| 1. |
- Banne, AF, et al.
(författare)
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Reduced level of serum thiols in patients with a diagnosis of active disease
- 2003
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Ingår i: Journal of Anti-Aging Medicine. - : Mary Ann Liebert Inc. - 1094-5458. ; 6:4, s. 327-334
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative stress, or the production of oxygen-centered free radicals, has been hypothesized as the major source of DNA damage that in turn can lead to altered genetic expression, disease, and aging of humans. Serum protein thiol levels in blood are a direct measure of the in vivo reduction/oxidation (redox) status in humans, because thiols react readily with oxygen-containing free radicals to form disulfides. Moreover, serum thiols also reflect DNA repair capacity and the possible eventual accumulation of genetic damage, since a key DNA repair enzyme, poly ADP-ribose polymerase (PARP), is thiol/disulfide redox regulated. This study tests the hypothesis that serum protein thiols can be used to estimate individual aging status by comparing the levels of apparently healthy subjects (n = 90) to those of individuals (n = 306) with an active disease diagnosis. Nine categories of human disorders all showed highly significant reductions in serum protein thiols from 46 to 91 nM cysteine/200 muL serum (mean +/- S.D. = 59 +/- 40) compared to a control mean of 128 +/- 39 nM cysteine/200 muL serum (p <.001). These data strongly confirm an important role of oxidative stress in human disease development, and identify serum thiol status as a potential biochemical endpoint useful in the assessment of aging.
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| 2. |
- Hua, Jianyi, et al.
(författare)
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Pharmacokinetics and splenic accumulation of N-acetylamino-3-chloro-N-(2-diethylamino-ethyl) benzamide after a single administration to rats.
- 2004
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Ingår i: Biopharmaceutics & Drug Disposition. - : Wiley. - 0142-2782 .- 1099-081X. ; 25:7, s. 313-322
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to measure the pharmacokinetics and tissue accumulation of N-acetylamino-3-chloro-N-(2-diethylamino-ethyl) benzamide (NACPA) after oral or intravenous administration at a single dose of 25 mg/kg to female W/Fu rats. The serum pharmacokinetics of NACPA were characterized by rapid absorption, distribution and elimination. However, in comparison with its parent compound, 4-amino-3-chloro-N-(2-diethylamino-ethyl) benzamide (3-CPA), NACPA displayed a higher Cmax (mean+/-SD, 201+/-21 vs 33.6+/-0.5 nmol/ml, p < 0.05), and a longer elimination half-life (50+/-0.8 vs 36.6+/-1.1 min, p < 0.05) following intravenous administration. Bioavailability of NACPA was significantly greater than that of 3-CPA (50% compared with 14%, p < 0.05). The tissue accumulation of NACPA was generally higher than that of 3-CPA. NACPA was deposited at higher concentrations in the spleen than in the kidney and liver. Cellular pharmacokinetics indicated that NACPA accumulated more readily in lymphocyte related cells than in liver related cells. Furthermore, incubation of human peripheral lymphocytes with NACPA resulted in inhibition of lymphocyte proliferation, INF-gamma production and chemotaxis. All these results suggest that NACPA may be a good candidate drug for oral administration for immune modulation
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| 3. |
- Kjellén, Elisabeth, et al.
(författare)
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A Phase I/II Evaluation of Metoclopramide as a Radiosensitiser in Patients with Inoperable Squamous Cell Carcinoma of the Lung
- 1995
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 31:13-14, s. 2196-2202
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Tidskriftsartikel (refereegranskat)abstract
- The feasibility of administering metoclopramide (MCA) as a radiosensitizer has been evaluated in 23 patients with a pathological or cytological diagnosis of a squamous cell carcinoma of the lung, clinically evaluated as inoperable. All patients received 40-60 Gy radiotherapy fractionated into 1.8 Gy fractions 5 times per week (Monday-Friday). Two MCA treatment regimens were used: (i) MCA at 2 mg/kg administered by intravenous infusion 1-2 h prior to radiotherapy 3 times per week (Monday, Wednesday, Friday); and (ii) MCA at 1 mg/kg administered by intravenous infusion 1-2 h prior to radiotherapy 5 times per week (Monday-Friday). 11 of the 23 patients treated with radiotherapy and MCA had none to mild pneumonitis or fibrosis and another 8 of the 23 had moderate levels. No patient had their therapy interrupted due to radiation-related side-effects. The MCA-related side-effects were as expected, i.e. 78% of the patients experienced sedation/tiredness and 48% expressed restlessness/anxiety symptoms. Both the total dose and serum levels of MCA were significantly associated to the MCA side-effect profile. Tumour response, duration of tumour response and survival were significantly positively correlated to the total and weekly doses of MCA administered to the patients during their radiotherapy treatment. These favourable phase II data have justified the initiation of a phase II/III randomised multicentred trial being carried out in Europe to evaluate MCA as a radiosensitiser.
