trials. Eight different herbal medicines were tested.A compound of Chinese herbs (IGM-1) showed significantly better effect than placebo in improvement of health-related quality of life in 30 symptomatic HIV-infected patients (WMD 0.66, 95% CI 0.05 to 1.27). IGM-1 appeared not to affect overall health perception, symptom severity, CD4 count, anxiety or depression (Burack 1996a). An herbal formulation of 35 Chinese herbs did not affect CD4 cell counts, viral load, AIDS events, symptoms, psychosocial measure, or quality of life (Weber 1999). There was no statistical difference between SPV30 and placebo in new AIDS-defining events, CD4 cell counts, or viral load (Durant 1998) although an earlier pilot trial showed positive effect of SPV30 on CD4 cell count (Durant 1997). Combined treatment of Chinese herbal compound SH and antiretroviral agents showed increased antiviral benefit compared with antiretrovirals alone (Sangkitporn 2004). SP-303 appeared to reduce stool weight (p = 0.008) and abnormal stool frequency (p = 0.04) in 51 patients with AIDS and diarrhoea (Holodniy 1999). Qiankunning appeared not to affect HIV-1 RNA levels (Shi 2003), Curcumin ineffective in reducing viral load or improving CD4 cell counts (Hellinger 1996), and Capsaicin ineffective in relieving pain associated with HIV-related peripheral neuropathy (Paice 2000). The occurrence of adverse effects was higher in the 35 Chinese herbs preparation (19/24) than in placebo (11/29) (79% versus 38%, p = 0.003) (Weber 1999). Qiankunning was associated with stomach discomfort and diarrhoea (Shi 2003). AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of herbal medicines in HIV-infected individuals and AIDS patients. Potential beneficial effects need to be confirmed in large, rigorous trials.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Synthesis and in vitro antioxidant activity of some new fused pyridine analogs.

A new series of pyrano[3,2-c]pyridines, pyrazolo[4,3-c]pyridines, and pyrido[4,3-d]pyrimidines were synthesized and screened for their in vitro antioxidant activity. Compounds 13, 14, 15, 23, 29, 30, and 31 exhibited the most active oxygen free-radical scavenger activity with percentage inhibitions of 99.4, 99.6, 99.8, 97.3, 99.0, 99.3, and 99.5%; respectively, which is comparable to the curcumin potency. Most of the tested compounds proved to be safe towards peripheral multinuclear neutrophils (PMNs). The detailed synthesis and antioxidant activity data are reported.

Adenosine Triphosphate↗

PubMed2004

MEK/ERK and signal transducer and activator of transcription signaling pathways modulate oncostatin M-stimulated CCL2 expression in human osteoblasts through a common transcription factor.

OBJECTIVE: To analyze the effects of oncostatin M (OSM), a gp130-type cytokine, on CCL2 expression in MG-63 cells, a human osteosarcoma cell line with a characteristic osteoblastic phenotype, and to investigate the signaling pathway involved. METHODS: The expression of messenger RNA (mRNA) for CCL2 and c-Fos was analyzed by Northern blotting. Amounts of CCL2 released into the supernatant were measured by enzyme-linked immunosorbent assay. Western blotting was used to examine the activation of MAPK signaling pathways. Interactions between activator protein 1 (AP-1) and DNA were evaluated by electrophoretic mobility shift assay. RESULTS: OSM stimulated CCL2 expression at both the mRNA and the protein levels. Cyclooxygenase 2 (COX-2) was also induced by OSM. However, the up-regulation of CCL2 mRNA was COX-2-independent but required tyrosine kinase and protein kinase C (PKC). OSM stimulated the phosphorylation of MEK-1/2 and ERK-1/2 but not p38 and JNK. A transient elevation of c-Fos mRNA was induced by OSM, but PD 98059 (MEK inhibitor), fludarabine (signal transducer and activator of transcription 1 [STAT-1] inhibitor), and piceatannol (STAT-3 and STAT-5 inhibitor) abolished this effect. Electrophoretic mobility shift assay revealed that OSM stimulated AP-1-DNA binding, which was also abolished by PD 98059, fludarabine, and piceatannol. Supershift study further confirmed the role of c-Fos in the above interaction. PD 98059, fludarabine, piceatannol, and curcumin (AP-1 inhibitor) inhibited the OSM-induced expression of CCL2. CONCLUSION: OSM induces CCL-2 expression in osteoblasts. Activation of the MEK/ERK and STAT pathways, which leads to c-Fos expression and AP-1-DNA binding, is involved in the process. The signaling requires tyrosine kinase and PKC but not COX-2.

