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  • 1.
    Al Shemaili, Jasem
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mensah-Brown, E.
    Parekh, K.
    Thomas, S. A.
    Attoub, S.
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Adem, A.
    Collin, P.
    Adrian, T. E.
    Frondoside A enhances the antiproliferative effects of gemcitabine in pancreatic cancer2014Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, nr 7, s. 1391-1398Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pancreatic cancer has a very poor prognosis. While gemcitabine is the mainstay of therapy and improves quality of life, it has little impact on survival. More effective treatments are desperately needed for this disease. Frondoside A is a triterpenoid glycoside isolated from the Atlantic sea cucumber, Cucumaria frondosa. Frondoside A potently inhibits pancreatic cancer cell growth and induces apoptosis in vitro and in vivo. The aim of the present study was to investigate whether frondoside A could enhance the anti-cancer effects of gemcitabine. Effects of frondoside A and gemcitabine alone and in combination on proliferation were investigated in two human pancreatic cancer cell lines, AsPC-1 and S2013. To investigate possible synergistic effects, combinations of low concentrations of the two drugs were used for a 72 h treatment period in vitro. Growth inhibition was significantly greater with the drug combinations than their additive effects. Combinations of frondoside A and gemcitabine were tested in vivo using the athymic mouse model. Xenografts of AsPC-1 and S2013 cells were allowed to form tumours prior to treatment with the drugs alone or in combination for 30 days. Tumours grew rapidly in placebo-treated animals. Tumour growth was significantly reduced in all treatment groups. At the lowest dose tested, gemcitabine (4 mg/kg/dose), combined with frondoside A (100 mu g/kg/day) was significantly more effective than with either drug alone. To conclude: The present data suggest that combinations of frondoside A and gemcitabine may provide clinical benefit for patients with pancreatic cancer.

  • 2.
    Al Shemaili, Jasem
    et al.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Parekh, Khatija A.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Newman, Robert A.
    Phoenix Biotechnol Inc, San Antonio, TX 78217 USA..
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Woodward, Carl
    Coastside Bio Resources, Deer Isle, ME 04627 USA..
    Adem, Abdu
    United Arab Emirates Univ, Dept Pharmacol, Fac Med, POB 17666, Al Ain, U Arab Emirates..
    Collin, Peter
    Coastside Bio Resources, Deer Isle, ME 04627 USA..
    Adrian, Thomas E.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer2016Ingår i: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 14, nr 6, artikel-id 115Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The frondosides are triterpenoid glycosides from the Atlantic sea cucumber Cucumaria frondosa. Frondoside A inhibits growth, invasion, metastases and angiogenesis and induces apoptosis in diverse cancer types, including pancreatic cancer. We compared the growth inhibitory effects of three frondosides and their aglycone and related this to the pharmocokinetics and route of administration. Frondoside A potently inhibited growth of pancreatic cancer cells with an EC50 of similar to 1 mu M. Frondoside B was less potent (EC50 similar to 2.5 mu M). Frondoside C and the aglycone had no effect. At 100 mu g/kg, frondoside A administered to CD2F1 mice as an i.v. bolus, the Cp-max was 129 nM, Cl-tb was 6.35 mL/min/m(2), and half-life was 510 min. With i.p. administration the Cp-max was 18.3 nM, Cl-tb was 127 mL/min/m(2) and half-life was 840 min. Oral dosing was ineffective. Frondoside A (100 mu g/kg/day i.p.) markedly inhibited growth cancer xenografts in nude mice. The same dose delivered by oral gavage had no effect. No evidence of acute toxicity was seen with frondoside A. Frondoside A is more potent inhibitor of cancer growth than other frondosides. The glycoside component is essential for bioactivity. Frondoside A is only effective when administered systemically. Based on the current and previous studies, frondoside A appears safe and may be valuable in the treatment of cancer.

