Objective To study the effect of topical cyclosporine on lymphocyte activation within the conjunctiva of patients with moderate to severe dry eye syndrome (Sjogren and non-Sjogren). Methods Biopsy specimens were obtained at baseline and after 6 months of cyclosporine treatment from eyes of 32 patients with moderate to severe dry eye syndrome; 19 were cyclosporine treated (0.05% cyclosporine, n = 13; 0.1% cyclosporine, n = 6) and 13 were vehicle treated. Within this group there were 12 with Sjogren syndrome and 20 with non–Sjogren syndrome. Biopsy tissue was analyzed using immunohistochemical localization of binding of monoclonal antibodies to lymphocytic markers CD3, CD4, and CD8 as well as lymphocyte activation markers CD11a and HLA-DR. Results In cyclosporine-treated eyes, biopsy results of conjunctivae showed decreases in the number of cells positive for CD3, CD4, and CD8, while in vehicle-treated eyes, results showed increases in these markers, although these differences were not statistically significant. Following treatment with 0.05% cyclosporine, there was a significant decrease in the number of cells expressing the lymphocyte activation markers CD11a (P Conclusion Treatment of dry eye syndrome with topical cyclosporine significantly reduced the numbers of activated lymphocytes within the conjunctiva.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/413825/ecs90290.pdf

Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes.

Infections with flaviviruses, such as dengue, West Nile virus and the recently re-emerging Zika virus, are an increasing and probably lasting global risk. This Review summarizes and comments on the opportunities for broad-spectrum agents that are active against multiple flaviviruses. Broad-spectrum activity is particularly desirable to prepare for the next flaviviral epidemic, which could emerge from as-yet unknown or neglected viruses. Potential molecular targets for broad-spectrum antiflaviviral compounds include viral proteins, such as the viral protease or polymerase, and host targets that are exploited by these viruses during entry and replication, including α-glucosidase and proteins involved in nucleoside biosynthesis. Numerous compounds with broad-spectrum antiviral activity have already been identified by target-specific or phenotypic assays. For other compounds, broad-spectrum activity can be anticipated because of their mode of action and molecular targets.

/pdf/broad-spectrum-agents-for-flaviviral-infections-dengue-zika-4v9uigqi3l.pdf

Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond

In man the immunosuppressive drug Cyclosporine A (CsA) has been used successfully in organ transplantation and in the treatment of autoimmune disorders. The drug, however, causes side effects which occur mainly in the kidney but also in the liver. The mechanisms leading to the hepatic side effects are not yet fully understood. Because reactive oxygen production is a common mechanism of drug toxicity, the goal of this study was to evaluate whether CsA induces oxidative stress in rat liver cells. In primary rat hepatocyte 20-h cultures, CsA caused a concentration-dependent increase of free reactive oxygen species, thiobarbituric acid reactive substances, loss of protein thiols and decrease of molar ratios of glutathione and glutathione disulfide in the range of 0 to 50 microM CsA. The weakening or enforcement of the cellular glutathione state by the glutathione synthesis inhibitor buthionine sulfoximine or the glutathione disulfide -reducing agent dithiothreitol either increased or inhibited the CsA cytotoxicity, as determined by lactate dehydrogenase release. CsA also decreased the level of endogenous antioxidant ascorbic acid and increased its oxidation product dehydroascorbic acid. Supplementation of the cell cultures with ascorbic acid significantly reduced the CsA toxicity. The antioxidant DL-alpha-tocopherol-polyethylene-glycol-1000-succinate partly decreased CsA-mediated reactive oxygen species formation, totally decreased thiobarbituric acid reactive substances formation, prevented the loss of protein-bound sulfhydryl groups and in addition totally inhibited the CsA cytotoxicity. The present data provide good evidence that oxidative stress is part of the mechanism by which CsA causes toxicity in rat liver cells.