Cells, Cultured↗

PubMed1998

An ethanolic-aqueous extract of Curcuma longa decreases the susceptibility of liver microsomes and mitochondria to lipid peroxidation in atherosclerotic rabbits.

Atherosclerosis is characterized by oxidative damage which affects lipoproteins, the walls of blood vessels and subcellular membranes. This study evaluates the antioxidant capacity of a Curcuma longa extract on the lipid peroxidation of liver mitochondria and microsome membranes in atherosclerotic rabbits. Male rabbits fed a 3% (w/w) lard and 1.3% (w/w) cholesterol diet were randomly assigned to three groups. Two groups were treated with different dosages of a turmeric extract (A and B) and the third group (control) with a curcumin-free solution. Basal and in vitro 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH)-induced hydroperoxide and TBARS productions in liver mitochondria and microsomes were analyzed. Group A had the lowest concentration of mitochondrial hydroperoxides. In microsomes, the basal hydroperoxide levels were similar in all groups but, after the induction of oxidation, group C registered the highest value; TBARS production followed the same trend in mitochondria. These findings suggest that active compounds in curcuma extract may be protective in preventing lipoperoxidation of subcellular membranes in a dosage-dependent manner.

Animals↗

PubMed2004

Studies with the azoxymethane-rat preclinical model for assessing colon tumor development and chemoprevention.

During recent years, multidisciplinary studies in epidemiology and molecular biology have contributed to our understanding of the etiology of colorectal cancer; more importantly they have enabled us to approach its prevention. An impressive body of epidemiological data suggests an inverse relationship between colorectal cancer risk and consumption of diets rich in omega (omega)-3 fatty acids (n-3 PUFAs) or the regular use of nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin. The development of strategies for the chemoprevention of colorectal cancer have been facilitated by the use of relevant animal models mimicking the neoplastic processes that occur in humans, including similarities in histopathology and molecular and genetic lesions during both the early and promotion/progression stages of carcinogenesis. Studies with the azoxymethane-F344 rat model indicate that diets rich in n-3 PUFAs, NSAIDs, selective cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) inhibitors, and curcumin can reduce the incidence of colon cancer. Advances in the knowledge of the mechanisms by which chemopreventive agents act offer opportunities to use combinations of specific chemopreventive agents, having clinically beneficial aggregate activity with minimal toxicity. This approach is extremely important when a promising chemopreventive agent demonstrates apparent efficacy but may produce toxic effects at high doses. Our studies show that a combination of very low doses of piroxicam (NSAID) and difluoromethylornithine, a specific inhibitor of ornithine decarboxylase, or very low doses of COX-2 and HMG-CoA reductase inhibitors are more effective in inhibiting colon carcinogenesis than administration of these compounds as single agents even at higher levels. The natural history of colorectal cancer, from dysplastic aberrant crypts to adenomas and adenocarcinomas, offers multiple opportunities for assessment and intervention. Of further importance is to identify whether the molecular targets that are critical in the growth and survival of the malignant colorectal cell are modulated by n-3 PUFAs, NSAIDs, or COX-2 and iNOS inhibitors.

Animals↗

PubMed2003

In vitro influence of spices and spice-active principles on digestive enzymes of rat pancreas and small intestine.

In vitro influence of 14 individual spices (curcumin, capsaicin, piperine, garlic, onion, ginger, mint, coriander, cumin, ajowan, fennel, fenugreek, mustard, and asafoetida) on the activities of digestive enzymes of rat pancreas and small intestine was examined by including them in the reaction mixture at two different concentrations. A majority of spices enhanced the activity of pancreatic lipase and amylase when they are directly in contact with the enzyme. It is inferred that this positive influence on the activity of enzymes may have a supplementary role in the overall digestive stimulant action of spices, besides causing an enhancement of the titres of digestive enzymes in pancreatic tissue.

Amylases↗

PubMed1996

New agents for cancer chemoprevention.

