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PubMed1992

The cytotoxicity, DNA crosslinking ability and DNA sequence selectivity of the aniline mustards melphalan, chlorambucil and 4-[bis(2-chloroethyl)amino] benzoic acid.

Three aniline derivatives melphalan (L-PAM), chlorambucil (CHL) and 4-[bis(2-chloroethyl)amino] benzoic acid (BAM) have been compared on the basis of their in vitro cytotoxicities, DNA interstrand crosslinking ability and DNA sequence selectivity. Cytotoxicity was assessed in the human colonic adenocarcinoma LS174T and leukaemic K562 cell lines using the sulpho-rhodamine B and tetrazolium dye reduction assays. The order of cytotoxicities was L-PAM greater than CHL greater than BAM in both cell lines with K562 being less sensitive than LS174T. This was different from the order CHL greater than L-PAM greater than BAM which would be predicted from simple chemical reactivity or rate of hydrolysis, parameters which have been used previously as indicators of biological potency for aromatic nitrogen mustards. DNA interstrand crosslinking in cells as determined by alkaline elution showed a correlation with IC50 values. The ranking order of activity was further predicted by the ability of the agents to produce interstrand crosslinks in isolated DNA. The extent of guanine N-7 alkylation, assessed using a modified DNA sequencing technique, mirrored cytotoxicity and crosslinking ability, but at equivalent levels of alkylation there was no significant difference in DNA sequence selectivity. These data demonstrates that simple chemical reactivity or hydrolysis rate is not a good indicator of DNA reactivity or cytotoxicity for a number of aniline mustards, whereas DNA interstrand crosslinking ability either measured directly in cells or in isolated DNA, gives a good indication of biological activity.

4-Aminobenzoic Acid↗

PubMed2001

Novel esters of glaucarubolone as inducers of terminal differentiation of promyelocytic HL-60 cells and inhibitors of 7,12-dimethylbenz[a]anthracene-induced preneoplastic lesion formation in mouse mammary organ culture.

In an effort to discover new chemotherapeutic/chemopreventive agents from natural sources, brusatol (1) was found to induce HL-60 cellular differentiation, accompanied by strong antiproliferative and cytotoxic effects. A series of natural and semisynthetic quassinoids (1-48) was designed to effect both antiproliferative and differentiation-inducing properties. Compounds were assessed in vitro using the HL-60 promyelocytic cell model. Changes in activity due to structural modification of the core structure glaucarubolone (24) were consistent with activities reported in other cell systems. However, the following were novel SAR findings: (1) semisynthetic analogues with a hydroxylated ring at the beta-position of the ester side chain at C-15 were able to induce cellular differentiation at concentrations lower than those inducing cell growth arrest, and (2) quassinoids inhibiting DNA synthesis with greater efficacy than reducing cellular viability possessed alkyl substitutions at the alpha-position of the C-15 ester side chain. Analogues from this latter group and brusatol (1) and bruceantin (2) inhibited dimethylbenz(a)anthracene-induced preneoplastic lesion formation in a mouse mammary organ culture. The novel finding of 1 and glaucarubolone analogues as potent inducers of differentiation leads to potential novel applications in the field of cancer.

9,10-Dimethyl-1,2-benzanthracene↗

PubMedDate not supplied

Cytotoxicity evaluation of natural coptisine and synthesis of coptisine from berberine.

The crude extract (80% MeOH in water) of Chelidonii herba exhibited very interesting cytotoxicity against brine shrimp (Artemia salina Leach) nauplii and cultured human tumour cell in vitro, the colon carcinoma HT 29 (144 h treatment). Fractionation of the crude extract and bioassay-guided procedures showed that the cytotoxic and the antitumour activities were concentrated in the basic extract. On the basis of IR, MS and 1H NMR the compound responsible of the cytotoxic activity was determined to be coptisine. Cytotoxicity evaluation of coptisine was next extended to a panel of human and murine cell lines in comparison with the established antitumour drugs mitoxantrone, doxorubicin (Dx) and cisplatin (CDDP). Coptisine was cytotoxic on LoVo and HT 29 and less potent on L-1210, and it was partially crossresistant on the human tumour colon cell line resistant to Dx, LoVo/Dx, whereas it was not significantly crossresistant on the murine leukaemia cell line resistant to CDDP, L-1210/CDDP. Coptisine alkaloid was then synthesised in gram amount from commercial berberine. A four-step synthetic route was elaborated. The overall yield was about 8-10%. The structural identity of synthetic coptisine was verified by IR and NMR methods. A comparison of the cytotoxic effects on the human tumour colon cell line LoVo and on the murine leukaemia L1210 showed, for both natural and synthetic coptisines, a comparable cytotoxic activity more evident against HT 29 cell line and LoVo cell line, while the activity was lower against the L1210 cell line.

