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Local Proinflammatory Effects of Repeated Skin Exposure to Warfarin, An Anticoagulant Rodenticide in Rats

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Biomedical and Environmental Sciences 2011年第2期24卷 180-189页

作者： Aleksandra POPOV Ivana MIRKOV Lidija ZOLOTAREVSKI milena JOVIC Sandra BELIJ Dragan kataranovski milena kataranovski Department of Ecology Institute for Biological Research "Sinisa Stankovic" University of Belgrade Institute for Pathology Military Medical Academy Institute of Zoology Faculty of Biology University of Belgrade Institute of Physiology and Biochemistry Faculty of Biology University of Belgrade

Objective： To evaluate the effects of epicutaneous application of anticoagulant warfarin, by examining the presence of tissue injury and immune/inflammatory activity in exposed skin. Methods： Rats were exposed to warfarin by applying 10 μg of warfarin‐sodium to 10‐12 cm 2 skin （range 0.8‐1 μg per 1 cm 2 ） for 3 consecutive days. Tissue injury was evaluated by lipid peroxidation, histomorphological changes and signs of reparative activity in skin. T cell infiltration and selected aspects of epidermal cell activity were examined as indicators of immune/inflammatory skin response to warfarin application. Results： Repeated warfarin application exerted no effect on skin metabolic viability, but resulted in tissue injury （increased malondialdehyde, MDA, production, evident histo‐morphological changes in epidermis and dermis depicting cell injury and death）. Increased numbers of proliferating cell nuclear antigen （PCNA ＋） cells indicated reparative processes in injured skin. Infiltration of CD3 ＋ cells （T lymphocytes） along with the increased production of tumor necrosis factor‐α （TNF‐α） by epidermal cells from warfarin‐treated skin and their co‐stimulatory effect in an in vitro T‐cell activation assay demonstrated immunomodulatory effects of epicutaneous warfarin. Conclusion： Presented data have documented tissue damage associated with immune/ inflammatory activity in skin exposed to warfarin. Observed effects are relevant to immunotoxic potential of this anticoagulant in settings of external exposure.

关键词： Rats Warfarin Epicutaneous exposure Tissue damage Skin inflammation

Immune defense of wild-caught Norway rats is characterized by increased levels of basal activity but reduced capability to respond to further immune stimulation

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Integrative Zoology 2018年第2期13卷 180-193页

作者： Ivana MIRKOV Aleksandra POPOV ALEKSANDROV Vesna SUBOTA Dragan kataranovski milena kataranovski Immunotoxicology Group Department of EcologyInstitute for Biological Research“Sinisa Stankovic”University of BelgradeBelgradeSerbia Institute for Medical Biochemistry Military Medical AcademyBelgradeSerbia Institute of Zoology Faculty of BiologyUniversity of BelgradeBelgradeSerbia Institute of Physiology and Biochemistry Faculty of BiologyUniversity of BelgradeBelgradeSerbia

Studies of wild animals’immunity often use comparison with laboratory-raised *** such an approach,various data were obtained concerning wild Norway rat’s *** or higher potential of immune system cells to respond to activation stimuli were shown,because of analysis of disparate parameters and/or small number of analyzed *** differences between laboratory and wild rats were shown too,owing to great response variability in wild *** hypothesized that wild rats will express more intense immune activity compared to their laboratory counterparts which live in a less demanding *** test this,we analyzed the circulating levels of inflammatory cytokine interleukin-6(IL-6),a mediator which has a central role in host immune *** addition,we examined the activity of the central immune organ,the spleen,including cell proliferation and production of pro-inflammatory cytokines interferon-γ(IFN-γ)and interleukin-17(IL-17),which are major effectors of cellular adaptive immune *** order to obtain reasonable insight into the immunity of wild Norway rats,analysis was conducted on a much larger number of individuals compared to other *** levels of plasma IL-6,higher spleen mass,cellularity and basal IFN-γproduction concomitantly with lower basal production of anti-inflammatory cytokine interleukin-10(IL-10)revealed more intense immune activity in the wild compared to laboratory ***,lower responsiveness of their spleen cells’proinflammatory cytokine production to concanavalin A(ConA)stimulation,along with preserved capacity of IL-10 response,might be perceived as an indication of wild rats’reduced capability to cope with incoming environmental stimuli,but also as a means to limit tissue damage.

