Neurodegenerative disorders including Alzheimer＇s disease are characterized by chronic in- flammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astro...Neurodegenerative disorders including Alzheimer＇s disease are characterized by chronic in- flammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease specific stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inflammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inflamma- tory drugs （NSAIDs） is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinflammation after disease processes are fully established. Gold thiol compounds, including auranofin, comprise an- other class of medications effective at reducing peripheral inflammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inflammatory conditions could be helpful in neu- rodegenerative disease. Three different classes of anti-inflammatory compounds, which have a potential to inhibit neuroinflammation are highlighted below.展开更多
Today colorectal cancer(CRC)is one of the leading causes of cancer death worldwide.This disease is poorly chemo-sensitive toward the existing medical treatments so that new and more effective therapeutic agents are ur...Today colorectal cancer(CRC)is one of the leading causes of cancer death worldwide.This disease is poorly chemo-sensitive toward the existing medical treatments so that new and more effective therapeutic agents are urgently needed and intensely sought.Platinum drugs,oxaliplatin in particular,were reported to produce some significant benefit in CRC treatment,triggering the general interest of medicinal chemists and oncologists for metal-based compounds as candidate anti-CRC drugs.Within this frame,gold compounds and,specifically,the established antiarthritic drug auranofin with its analogs,form a novel group of promising anticancer agents.Owing to its innovative mechanism of action and its favorable pharmacological profile,auranofin together with its derivatives are proposed here as novel experimental agents for CRC treatment,capable of overcoming resistance to platinum drugs.Some encouraging results in this direction have already been obtained.A few recent studies demonstrate that the action of auranofin may be further potentiated through the preparation of suitable pharmaceutical formulations capable of protecting the gold pharmacophore from unselective reactivity or through the design of highly synergic drug combinations.The perspectives of the research in this field are outlined.展开更多
AIM To study the sensitivity and antioxidant enzyme response in two clinical isolates of Entamoeba histolytica(E. histolytica) during treatment with antiamoebic drugs,auranofin and metronidazole. METHODS E. histolytic...AIM To study the sensitivity and antioxidant enzyme response in two clinical isolates of Entamoeba histolytica(E. histolytica) during treatment with antiamoebic drugs,auranofin and metronidazole. METHODS E. histolytica were isolated from stool samples and maintained in Robinson's biphasic culture medium. Clinial isolates were maintained in xenic culture medium,and harvested for determination of minimum inhibitory concentrations to the two antiamoebic drugs,Metronidazole and Auranofin using microtiter plate tests. The percent survival of the two isolates were determined using the trypan blue cell count. Isolate 980 was treated with 70 μmol/L and 2 μmol/L while isolate 989 was treated with 20 μmol/L and 0.5 μmol/L of metronidazole and auranofin respectively for 24 h. Fifty thousand cells of each isolate were harvested after 24 h of treatment for analysis of the mRNA expressions of the antioxidant enzymes,thioredoxin reductase,peroxiredoxin and FeSOD using the specific primers. Cell lysate was used for determination of enzyme activity of thioredoxin reductase by measuring DTNB reduction spectrophotometrically at412 nm.RESULTS Minimum inhibitory concentration of the clinical isolates 980 and 989 for auranofin was 3 μmol/L and 1 μmol/L respectively while that for metronidazole was 80 μmol/L and 30 μmol/L respectively. Thioredoxin reductase,peroxiredoxin and FeSOD expression levels were significantly reduced in the isolate 980 when treated with Auranofin. Metronidazole treatment showed a down regulation of thioredoxin reductase. Though not significant both at the mRNA and the enzyme activity levels. Peroxiredoxin and FeSOD however remained unchanged. Auranofin treatment of isolate 989,showed an upregulation in expression of thioredoxin reductase while Peroxiredoxin and FeSOD did not show any change in expression. Upon treatment with metronidazole,isolate 989 showed an increase in thioredoxin reductase expression. Peroxiredoxin and FeSOD expressions however remain unchanged both at mRNA and enzyme activity level.CONCLUSION Clinical isolates from New Delhi NCR region show different sensitivities to antiamoebic drugs. Auranofin is effective against isolate showing higher tolerance to metronidazole as shown by its inhibition in thioredoxin reductase activity.展开更多
基金supported by a grant from the Jack BrownFamily Alzheimer’s Disease Research Foundation
文摘Neurodegenerative disorders including Alzheimer＇s disease are characterized by chronic in- flammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease specific stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inflammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inflamma- tory drugs （NSAIDs） is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinflammation after disease processes are fully established. Gold thiol compounds, including auranofin, comprise an- other class of medications effective at reducing peripheral inflammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inflammatory conditions could be helpful in neu- rodegenerative disease. Three different classes of anti-inflammatory compounds, which have a potential to inhibit neuroinflammation are highlighted below.
