{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T19:21:25Z","timestamp":1777576885428,"version":"3.51.4"},"reference-count":43,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2014,2,27]],"date-time":"2014-02-27T00:00:00Z","timestamp":1393459200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["Intramural project"],"award-info":[{"award-number":["Intramural project"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2014,3]]},"abstract":"Background and Purpose<\/jats:title>The combination of paromomycin\u2013miltefosine is a successful anti\u2010leishmanial therapy in visceral leishmaniasis (VL<\/jats:styled-content>). This encouraged us to study its effect on T<\/jats:styled-content>oll\u2010like receptor (TLR<\/jats:styled-content>)\u2010mediated immunomodulation of dendritic cells (DC<\/jats:styled-content>), as DC<\/jats:styled-content> maturation and activation is crucial for anti\u2010leishmanial activity.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>In silico<\/jats:italic> protein\u2013ligand interaction and biophysical characterization of TLR9<\/jats:styled-content>\u2013drug interaction was performed. Interaction assays of HEK293<\/jats:styled-content> cells with different concentrations of miltefosine and\/or paromomycin were performed, and NF<\/jats:styled-content>\u2010\u03baB<\/jats:styled-content> promoter activity measured. The role of TLR9<\/jats:styled-content> and MyD88<\/jats:styled-content> in paromomycin\/miltefosine\u2010induced maturation and activation of DCs was evaluated through RNA<\/jats:styled-content> interference techniques. The effect of drugs on DCs<\/jats:styled-content> was measured in terms of counter\u2010regulatory production of IL\u201012<\/jats:styled-content> over IL\u201010<\/jats:styled-content>, and characterized by chromatin immunoprecipitation assay at the molecular level.<\/jats:p><\/jats:sec>Key Results<\/jats:title>Computational and biophysical studies revealed that paromomycin\/miltefosine interact with TLR9<\/jats:styled-content>. Both drugs, as a monotherapy\/combination, induced TLR9<\/jats:styled-content>\u2010dependent NF<\/jats:styled-content>\u2010\u03baB<\/jats:styled-content> promoter activity through MyD88<\/jats:styled-content>. Moreover, the drug combination induced TLR9<\/jats:styled-content>\/MyD88<\/jats:styled-content>\u2010dependent functional maturation of DCs<\/jats:styled-content>, evident as an up\u2010regulation of co\u2010stimulatory markers, enhanced antigen presentation by increasing MHC II<\/jats:styled-content> expression, and increased stimulation of naive T<\/jats:styled-content>\u2010cells to produce IFN<\/jats:styled-content>\u2010\u03b3<\/jats:styled-content>. Both drugs, by modifying histone H3 at the promoter level, increased the release of IL\u201012<\/jats:styled-content>, but down\u2010regulated IL\u201010<\/jats:styled-content> in a TLR9<\/jats:styled-content>\u2010dependent manner.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>These results provide the first evidence that the combination of paromomycin\u2013miltefosine critically modifies the maturation, activation and development of host DCs<\/jats:styled-content> through a mechanism dependent on TLR9<\/jats:styled-content> and MyD88<\/jats:styled-content>. This has implications for evaluating the success of other combination anti\u2010leishmanial therapies that act by targeting host DCs<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12530","type":"journal-article","created":{"date-parts":[[2013,11,26]],"date-time":"2013-11-26T05:21:54Z","timestamp":1385443314000},"page":"1260-1274","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["TLR9<\/scp> and MyD88<\/scp> are crucial for the maturation and activation of dendritic cells by paromomycin\u2013miltefosine combination therapy in visceral leishmaniasis"],"prefix":"10.1111","volume":"171","author":[{"given":"Sushmita","family":"Das","sequence":"first","affiliation":[{"name":"Department of Molecular Parasitology Rajendra Memorial Research Institute of Medical Sciences Indian Council of Medical Research Bihar 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