关键词： circulating interleukin-6 levels spleen cell cytokine production spleen cell proliferation

Gender Differences in Acute Cadmium-Induced Systemic Inflammation in Rats

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Biomedical and Environmental Sciences 2009年第1期22卷 1-7页

作者： milena kataranovski SRDJA JANKOVIC DRAGAN kataranovski JELENA STOIC DESA BOGOJEVIC Department of Ecology Institute for Biological Research"Sinia Stankovi"Bulevar Despota Stefana 14211060 BelgradeSerbia Department of Molecular Biology Institutefor Biological Research"Sinia Stankovi"Bulevar Despota Stefana 14211060 BelgradeSerbia

Objective To examine the presence of gender differences in pro-inflammatory potential of cadmium in rats by comparing systemic inflammatory response to acute cadmium intoxication in animals of the two sexes. Methods Basic aspects of this response were evaluated, including plasma levels of inflammatory cytokines tumor necrosis factor （TNF） and interleukin-6 （IL-6） and of major rat acute phase protein alpha 2-macroglobulin （alpba2-M）, as soluble indicators of inflammation, and the number and activity of peripheral blood leukocytes, as cellular indicators of inflammation. Results Differential increases of IL-6 and alpha 2-M （higher in males than in females） in peripheral blood cell counts and types （leukocytosis and shift in the ratio of granulocytes to lymphocytes more pronounced in males vs females） and in levels of neutrophil priming （higher in males vs females） were noted. Conclusion The data document a more intense inflammatory response to cadmium administration in males. The sex differences in inflammatory effects of cadmium might be taken into consideration in studying the toxicity of this heavy metal.

关键词： Cadmium Sex Rats Inflammation

Gender Differences in Pulmonary Inflammation Following Systemic Cadmium Administration in Rats

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Biomedical and Environmental Sciences 2010年第4期23卷 293-299页

作者： JELENA STOSIC IVANA MIRKOV SANDRA BELIJ MIROSLAV NIKOLIC ALEKSANDRA POPOV DRAGAN kataranovski milena kataranovski Department of Ecology Institute for Biological Research "Sinisa Stankovic" Institute for Multidisciplinary Research University of Belgrade Institute of Zoology Faculty of BiologyUniversity of Belgrade Institute of Physiology and Biochemistry Faculty of BiologyUniversity of Belgrade

Objective To examine the presence of gender differences in pulmonary inflammation evoked by acute systemic cadmium administration in rats. Methods Presence of basic indicators of lung inflammation （inflammatory cytokine lung content, leukocyte infiltration and activity of cells recovered from lungs by enzyme digestion） was analyzed and compared in animals of the two sexes. Results Intraperitoneal administration of cadmium （1.0 mg/kg） resulted in higher cadmium content in lungs of female rats. Higher tumor necrosis factor （TNF） content was noted in lung homogenates of male rats, while interleukin-6 （IL-6） content was slightly, but signifaicantly greater in lungs of female rats. Increased leukocyte infiltration was observed in lungs of male rats, mainly due to neutrophils. Increased responsiveness to phorbol myristate acetate （PMA） stimulation was noted in cells recovered from lungs of male rats. Rise in intracellular content of myeloperoxidase （MPO） was noted in lung cells from cadmium-treated rats of both sexes, but higher in cells from male rats. Conclusion Presented data documented a more intense pulmonary inflammatory response to systemic cadmium administration in males, with higher IL-6 levels in lungs of female individuals. These sex differences in proinflamatory activity of cadmium in lungs should be taken into consideration in studying the remote toxicity of this heavy metal.

关键词： Rats Sex Intraperitoneal cadmium Pulmonary inflammation

Aryl Hydrocarbon Receptor is Involved in the Proinflammatory Cytokine Response to Cadmium

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Biomedical and Environmental Sciences 2021年第3期34卷 192-202页

作者： KULAS Jelena TUCOVIC Dina ZELJKOVIC Milica POPOVIC Dusanka POPOV ALEKSANDROV Aleksandra kataranovski milena MIRKOV Ivana Immunotoxicology Group Department of EcologyInstitute for Biological Research‘Sinisa Stankovic'-National Institute of Republic of SerbiaUniversity of Belgrade142 Bulevar despota StefanaBelgrade 11000Serbia

Objective To investigate involvement of the aryl hydrocarbon receptor(Ah R)in the immunomodulatory effects of cadmium(Cd).Methods The effect of Cd on Ah R activation(CYP1 A1 and CYP1 B1 m RNA expression)was examined in lung leukocytes of Cd-exposed rats(5 and 50 mg/L,30 d orally)and by in vitro leukocyte *** involvement of Ah R signaling in the effects of Cd on the interleukin(IL)-1β,IL-6,and tumor necrosis factor(TNF)lung leukocyte response was investigated in vitro using the receptor antagonist *** Cd increased CYP1 B1(in vivo and in vitro)and CYP1 A1(in vitro)m RNA,indicating Ah R involvement in the action of *** response to Cd,lung leukocytes increased IL-6 and decreased TNF at the gene expression and protein levels,but decreased IL-1βproduction due to reduced *** Ah R antagonist CH-223191 abrogated the observed effects of Cd on the cytokine *** absence of Ah R reactivity and cytokine response to Cd of leukocytes from the lungs of a rat strain that is less sensitive to Cd toxicity coincided with a high Ah R repressor m RNA *** Ah R signaling is involved in the lung leukocyte proinflammatory cytokine response to *** relevance of the Ah R to the cytokine response to Cd provides new insight into the mechanisms of Cd immunotoxicity.

