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  • The mechanism study demonstrated that BDNF is one of


    The mechanism study demonstrated that BDNF is one of the fundamental mechanisms underlying JMJD2A effects during neuropathic pain. BDNF is a neurotrophin with essential functions in neuronal development and neuroplasticity. Accumulating evidence suggests that alterations in BDNF expression levels underlie a variety of psychiatric and neurological disorders [29]. Epigenetic regulation of BDNF expression is widely investigated. The BDNF gene structure and tissue expression pattern is complex, controlled in humans by nine different gene promoters. Recently, epigenetic changes at the BDNF gene locus have been proposed to provide a link between gene and environment [30]. Histone modifications around individual BDNF gene promoters in prefrontal GW788388 australia are associated with extinction of conditioned fear [31]. More specifically, various environmental factors, particularly when occurring during development, have been claimed to produce long-lasting epigenetic changes in the BDNF gene, thereby affecting availability and function of the BDNF protein [22]. Our evidence showed that the histone demethylase JMJD2A could promote the expression of Bdnf. During CCI and SNI-induced neuropathic pain, 5-HT mediated the upregulation of JMJD2A. JMJD2A bound to the promoter of Bdnf, where it demethylated H3K9me3 and H3K36me3 to activate the expression of Bdnf induced by neuropathic pain insults. However, 5-HT increased BDNF irrespective of the presence or absence of Jmjd2a, other mechanisms may also contribute to the effect of 5-HT on BDNF expression. For example, activation of 5-HT receptors coupled to cAMP production and cAMP-response element binding protein (CREB) activation can induce transcription of the BDNF gene. 5-HT could facilitate learning and memory during aging by stimulating the expression of BDNF [32]. BDNF is a factor critically involved in neuropathic pain [22]. However, further study is needed to investigate whether BDNF is critically required for JMJD2A-mediated promotion during neuropathic pain and other mechanisms may also contribute to the function of JMJD2A in neuropathic pain. Another limitation for this study is that we isolated neurons from whole brain tissues. Brain neurons include both excitatory and inhibitory subpopulations. Using whole brain tissues to isolate neurons has its own deficits, which may make our story less specificity.
    Conflict of interest
    Introduction Liver fibrosis occurs following a wide range of injurious stimuli including hepatotoxic chemicals, cholestasis, and liver-inhabiting pathogens [1]. Regardless of the etiology, fibrogenesis in the liver is dictated by myofibroblasts, which transition from a dormant state to an active phenotype characterized by the augmented ability to synthesize both contractile proteins and extracellular matrix proteins [2]. Despite the staggering amount of time and efforts invested in combating liver fibrosis, effective remedies that can block or reverse this devastating pathology remain elusive. It is believed that fibrosis can proceed in a cell-autonomous manner inevitably and irreversibly progressing to cirrhosis and hepatocellular carcinoma even when the original stimulus has been eliminated [3]. The controversy with regard to their origins notwithstanding, myofibroblasts are in most cases derived from hepatic stellate cells (HSCs) [4]. Quiescent HSCs serve as a depot for vitamin A and lipids in the liver. When exposed to one or more of the triggering factors, HSCs quickly embark on a differentiation process to become myofibroblasts. HSC trans-differentiation is trademarked by an overhaul of its gene expression patterns. For instance, genes involved in lipid metabolism such as peroxisome proliferator activated receptor gamma (Pparg) are down-regulated in activated HSCs compared to quiescent HSCs. On the contrary, proteins that define the functionalities of myofibroblasts such as alpha smooth muscle actin (Acta2) are up-regulated [5]. Clear elucidation of the mechanism that underscores differential regulation of gene expression during HSC trans-differentiation furthers our understanding of the pathogenesis of liver fibrosis and is imperative to devising an effective therapeutic strategy.