Animals↗

PubMed2002

SN-38 induces cell cycle arrest and apoptosis in human testicular cancer.

OBJECTIVE: CPT-11 is one of the most widely used camptothecin analogues and is converted to form the active metabolite SN-38. Clinical trials are ongoing to better characterize its spectra of clinical activity, to determine the optimal schedules of administration, and to define the usage in combination with other chemotherapeutic compounds. MATERIALS AND METHODS: KU-MT, an AFP-producing testicular carcinoma cell line, was exposed to SN-38, etoposide, or cisplatin for 24 h, and the resulting cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) assay. This paper describes the effects of SN-38 on the cell proliferation and cell cycle of testicular tumor cells in culture. RESULTS: SN-38 was shown to inhibit KU-MT cell growth more potently than either etoposide or cisplatin. A marked decrease in the percentage of S phase cells was accompanied by the enhancement of cyclin E levels. In concentrations of >30 nmol/l, SN-38 arrested the cell cycle in G2 and induced cell death via apoptosis. The apoptosis was promoted by Bax and p53 protein, which were both shown to be present by flow cytometric and Western blot analyses. CONCLUSION: These results suggest that CPT-11, a pro-drug of SN-38, may be clinically useful for the treatment of testicular cancer, and that the mechanism of this agent's cytotoxicity consists of cell cycle arrest and concomitant apoptosis.

Antineoplastic Agents, Phytogenic↗

PubMed1991

Sequence-dependent cytotoxic effects of the combination of a new nitrosourea, fotemustine, with 5-fluorouracil plus folinic acid.

The present study was designed to analyse the cytotoxic effects of the combination of fotemustine with 5-fluorouracil (5-FU) plus folinic acid (FA). Two human tumor cell lines were used; one line was derived from colon cancer (WIDR) and the other, from a non-small-cell lung cancer (CAL 12). Cytotoxic effects were assessed using the MTT (tetrazolium bromide) semi-automated test in 96-well incubation plates. The effects of various drug combinations were evaluated by the isobologram method. The drug combinations tested included fotemustine concentrations of 20, 30, 40, 50 and 70 micrograms/ml, 5-FU concentrations of 5, 15 and 30 micrograms/ml, and a constant FA concentration of 10(-5) M. A total of 180 different experimental conditions were tested. When cells were exposed to fotemustine prior to treatment with 5-FU, the final cytotoxic effects on both cell lines were additive or synergistic in the majority of cases (P less than 0.001). The 5-FU concentration was a determinant factor that modified the effects of the drug combination from antagonism (at low 5-FU concentrations) to synergism (high 5-FU concentrations; P less than 0.001). The addition of FA (10(-5) M) resulted in a significant shift towards synergistic associations in both cell lines. Administration of 5-FU prior to treatment with fotemustine caused marked antagonism, which 10(-5) M FA could not significantly shift towards simple additivity.

Antineoplastic Agents↗

PubMed2006

c-Myc inhibition negatively impacts lymphoma growth.

BACKGROUND: Proto-oncogene c-Myc dysregulation is commonly found in aggressive tumors. Dysregulation is central to lymphomagenesis in Burkitt lymphoma and other non-Hodgkin's lymphomas. This suggests targeting c-Myc as a treatment for myc-associated malignancies. METHODS: Microarrays showed c-Myc dysregulation in a B-lymphoblastoid line, TIB-215. This was confirmed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and extended to 3 additional Burkitt lymphoma lines. Growth effects of a c-Myc inhibitor, compound 10058-F4, were determined in these 4 lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analyses and direct cell counts. Drug effects on c-Myc gene expression levels were measured using minor groove binding-TaqMan real-time reverse transcriptase-polymerase chain reaction. Drug specificity was analyzed in rat c-Myc knockout (-/-) and Myc-transfected cells. RESULTS: c-Myc dysregulation was shown to be cell-cycle independent without rapid decay of c-Myc mRNA levels in all 4 lines. Using a c-Myc inhibitor, we found that growth inhibition was time- and dose-dependent. This inhibition caused unexpected downregulation (> or =65%) of c-Myc mRNAs. CONCLUSIONS: The inhibition of c-Myc decreased growth in aggressive lymphoma cells. This mechanism included c-Myc mRNA downregulation and dissociation of c-Myc/Max protein heterodimer. These results support targeting c-Myc in tumors with high morbidity and mortality.

