Fig. 2

miRNA modulation. Two methods are employed for miRNA therapeutics restoration of miRNA or inhibition. Restoring miRNA is through the use of double-stranded RNA, which is composed of a guide and passenger strand that is chemically modified usually by a cholesterol modification. The guide strand is identical to the miRNA that is diminished. This is then incorporated into the RISC complex and the target mRNAs reduced. Inhibition of miRNA function is achieved through single-stranded chemically modified LNA antagomirs which can be cholesterol-conjugated and have increased stability. These molecules bind the mature miRNA and stop them from being loaded into the RISC, therefore increasing the mRNA target(s). In the context of fibrosis, to the right of the illustrations are examples of miRNA as both a mimic and antagomir binding the target mRNA and altering the protein output. Smad7 is a negative regulator of the fibrotic cascade, so elevated levels reduce fibrosis. PPAR-α is also a negative regulator of fibrosis and thus its restoration is positive. miRNA, MicroRNA, PPARα peroxisome proliferator activator receptor-alpha, RISC RNA-induced silencing complex