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R S Pardini

Publications and source records attributed to R S Pardini.

At least 37 records · Page 2Linked to original sources
PubMed1992

Oxygen dependence of hypericin-induced phototoxicity to EMT6 mouse mammary carcinoma cells.

The photodynamic effect of hypericin on EMT6 mouse mammary carcinoma cells was investigated in vitro under aerobic and hypoxic conditions. Under aerobic conditions, hypericin-induced photocytotoxicity was dose dependent within a 1-50 microM range. Under hypoxic conditions, cells were resistant to hypericin-induced phototoxicity. In the dark, no cytotoxicity was observed at any hypericin concentration tested either aerobically or hypoxically. Cellular accumulation of hypericin, examined by chemical extraction and spectroscopy, occurred under both hypoxic and aerobic conditions. Fluorescence photomicrographs of cells exposed to hypericin corroborate drug uptake in the plasma membrane and subcellular regions. Our results demonstrate that hypericin cytotoxicity to EMT6 mouse mammary carcinoma cells in vitro is both light and oxygen-dependent. These results suggest that EMT6 cell kill caused by photoactivated hypericin is mediated by an oxygen-dependent mechanism, rather than by a type I oxygen-independent mechanism.

Aerobiosis↗
PubMed1990

Mechanisms for regulating oxygen toxicity in phytophagous insects.

The antioxidant enzymatic defense of insects for the regulation of oxygen toxicity was investigated. Insect species examined were lepidopterous larvae of the cabbage looper (Trichoplusia ni), southern armyworm (Spodoptera eridania), and black swallowtail (Papilio polyxenes). These phytophagous species are subject to both endogenous and exogenous sources of oxidative stress from toxic oxygen radicals, hydrogen peroxide (H2O2) and lipid peroxides (LOOH). In general, the constitutive levels of the enzymes superoxide dismutase (SOD), catalase (CAT), glutathione transferase (GT), and its peroxidase activity (GTpx), and glutathione reductase (GR), correlate well with natural feeding habits of these insects and their relative susceptibility to prooxidant plant allelochemicals, quercetin (a flavonoid), and xanthotoxin (a photoactive furanocoumarin). Induction of SOD activity which rapidly destroys superoxide radicals, appears to be the main response to dietary prooxidant exposure. A unique observation includes high constitutive activity of CAT and a broader subcellular distribution in all three insects than observed in most mammalian species. These attributes of CAT appear to be important in the prevention of excessive accumulation of cytotoxic H2O2. Unlike mammalian species, insects possess very low levels of a GPOX-like activity toward H2O2. Irrefutable proof that this activity is due to a selenium-dependent GPOX found in mammals, is lacking at this time. However, the activity of selenium-independent GTpx is unusually high in insects, suggesting that GTpx and not GPOX plays a prominent role in scavenging deleterious LOOHs. The GSSG generated from the GPOX and GTpx reactions may be reduced to GSH by GR activity. A key role of SOD in protecting insects from prooxidant toxicity was evident when its inhibition resulted in enhanced toxicity towards prooxidants. The role of antioxidant compounds in protecting these insects from toxic forms of oxygen has not been explored in depth. A major finding, however, is that these insects are lutein accumulators. Lutein is a dihydroxy (diol) derivative of beta-carotene, and it is a good quencher of activated forms of oxygen and free radicals. Levels of lutein are highest in P. polyxenes which specializes in feeding on prooxidant-containing plants.

Animals↗
PubMed1990

Antioxidant enzyme level response to prooxidant allelochemicals in larvae of the southern armyworm moth, Spodoptera eridania.

Larvae of the southern armyworm, Spodoptera eridania, are highly polyphagous feeders which frequently encounter and feed upon plants containing high levels of prooxidant allelochemicals. While ingestion of moderate quantities of prooxidants can be tolerated by these larvae, ingestion of larger quantities can result in toxicity. Studies were conducted to assess the role of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GR) in the protection of S. eridania against redox active prooxidant plant allelochemicals. Dietary exposure of mid-fifth-instar larvae to either quercetin (a flavonoid) or xanthotoxin (a photoactive furanocoumarin), which generate superoxide radical, and singlet oxygen, respectively, resulted in an increase in SOD levels. CAT levels increased in all groups of S. eridania including control insects. This may have been due to the sudden exposure to food following an extended fast of 18 h (to insure that larvae would not reject the diet because of the prooxidants' bitter taste) with an eventual lowering of CAT values with time. GR activities did not significantly change except for a slight inhibition at the highest prooxidant concentrations used at 12-h post-ingestion. The data from these studies suggest that SOD responds to prooxidant challenges in these insects and together with CAT and GR contributes to the insect's defense against potentially toxic prooxidant compounds.

Animals↗
PubMed1989

Pentagastrin stimulation of human colon carcinoma.

