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Exosomal MicroRNAs Associate With Neuropsychological Performance in Individuals With HIV Infection on Antiretroviral Therapy.
BackgroundNeurocognitive dysfunction remains prevalent among people living with HIV (PLWH), even after viral suppression on combination antiretroviral therapy (cART). We investigated associations between neuropsychological performance (NP) and patterns of circulating exosomal microRNA (exo-miRNA) expression in PLWH on cART.SettingA cross-sectional examination of plasma exo-miRNA among PLWH on cART with systemic viral suppression and volunteers without HIV infection.MethodsThirty-one PLWH who started cART during early infection (n = 19) or chronic infection (n = 12) participated in phlebotomy and an 11-test neuropsychological battery after >1 year on treatment. NP higher- or lower-performing participants were categorized based on normalized neuropsychological scores. Total RNA was extracted from purified exosomes of 31 PLWH and 5 volunteers without HIV and subject to small RNA sequencing. Differential expression of exo-miRNAs was examined and biological functions were predicted.ResultsEleven exo-miRNAs were up-regulated in NP lower-performing (n = 18) relative to higher-performing PLWH (n = 13). A high proportion of the differentiating exo-miRNA target the axon guidance KEGG pathway and neurotrophin tyrosine receptor kinase signaling Gene Ontology pathway. Differential expression analysis of exo-miRNAs between NP lower- (n = 7) and higher-performing (n = 12) PLWH within the early infection group alone confirmed largely consistent findings.ConclusionsPlasma exo-miRNA content differed between NP higher- and lower-performing PLWH. Several differentially expressed exo-miRNAs were predicted to be involved in inflammation and neurodegeneration pathways. Exo-miRNA in plasma may indicate cross-talk between the circulation and central nervous system and thus may be clinically relevant for neurocognitive dysfunction in PLWH
Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin
We describe oral nanocarriers, termed “NanoPills” (NPs), for simultaneous short-term control and long-term reversal of pancreatic inflammation. We hypothesized that since bile acids emulsify fats during digestion, regulate glucose and modulate immunity, that NPs constructed from polymeric bile acid will be effective, multifunctional, oral therapeutics. Polymerized ursodeoxycholic acid (pUDCA) NP protected encapsulated agent in the stomach, permeated intestinal epithelia, then bound macrophage bile receptors with high avidity. Strikingly, pUDCA NPs localized to the pancreas after oral ingestion through macrophage-mediated transport and particle enterohepatic circulation. In a drug-induced pancreatic inflammation model, rapamycin-loaded NPs prevented disease. In a spontaneous model of type I diabetes (T1D), NP alone restored normoglycemia for 2 weeks and reversed disease with loaded insulin. Thus, for the first time, an integrative approach is presented enabling oral delivery through a carrier that intrinsically restores endogenous pancreatic insulin secretion, and tolerogenic immunity for rapid control and long-term regulation of T1D