关键词： Cadmium Lung leukocytes Aryl hydrocarbon receptor Cytokine(IL-6,TNF,IL-1β)response

Oral Cadmium Intake Enhances Contact Allergen-induced Skin Reaction in Rats

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Biomedical and Environmental Sciences 2022年第11期35卷 1038-1050页

作者： Dina Tucovic Jelena Kulas Ivana Mirkov Dusanka Popovic Lidija Zolotarevski Marta Despotovic milena kataranovski Aleksandra Popov Aleksandrov Immunotoxicology Group Department of EcologyInstitute for Biological Research"Sinisa Stankovic"-National Institute of Republic of SerbiaUniversity of Belgrade142 Bulevar despota Stefana11060 BelgradeSerbia Medical College of Applied Sciences 254 Cara Dusana11080 BelgradeSerbia Centre of Research Excellence in Nutrition and Metabolism Institute for Medical ResearchUniversity of Belgrade11 Tadeusa Koscuska 111000 BelgradeSerbia

Objective The effect of oral cadmium(Cd)intake to influence contact skin allergies was examined,since it is known that Cd is a heavy metal that affects many tissues,including the skin,in which it disturbs homeostasis,thus resulting in inflammation and *** Male rats were evoked with experimental contact hypersensitivity reaction(CHS)to hapten dinitrochlorobenzene(DNCB),after prolonged(30 day)oral exposure to an environmentally relevant Cd dose(5 ppm).The ear cell population was analyzed with flow *** production by ear skin cells and the activity of skin-draining lymph node(DLN)cells were measured using enzyme-linked immunosorbent assay(ELISA).Results Orally acquired Cd(5 ppm)increased CHS intensity only in Dark Agouti(DA)rats by affecting inflammatory responses in both the sensitization(an increase of IFN-γ and IL-17 cytokine production)and challenge(an increase of CD8^(+)and CD4^(+)cell number and TNF,IFN-γ and IL-17 cytokine production)*** increased CHS reaction was seen in Albino Oxford(AO)rats only at a high Cd dose(50 ppm),during the challenge phase(an increase of CD8^(+)and CD4^(+)cell number and TNF,IFN-γ and IL-17 cytokine production).Conclusion These novel data indicate that oral Cd intensifies the skin response to sensitizing chemicals such as DNCB.

关键词： Cadmium(Cd) Contact hypersensitivity reaction(CHS) Dinitrochlorobenzene(DNCB)

Pulmonary Immune Responses to Aspergillus Fumigatus in Rats

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Biomedical and Environmental Sciences 2014年第9期27卷 684-694页

作者： MIRKOV Ivana EL-MUZGHI Amal Atia Mhfuod DJOKIC Jelena NINKOV Marina POPOV ALEKSANDROV Aleksandra GLAMOCLIJA Jasmina kataranovski milena Department of Ecology Institute for Biological Research ‘Sinisa Stankovic'University of Belgrade Department of Plant Physiology (Mycology Lab) Institute for Biological Research ‘Sinisa Stankovic'University of Belgrade Institute of Physiology and Biochemistry Faculty of BiologyUniversity of Belgrade

Objective To evaluate immunologic mechanisms underlying Aspergillus fumigatus pulmonary infections in immunocompetent Dark Agouti （DA） and Albino Oxford （AO） rats recognized as being susceptible to some inflammatory diseases in different manners. Methods Lung fungal burden （quantitative colony forming units, CFU, assay）, leukocyte infiltration （histology, cell composition） and their function （phagocytosis, oxidative activity, CDllb adhesion molecule expression） and cytokine interferon-y （IFN-y） and interleukin-17 and -4 （IL-17 and IL-4） lung content were evaluated following infection （intratracheally, lxl07 conidia）. Results Slower reduction of fungal burden was observed in AO rats in comparison with that in DA rats, which was coincided with less intense histologically evident lung cell infiltration and leukocyte recovery as well as lower level of most of the their activities including intracellular myeloperoxidase activity, the capacity of nitroblue tetrazolium salt reduction and CDllb adhesion molecule expression （except for phagocytosis of conidia） in these rats. Differential patterns of changes in proinflammatory cytokine levels （unchanged levels of IFN-v and transient increase of IL-17 in AO rats vs continuous increase of both cytokines in DA rats） and unchanged levels of IL-4 were observed. Conclusion Genetically-based differences in the pattern of antifungal lung leukocyte activities and cytokine milieu, associated with differential efficiency of fungal elimination might be useful in the future use of rat models in studies of pulmonary aspergillosis.