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  • 3.
    Andersson, Maria A.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Petersson Grawé, Kierstin
    Karlsson, Oskar M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Abramsson-Zetterberg, Lilianne A-G
    Hellman, Björn E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Evaluation of the potential genotoxicity of chromium picolinate in mammalian cells in vivo and in vitro2007Ingår i: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 45, nr 7, s. 1097-1106Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chromium picolinate (CrPic) is a synthetic nutritional supplement primarily used for weight loss and muscle building. Recent studies have indicated that CrPic might be genotoxic and these findings together with the wide-spread consumer use, have increased the concern about its safety. In the present study we investigated the potential genotoxicity of CrPic in mice given a single intraperitoneal injection (up to 3 mg/kg b.wt.) by evaluating the frequency of micronucleated polychromatic erythrocytes (fMNPCE) in peripheral blood, and DNA damage in lymphocytes and hepatocytes. The fMNPCE was evaluated after 42 h and DNA damage after 16 h. Using the Comet assay DNA damage was also monitored in extended-term cultures of human lymphocytes and in L5178Y mouse lymphoma cells that had been exposed for 3 h to 500 μM CrPic under different exposure conditions.

    A slight, but significant CrPic-induced increase in DNA damage (P < 0.001) was observed in the human lymphocytes, but only when these cells were exposed in the absence of serum. In all other experiments CrPic was found to be without genotoxic effects, both in vivo and in vitro. Taken together, our results suggest that a high concentration of CrPic might be DNA damaging, but only under non-physiological conditions.

  • 4.
    Andersson, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Evaluation of catechol-induced DNA damage in human lymphocytes: A comparison between freshly isolated lymphocytes and T-lymphocytes from extended-term cultures2007Ingår i: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 21, nr 4, s. 716-722Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Extended-term cultures of proliferating human T-lymphocytes (ETC) may be a practical alternative to freshly isolated non-proliferating peripheral blood lymphocytes (PBL) when studying genotoxicity in vitro. To investigate if the pattern of DNA damage differs between the two in vitro systems, catechol-induced DNA damage was evaluated in PBL and ETC derived from the same blood sample, using three different donors. DNA damage was monitored using the comet assay. Whereas 3 h of exposure to 0.5 mM catechol was found to be without DNA damaging effects, 3 mM was found to induce significant damage both in the PBL and the ETC (the latter being clearly less sensitive). The level of reactive oxygen species (ROS) was also measured in the ETC using the fluorescent probe carboxy-H2DCFA. ROS was found to be considerably increased both at 0.5 and 3 mM catechol. The demonstrated difference in sensitivity towards catechol-induced DNA damage between PBL and ETC may be due to their different proliferative status, but despite this difference both in vitro systems were able to identify catechol as a DNA damaging agent at the same concentration.

  • 5.
    Andersson, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Stenqvist, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Interindividual differences in initial DNA repair capacity when evaluating H2O2-induced DNA damage in extended-term cultures of human lymphocytes using the comet assay2007Ingår i: Cell Biology and Toxicology, ISSN 0742-2091, E-ISSN 1573-6822, Vol. 23, nr 6, s. 401-411Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It has been suggested that extended-term cultures of human lymphocytes could be used as a complement to cell lines based on transformed cells when testing the genotoxicity of chemicals. To investigate whether the pattern of induced DNA damage and its subsequent repair differs significantly between cultures based on different blood donors, hydrogen peroxide (H2O2)-induced DNA damage was measured in cultures from four different subjects using the comet assay. The DNA damage was significantly increased in all cultures after 10 min exposure to 0.25 mmol/L H2O2, and there was a significant decrease in the H2O2-induced DNA damage in all cultures after 30 min of DNA repair. The level of damage varied between the different donors, especially after the repair. Using PCR and DNA sequencing, exon 5 of the p53 gene was sequenced in the lymphocytes from the donors with the lowest and highest residual damage. No such mutation was found. Mouse lymphoma L5178Y cells carrying the p53 mutation in exon 5 were included as a reference. These cells were found to be less sensitive toward the H2O2-induced DNA damage, and they were also found to have a rather low DNA repair capacity. The demonstrated variation in H2O2-induced DNA damage and DNA repair capacity between the cultures from the different subjects may be important from a risk assessment perspective, but is obviously not of decisive importance when it comes to the development of a routine assay for genotoxicity.

