Ascomycin(FK 520)

Ascomycin (FK 520, FR900520) is a novel neutral macrolide immunosuppressant, isolated from the cultured broth of Streptomyces hygroscopicus subsp. yakushimaensis No. 7238.

In vitro: Ascomycin (FK 520, FR900520) suppressed lymphocyte reaction in a dose dependent fashion. Ascomycin was non-toxic at concentrations less than 3,200 nM, at which the percent inhibition was 18.9%. Ascomycin showed antifungal activity against Aspergillus fumigatus IFO 5840. Ascomycin had no inhibitory effect on bacteria or yeast at 100 μg/ml [1].

In vivo: Ascomycin was dose-dependently effective and clearly prolonged skin allograft survival at 3.2 mg/kg or more, though all skin allografts were rejected within 7 days in rats treated intramuscularly with olive oil. Ascomycin, dissolved in olive oil, showed no adverse effect when administered intraperitoneally to ddY mice (male, 8 weeks old) at 100 mg/kg [1].

Clinical trial: Ascomycin macrolactam derivative, Pimecrolimus, had been tested in both adults and pediatric patients with Atopic Dermatitis in two seperate clinical trials.

Reference:
[1] Hatanaka H, Kino T, Miyata S, Inamura N, Kuroda A, Goto T, Tanaka H, Okuhara M.  FR-900520 and FR-900523, novel immunosuppressants isolated from a Streptomyces. II. Fermentation, isolation and physico-chemical and biological characteristics. J Antibiot (Tokyo). 1988;41(11):1592-601.

The performance of five different dried blood spot cards for the analysis of six immunosuppressants.[Pubmed:26045003]

Bioanalysis. 2015;7(10):1225-35.

BACKGROUND: The relation between hematocrit, substance concentration, extraction recovery and spot formation of tacrolimus, sirolimus, everolimus, ascomycin, temsirolimus and cyclosporin A was investigated for Whatman 31 ET CHR, Whatman FTA DMPK-C, Whatman 903, Perkin Elmer 226 and Agilent Bond Elut DMS DBS cards. RESULTS & DISCUSSION: We found that all DBS cards showed the same hematocrit and concentration-dependent recovery patterns for sirolimus, everolimus and temsirolimus. At high concentrations, the total hematocrit effects were much more pronounced than at low concentrations for tacrolimus, sirolimus, everolimus, ascomycin and temsirolimus. CONCLUSION: The tested card types showed differences in performance, especially at extreme concentrations and hematocrit values. It may be useful to investigate the performance of different types of DBS cards prior to analytical method validation.

The Dynamic Role of the IL-33/ST2 Axis in Chronic Viral-infections: Alarming and Adjuvanting the Immune Response.[Pubmed:27397514]

EBioMedicine. 2016 Jul;9:37-44.

UNLABELLED: Interleukin 33 (IL-33), a member of the IL-1 family, is constitutively expressed in epithelial and in endothelial cells at barrier sites, acting as a danger signal and adjuvanting the immune response following tissue damage and infection. Originally implicated in allergy, IL-33 is also known to be involved in innate and adaptive immune responses by enhancing natural killer, Th1, and CD4 and CD8 T-cell functions. The nature of the antiviral immune response orchestrated by IL-33 depends on the site of infection, the duration of the disease and the cytokine milieu. In this review, we focus on the distinctive contribution of IL-33 as an anti-infective and proinflammatory cytokine in response to cell death and viral infections. The dynamic role of IL-33 in the acute and chronic phases of infection with HIV, hepatitis B and C viruses, and with CMV is highlighted. This review will also discuss the potential immunotherapeutic and adjuvant roles of IL-33. SEARCH STRATEGY AND SELECTION CRITERIA: English language, indexed publications in PubMed were searched using combinations of following key words: "interleukin-33", "IL-33", "suppression of tumorigenicity 2", ST2", "sST2", "HIV", "HBV", "HCV", "CMV", "HPV", "immunotherapy" and "vaccine". Except for seminal studies, only articles published between 2010 and 2016 were included.