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| 4. |
- Kjellén, Elisabeth, et al.
(författare)
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Comparison of low dose nicotinamide versus benzamide, administered per os, as radiosensitizers in a C3H mammary carcinoma
- 1988
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 1879-0887 .- 0167-8140. ; 12:4, s. 327-331
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Tidskriftsartikel (refereegranskat)abstract
- We have evaluated if any differences in tumor radiosensitization exist between the two adenosine diphosphate ribosyl transferase (ADPRT) inhibitors nicotinamide and benzamide at fractionated low doses. A significant radiosensitizing effect with nicotinamide at a 10 mg/kg per day dose was found in the tumor model used. We found, however, no radiosensitizing effect with benzamide given according to this schedule.
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| 5. |
- Kjellén, Elisabeth, et al.
(författare)
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Effect of hyperthermia and/or nicotinamide on the radiation response of a C3H mammary carcinoma
- 1989
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Ingår i: European journal of cancer & clinical oncology. - : Elsevier BV. - 0277-5379. ; 25:12, s. 1733-1737
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Tidskriftsartikel (refereegranskat)abstract
- The effect of hyperthermia and/or nicotinamide (200 mg/kg of body weight) on the tumour growth delay induced by radiation was evaluated in a C3H mouse mammary adenocarcinoma. The study showed a radiosensitizing effect of hyperthermia and of nicotinamide but the combination of all three modalitites showed no increased tumor growth delay compared to hyperthermia and radiation alone. The tumour growth delay induced by hyperthermia was not modified by nicotinamide.
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| 6. |
- Lindgren, Hanna, et al.
(författare)
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Differential usage of IκBα and IκBβ in regulation of apoptosis versus gene expression
- 2003
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Ingår i: Biochemical and Biophysical Research Communications. - 1090-2104. ; 301:1, s. 204-211
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Tidskriftsartikel (refereegranskat)abstract
- n this study we use the N-substituted benzamides declopramide (3-CPA) and N-acetyl declopramide (Na-3-CPA) to investigate the involvement of the transcription factor NF-κB in the induction of apoptosis and surface immunoglobulin κ (Igκ) expression in the mouse pre-B cell line 70Z/3. We first showed that 3-CPA-induced apoptosis at doses around 500 μM and that the 3-CPA-induced apoptosis could be suppressed by over-expression of the Bcl-2 protein. Na-3-CPA was shown to be non-apoptotic at doses up to 1–2 mM. On the other hand, Na-3-CPA inhibited LPS-induced Igκ expression while 3-CPA had no effect. Further analysis showed that while 3-CPA inhibited breakdown of IκBα, Na-3-CPA inhibited breakdown of IκBβ. In addition, we used a 70Z/3 cell line expressing a dominant negative IκBα (70Z/3ΔNIκBα). The 70Z/3ΔNIκBα cell line was shown to be more sensitive to apoptosis and cytotoxicity induced by 3-CPA as well as by LPS, probably due to a defect in NF-κB rescue mechanism. Taken together, our data implicate distinct roles for IκBα and IκBβ in regulating various NF-κB activities.
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| 7. |
- Lybak, Stein, et al.