基金funding the project“Advanced mass spectrometry tools for cancer research:novel applications in proteomics,metabolomics and nanomedicine”(Multi-user Equipment Program 2016,Ref.code 19650)the Beneficentia Stiftung,Vaduz(BEN2019/48 and University of Pisa(Rating Ateneo 2019-2020)for the financial support+1 种基金supported by the University of Pisa under the“PRA-Progetti di Ricerca di Ateneo”Institutional Research Grants-Project no.PRA_2020_58“Agenti innovativi e nanosistemi per target molecolari nell’ambito dell’oncologia di precisione”to Marzo Tthe financial support(two-year fellowship for Italy“Marcello e Rosina Soru”-Project Code:23852).
文摘Today colorectal cancer(CRC)is one of the leading causes of cancer death worldwide.This disease is poorly chemo-sensitive toward the existing medical treatments so that new and more effective therapeutic agents are urgently needed and intensely sought.Platinum drugs,oxaliplatin in particular,were reported to produce some significant benefit in CRC treatment,triggering the general interest of medicinal chemists and oncologists for metal-based compounds as candidate anti-CRC drugs.Within this frame,gold compounds and,specifically,the established antiarthritic drug auranofin with its analogs,form a novel group of promising anticancer agents.Owing to its innovative mechanism of action and its favorable pharmacological profile,auranofin together with its derivatives are proposed here as novel experimental agents for CRC treatment,capable of overcoming resistance to platinum drugs.Some encouraging results in this direction have already been obtained.A few recent studies demonstrate that the action of auranofin may be further potentiated through the preparation of suitable pharmaceutical formulations capable of protecting the gold pharmacophore from unselective reactivity or through the design of highly synergic drug combinations.The perspectives of the research in this field are outlined.
基金Supported by WOS-A grant from Department of Science and Technology,New Delhi,Government of India to Iyer LR,No.SR/WOS-A/LS-98/2007"Programme support on molecular parasitology",Department of Biotechnology,New Delhi,India to Paul J,No.BT/01/CEIB/11/v/08
文摘AIM To study the sensitivity and antioxidant enzyme response in two clinical isolates of Entamoeba histolytica(E. histolytica) during treatment with antiamoebic drugs,auranofin and metronidazole. METHODS E. histolytica were isolated from stool samples and maintained in Robinson's biphasic culture medium. Clinial isolates were maintained in xenic culture medium,and harvested for determination of minimum inhibitory concentrations to the two antiamoebic drugs,Metronidazole and Auranofin using microtiter plate tests. The percent survival of the two isolates were determined using the trypan blue cell count. Isolate 980 was treated with 70 μmol/L and 2 μmol/L while isolate 989 was treated with 20 μmol/L and 0.5 μmol/L of metronidazole and auranofin respectively for 24 h. Fifty thousand cells of each isolate were harvested after 24 h of treatment for analysis of the mRNA expressions of the antioxidant enzymes,thioredoxin reductase,peroxiredoxin and FeSOD using the specific primers. Cell lysate was used for determination of enzyme activity of thioredoxin reductase by measuring DTNB reduction spectrophotometrically at412 nm.RESULTS Minimum inhibitory concentration of the clinical isolates 980 and 989 for auranofin was 3 μmol/L and 1 μmol/L respectively while that for metronidazole was 80 μmol/L and 30 μmol/L respectively. Thioredoxin reductase,peroxiredoxin and FeSOD expression levels were significantly reduced in the isolate 980 when treated with Auranofin. Metronidazole treatment showed a down regulation of thioredoxin reductase. Though not significant both at the mRNA and the enzyme activity levels. Peroxiredoxin and FeSOD however remained unchanged. Auranofin treatment of isolate 989,showed an upregulation in expression of thioredoxin reductase while Peroxiredoxin and FeSOD did not show any change in expression. Upon treatment with metronidazole,isolate 989 showed an increase in thioredoxin reductase expression. Peroxiredoxin and FeSOD expressions however remain unchanged both at mRNA and enzyme activity level.CONCLUSION Clinical isolates from New Delhi NCR region show different sensitivities to antiamoebic drugs. Auranofin is effective against isolate showing higher tolerance to metronidazole as shown by its inhibition in thioredoxin reductase activity.