  • 6.
    Bivehed, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gustafsson, Anton
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Berglund, Anders
    Statstikakademin AB, S-75321 Uppsala, Sweden.
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Evaluation of Potential DNA-Damaging Effects of Nitenpyram and Imidacloprid in Human U937-Cells Using a New Statistical Approach to Analyse Comet Data2019Ingår i: EXPOSURE AND HEALTH, ISSN 2451-9766Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Even if the two neonicotinoids nitenpyram and imidacloprid have been considered safe for humans, their potential genotoxicity still remains a matter of discussion. The DNA-damaging effects of these two compounds were therefore evaluated in a lymphoma cell line of human origin (U-937) using the comet assay after 3-h exposure to up to 50 mu M, with or without metabolic activation using S9 from human liver. The comet data were analysed using a traditional one-way ANOVA after pooling the data on cellular level, and a new alternative approach we have called Uppsala Comet Data Analysis Strategy (UCDAS). UCDAS is a proportional odds model tailored to continuous outcomes, taking the number of pooled cultures, slides and cells into consideration in the same analysis. To the best of our knowledge, the UCDAS approach when analysing comet data has never been presented before. Without metabolic activation, no increase in DNA damage was observed in the neonicotinoide-exposed cells. Nitenpyram was also without DNA-damaging effects when S9 was added. However, in the presence of S9, imidacloprid was found to increase the level of DNA damage. Whereas the ANOVA showed an increase (P<0.001) both at 5 and 50 mu M, UCDAS showed an increase only at the lowest concentration (P<0.001). Based on these findings, the two neonicotinoids seem to be of little concern when it comes to their potential genotoxicity. However, since the U-937 cells were rather resistant to our positive controls, they may not be the best cells to use when evaluating potential genotoxicity of chemicals.

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  • 7.
    Demma, Jemal
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Engidawork, Ephrem
    Aboye, Teshome Leta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    An in vitro Study on the DNA Damaging Effects of Phytochemicals Partially Isolated from an Extract of Glinus lotoides2013Ingår i: Phytotherapy Research, ISSN 0951-418X, E-ISSN 1099-1573, Vol. 27, nr 4, s. 507-514Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An extract of Glinus lotoides, a medicinal plant used in Africa and Asia for various therapeutic purposes, was recently shown to cause DNA damage in vitro. To further explore the potential genotoxicity of this plant, fractionation of the crude extract was performed using reverse phase solid-phase extraction and a stepwise gradient elution of methanol in water. Four fractions were collected and subsequently analysed for their DNA damaging effects in mouse lymphoma cells using an alkaline version of the comet assay. To identify potential genotoxic and non-genotoxic principles, each fraction was then subjected to liquid chromatography coupled to mass spectrometry, LC-MS/MS. 1D and 2D nuclear magnetic resonance analyses were used to confirm the identity of some saponins. Although fractions containing a mixture of flavonoids and oleanane-type saponins or oleanane-type saponins alone produced no DNA damage, those containing hopane-type saponins exhibited a pronounced DNA damaging effect without affecting the viability of the cells. To conclude, even if this study presents evidence that hopane-type of saponins are endowed with a DNA damaging ability, further studies are needed before individual saponins can be cited as a culprit for the previously reported genotoxicity of the crude extract of G. lotoides.