This study examines the trophic effects of pentagastrin administration on the growth of transplanted human colon carcinoma in mice. Three different human colon carcinomas were implanted into dorsal subcutaneous pouches of BALB-C athymic mice-tumor A, COLO 320 DM undifferentiated carcinoma; tumor B, WiDr epithelial carcinoma; and tumor C, mucus-producing signet-ring cell adenocarcinoma from a patient volunteer. Tumors grew for four to six weeks and then groups were randomly assigned to receive either saline injections or pentagastrin, 2.0 mg/kg three times a day for 14 days before harvest. Tumors were homogenized and analyzed for DNA, RNA, and protein contents. Each tumor type showed a different biochemical pattern of response to pentagastrin stimulation. The data confirm that pentagastrin is trophic to human colon carcinoma and suggest a possible clinical role for hormonal manipulation.

Adenocarcinoma↗
PubMed1989

Effects of dietary fish oil on human mammary carcinoma and on lipid-metabolizing enzymes.

The growth rate of a human mammary carcinoma, MX-1, was significantly reduced in athymic "nude" mice fed fish oil. Tumors from the fish oil-fed animals also showed a greater sensitivity to two anti-neoplastic agents, mitomycin C and doxorubicin. Mitochondria were isolated from control livers, host livers and tumors from fish oil- and corn oil-fed animals, and increased levels of 20:5n-3 and 22:6n-3 were found in mitochondrial lipids in all three tissues from the fish oil-fed animals. To investigate the effect of dietary n-3 fatty acids on lipid metabolism, the activity of the acyl-CoA:carnitine acyltransferase and three acyl-CoA desaturases were measured. Carnitine acyltransferase activity toward all four acyl-CoA substrates tested was markedly increased in mitochondria from liver by feeding fish oil. In mitochondria from tumors, feeding fish oil resulted in an increased activity toward only 18:3n-3. These data suggest that fish oil may induce an increase in the oxidation of fatty acids. The delta 9-desaturase activity was decreased in microsomes from liver and tumor from fish oil-fed animals. However, both the delta 6 and delta 5 desaturases were increased in tumor and in control liver as a result of feeding fish oil. The delta 5 desaturase was not altered in microsomes from the host animals. The effect of fish oil on the delta 5 and delta 6 desaturases may involve alterations to metabolism of specific polyunsaturated fatty acids especially in the tumor tissue.

Acyltransferases↗
PubMed1988

Electrochemistry of flavonoids. Relationships between redox potentials, inhibition of mitochondrial respiration, and production of oxygen radicals by flavonoids.

We have investigated the redox behavior of a series of structurally related flavonoids employing cyclic voltammetry under physiological conditions. The flavonoids that auto-oxidized and produced oxygen radicals had oxidation potentials (E 1/2) significantly lower [-30 to +60 mV vs (SCE)] than those that did not undergo auto-oxidation (+130 to +340 mV vs SCE). The range of E 1/2 values for the auto-oxidizable flavonoids was comparable to the E 1/2 range reported for the optimum quinone induced production of superoxide (O2 pi) in mitochondrial NADH-CoQ reductase (complex I). The most potent flavonoid inhibitors of mitochondrial succinate-CoQ reductase (complex II) possessed hydroxyl configurations capable of supporting redox reactions. For a series of 3,5,7-trihydroxyflavones that differed by b-ring hydroxylation it was found that decreasing E 1/2 of the flavonoids was associated with decreasing I50 values towards succinoxidase. These findings suggest that the electrochemical properties of the flavonoids may contribute to their biological activity.

Animals↗
PubMed1988

Antioxidant enzymes of larvae of the cabbage looper moth, Trichoplusia ni: subcellular distribution and activities of superoxide dismutase, catalase and glutathione reductase.

In the mid-fifth instar larvae of the cabbage looper moth, Trichoplusia ni, the subcellular distribution of total superoxide dismutase was as follows: 3.05 units (70.0%), 0.97 units (22.3%), and 0.33 units (7.6%) mg-1 protein in the mitochondrial, cytosolic and nuclear fractions, respectively. No superoxide dismutase activity was detected in the microsomal fraction. Catalase activity was unusually high and as follows: 283.4 units (47.3%), 150.1 units (25.1%), 142.3 units (23.8%), and 22.9 units (3.8%) mg-1 protein in the mitochondrial, cytosolic, microsomal (containing peroxisomes), and nuclear fractions. No glutathione peroxidase activity was found, but appreciable glutathione reductase activity was detected with broad subcellular distribution as follows: 3.86 units (36.1%), 3.68 units (34.0%), 2.46 units (23.0%), and 0.70 units (6.5%) mg-1 protein in the nuclear, mitochondrial, and cytosolic fractions, respectively. The unusually wide intracellular distribution of catalase in this phytophagous insect is apparently an evolutionary adaptation to the absence of glutathione peroxidase; hence, lack of a glutathione peroxidase-glutathione reductase role in alleviating stress from lipid peroxidation. Catalase working sequentially to superoxide dismutase, may nearly completely prevent the formation of the lipid peroxidizing .OH radical from all intracellular compartments by the destruction of H2O2 which together with O2- is a precursor of .OH.

Animals↗
PubMed1987

Heterotransplantation of canine sarcoma cells (BLU284) in athymic (nude) mice.