Animals↗

PubMed2003

Formation of natural biofilms during chlorine dioxide and u.v. disinfection in a public drinking water distribution system.

AIMS: The influence of two disinfection techniques on natural biofilm development during drinking water treatment and subsequent distribution is compared with regard to the supply of a high-quality drinking water. METHODS AND RESULTS: The growth of biofilms was studied using the biofilm device technique in a real public technical drinking water asset. Different pipe materials which are commonly used in drinking water facilities (hardened polyethylene, polyvinyl chloride, steel and copper) were used as substrates for biofilm formation. Apart from young biofilms, several months old biofilms were compared in terms of material dependence, biomass and physiological state. Vital staining of biofilms with 5-cyano-2,3-ditolyl tetrazolium chloride (CTC) and the DNA-specific 4',6-diamidino-2-phenylindole (DAPI) staining resulted in a significant difference in physiological behaviour of biofilm populations depending on the disinfection technique. Compared with chlorine dioxide disinfection (0.12-0.16 mg l-1), the respiratory activities of the micro-organisms were increased on all materials during u.v. disinfection (u.v.254; 400 J m-2). The biofilm biocoenosis was analysed by in situ hybridization with labelled oligonucleotides specific for some subclasses of Proteobacteria. Using PCR and additional hybridization techniques, the biofilms were also tested for the presence of Legionella spp., atypical mycobacteria and enterococci. The results of the molecular-biological experiments in combination with cultivation tests showed that enterococci were able to pass the u.v. disinfection barrier and persist in biofilms of the distribution system, but not after chlorine dioxide disinfection. CONCLUSIONS: The results indicated that bacteria are able to regenerate and proliferate more effectively after u.v. irradiation at the waterworks, and chlorine dioxide disinfection appears to be more applicative to maintain a biological stable drinking water. SIGNIFICANCE AND IMPACT OF THE STUDY: As far as the application of u.v. disinfection is used for conditioning of critical water sources for drinking water, the efficiency of u.v. irradiation in natural systems should reach a high standard to avoid adverse impacts on human health.

Biofilms↗

PubMed1999

Combination of a calcium antagonist, a lipid-peroxidation inhibitor, and an angiotensin AT1-receptor antagonist provides additive myocardial infarct size-limiting effect in pigs.

The calcium antagonist felodipine, the lipid-peroxidation inhibitor H290/51, and the angiotensin II type 1 (AT1)-receptor antagonist candesartan all exert beneficial effects on myocardial ischemia/reperfusion injury. This study was undertaken to test the hypothesis that a combination of these drugs with different pharmacologic properties could exert additive cardioprotective effects. Anesthetized pigs were subjected to 45 min of left anterior descending coronary artery occlusion followed by 240 min of reperfusion. Five groups of pigs were randomly given either 0.65 microM (7 nmol/kg) felodipine, 1.0 microM (3.1 microg/kg) H 290/51, 4.2 microM (20 microg/kg) candesartan, a cocktail of these three drugs, or vehicle (n = 6 for each) for 30 min starting at 5 min before reperfusion by coronary venous retroinfusion, which delivers drugs specifically to the ischemic regions. Systolic segment shortening (%SS) was measured by sonomicrometer. The myocardial area at risk and the final infarct size were determined by Evans blue and 2,3,5-triphenyl tetrazolium chloride staining. The hemodynamics did not change significantly during the study. In the vehicle group, the recovery of coronary flow was not maintained during reperfusion, and it was significantly lower after 240 min of reperfusion than during the preischemic period (p < 0.05). The coronary flow in the drug-treated groups was approximately the same by the end of the reperfusion period as that before the induction of ischemia. In the ischemic myocardium, %SS slightly recovered during reperfusion in the four drug-treated groups, but not in the vehicle group. The infarct size, expressed as a percentage of the myocardial area at risk, was smaller in all four drug-treated groups compared with the vehicle group. The infarct size in the cocktail group was significantly smaller than that in the groups given felodipine, H290/51, or candesartan alone. These results demonstrate that a combination of a calcium antagonist, a lipid-peroxidation inhibitor, and an angiotensin AT1-receptor antagonist has an additive effect on infarct limitation, indicating that combined therapy with agents having different pharmacologic modes of action may provide better cardioprotection than any of the drugs alone. The findings also support the view that reperfusion injury is possibly mediated by a combination of mechanisms.