Clinical chemoprevention trials of more than 30 agents and agent combinations are now in progress or being planned. The most advanced agents are well known and are in large Phase III chemoprevention intervention trials or epidemiological studies. These drugs include several retinoids [e.g., retinol, retinyl palmitate, all-trans-retinoic acid, and 13-cis-retinoic acid], calcium, Beta carotene, vitamin E, tamoxifen, and finasteride. Other newer agents are currently being evaluated in or being considered for Phase II and early Phase III chemoprevention trials. Prominent in this group are all-trans-N-(4-hydroxy phenyl)retinamide (4-HPR) (alone and in combination with tamoxifen), 2-difluoromethylornithine (DFMO), nonsteroidal antiinflammatory drugs (aspirin, piroxicam, sulindac), oltipraz, and dehydroepiandrostenedione (DHEA). A third group is new agents showing chemopreventive activity in animal models, epidemiological studies, or in pilot clinical intervention studies. They are now in preclinical toxicology testing or Phase I safety and pharmacokinetics trials preparatory to chemoprevention efficacy trials. These agents include S-allyl-l-cysteine, curcumin, DHEA analog 8354 (fluasterone), genistein, ibuprofen, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, sulindac sulfone, tea extracts, ursodiol, vitamin D analogs, and p-xylyl selenocyanate. A new generation of agents and agent combinations will soon enter clinical chemoprevention studies based primarily on promising chemopreventive activity in animal models and in mechanistic studies. Among these agents are more efficacious analogs of known chemopreventive drugs including novel carotenoids (e.g., alpha-carotene and lutein). Also included are safer analogs which retain the chemopreventive efficacy of the parent drug such as vitamin D3 analogs. Other agents of high interest are aromatase inhibitors (e.g., (+)-vorozole), and protease inhibitors (e.g., Bowman-Birk soybean trypsin inhibitor). Combinations are also being considered, such as vitamin E with l-selenomethionine. Analysis of signal transduction pathways is beginning to yield classes of potentially active and selective chemopreventive drugs. Examples are ras isoprenylation and epidermal growth factor receptor inhibitors.

Animals↗

PubMed1996

Strategy and planning for chemopreventive drug development: clinical development plans II.

This is the second publication of Clinical Development Plans from the National Cancer Institute, Division of Cancer Prevention and Control, Chemoprevention Branch and Agent Development Committee. The Clinical Development Plans summarize the status of promising chemopreventive agents regarding evidence for safety and chemopreventive efficacy in preclinical and clinical studies. They also contain the strategy for further development of these drugs, addressing pharmacodynamics, drug effect measurements, intermediate biomarkers for monitoring efficacy, toxicity, supply and formulation, regulatory approval, and proposed clinical trials. Sixteen new Clinical Development Plans are presented here: curcumin, dehydroepiandrosterone, folic acid, genistein, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, 13-cis-retinoic acid, l-selenomethionine and 1, 4-phenylenebis(methylene)selenocyanate, sulindac sulfone, tea, ursodiol, vitamin A, and (+)-vorozole. The objective of publishing these plans is to stimulate interest and thinking among the scientific community on the prospects for developing these and future generations of chemopreventive drugs.

Animals↗

PubMed2007

MAP kinase-dependent, NF-kappaB-independent regulation of inhibitor of apoptosis protein genes by TNF-alpha.

The inhibitor of apoptosis protein (IAP) family of molecules regulates apoptotic processes triggered by various stimuli. However, the mechanisms involved in the regulation of the IAP genes are not fully understood. In this report, we examined roles of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein (MAP) kinases in tumor necrosis factor-alpha (TNF-alpha)-induced expression of IAP genes. In human endothelial cells, TNF-alpha induced c-IAP1 and c-IAP2, but not XIAP and TIAP/Survivin, at the transcriptional level. Inactivation of NF-kappaB by overexpression of a super-repressor mutant of IkappaBalpha did not affect the induction of IAPs by TNF-alpha. In contrast, extracellular signal-regulated kinase, p38 MAP kinase, and c-Jun N-terminal kinase were activated after stimulation with TNF-alpha, and inhibition of each kinase by PD098059, SB203580, curcumin, or SP600125 substantially attenuated the TNF-alpha-induced c-IAP1 and c-IAP2 expression. To examine whether the MAP kinases-mediated induction of IAPs contributes to survival of TNF-alpha-exposed cells, cells were pretreated with MAP kinase inhibitors and stimulated with TNF-alpha. Treatment with kinase inhibitors alone did not induce apoptosis but enhanced markedly TNF-alpha-triggered apoptosis. Furthermore, overexpression of either c-IAP1 or c-IAP2 diminished the apoptosis-promoting effects of MAP kinase inhibitors. These data indicated that TNF-alpha induced expression of c-IAP1 and c-IAP2 via MAP kinases, but not via NF-kappaB, and that MAP kinases participated in the inhibition of apoptosis by induction of c-IAPs in TNF-alpha-stimulated endothelial cells.