  • 8.
    Demma, Jemal
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Engidawork, E
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Potential genotoxicity of plant extracts used in Ethiopian traditional medicine2009Ingår i: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 122, nr 1, s. 136-142Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim of the study: Although traditional herbal medicines are widely used in Ethiopia, no information is available on their potential genotoxicity. In the present study, hydroalcoholic extracts of Glinus lotoides, Plumbago zeylanica, Rumex steudelii and Thymus schimperi were evaluated for their DNA damaging effects using the comet assay. Material and methods: Mouse lymphoma L5178Y cells were exposed to different concentrations of the extracts for 3 h with and without metabolic activation (S9-mix) using 4-nitroquinoline-N-oxide and benzo(a)pyrene as positive controls, and vehicles as negative controls. Results: In the absence of S9, all extracts were found to induce significant DNA damage without affecting the cell viability. T schimperi and R. steudelii were the most potent DNA-damaging extracts, and G. lotoides and P. zeylanica the least potent. The addition of S9 had different effects on the DNA damage induced by the extracts: it lowered the DNA damaging effect of P. zeylanica, did not affect the DNA damaging effect of T. schimperi, and increased the DNA damaging effects of R. steudelii and G. lotoides. Conclusion: The findings of the present study suggest that all extracts evaluated have a genotoxic potential in vitro which needs to be substantiated by further studies.

  • 9.
    Demma, Jemal
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hallberg, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Genotoxicity of plumbagin and its effects on catechol and NQNO-induced DNA damage in mouse lymphoma cells2009Ingår i: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 23, nr 2, s. 266-271Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Plumbagin, a naphtoquinone present in the roots of Plumbago zeylanica, has been reported to have many beneficial effects such as antibacterial, antifungal, anticancer, antimutagenic and antioxidant effects, but this compound has also been reported to have many side   effects. Given the wide use of P. zeylanica in traditional medicine and the various potential therapeutic uses of plumbagin, the present study was carried out to further elucidate the potential genotoxicity and antigenotoxicity of plumbagin in mouse lymphoma L5178Y cells, using the comet assay. Without affecting the cell viability, plumbagin itself was found to induce significant DNA damage at concentrations as low as 0.25 ng/ml. When the cells were exposed to non-DNA damaging concentrations of plumbagin, together with NQNO (known to interact with DNA in many different ways) or catechol (known to induce oxidative DNA damage), plumbagin was found to significantly reduce the catechol-induced DNA   damage, but to be without protective effect against the NQNO-induced damage. The fact that non-DNA damaging concentrations of plumbagin diminished the DNA damage induced by catechol, provides further support for the idea that plumbagin may act as an antioxidative agent at low concentrations.

  • 10.
    Hellman, Björn
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Toxikologi.
    General Toxicology2006Ingår i: Pharmaceutical Toxicology: Safety Sciences of Drugs, Pharmaceutical Press, London , 2006, s. 1-39Kapitel i bok, del av antologi (Refereegranskat)
  • 11.
    Hellman, Björn
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Toxikologi.
    Genotoxicity2006Ingår i: Pharmaceutical Toxicology: Safety Sciences of Drugs, Pharmaceutical Press, London , 2006, s. 105-121Kapitel i bok, del av antologi (Refereegranskat)
  • 12. Hellman, Björn
    et al.
    Brodin, David
    Andersson, Maria
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Dahlman-Wright, Karin
    Isacsson, Ulf
    Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. Onkologi.
    Brattstrom, Daniel
    Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. Onkologi.
    Bergqvist, Michael
    Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. Onkologi.
    Radiation-induced DNA-damage and gene expression profiles in human lung cancer cells with different radiosensitivity.2005Ingår i: Exp Oncol, ISSN 1812-9269, Vol. 27, nr 2, s. 102-7Artikel i tidskrift (Refereegranskat)
  • 13.
    Hellman, Björn
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Vaghef, Hamid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Boström, Bernt
    The concepts of tail moment and tail inertia in the single cell gel electrophoresis assay1995Ingår i: Mutation research, ISSN 0027-5107, E-ISSN 1873-135X, Vol. 336, nr 2, s. 123-131Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Single cell gel electrophoresis under alkaline conditions is a technique used to detect primary DNA damage in individual mammalian cells. Cells embedded in agarose on microscope slides are subjected to lysis, unwinding of DNA and electrophoresis at high pH. After staining with a fluorescent dye, cells with DNA damage display increased migration of genetic material from the cell nucleus. The damage is quantified by measuring the displacement between the genetic material of the nucleus ('comet head') and the resulting 'tail'. The torsional moment of the tail ('tail moment') has been suggested to be an appropriate index of induced DNA damage in considering both the migration of the genetic material as well as the relative amount of DNA in the tail. In the present paper it will be shown that the moment of inertia ('tail inertia'), a not previously described tail parameter, provides a more precise description of the distribution of individual DNA fragments within the tails. The tail inertia was also found to be the most sensitive indicator of the DNA damage induced in peripheral lymphocytes from mice given a single intraperitoneal injection of cyclophosphamide (150 mg/kg b.w.). It is concluded that the tail inertia is an important complement to other tail parameters when looking for damage of DNA with the single cell gel electrophoresis assay.