Anesthesia↗

PubMedDate not supplied

Role of quinone methide in the in vitro toxicity of the skin tumor promoter butylated hydroxytoluene hydroperoxide.

An electrophilic quinone methide (2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone, BHT-QM) functions in the toxicity of butylated hydroxytoluene (BHT) in both rodent liver and lung. BHT-QM has also been demonstrated to mediate tumor promotion in mouse skin by another metabolite of BHT, 2,6-di-tert-butyl-4-hydroperoxy-4-methyl-2,5-cyclohexadienone (BHTOOH). In the present study, the role of BHT-QM in the cytotoxicity of BHTOOH was investigated. The toxicity of BHTOOH was potentiated by glutathione depletion and inhibited by thiol compounds, indicating that BHTOOH is activated to a thiol-reactive, toxic intermediate. This activation process was suggested to be iron-dependent by the ability of an Fe(III)-specific chelator to inhibit BHTOOH toxicity. Comparative study of analogs of BHTOOH in which the 4-methyl group was substituted with CD3, ethyl, isopropyl or tert-butyl supported the hypothesis that BHT-QM mediates this toxicological response. The decreased rate of reactivity of quinone methides that occurs as the 4-alkyl group is enlarged was accompanied by a corresponding reduction in toxic potency. The structural requirements for quinone methide toxicity were also explored with a series of BHTOOH analogs substituted at the 2- and 6-positions of the molecule. Reducing the lipophilicity of the 2,6-tert-butyl groups is known to increase quinone methide reactivity with glutathione but does not diminish the rate of quinone methide formation from the hydroperoxide. Interestingly, alteration of only one of the tert-butyl groups did not change the toxic potency, whereas removal or replacement of both tert-butyl groups dramatically reduced the toxicity in control cells but not glutathione-depleted cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2006

Tobacco nectaries express a novel NADPH oxidase implicated in the defense of floral reproductive tissues against microorganisms.

Hydrogen peroxide produced from the nectar redox cycle was shown to be a major factor contributing to inhibition of most microbial growth in floral nectar; however, this obstacle can be overcome by the floral pathogen Erwinia amylovora. To identify the source of superoxide that leads to hydrogen peroxide accumulation in nectary tissues, nectaries were stained with nitroblue tetrazolium. Superoxide production was localized near nectary pores and inhibited by diphenylene iodonium but not by cyanide or azide, suggesting that NAD(P)H oxidase is the source of superoxide. Native PAGE assays demonstrated that NADPH (not NADH) was capable of driving the production of superoxide, diphenyleneiodonium chloride was an efficient inhibitor of this activity, but cyanide and azide did not inhibit. These results confirm that the production of superoxide was due to an NADPH oxidase. The nectary enzyme complex was distinct by migration on gels from the leaf enzyme complex. Temporal expression patterns demonstrated that the superoxide production (NADPH oxidase activity) was coordinated with nectar secretion, the expression of Nectarin I (a superoxide dismutase in nectar), and the expression of NOX1, a putative gene for a nectary NADPH oxidase that was cloned from nectaries and identified as an rbohD-like NADPH oxidase. Further, in situ hybridization studies indicated that the NADPH oxidase was expressed in the early stages of flower development although superoxide was generated at later stages (after Stage 10), implicating posttranslational regulation of the NADPH oxidase in the nectary.

Azides↗

PubMed1996

Synergistic antitumor activity of vitamins C and K3 on human urologic tumor cell lines.