关键词： A. fumigatus Rats Lung immune responses

Subchronic Oral Cadmium Exposure Exerts both Stimulatory and Suppressive Effects on Pulmonary Inflammation/Immune Reactivity in Rats

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Biomedical and Environmental Sciences 2019年第7期32卷 508-519页

作者： KULAS Jelena NINKOV Marina TUCOVIC Dina POPOV Aleksandrov Aleksandra UKROPINA Mirela CAKIC MILOSEVIC Maja MUTIC Jelena kataranovski milena MIKROV Ivana Immunotoxicology group Department of Ecology Institute for Biological Research 'Sinisa Stankovic ' University of Belgrade 142 Bulevar despota Stefana Belgrade 11000 Serbia Institute of Zoology Faculty of Biology University of Belgrade 16 Studentskitrg Belgrade 11000 Serbia Innovation center of the Faculty of Chemistry University of Belgrade 12-16 Studentskitrg 11000 Belgrade Serbia Institute of Physiology and Biochemistry Faculty of Biology University of Belgrade 16 Studentskitrg Belgrade 11000 Serbia

Objective The aim of this study is to investigate the effects of oral cadmium(Cd) ingestion on the pulmonary immune response. Methods Determination of Cd content in lungs and histopathological evaluation of the tissue was performed in rats following 30-day oral Cd administration(5 and 50 mg/L). Antioxidant enzyme defense(superoxide dismutase and catalase), cell infiltration, and production of tumor necrosis factor(TNF) and interferon(IFN)-γ, as well as the activity of myeloperoxidase(MPO), nitric oxide(NO), and various cytokines [interleukin(IL)-1β, IL-6, IL-10, and IL-17] were investigated. Results Cd caused tissue damage and cell infiltration in the lungs, and this damage was more pronounced at higher doses. Cd deposition resulted in lung inflammation characterized by a dose-dependent IL-1β increase in lung homogenates, increased TNF levels at both doses, and IL-6 stimulation at low doses with inhibition observed at higher doses. Cd exerted differential effects on lung leukocytes isolated by enzyme digestion, and these effects were characterized by a lack of change in the production of reactive oxygen and nitrogen species, an inhibition of IL-1β and TNF, and stimulation of MPO and IFN-γ. The higher capacity of Cd-exposed lung cells to respond to the opportunistic pathogen Staphylococcus epidermidis was demonstrated in vitro. Conclusion The potential of ingested Cd to exert both proinflammatory and immunosuppressive effects on pulmonary tissue inflammation and immune reactivity highlights the complex immunomodulatory actions of this metal.

关键词： Rats Oral cadmium administration Lungs Cytokine response

Novel insights into autophagy in gastrointestinal pathologies,mechanisms in metabolic dysfunction-associated fatty liver disease and acute liver failure

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World Journal of Gastroenterology 2024年第27期30卷 3273-3277页

作者： Tsvetelina Velikova milena Gulinac Medical Faculty Sofia University St Kliment OhridskiSofia 1407Bulgaria Department of General and Clinical Pathology Medical University of PlovdivPlovdiv 4002Bulgaria

In this editorial,we comment on three articles published in a recent issue of World Journal of *** is a pressing need for new research on autophagy's role in gastrointestinal(GI)disorders,and also novel insights into some liver conditions,such as metabolic dysfunction-associated fatty liver disease(MAFLD)and acute liver failure(ALF).Despite advancements,understanding autophagy's intricate mechanisms and implications in these diseases remains ***,MAFLD's pathogenesis,encompassing hepatic steatosis and metabolic dysregulation,require further ***,the mechanisms underlying ALF,a severe hepatic dysfunction,are poorly *** studies exploring the interplay between autophagy and GI disorders,as well as defined mechanisms of MAFLD and ALF,are crucial for identifying therapeutic targets and enhancing diagnostic and treatment strategies to mitigate the global burden of these diseases.

关键词： Gastrointestinal diseases Autophagy Metabolic dysfunction-associated fatty liver disease High-normal alanine aminotransferase level Silent information regulator sirtuin 1 Acute liver failure