  • 14.
    Kahaliw, Wubayehu
    et al.
    Univ Gondar, Sch Pharm, Dept Pharmacol, Coll Med & Hlth Sci, POB 196, Gondar, Ethiopia..
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Engidawork, Ephrem
    Addis Ababa Univ, Sch Pharm, Dept Pharmacol & Clin Pharm, Coll Hlth Sci, POB 1176, Addis Ababa, Ethiopia..
    Genotoxicity study of Ethiopian medicinal plant extracts on HepG2 cells2018Ingår i: BMC Complementary and Alternative Medicine, ISSN 1472-6882, E-ISSN 1472-6882, Vol. 18, artikel-id 45Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Most of herbal medicines are used without any standard safety and toxicological trials although common assumption is that these products are nontoxic. However, this assumption is incorrect and dangerous, so toxicological studies should be done for herbal drugs. Although Pterolobium stellatum, Otostegia integrifolia and Vernonia amygdalina root extracts are frequently used in Ethiopian traditional medicine, there are no evidences of their active toxic compounds. Therefore, we made an effort to assess probable genotoxic effect of these plant extracts on DNA of human hematoma (HepG(2)) cells using alkaline comet assay.

    Methods: Genotoxic effects of extracts were evaluated using single cell gel electrophoresis (SCGE) method on HepG(2) cell. Regarding comet data, the average mean tail intensities (TI) from each individual experiment and treatment (usually at least 3 cultures/treatment) were pooled and the average mean TI was used as an indicator of DNA damage and the standard error of mean (SEM) as the measure of variance.

    Results: DNA damage in the form of comet tail has been observed for 1 and 0.5 mg/ml P. stellatum chloroform and 80% methanol extracts on HepG(2) cells, respectively. The chloroform extract of P. stellatum showed increased tail DNA percentage in a concentration dependent manner. Comet tail length in the chloroform P. stellatum extract treated cells (1 mg/ml) was significantly higher by 89% (p < 0.05) compared to vehicle treated controls. The rest of test extracts seemed to be without genotoxic effect up to a concentration of 0.5 mg/ml.

    Conclusions: Our findings show that two extracts from one plant evaluated have a genotoxic potential in vitro which calls for a more thorough safety evaluation. Such evaluation should include other end-points of genotoxicity apart from DNA damage, and possibly also pure compounds.