A micro-tetrazolium assay was employed to evaluate vitamin C (VC), vitamin K3 (VK3) and vitamin C/vitamin K3 combinations (VC/VK3) for their antitumor activity against eight human urologic tumor cell lines. While the individual vitamins exhibited antitumor activity at high concentrations, co-administration of the vitamins in a VC : VK3 ratio of 100 : 1 potentiated antitumor activity 4- to 61-fold even when exposure times were as short as 1 hour. Administration of exogenous catalase destroyed the antitumor activity of the vitamins and suggested that hydrogen peroxide and perhaps other reactive oxygen species were involved in the antitumor mechanism of these vitamins. Electron micrographs taken in a previous study demonstrated that vitamin treatment damaged mitochondria and may have impaired ATP synthesis. Analysis of cellular ATP and thiol levels as well as DNA and protein synthesis during the first five hours following a one hour VC/VK3 treatment, revealed: a transient increase in ATP production, a substantial decrease in DNA synthesis, an increase in protein synthesis and a decrease in thiol levels. These results suggested that redox cycling of the vitamin combination increased oxidative stress until it surpassed the reducing ability of the cellular thiols and cellular or genetic damage ensued.

Adenosine Triphosphate↗

PubMed2002

Sperm MTT viability assay: a new method for evaluation of human sperm viability.

PURPOSE: MTT (3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay is commonly used as a cell proliferation assay. The objective of this study was to evaluate the capability of MTT assay to discriminate between viable and nonviable sperms and compare it sefficiency with E&N (eosin and nigrosin) and HOST (hypo-osmotic swelling test). METHODS: MTT assay was modified to obtain optimal result for assessment of sperm viability. After standardization of method, MTT, E&N, and HOST were carried out simultaneously on 57 semen samples from patients referring to Isfahan Fertility and Infertility Center. The correlation coefficient between these tests and sperm motility was calculated using the SPSS statistical program. Specificity and sensitivity of each test was also obtained. RESULTS: The optimal conditions for sperm MTT viability assay were 2 h after addition of sperm to MTT in HAM'S F10 + 25 mM HEPES + 10% HSA at 37 degrees C and pH 7.4-7.45. Inter- and intra-assay coefficients of variations were 9 and 7%, respectively. The sensitivity and specificity for sperm MTT viability assay, E&N, and HOST were 97,98, and 99%, and 100, 100, and 83% respectively. High significant correlations were obtained between sperm MTT viability assay, E&N, HOST and motility. CONCLUSIONS: Sperm MTT viability assay can be used as a diagnostic test for discrimination of viable sperms from sperm population.

Aniline Compounds↗

PubMed2005

Toxic potential of five freshwater Phormidium species (Cyanoprokaryota).

Among the Cyanoprokaryota (blue-green algae), the genus Phormidium has thus far rarely been studied with respect to toxin production and potentially resulting human and environmental health effects. We here show that five previously unexplored freshwater species of this genus (Ph. bijugatum, Ph. molle, Ph. papyraceum, Ph. uncinatum, Ph. autumnale) are indeed capable of producing bioactive compounds. Phormidium extracts caused weight loss as well as neuro/hepatotoxic symptoms in mice, and in the case of Ph. bijugatum even death. Very low levels of saxitoxins and microcystins, as confirmed by ELISA, were insufficient to explain this toxicity and the differing toxic potencies of the Phormidium species. Qualitative HPLC analyses confirmed different substance patterns and in the future could aid in the separation of fractions for more detailed substance characterisation. The results in vivo were confirmed in vitro using cells of human, mouse and fish. The fish cells responded least sensitive but proved useful in studying the temperature dependence of the toxicity by the Phormidium samples. Further, the human cells were more sensitive than the mouse cells thus suggesting that the former may be a more appropriate choice for studying the impact of Phormidium to man. Among the human cells, two cancer cell lines were more responsive to one of the samples than a normal cell line, thereby indicating a potential anti-tumour activity. Thus, the five freshwater Phormidium species should be considered in environmental risk assessment but as well, as a source of therapeutic agents.

Animals↗

PubMed2001

Characterization of the flavoprotein domain of gp91phox which has NADPH diaphorase activity.