Apoptosis↗

PubMed2005

Biological and chemical inhibitors of NF-kappaB sensitize SiHa cells to cisplatin-induced apoptosis.

Cisplatin, a chemotherapeutic agent, is known to induce apoptosis of cancer cells. We examined the role of NF-kappaB during cisplatin-induced apoptosis in two human cervical cancer cell lines, HeLa and SiHa, known to differ in their response to cisplatin treatment. We found that SiHa cells were relatively more resistant than HeLa cells to the cytotoxic effects induced by cisplatin as measured by MTT assays. HeLa cells were more sensitive to the apoptotic effects induced by cisplatin as shown by increases in annexin staining, DNA fragmentation, and loss of mitochondrial membrane potential. Similarly the activities of caspases 3, 8, and 9 and cleavage of PARP induced by cisplatin were more in HeLa than SiHa cells. Cisplatin induced NF-kappaB DNA binding activity in HeLa and SiHa cells but not in primary cervical cells and the active DNA binding complex in SiHa cells consists of p50 and RelA heterodimers. However, when NF-kappaB DNA binding activity was blocked by chemical (curcumin, PDTC, or salicylic acid) or biological inhibitors (NIK-KM or IKK-beta DN), the cell viability was less in SiHa cells with cisplatin treatment, but these effects were not observed in HeLa cells. Similarly upon treatment with cisplatin SiHa cells had more activation of caspases compared to that seen in HeLa cells under conditions of NF-kappaB inhibition by biological or chemical inhibitors. These results suggest that NF-kappaB may contribute to the resistance of human cervical cancer cells to cisplatin and highlight the potential use of combination therapy involving cisplatin and NF-kappaB inhibitors.

Apoptosis↗

PubMed2005

Simulation of intrafollicular conditions prevents GVBD in bovine oocytes: a better alternative to affect their developmental capacity after two-step culture.

To increase the developmental competence of bovine oocytes isolated from small, medium, and large follicles (2-3, 3-4, and 4-6 mm in diameter, respectively), we tried to modify the conditions for their in vitro culture. The first step involved conditions maintaining at least for 48 hr a reversible inhibition of the germinal vesicle breakdown (GVBD) and the second step stimulated the resumption of meiosis and completion of nuclear and cytoplasmic maturation during the subsequent 20-22 hr of culture. The effectiveness of this model depended mainly on the medium composition (reduced NaHCO3, substitution of serum with serum albumin, addition of antioxidants (curcumin), increased viscosity by agar, the reduction of oxygen concentration (within 6%-8%), the reduction of the proportion between the number of cumulus-oocyte complexes (COCs), and the reduction of the amount of a medium (within 6-7 mul per COC) to amplify the GVBD-inhibitory effect of oocyte surrounding granulosa cells. The COCs were incubated in clumps of 6-7 COCs. The effectiveness and reversibility of GVBD inhibition depended also on the duration of COCs isolation. The full reversibility of the GV block was controlled morphologically and also by measuring histone H1 and MAP kinase activities. The two-step versus one-step (24 hr) maturation technique was evaluated by the percentage of total and hatched blastocysts at day 9. When compared with one-step maturation, the two-step culture showed a slightly increased proportion of total and hatched blastocysts developed from growing follicles, mainly from the smallest category (13.9% vs. 7.1% and 9.2% vs. 3.3% for total blastocysts and hatched, respectively). However, the two-step culture of oocytes from large regressing follicles substantially reduced the blastocyst yield (9.7% vs. 39.1% and 4.9% vs. 26.7% for total blastocysts and hatched, respectively). The transfer of ten blastocysts (developed after two-step culture) to ten recipients resulted in seven pregnancies.

Animals↗

PubMed2004

Abnormal PcG protein expression in Hodgkin's lymphoma. Relation with E2F6 and NFkappaB transcription factors.

