ABSTRACT
Phosphorylation of the serine 139 of the histone variant H2AX (γH2AX) is a DNA damage marker that regulates DNA damage response and various diseases. However, whether γH2AX is involved in neuropathic pain is still unclear. We found the expression of γH2AX and H2AX decreased in mice dorsal root ganglion (DRG) after spared nerve injury (SNI). Ataxia telangiectasia mutated (ATM), which promotes γH2AX, was also down-regulated in DRG after peripheral nerve injury. ATM inhibitor KU55933 decreased the level of γH2AX in ND7/23 cells. The intrathecal injection of KU55933 down-regulated DRG γH2AX expression and significantly induced mechanical allodynia and thermal hyperalgesia in a dose-dependent manner. The inhibition of ATM by siRNA could also decrease the pain threshold. The inhibition of dephosphorylation of γH2AX by protein phosphatase 2A (PP2A) siRNA partially suppressed the down-regulation of γH2AX after SNI and relieved pain behavior. Further exploration of the mechanism revealed that inhibiting ATM by KU55933 up-regulated extracellular-signal regulated kinase (ERK) phosphorylation and down-regulated potassium ion channel genes, such as potassium voltage-gated channel subfamily Q member 2 (Kcnq2) and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in vivo, and KU559333 enhanced sensory neuron excitability in vitro. These preliminary findings imply that the down-regulation of γH2AX may contribute to neuropathic pain.
Subject(s)
Neuralgia , Peripheral Nerve Injuries , Animals , Mice , Ganglia, Spinal/metabolism , Hyperalgesia/genetics , Hyperalgesia/metabolism , Neuralgia/etiology , Neuralgia/metabolism , Peripheral Nerve Injuries/metabolism , Potassium/metabolism , RNA, Small Interfering/metabolism , Sensory Receptor Cells/metabolism , Shal Potassium Channels/metabolismABSTRACT
Metabolically associated fatty liver disease (MAFLD) is a common cause of chronic liver disease, the hepatic manifestation of metabolic syndrome. Despite the increasing incidence of MAFLD, no effective treatment is available. Recent research indicates a link between the intestinal microbiota and liver diseases such as MAFLD. The composition and characteristics of the intestinal microbiota and therapeutic perspectives of MAFLD are reviewed in the current study. An imbalance in the intestinal microbiota increases intestinal permeability and exposure of the liver to adipokines. Furthermore, we focused on reviewing the latest "gut-liver axis" targeted therapy.