A series of truncated forms of gp91phox were expressed in Escherichia coli in which the N-terminal hydrophobic transmembrane region was replaced with a portion of the highly soluble bacterial protein thioredoxin. TRX-gp91phox (306-569), which contains the putative FAD and NADPH binding sites, showed weak NADPH-dependent NBT (nitroblue tetrazolium) reductase activity, whereas TRX-gp91phox (304-423) and TRX-gp91phox (424-569) were inactive. Activity saturated at about a 1:1 molar ratio of FAD to TRX-gp91phox (306-569), and showed the same K(m) for NADPH as that for superoxide generating activity by the intact enzyme. Activity was not inhibited by superoxide dismutase, indicating that it was not mediated by superoxide, but was blocked by an inhibitor of the respiratory burst oxidase, diphenylene iodonium. In the presence of Rac1, the cytosolic regulatory protein p67phox stimulated the NBT reductase activity, but p47phox had no effect. Truncated p67phox containing the activation domain (residues 199-210) [C.-H. Han, J.R. Freeman, T. Lee, S.A. Motalebi, and J.D. Lambeth (1998) J. Biol. Chem. 273, 16663-16668] stimulated activity approximately 2-fold, whereas forms mutated or lacking this region failed to stimulate the activity. Our data indicate that: (i) TRX-gp91phox (306-569) contains binding sites for both pyridine and flavin nucleotides; (ii) this flavoprotein domain shows weak diaphorase activity; and (iii) the flavin-binding domain of gp91phox is the target of regulation by the activation domain of p67phox.

Binding Sites↗

PubMed2003

Upregulation of angiotensin II type 2 receptor and limitation of myocardial stunning by angiotensin II type 1 receptor blockers during reperfused myocardial infarction in the rat.

BACKGROUND: We have previously shown that angiotensin II type 1 receptor blockers induce cardioprotection and upregulate angiotensin II type 2 receptor during in vivo postischemic-reperfusion in dogs. Whether angiotensin II type 1 receptor blockers upregulate angiotensin II type 2 receptors in rats is controversial, and whether surmountable and insurmountable angiotensin II type 1 receptor blockers exert similar protective effects during reperfused myocardial infarction is not known. METHODS: We assessed the effects of the surmountable angiotensin receptor blocker valsartan, and the insurmountable angiotensin receptor blocker irbesartan, on hemodynamics and left ventricular systolic and diastolic function (echocardiography/Doppler) in vivo and infarct size (triphenyl tetrazolium chloride method), and regional angiotensin II type 1 receptor and angiotensin II type 2 receptor expression (immunoblots) ex vivo, after anterior reperfused myocardial infarction in rats. The rats were randomized to four groups: intravenous valsartan (10 mg/kg, n = 8), irbesartan (10 mg/kg, n = 8), or saline vehicle (controls, n = 14) over 30 minutes before reperfused myocardial infarction, and sham (n = 8). Angiotensin II type 1 receptor blockade was assessed by the inhibition of angiotensin II pressor responses. RESULTS: Compared with the control group, both angiotensin receptor blockers significantly decreased infarct size, limited the increase in left atrial pressure, improved positive left ventricular dP/dtmax and dP/dtmin, improved left ventricular ejection fraction and diastolic function, and limited infarct expansion after reperfused myocardial infarction. Both angiotensin receptor blockers increased angiotensin II type 2 receptor protein in the postischemic-reperfused zone, with no change in angiotensin II type 1 receptor protein. There were no changes in the sham group. CONCLUSION: The overall results indicate that the angiotensin receptor blockers valsartan and irbesartan both induce cardioprotection, limit myocardial stunning, and upregulate angiotensin II type 2 receptor protein expression after reperfused myocardial infarction in the rat. Patients who are already receiving angiotensin receptor blockers and develop acute coronary syndromes might benefit from these cardioprotective effects during reperfusion therapy.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2001

Oleanonic acid, a 3-oxotriterpene from Pistacia, inhibits leukotriene synthesis and has anti-inflammatory activity.

One of the best known bioactive triterpenoids is oleanolic acid, a widespread 3-hydroxy-17-carboxy oleanane-type compound. In order to determine whether further oxidation of carbon 3 affects anti-inflammatory activity in mice, different tests were carried out on oleanolic acid and its 3-oxo-analogue oleanonic acid, which was obtained from Pistacia terebinthus galls. The last one showed activity on the ear oedema induced by 12-deoxyphorbol-13-phenylacetate (DPP), the dermatitis induced by multiple applications of 12-O-tetradecanoyl-13-acetate (TPA) and the paw oedemas induced by bradykinin and phospholipase A2. The production of leukotriene B4 from rat peritoneal leukocytes was reduced by oleanonic acid with an IC50 of 17 microM. Negligible differences were observed in the response of both triterpenes to DPP, bradykinin, and phospholipase A2, while oleanonic acid was more active on the dermatitis by TPA and on the in vitro leukotriene formation. In conclusion, the presence of a ketone at C-3 implies an increase in the inhibitory effects on models related to 5-lipoxygenase activity and on associated in vivo inflammatory processes.