[Inverse psoriasis].[Pubmed:25896586]

Hautarzt. 2015 Jun;66(6):408-12.

Inverse psoriasis is clinically defined by chronic inflammatory lesions in intertrigineous areas. Colonisation or infection with Candida ssp. or bacteria is common. The disease-related quality of life is significantly reduced especially regarding sexual behavior. After the exclusion of relevant differential diagnoses, therapy should be adapted to the clinical outcome and potential comorbidities. Substances which are efficacious in psoriasis vulgaris are generally efficacious in inverse psoriasis, but have to be used off-label. Controlled clinical studies are only available for topical ascomycin.

The calcineurin inhibitor Ascomicin interferes with the early stage of the epileptogenic process induced by Latrunculin A microperfusion in rat hippocampus.[Pubmed:25104570]

J Neuroimmune Pharmacol. 2014 Dec;9(5):654-67.

Latrunculin A microperfusion in rat hippocampus has shown to be an effective model of acute and chronic seizures for neurochemical studies. The intervention over early synaptic plasticity changes after the epileptogenesis onset represents a big challenge on the design of a suitable therapy to impair the epilepsy development. We previously suggested that receptor location might be essential for controlling neuronal excitability, and that disruption of local cytoskeletal dynamics followed by drastic changes in the synaptic/extrasynaptic ratio of NMDA, AMPA receptors and their subsequent downstream signalling may play an important role in the pathogenesis of seizures. In the present study, we performed a pharmacological intervention in the Latrunculin model by using Ascomicin (ASC) and Phenytoin (PHT). We pointed out the inhibitory action of ASC over the protein phosphatase 2B (PP2B). PP2B pathological mechanism involves changes in actin cytoskeleton and showed to avoid those subsequent changes previously observed in PSD components. On the contrary, PHT didn't seem to modify the F-actin depolymerization process induced, showing a similar redistribution pattern from the PSD towards the extrasynaptic site of several molecular components with more or less dependence on actin for their location, including glutamate receptors. Overall, we propose that the early intervention over changes on the synapse during the epileptogenic process might represent the best approach to avoid the onset of chronic refractory seizures our model. On this regard, the therapeutic potential of ASC, FK506 and derivatives should be further explored as a possible tool in the intervention over epilepsy and other brain diseases.

Differential targeting of dynamin-1 and dynamin-3 to nerve terminals during chronic suppression of neuronal activity.[Pubmed:25827095]

Mol Cell Neurosci. 2015 Sep;68:36-45.

Neurons express three closely related dynamin genes. Dynamin 1 has long been implicated in the regulation of synaptic vesicle recycling in nerve terminals, and dynamins 2 and 3 were more recently shown also to contribute to synaptic vesicle recycling in specific and distinguishable ways. In cultured hippocampal neurons we found that chronic suppression of spontaneous network activity differentially regulated the targeting of endogenous dynamins 1 and 3 to nerve terminals, while dynamin 2 was unaffected. Specifically, when neural activity was chronically silenced for 1-2weeks by tetrodotoxin (TTX), the clustering of dynamin 1 at nerve terminals was reduced, while the clustering of dynamin 3 significantly increased. Moreover, dynamin 3 clustering was induced within hours by the sustained blockade of AMPA receptors, suggesting that AMPA receptors may function to prevent Dyn3 accumulation within nerve terminals. Clustering of dynamin 3 was induced by an antagonist of the calcium-dependent protein phosphatase calcineurin, but was not dependent upon intact actin filaments. TTX-induced clustering of Dyn3 occurred with a markedly slower time-course than the previously described clustering of synapsin 1. Potassium-induced depolarization rapidly de-clustered dynamin 3 from nerve terminals within minutes. These results, which have implications for homeostatic synapse restructuring, indicate that the three dynamins have evolved different regulatory mechanisms for trafficking to and from nerve terminals in response to changes in neural activity.