Cyclosporine A-Induced Oxidative Stress in Rat Hepatocytes

Preface Contributors Chapter 1 Fungal Secondary Metabolites in the "OMICS" Era Susanne Zeilinger, Carlos Garcia-Estrada, and Juan-Francisco Martin Chapter 2 Key Players in the Regulation of Fungal Secondary Metabolism Benjamin P Knox and Nancy P Keller Chapter 3 Epigenetics of Fungal Secondary Metabolism Related Genes Ming-Yueh Wu and Jae-Hyuk Yu Chapter 4 Genome Mining for Fungal Secondary Metabolic Gene Clusters Grayson T Wawrzyn, Mark A Held, Sarah E Bloch, and Claudia Schmidt-Dannert Chapter 5 Metagenomics and Metatranscriptomics for the Exploration of Natural Products from Soil Fungi Irshad Ul Haq and Jan Dirk van Elsas Chapter 6 Metabolomics and Secondary Metabolite Profiling of Filamentous Fungi Bernhard Kluger, Sylvia Lehner, and Rainer Schuhmacher Chapter 7 Fungal Chemotaxonomy Jens C Frisvad Chapter 8 Endophytic Fungi as a Source of Novel Metabolites Fernanda O Chagas, Andres Mauricio Caraballo-Rodriguez, and Monica T Pupo Chapter 9 Fungal Secondary Metabolism in the Light of Animal-Fungus Interactions: From Mechanism to Ecological Function Marko Rohlfs Chapter 10 Fusarium Mycotoxins and Their Role in Plant-Pathogen Interactions Gerhard Adam, Gerlinde Wiesenberger, and Ulrich Guldener Chapter 11 Biosynthesis and Molecular Genetics of Peptaibiotics - Fungal Peptides Containing Alpha, Alpha - Dialkyl Amino Acids Xiao-Yan Song, Bin-Bin Xie, Xiu-Lan Chen, Yu-Zhong Zhang

Biosynthesis and molecular genetics of fungal secondary metabolites

Cyclosporin A (CsA) is highly neuroprotective in several animal models of acute neurological damage and neurodegenerative disease with inhibition of the mitochondrial permeability transition (mPT) having emerged as a possible mechanism for the observed neuroprotection. In the present study, we have evaluated two new nonimmunosuppressive cyclosporin analogs NIM811 (Novartis) and UNIL025 (Debiopharm) for their ability to inhibit mPT in rat brain-derived mitochondria. Both NIM811 and UNIL025 were found to be powerful inhibitors of calcium-induced mitochondrial swelling under energized and deenergized conditions, and the maximal effects were identical to those of native CsA. The potencies of mPT inhibition by NIM811 and UNIL025 were stronger, with almost one order of magnitude higher potency for UNIL025 compared to CsA, correlating to their respective inhibitory action of cyclophilin activity. These compounds will be instrumental in the evaluation of mPT as a central target for neuroprotection in vivo.

The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria.

Publisher Summary The powerful immunosuppressive activity of ciclosporin (CS), which is apparently restricted at the cellular level of certain T lymphocytes, is recognized as a breakthrough in immunopharmacology. CS is a potent inhibitor of chronic or immune-mediated inflammatory reactions, but has no effect in models of acute inflammation. Its importance for exploring the pathogenesis and treatment of some acute and chronic inflammatory diseases, generally grouped as suspected autoimmune.diseases, is clearly emerging in the clinic. The use of CS in the treatment of several such diseases has revealed its potential to counteract the imbalance of the immune system by improving the condition of both experimental animals and patients. After a difficult learning process in which the efficacy and the side effects of the drug were explored, CS has proved to be of permanent clinical value and has, in consequence, revitalized the field of organ transplantation. In contrast to classical immunosuppressants, CS exerts a specific action on lymphocytes but is not detrimental to the functions of phagocytes or hemopoietic stem cells. Besides being an immunosuppressive drug, CS is also widely used as an experimental probe in basic research. While evidence for this concept is compelling, various phenomena in vivo are not readily explained by this model. This review shows that in vitro several pathways can be used to induce gene transcription in lymphocytes. Whether the alternative pathways, that is, those bypassing the T-cell receptor, are also relevant in vivo remains another question. However, only the pathways involving mobilization of intracellular calcium are CS-sensitive.

In Vivo Pharmacological Effects of Ciclosporin and Some Analogues

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In Vivo Pharmacological Effects of Ciclosporin and Some Analogues