Animals↗

PubMed2006

Parameters for cellular viability and membrane function in chenopodium cells show a specific response of extracellular pH to heat shock with extreme Q10.

The effect of brief heat shock on Chenopodium cells was investigated by measuring biochemical parameters for cellular vitality, membrane function and integrity: extracellular pH, release of osmotic compounds, phosphatase, protein and betalain, and cellular reduction of DCPIP and MTT. A threshold temperature was found at 45 degrees C, where release of osmotic compounds, protein and betalain, and reduction of DCPIP and MTT indicate loss of vitality. Extracellular pH and an alkaline phosphatase responded 10-20 degrees C below this threshold, suggesting that extracellular alkalinization, and probably the release of a phosphatase, are part of a specific cellular response to abiotic stress induced by heat shock. The extracellular proton concentration did not increase above 45 degrees C: this may indicate equilibration of gradients driving this process or an inactivation of cellular mechanisms responsible for extracellular alkalinization. The response of extracellular pH to heat shock in Chenopodium cell suspensions was fast, i.e., up to +1 pH in 5 min. Addition of the K+/H+ antiporter nigericin to Chenopodium cells caused an extracellular alkalinization similar to heat shock. The heat shock-induced extracellular alkalinization was characterized by Q10 values for distinct ranges of temperature (Q10 of 56 for 24-31 degrees C, 2.3 for 31-42 degrees C, and 1.0 for 42-50 degrees C). To the author's knowledge, the Q10 of 56 is the highest found up to now. These results suggest that extracellular protons are involved in temperature sensing and signalling in plant cells, probably via a channel-mediated pathway.

2,6-Dichloroindophenol↗

PubMedDate not supplied

Characterization of the human hepatocellular carcinoma (hepg2) cell line as an in vitro model for cadmium toxicity studies.

Biochemical indicators and in vitro models, if they mimic in vivo responses, offer potentially sensitive tools for inclusion in toxicity assessment programs. The purpose of this study was to determine whether the HepG2 cell line would mimic known in vivo or in vitro (or both) responses of mammalian systems when confronted with cadmium (Cd2+). Uptake and compartmentalization of Cd2+, metallothionein (MT) compartmentalization, and glutathione (GSH) depletion were examined. In addition, several cytotoxic and stress effects, e.g., viability (neutral red [NR] uptake, 3-[4,5-dimethylthiozole-2-yl]-2,5,-biphenyl tetrazolium bromide [MTT] dye conversion, and live/dead [L/D]), membrane damage (lactate dehydrogenase leakage), metabolic activity (adenosine triphosphate levels), and detoxification capabilities (GSH content, cytochrome P4501A1/2 [EROD (ethoxyresorufin-o-deethylase)] activity, and MT induction), were measured in both naive (no previous exposure) and Cd2+ preexposed cells. Cadmium uptake increased during a 24-h period. Metallothionein induction occurred in response to both Cd2+ and ZnCl2; however, Cd2+ was the more potent inducer. Both Cd2+ and MT were localized primarily in the cytoplasmic compartment. All biochemical responses, except EROD, showed concentration- response relationships, after 24-h exposure to Cd2+ (ranges 0-3 ppm [26.7 microM]). Cadmium effects were reduced in preexposed cells, indicating adaptive tolerance or increased resistance had occurred. Twenty-four-hour LC50, dose causing death of 50% of the test subjects, values were 0.97, 0.69, and 0.80 ppm (8.7, 6.2, and 7.2 microM) for naive cells and 1.45, 1.21, and 1.39 ppm (12.9, 10.7, and 12.3 microM) for preexposed cells based on the NR, MTT, and L/D assays, respectively. These data indicate that this carcinoma cell line is a useful in vitro model for cadmium toxicity studies.

Biomarkers↗