(författare)
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Normal tissue reactions in mice after combined treatment with metoclopramide and ionizing radiation
- 1992
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 31:4, s. 469-474
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Tidskriftsartikel (refereegranskat)abstract
- We have previously shown that metoclopramide potentiates the effect of ionizing radiation and cisplatin treatment of human squamous cell carcinomas from the head and neck region xenografted to nude mice. In the present tumor study, the dose scheduling of metoclopramide in combination with radiation was evaluated, and metoclopramide was shown to be most effective in potentiating the cytotoxic effect of radiation when administered one hour before radiation. The effect of radiation in combination with metoclopramide on normal tissue was also studied in two well-established models. Acute skin reactions to radiation exposure were studied in 129-type mice, and metoclopramide did not enhance the acute skin reaction in this in vivo model. Survival after whole body irradiation was studied in heterozygote Balb/c nu/+ mice as a measure of bone marrow toxicity. Metoclopramide was not found to affect the LD50/30 in this in vivo model. The absence of potentiation of radiation damage to normal tissue in these animal studies, makes metoclopramide an interesting possibility for future clinical evaluation.
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| 8. |
- Olsson, A R, et al.
(författare)
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Mechanism of action for N-substituted benzamide-induced apoptosis.
- 2002
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Ingår i: British Journal of Cancer. - 1532-1827. ; 86:6, s. 971-978
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Tidskriftsartikel (refereegranskat)abstract
- We have analysed the mechanism of action for induction of apoptosis by N-substituted benzamides using declopramide as a lead compound. We show here that declopramide at doses above 250 microM in the mouse 70Z/3 pre-B cell line or in the human promyeolocytic cancer cell line HL60 induced cytochrome c release into the cytosol and caspase-9 activation. The broad spectrum caspase inhibitor zVADfmk and caspase-9 inhibitor zLEDHfmk inhibited apoptosis and improved cell viability when administrated to cells 1 h before exposure to declopramide, whereas the caspase-8 inhibitor zIEDHfmk had less effect. Also, the over expression of Bcl-2 by transfection in 70Z/3 cells inhibited declopramide-induced apoptosis. Prior to the induction of apoptosis, a G(2)/M cell cycle block was induced by declopramide. The cell cycle block was also observed in the presence of broad spectrum caspase inhibitor zVADfmk and in a transfectant expressing high levels of Bcl-2. Furthermore, while p53 was induced in 70Z/3 cells by declopramide, neither the apoptotic mechanism nor the G(2)/M cell cycle block were dependent on p53 activation since both effects were also seen in p53 deficient HL60 cells after addition of declopramide.
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| 9. |
- Pero, Ronald, et al.
(författare)
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Comparison of a broad spectrum anti-aging nutritional supplement with and without the addition of a DNA repair enhancing cat's claw extract
- 2002
-
Ingår i: Journal of Anti-Aging Medicine. - : Mary Ann Liebert Inc. - 1094-5458. ; 5:4, s. 345-353
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Tidskriftsartikel (refereegranskat)abstract
- Dietary supplements, designed to fortify the antioxidant status of human metabolism, are intended to provide nutritional support against the aging process. The strategy is based on the observation that environmental and metabolic sources of oxidatively generated free radicals damage key macromolecules, such as DNA, that in turn alter physiologic processes, and in turn may contribute to aging and age-related diseases such as cancer, as well as cardiovascular and immunologic disorders. This study investigates whether a commercially available, broad spectrum anti-oxidant formulation containing 12 vitamins, 8 minerals, 2 agents to provide "blood sugar/insulin support," 3 botanical antioxidants, one methylating factor, two "fat metabolizers," an "absorption enhancer," a "brain enhancer," a "whole food" ingredient, 2 "cellular energizers," a nucleotide precursor, 2 amino acids, a fatty acid complex, a "probiotic complex," and a digestive enzyme (formula one) could be improved through inclusion of an ingredient that enhances DNA repair (C-Med-100). The two formulations were compared using four intermediate endpoint biomarkers: 8-OH guanine DNA adducts, serum thiols, and Interleukins 1a and 1. Whereas both were shown to be effective at reducing DNA damage, the second, more inclusive formulation appeared to be more effective.
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| 10. |
- Pero, Ronald, et al.
(författare)
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Dietary quinic acid supplied as the nutritional supplement AIO + AC-11® leads to induction of micromolar levels of nicotinamide and tryptophan in the urine.