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  • 15.
    Lundqvist, J.
    et al.
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, SE-75007 Uppsala, Sweden..
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Oskarsson, A.
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, SE-75007 Uppsala, Sweden..
    Fungicide prochloraz induces oxidative stress and DNA damage in vitro2016Ingår i: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 91, s. 36-41Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prochloraz is widely used in horticulture and agriculture, e.g. as a post-harvest anti-mold treatment. Prochloraz is a known endocrine disruptor causing developmental toxicity with multiple mechanisms of action. However, data are scarce concerning other toxic effects. Since oxidative stress response, with formation of reactive oxygen species (ROS), is a common mechanism for different toxic endpoints, e.g. genotoxicity, carcinogenicity and teratogenicity, the aim of this study was to investigate if prochloraz can induce oxidative stress and/or DNA damage in human cells. A cell culture based in vitro model was used to study oxidative stress response by prochloraz, as measured by the activity of the nuclear factor erythroid 2-related factor 2 (Nrf2), a key molecule in oxidative defense mechanisms. It was observed that prochloraz induced oxidative stress in cultured human adrenocortical H295R and hepatoma HepG2 cells at non-toxic concentrations. Further, we used Comet assay to investigate the DNA damaging potential of prochloraz, and found that non-toxic concentrations of prochloraz induced DNA damage in HepG2 cells. These are novel findings, contradicting previous studies in the field of prochloraz and genotoxicity. This study reports a new mechanism by which prochloraz may exert toxicity. Our findings suggest that prochloraz might have genotoxic properties.

  • 16.
    Mohotti, S.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi. Univ Colombo, Fac Sci, Dept Chem, Thurstan Rd, Colombo 00300, Sri Lanka..
    Rajendran, S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Muhammad, Taj
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Strömstedt, Adam A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Burman, R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    de Silva, E. D.
    Univ Colombo, Fac Sci, Dept Chem, Thurstan Rd, Colombo 00300, Sri Lanka..
    Goransson, U.
    Univ Colombo, Fac Sci, Dept Chem, Thurstan Rd, Colombo 00300, Sri Lanka..
    Hettiarachchi, C. M.
    Univ Colombo, Fac Sci, Dept Chem, Thurstan Rd, Colombo 00300, Sri Lanka..
    Gunasekera, Sunithi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    A bioactivity-guided screening of Sri Lankan plants in the search for novel antibacterial and anticancer agents2016Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Artikel i tidskrift (Övrigt vetenskapligt)
  • 17.
    Rosenmai, Anna Kjerstine
    et al.
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, SE-75007 Uppsala, Sweden.
    Lundqvist, Johan
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, SE-75007 Uppsala, Sweden.
    le Godec, Theo
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, SE-75007 Uppsala, Sweden.
    Ohisson, Asa
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, SE-75007 Uppsala, Sweden.
    Troger, Rikard
    Swedish Univ Agr Sci, Dept Aquat Sci & Assessment, Box 7050, SE-75007 Uppsala, Sweden.
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Oskarsson, Agneta
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, SE-75007 Uppsala, Sweden.
    In vitro bioanalysis of drinking water from source to tap2018Ingår i: Water Research, ISSN 0043-1354, E-ISSN 1879-2448, Vol. 139, s. 272-280Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The presence of chemical pollutants in sources of drinking water is a key environmental problem threatening public health. Efficient removal of pollutants in drinking water treatment plants (DWTPs) is needed as well as methods for assessment of the total impact of all present chemicals on water quality. In the present study we have analyzed the bioactivity of water samples from source to tap, including effects of various water treatments in a DWTP, using a battery of cell-based bioassays, covering health-relevant endpoints. Reporter gene assays were used to analyze receptor activity of the aryl hydrocarbon receptor (AhR), estrogen receptor (ER), androgen receptor (AR), peroxisome proliferator-activated receptor alpha (PPAR alpha) and induction of oxidative stress by the nuclear factor erythroid 2-related factor 2 (Nrf2). DNA damage was determined by Comet assay. Grab water samples were concentrated by HLB or ENV solid phase extraction and the water samples assayed at a relative enrichment factor of 50. The enrichment procedure did not induce any bioactivity. No bioactivity was detected in Milli-Q water or drinking water control samples. Induction of AhR, ER and Nrf2 activities was revealed in source to tap water samples. No cytotoxicity, PPAR alpha or AR antagonist activity, or DNA damage were observed in any of the water samples. A low AR agonist activity was detected in a few samples of surface water, but not in the samples from the DWTP. The treatment steps at the DWTP, coagulation, granulated activated carbon filtration, UV disinfection and NH2CI dosing had little or no effect on the AhR, Nrf2 and ER bioactivity. However, nano filtration and passage through the distribution network drastically decreased AhR activity, while the effect on Nrf2 activity was more modest and no apparent effect was observed on ER activity. The present results suggest that bioassays are useful tools for evaluation of the efficiency of different treatment steps in DWTPs in reducing toxic activities. Bioassays of AhR and Nrf2 are useful for screening of effects of a broad range of chemicals in drinking water and ER activity can be monitored with a high sensitivity.

