Extracellular RNAs-TLR3 signaling contributes to cognitive impairment after chronic neuropathic pain in mice

Chronic pain is often associated with cognitive decline,which could influence the quality of the patient’s life.Recent studies have suggested that Toll-like receptor 3(TLR3)is crucial for memory and learning.Nonetheless,the contribution of TLR3 to the pathogenesis of cognitive decline after chronic pain remains unclear.The level of TLR3 in hippocampal neurons increased in the chronic constriction injury(CCI)group than in the sham group in this study.Importantly,compared to the wild-type(WT)mice,TLR3 knockout(KO)mice and TLR3-specific neuronal knockdown mice both displayed improved cognitive function,reduced levels of inflammatory cytokines and neuronal apoptosis and attenuated injury to hippocampal neuroplasticity.Notably,extracellular RNAs(exRNAs),specifically double-stranded RNAs(dsRNAs),were increased in the sciatic nerve,serum,and hippocampus after CCI.The co-localization of dsRNA with TLR3 was also increased in hippocampal neurons.And the administration of poly(I:C),a dsRNA analog,elevated the levels of dsRNAs and TLR3 in the hippocampus,exacerbating hippocampus-dependent memory.In additon,the dsRNA/TLR3 inhibitor improved cognitive function after CCI.Together,our findings suggested that exRNAs,particularly dsRNAs,that were present in the condition of chronic neuropathic pain,activated TLR3,initiated downstream inflammatory and apoptotic signaling,caused damage to synaptic plasticity,and contributed to the etiology of cognitive impairment after chronic neuropathic pain.

Allosteric Modulation of Human Serum Albumin Induced by Peptide Ligand

Human serum albumin （HSA） is an abundant protein in plasma that can bind and transport many small molecules, and the corresponding affinity-controlled drug delivery shows great advantage in the biological system. Peptide SA06 is a reported ligand comprising 20 amino acids, and is known to non-covalently bind with HSA to extend the lifetime and improve the pharmacokinetic performance. The structural information of the HSA-peptide complex is keen for obtainingmolecular insight of the binding mechanism. We studied the secondary structural change and structure-affinity relations of Peptide SA06 with HSA by using circular dichroism （CD） spectroscopy in solution. Noticeable allosteric effect can be identified by compositional increase of a-helix structures when the peptide was co-incubated with HSA. Furthermore, the equilibrium dissociation constant of Peptide SA06 with HSA can be determined by CD-baged method. This work provides structural evidence on the allosteric interaction between peptide ligand and HSA, and sheds light on optimization of therapeutic properties in the affinity-controlled delivery systems.