Undifferentiated canine sarcoma cells from a primary lesion were implanted subcutaneously in athymic (nude) mice. Tumors were implanted at 2 sites in each of 4 mice, and 6 of the 8 inoculation sites developed into tumors. Tumors grew and invaded surrounding tissues, as shown by histologic examination. Karyotype analysis verified that tumors were of canine origin. Cells from this tumor were serially heterotransplanted 26 times without consistent change in growth rate. Once established in nude mice, samples from 2 generations of this canine sarcoma cell line were stored cryogenically and were implanted into nude mice. Over 26 generations, 93.7% of fresh implants developed into tumors. Preliminary screening of antineoplastic drugs indicated that this tumor line was sensitive to cyclophosphamide and vincristine. The difference in sensitivity of this heterotransplanted tumor in nude mice toward the various antineoplastic agents provides a useful model for the elucidation of biochemical bases of antineoplastic drug resistance in tumors.

Animals↗
PubMed1986

Relationship between inhibition of mitochondrial respiration by naphthoquinones, their antitumor activity, and their redox potential.

The physicochemical properties of a series of 1,4-naphthoquinones were correlated with their activities against Sarcoma-180 by Hodnett et al. [J. med. Chem. 26, 570 (1983)]. Redox potential was the most important molecular parameter determining antitumor activity in this series of compounds, suggesting that interference with electron transport contributes to their cytotoxicity. We evaluated this same series of quinones for their abilities to inhibit the beef heart mitochondrial succinoxidase and NADH-oxidase enzyme systems. They exhibited a broad range of inhibitory potencies. There was a strong relationship between succinoxidase inhibition, antitumor activity (T/C ratio), and redox potential. The redox potentials of the quinones which inhibited succinoxidase lay within the narrow range of endogenous components of the respiratory chain. In contrast, inhibition of NADH-oxidase was related to redox potential but did not significantly predict antitumor activity. These results suggest that inhibition of mitochondrial succinoxidase may be a useful preliminary screen for antitumor activity.

Animals↗
PubMed1986

Comparison of the effects on mitochondrial function of a series of 2-methyl substituted 1,4-naphthoquinones to their 6-methyl counterparts.

Seven derivatives of 2-methyl-1,4-naphthoquinone were compared to an equivalent series of 6-methyl-1,4-naphthoquinone derivatives for their abilities to interact with mitochondrial membranes and enzyme systems. The substituents on the methyl groups included various electron-withdrawing and -donating groups. The 6-methyl quinones were, in general, more potent inhibitors of NADH-oxidase and succinoxidase, depleted sulfhydryl groups more completely, produced greater rates of cyanide (CN-)-insensitive respiration (respiratory bursts), and induced more severe large-amplitude mitochondrial swelling than the analogous 2-methyl quinones. The NADH-oxidase system was more sensitive than succinoxidase to inhibition by both series, suggesting that Complex I is the primary site of inhibition by these quinones.

Animals↗
PubMed1986

Inhibition of mitochondrial respiration and production of toxic oxygen radicals by flavonoids. A structure-activity study.

A series of fourteen flavonoids were employed in a systematic structure-activity study to assess their abilities to inhibit succinoxidase and generate toxic oxygen species in beef heart mitochondria. By comparing I50 values toward succinoxidase activity, flavonoids with a catechol moiety on the b ring exhibited the following general order of potency: chalcone greater than flavone greater than flavonol greater than dihydroflavonol greater than anthocyanidin. Catechins were inactive. In a series of 3,5,7-trihydroxyflavones containing various configurations of the b ring hydroxyl groups, it was found that the flavonoids possessing adjacent trihydroxy (pyrogallol) and b ring ortho-hydroxy(catechol) configurations were the most potent inhibitors of succinoxidase, followed by those with meta-hydroxyl, monohydroxyl and unhydroxylated configurations. Four of the fifteen flavonoids tested exhibited substrate-independent, KCN-insensitive respiration. Two flavonols with a pyrogallol configuration, myricetin and quercetagetin, produced the largest respiratory bursts and were found to auto-oxidize. Evidence is presented that the mitochondrial respiratory bursts induced by both flavonols and their auto-oxidation resulted in the generation of O-2 and H2O2.

Animals↗
PubMed1986

Metabolic consequences of dietary 2,3-dichloro-1,4-naphthoquinone (CNQ) in the rat. Alteration in anti-oxidant enzyme activities.

Dietary exposure of rats to a high concentration of 2,3-dichloro-1,4-naphthoquinone (CNQ) (2 g/kg diet) for 60 days altered cardiac mitochondrial function and activities of anti-oxidant enzymes in hepatic and cardiac tissue. CNQ moderately depressed the cardiac mitochondrial respiratory control ratio (RCR) to 85% of control; this was exacerbated to 60% of control in animals fed alpha-tocopherol-deficient diets. Dietary CNQ increased hepatic superoxide dismutase (SOD) and catalase activities and increased cardiac SOD activity, but depressed cardiac glutathione reductase and hepatic glutathione peroxidase activities. These effects are consistent with previous in vitro findings that CNQ induces oxidative stress. No significant differences in heart weight or body weight were observed in rats fed CNQ as compared to untreated controls.

Animals↗