  • 18.
    Yeshak, Mariamawit Y
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Burman, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Genotoxicity and Cellular Uptake of Cyclotides: Evidence for Multiple Mode of Action2012Ingår i: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 747, nr 2, s. 176-181Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclotides are a family of ultra stable, head-to-tail cyclic plant mini-proteins with each member comprising about 30 amino acid residues. Their stability is associated with the unique structural topology where the cyclic backbone and two disulfide bonds make up an embedded ring which is knotted by a third disulfide bond. The cyclotides find potential applications in drug industry as a drug scaffolds for unstable drugs and also as medicinal agents due to the wide range of inherent pharmacological activities they possess. However, there is a lack of fundamental toxicological studies on these classes of compounds. The current study determined a possible DNA damaging effect of three cyclotides, i.e., cycloviolacin O2, vaby D, and kalata B1 in human lymphoma cells using the alkaline version of the comet assay. The three cyclotides induced massive DNA fragmentation at lethal concentrations. At a sublethal concentration, cycloviolacin O2 and vaby D gave a bell shaped dose-response curve for their DNA-damaging effect. Kalata B1 caused no significant DNA damage at sub cytotoxic concentrations. Single cell microautoradiography was carried out on tritium labeled cycloviolacin O2 in order to understand the mechanism behind the dose-response curve. The results revealed that the peptide is taken up into the cell, at both cytotoxic and at low concentrations. Most biological effects of the cyclotides have been taken to follow from the disruption of cell membranes, but even if the intracellular mechanisms/targets still remain unknown, the current study has unequivocally demonstrated that these compounds also must have other dose-dependent modes of action. 

  • 19.
    Åsgård, Rikard
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Haghdoost, Siamak
    Stockholm University.
    Osterman Golkar, Siv
    Stockholm University.
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Czene, Stefan
    Stockholm University.
    Evidence for different mechanisms of action behind the mutagenic effects of 4-NOPD and OPD: the role of DNA damage, oxidative stress and an imbalanced nucleotide pool2013Ingår i: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 28, nr 6, s. 637-644Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mutagenicity of 4-nitro-o-phenylenediamine (4-NOPD) and o-phenylenediamine (OPD) was compared using the Mouse Lymphoma Assay (MLA) with or without metabolic activation (S9). As expected, OPD was found to be a more potent mutagen than 4-NOPD. To evaluate possible mechanisms behind their mutagenic effects, the following end points were also monitored in cells that had been exposed to similar concentrations of the compounds as in the MLA: general DNA damage (using a standard protocol for the Comet assay); oxidative DNA damage (using a modified procedure for the Comet assay in combination with the enzyme hOGG1); reactive oxygen species (ROS; using the CM-H(2)DCFDA assay); and the balance of the nucleotide pool (measured after conversion to the corresponding nucleosides dC, dT, dG and dA using high-performance liquid chromatography). Both compounds increased the level of general DNA damage. Again, OPD was found to be more potent than 4-NOPD (which only increased the level of general DNA damage in the presence of S9). Although less obvious for OPD, both compounds increased the level of oxidative DNA damage. However, an increase in intracellular ROS was only observed in cells exposed to 4-NOPD, both with and without S9 (which in itself induced oxidative stress). Both compounds decreased the concentrations of dA, dT and dC. A striking effect of OPD was the sharp reduction of dA observed already at very low concentration, both with and without S9 (which in itself affected the precursor pool). Taken together, our results indicate that indirect effects on DNA, possibly related to an unbalanced nucleotide pool, mediate the mutagenicity and DNA-damaging effects of 4-NOPD and OPD to a large extent. Although induction of intracellular oxidative stress seems to be a possible mechanism behind the genotoxicity of 4-NOPD, this pathway seems to be of less importance for the more potent mutagen OPD.