- 2011
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Ingår i: Phytotherapy Research. - : Wiley. - 1099-1573 .- 0951-418X. ; 25:6, s. 851-857
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Tidskriftsartikel (refereegranskat)abstract
- Hippuric acid is synthesized and produced primarily by the gastrointestinal (GI) microflora. However, there is no known health benefit for hippuric acid except its catabolic conjugation of benzene-type compounds via glycine and subsequent excretion in the urine. For years the GI tract microflora were known to metabolize quinic acid to hippuric acid. Recently it was also proposed that DNA repair was strongly enhanced by quinic acid. In order to explain these quinic acid effects, Pero and colleagues have examined whether tryptophan and nicotinamide were also enhanced by quinic acid levels in urine. They were indeed, and so another study was designed using a natural supplement source of quinic acid called AIO + AC-11®, and then the effects of intervention were measured after only 21 days. It was possible to show profound increases in quinic acid that were again paralleled by increases in tryptophan and nicotinamide urinary levels. Because the high pressure liquid chromatography (HPLC) methods differed greatly between the two studies, differences in chemical analyses probably did not contribute to the data base. Copyright © 2010 John Wiley & Sons, Ltd.
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| 11. |
- Pero, Ronald, et al.
(författare)
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Formulation and in vitro/in vivo evaluation of combining DNA repair and immune enhancing nutritional supplements
- 2005
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Ingår i: Phytomedicine. - : Elsevier BV. - 0944-7113. ; 12:4, s. 255-263
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Tidskriftsartikel (refereegranskat)abstract
- Combining nutritional supplements to achieve synergistic benefit is a common practice in the nutraceutical industry. However, establishing. added health benefit from a combination of natural ingredients is often assumed, untested and without regard to the principle of metabolic competition between the active components. Here, we report on the combination of a cat's claw water extract (C-Med-100, carboxy alkyl esters = active ingredients) + medicinal mushroom extracts (Cordyceps sinensis, Grifola blazei, Grifola frondosa, Trametes versicolor and Ganoderma lucidum, polysaccharides = active ingredients) + nicotinamide + zinc into a formulation designed to optimize different modes of immunostimulatory action, and yet that would avoid metabolic antioxidant competition yielding less than expected efficacious effects. Isobole curve analyses of these two active classes of ingredients determined by growth inhibition of HL-60 human leukemic cells in vitro confirmed they were indeed synergistic when in combination, and not metabolically competitive. Furthermore, an in vivo study showed significant health benefit for 14 subjects treated for 4 weeks with the unique C-Med-100/mushroom extract formulation in that they had reduced pain, reduced fatigue, weight loss and a reduced presence of DNA damage in peripheral blood assessed by (8-OH) guanine DNA ad, ducts and elevation in serum protein thiols. Because this broad-based panel of clinical parameters indicating clinical efficacy has never been demonstrated before for either of the active ingredients evaluated alone in humans, these data were taken as strong evidence that the combination of C-Med-100 + mushroom extracts + nicotinamide + zinc gave additive or synergistic effects to health benefit, and thus supported no efficacious limits from metabolic competition regarding this particular formulation.
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| 12. |
- Pero, Ronald
(författare)
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Health Consequences of Catabolic Synthesis of Hippuric Acid in Humans.
- 2009
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Ingår i: Current Clinical Pharmacology. - 1574-8847.
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Tidskriftsartikel (refereegranskat)abstract
- Hippuric acid has been a major human metabolite for years. However, there is no well-known documented health benefit associated with it except for excretion of environmental-toxic exposures of aromatic compounds such as toluene, or from dietary protein degradation and re-synthesis by intestinal microflora metabolism of quinic acid via the shikimate pathway. Thus hippuric acid can appear in humans as an excretory product from natural or unnatural sources. It has been believed over the years that the major source of urinary hippuric acid levels in humans has come from environmental toxic solvent exposures. However, more recently it was been shown that approximately 1-2 mM hippuric acid is excreted daily in the urine, even in the absence of organic solvent exposure, signalling abundant metabolic dietary sources of hippuric acid are also apparent. One of these has been dietary proteins. The other is from the well-documented presence of quinic acid in healthy colored foodstuffs. Quinic acid is a key metabolite associated with the shikimate pathway existing only in plants, and it is responsible for essental amino acid biosynthesis such as tryptophan, phenylalanine and tyrosine. Here we review the evidence that the human gastrointestinal tract microflora are responsible for quinic acid metabolism not only to hippuric acid, but more importantly to efficacious antioxidant amino acids and vitamins.