The Polycomb group (PcG) of proteins comprises a family of repressors of homeobox genes that play key roles in body formation, haematopoiesis and cell cycle control. In this study, a large-scale analysis of PcG protein expression (BMI1, MEL18, PH1, RNF2, RING1, and RYBP) was performed in 321 Hodgkin's lymphoma (HL) biopsies and in reactive lymphoid tissues using tissue microarrays. The relevance of PcG proteins in HL was also investigated by the simultaneous analysis of PcG and other proteins involved in the control of cell cycle, transcription machinery and lymphoid differentiation. The analysis revealed increased expression of a set of PcG proteins (particularly RYBP and BMI1) in tumour cells in comparison with reactive lymphoid tissue. One of the most striking findings was anomalous RYBP expression in 55% of classical HL cases associated with an unfavourable response to treatment and shorter survival. The data obtained in this study also show an association of PcG proteins with E2F6 and NFkappaB transcription factors. The statistical relationship between PcG and NFkappaB activation was further explored in HL-derived cell lines treated with curcumin, an NFkappaB inhibitor, and TNFalpha. Up- or downregulation of MEL18 was paralleled by loss or gain of activated NFkappaB, which suggests that NFkappaB may regulate expression of this protein. Investigation of the relationship between E2F6 and RING1 by immunofluorescence and confocal analysis, in HL cell lines and paraffin sections, revealed co-expression of both proteins in the same tumour cells. These results allow us to propose that the formation of transcription complexes with E2F6 may modify the functional status of PcG proteins in HSR cells.

Apoptosis↗

PubMed2004

The effects of Pycnogenol on DNA damage in vitro and expression of superoxide dismutase and HP1 in Escherichia coli SOD and catalase deficient mutant cells.

The procyanidin-rich French maritime pine bark extract Pycnogenol (PYC) is believed to be an antioxidant. To access whether PYC protects DNA against Fenton reaction radicals, pUC 19 plasmid DNA was damaged by OH- radicals generated from Fe(II) plus H2O2 in the presence and absence of PYC. DNA damage was quantified by measuring decreases in supercoiled DNA (SC-DNA) using agarose gel electrophoresis. The results showed that PYC (50 microg/mL) did not inhibit DNA damage from Fenton reaction-generated oxyradicals, when the Fenton reaction was allowed to proceed. However, PYC did protect against DNA damage when added prior to the initiation of the Fenton reaction, suggesting that protection resulted from chelation of Fe rather than from the scavenging of radicals. Moreover, we unexpectedly observed PYC-associated DNA breakage, which was dose- and time- dependent. Other antioxidants such as desferrioxamine (DFO) including butylated hydroxyltoluene (BHT), curcumin and alpha-tocopherol exhibited protective effects against DNA damage caused by the Fenton reaction. Subsequently, we assessed the possible pro-oxidant function of PYC on DNA damage in E. coli SOD deficient mutants under oxidative stress, after observing that PYC can induce SOD under oxidative stress. Although, PYC did not enhance DNA damage, it likewise did not protect against oxidative stress-mediated DNA damage. All together, our data indicate that PYC under some circumstances can enhance oxidative stress-mediated DNA damage in vitro and in vivo.

Antioxidants↗

PubMed1994

Highlight on the studies of anticancer drugs derived from plants in China.

Recent progress on the study of anticancer drugs originating from plants in China is reviewed in this paper. Guided by the experience of traditional Chinese medicine, several new drugs have been found. Indirubin from Indigofera tinctoria is useful for the treatment of chronic myelocytic leukemia. Irisquinone from Iris latea pallasii and 10-hydroxy camptothecin from Camptotheca accuminata have exhibited definite activity on rodent tumors. Recent studies indicate that ginsenoside Rh2 is an inducer of cell differentiation in melanoma B-16 cells in vitro. Pharmacological studies have demonstrated that curcumin from Curcuma longa is an antimutagen as well as an antipromotor for cancer. Daidzein and acetyl boswellic acid have been shown to be effective inducers of cell differentiation in HL-60 cells. Guided by the chemotaxonomic principle of plants, harringtonine and homoharringtonine isolated from Cephalotaxus hainanesis have exhibited significant antileukemia activity and are widely used in clinics in China. Taxol from Taxus chinensis has been shown to be an important new anticancer drug with unique chemical structure and mechanism of action. The continuous search for new anticancer drugs from plants will be a fruitful frontier in cancer treatment and chemoprevention.

Antineoplastic Agents, Phytogenic↗