  • 20.
    Åsgård, Rikard
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Effect of beta-carotene on catechol-induced genotoxicity in vitro: Evidence of both enhanced and reduced DNA damage2013Ingår i: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 47, nr 9, s. 692-698Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Intake of antioxidants from the diet has been recognized to have beneficial health effects, but the potential benefit of taking antioxidants such as beta-carotene as supplements is controversial. The aim of the present study was to evaluate the potential protective effects of a physiologically relevant concentration (2 mu M) of beta-carotene on the DNA damaging effects of catechol in mouse lymphoma L5178Y cells. Two different exposure protocols were used: simultaneous exposure to beta-carotene and catechol for 3 h; and exposure to catechol for 3 h after 18 h pre-treatment with the vitamin. DNA damage was evaluated using the comet assay (employing one procedure for general damage, and another procedure, which also included oxidative DNA damage). Independent of exposure protocol and procedure for comet assay, beta-carotene did not increase the basal level of DNA damage. However, at the highest concentration of catechol (1 mM), beta-carotene was found to clearly increase the level of catechol-induced DNA damage, especially in the pre-treated cells. Interestingly, an opposite effect was observed at lower concentrations of catechol, but the beta-carotene related reduction of catechol-induced genotoxicity was significant (P < 0.05) only for the procedure including oxidative damage induced by 0.5 mM catechol. Taken together our results indicate that beta-carotene can both reduce and enhance the DNA damaging effects of a genotoxic agent such as catechol. This indicates that it is the level of catechol-induced DNA damage that seems to determine whether beta-carotene should be regarded as a beneficial or detrimental agent when it comes to its use as a dietary supplement.

  • 21.
    Åsgård, Rikard
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Håkansson, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lundin, Rickard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Evaluation of α-tocopherols effect on catechol and o-phenylenediamine induced DNA damage: An in vitro study using two different staining techniques in the comet assayArtikel i tidskrift (Refereegranskat)
    Abstract [en]

    Using the alkaline comet assay, the effect of a physiologically relevant concentration of a-tocopherol (20 mM) on the DNA damaging effects of catechol and o-phenylenedi- amine (OPD) was evaluated in mouse lymphoma L5178Y TK+/- cells. For compara- tive purposes, a third mutagenic agent, 4-nitro-o-phenylenediamine (4-NOPD), was also included in the study. a-Tocopherol was found to be without DNA damaging effects of its own after three hours exposure when tested in concentrations up to 500 mM, and this vitamin was also found to significantly reduce the DNA damage induced by 1 mM catechol. However, a-tocopherol did not reduce the level of DNA damage induced by OPD, indicating that catechol and OPD induce DNA damage by different mechanisms of action. As in a previous study, 4-NOPD did not increase the level of DNA damage, and a-tocopherol did not affect the level of damage when the cells were concomitantly exposed to both agents. The results from a separate ex- periment using different staining techniques for cells that had been exposed to dif- ferent concentrations of catechol, clearly indicated that the more hazardous chemical ethidium bromide could be substituted with the less hazardous chemical GelRedTM in the comet assay.

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