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| 13. |
- Pero, Ronald W, et al.
(författare)
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Antioxidant metabolism induced by quinic acid. increased urinary excretion of tryptophan and nicotinamide.
- 2009
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Ingår i: Phytotherapy Research. - : Wiley. - 1099-1573 .- 0951-418X. ; Oct 9, s. 335-346
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Tidskriftsartikel (refereegranskat)abstract
- For over 50 years, hippuric/quinic acids were believed to have no biological efficacy. Here data are presented to support the hypothesis that quinic acid is not responsible for any efficacy, but rather that quinic acid nutritionally supports the synthesis of tryptophan and nicotinamide in the gastrointestinal (GI) tract, and that this in turn leads to DNA repair enhancement and NF-kB inhibition via increased nicotinamide and tryptophan production.Moreover, it is shown that quinic acid is a normal constituent of our diet, capable of conversion to tryptophan and nicotinamide via the GI tract microflora, thus providing an in situ physiological source of these essential metabolic ingredients to humans. The concentrations of quinic and hippuric acids in the diet were dependent on each other when analysed in urine, as was evidenced by a significant linear regression analysis that included unsupplemented control subjects (n = 45, p < 0.001). Thus, these ingredients were identified as major dietary components, and not simply originating from environmental pollution as previously had been thought. Copyright (c) 2008 John Wiley & Sons, Ltd.
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| 14. |
- Pero, Ronald W., et al.
(författare)
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Elevation of ADP-ribosylation as an indicator of mononuclear leucocyte responsiveness in breast cancer patients treated with tamoxifen
- 1992
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Ingår i: European Journal of Cancer. - 0959-8049. ; 28:11, s. 1803-1806
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Tidskriftsartikel (refereegranskat)abstract
- 82 women who had had surgery for removal of breast cancer were randomised during the primary care period before initiation of any chemotherapy or radiotherapy into two groups: no drug treatment (n = 40) and 20 mg tamoxifen per day for 2 years (n = 42). Mononuclear leucocyte (MNL) fractions from blood samples were collected during the first 368 days of the study and ADP-ribosylation was quantified. Tamoxifen treatment resulted in a dose-duration increase in ADP-ribosylation. This was true even after adjustment for covariates such as age, smoking habits, oestrogen use, menstruation and tumour size. These data suggest that part of the antitumour effects of tamoxifen treatment in vivo relates to an enhanced immune cell responsiveness, as indicated by the increased MNL ADP-ribosylation.
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| 15. |
- Pero, Ronald W., et al.
(författare)
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Quality control program for storage of biologically banked blood specimens in the Malmo diet and cancer study
- 1998
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Ingår i: Cancer Epidemiology Biomarkers and Prevention. - 1055-9965. ; 7:9, s. 803-808
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Tidskriftsartikel (refereegranskat)abstract
- A biological bank has been developed to extend the biochemical and molecular research base for a prospective study on diet and cancer in the city of Malmo, Sweden. The study entered individuals 45-69 years of age, of which 30,382 individuals (45%) participated. Each individual entering the bank has stored samples of viable mononuclear leukocytes (MNLs; -140°C) and granulocytes (GRANs; -80°C) or buffy coats (-140°C), erythrocytes (- 80°C), and plasma/serum (-80°C). The bioassays developed to monitor the quality of storage conditions were: (a) viability and growth response to phytohemagglutinin for MNLs; (b) DNA strand breakage for GRANs; (c) NAD content for erythrocytes; and (d) thiol status for plasma/serum. The yield, purity, and storage conditions were all quality controlled, and the samples were determined to be of high standard after 137-190 weeks of storage. No differences in yield and purity were found in samples banked by different laboratory technicians. Growth responses of MNLs were severely reduced (90%) after 40 weeks of storage, which justified switching from the storage of purified MNLs and GRANs to the more cost-effective banking of buffy coats. We conclude that the quality of the banked material, based on the biochemical analysis done, indicate that the storage conditions are optimal at least up to 3.5 years, except for the growth response of MNLs.
