Veratridine Mammalian silent information regulator homolog S
Mammalian silent information regulator 2 homolog (SIRT1) is a nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase that removes acetyl groups from proteins, and functions in oxidative stress, apoptosis and autophagy . It is reported that SIRT1 plays critical roles in various types of pain, including inflammatory pain [9,10], neuropathic pain [11,12] and bone cancer pain . In rodent models of inflammatory pain and neuropathic pain, both the expression and activity of SIRT1 are down-regulated in neurons of dorsal root ganglion (DRG)  and spinal cord . In addition, chemical agents acting on SIRT1 activity have obvious effect on augmentation or alleviation of pain. SIRT1 agonist treatment alleviates spontaneous pain, thermal hyperalgesia, and mechanical allodynia [13,14], while SIRT1 inhibitor aggravates the nociceptive effect . Induction of pain is depended on activation of certain ion channels in pathways of pain perception. Metabotropic glutamate receptor (mGluR1) and mGluR5 plays essential roles in nociceptive processing via increasing the opening of cation channels (such as Ca2+, Na+ and K+ channels). SIRT1 is involved in the regulation of mGluR1/5 expression . Through regulating these receptors, SIRT1 is implicated in central sensitization of pain. In addition, SIRT1 was involved in periphery sensitization by regulating the expression of acid-sensing ion channels 3 (ASIC3) in DRG neuron . Accordingly, SIRT1 is a critical regulator of BCP and could be a potential therapeutic target for bone cancer pain.
Neurons are metabolically active Veratridine with high energy demands and particularly dependent on mitochondrial function . As a dynamic organelle, mitochondrion is known for its critical roles in energy metabolism, cell survival, and synaptic plasticity . Mitochondrial fission maintains mitochondrial structure, and alterations in fission process are linked to many human diseases, such as neurodegenerative disease [18,19], cancers  and metabolic disorders . Dynamin-related protein 1 (Drp1), a cytosolic GTPase, migrates between the cytosol and the mitochondrial network, binds to mitochondrial outer membrane, and drives mitochondrial fission . Drp1 homozygous knockout mice are lethal in embryos due to reduced mitochondrial fission . Drp1 gene mutations lead to abnormal brain development, optic atrophy and neonatal lethality . Dysregulation of Drp1 is related to mitochondrial dysfunction-mediated pain. In the perineural HIV coat glycoprotein gp120-induced neuropathic pain rats, increase of Drp1 expression in spinal cord is observed while antisense oligodeoxynucleotide against Drp1 treatment attenuated mechanical allodynia [24,25].
In order to evaluate the effect of SIRT1 on Drp1 expression and mitochondrial fission in bone cancer pain, we used SRT1720 (N-[2-[3-(piperazin-1-ylmethyl) imidazo [2,1-b] [1,3] thiazol-6-yl] phenyl] quinoxaline-2-carboxamide), a specific agonist of SIRT1 , to activate SIRT1 and detect Drp1 expression and mitochondrial-mediated apoptosis in BCP rats. Our data demonstrated that SIRT1 activation attenuated bone cancer pain via reversing Drp1-mediated mitochondrial fission.
Materials and methods
Introduction LIN28 was first discovered in the nematode Caenorhabditis elegans as a heterochronic gene involved in regulation of developmental timing . Since its initial discovery, LIN28 has been identified as a highly conserved RNA binding protein, implicated in cancers, stem cell pluripotency and differentiation, reprogramming, normal development, and glucose metabolism . LIN28 consists of two homologs, LIN28A and LIN28B, that have similar structural and functional characteristics and few differences . Both LIN28A and LIN28B selectively block expression of let-7 microRNAs and function as oncogenes by promoting tumorigenesis and invasiveness in cancers such as prostate, ovarian, gastric, glioblastoma, and breast cancer through individual modes of action . LIN28A recruits TUTase (zcchc11/TUTase4) to block the processing of let-7 in the cytoplasm while, LIN28B represses let-7 by inhibiting their processing by the Microprocessor .