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| 16. |
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| 17. |
- Silver, Christina, et al.
(författare)
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An extract of Uncaria tomentosa inhibiting cell division and NF-kappaB activity without inducing cell death.
- 2003
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Ingår i: International Immunopharmacology. - : Elsevier BV. - 1878-1705 .- 1567-5769. ; 3:13-14, s. 1889-1900
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Tidskriftsartikel (refereegranskat)abstract
- Previous reports have demonstrated that extracts of the plant Uncaria tomentosa inhibit tumor cell proliferation and inflammatory responses. We have confirmed that C-Med 100®, a hot water extract of this plant, inhibits tumor cell proliferation albeit with variable efficiency. We extend these findings by showing that this extract also inhibits proliferation of normal mouse T and B lymphocytes and that the inhibition is not caused by toxicity or by induction of apoptosis. Further, the extract did not interfere with IL-2 production nor IL-2 receptor signaling. Since there was no discrete cell cycle block in C-Med 100®-treated cells, we propose that retarded cell cycle progression caused the inhibition of proliferation. Collectively, these data suggested interference with a common pathway controlling cell growth and cell cycle progression. Indeed, we provide direct evidence that C-Med 100® inhibits nuclear factor κB (NF-κB) activity and propose that this at least partially causes the inhibition of proliferation.
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| 18. |
- Silver, Christina, et al.
(författare)
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C-Med 100, a hot water extract of Uncaria tomentosa, prolongs lymphocyte survival in vivo.
- 2003
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Ingår i: Phytomedicine. - : Elsevier BV. - 0944-7113. ; 10:1, s. 23-33
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Tidskriftsartikel (refereegranskat)abstract
- Water extracts of the bark of Uncaria tomentosa, a vine indigenous to South America, has been used for generations as an "immuno modulator". To understand the basis of this immuno modulatory effect we fed mice in their drinking water with C-Med 100, which is a commercially available water extract from Uncaria tomentosa. We found a dose-dependent increase in spleen cell numbers in the supplemented mice, but the proportions of B cells, T cells, NK cells, granulocytes, and memory lymphocytes were normal. However, there were no detectable changes of the lymphoid architecture of the spleen even after long-term treatment. Further, when C-Med 100 treatment was interrupted the cellularity returned to normal level within four weeks. The increased number of lymphocytes was most likely not due to increased production because C-Med 100 did not have any significant effect on precursor cells nor on the accumulation of recent thymic emigrants in the spleen. We conclude that accumulation is most likely due to prolonged cell survival, because adoptive transfer experiments demonstrated that C-Med 100 treatment significantly prolonged lymphocyte survival in peripheral lymphoid organs, without increasing their proliferation rate. Since the accumulation was reversible and without detectable pathological effects, these results suggest the use of C-Med 100 as a potential agent for clinically accelerating the recovery of patients from leukopenia.
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| 19. |
- Silver, Christina, et al.
(författare)
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Quinic acid is a biologically active component of the Uncaria tomentosa extract C-Med 100(R).
- 2005
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Ingår i: International Immunopharmacology. - : Elsevier BV. - 1878-1705 .- 1567-5769. ; 5:1, s. 219-229
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Tidskriftsartikel (refereegranskat)abstract
- We have previously reported that the C-Med 100® extract of the plant Uncaria tomentosa induces prolonged lymphocyte half life and hence increased spleen cell number in mice receiving the extract in their drinking water. Further, the extract induces cell proliferation arrest and inhibits activation of the transcriptional regulator nuclear factor κB (NF-κB) in vitro. We now report that mice exposed to quinic acid (QA), a component of this extract, had significantly increased number of spleen cells, thus recapitulating the in vivo biological effect of C-Med 100® exposure. Commercially supplied QA (H+ form) did not, however, inhibit cell proliferation in vitro, while the ammonia-treated QA (QAA) was a potent inhibitor. Both QA and QAA inhibited NF-κB activity in exposed cells at similar concentrations. Thus, our present data identify QA as a candidate component for both in vivo and in vitro biological effects of the C-Med 100® extract
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