No abstract

Emerging evidence indicates that CXCL12/ CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mechanism. Here, we determined that spared nerve injury (SNI) increased the expression of CXCL12 and its cognate receptor CXCR4 in lumbar 5 dorsal root ganglia (DRG) neurons and satellite glial cells. SNI also induced longlasting upregulation of CXCL12 and CXCR4 in the ipsilateral L4-5 spinal cord dorsal horn, characterized by CXCL12 expression in neurons and microglia, and CXCR4 expression in neurons and astrocytes. Moreover, SNIinduced a sustained increase in TNF-a expression in the DRG and spinal cord. Intraperitoneal injection (i.p.) of the TNF-a synthesis inhibitor thalidomide reduced the SNI-induced mechanical hypersensitivity and inhibited the expression of CXCL12 in the DRG and spinal cord. Intrathecal injection (i.t.) of the CXCR4 antagonist AMD3100, both 30 min before and 7 days after SNI, reduced the behavioral signs of allodynia. Rats given an i.t. or i.p. bolus of AMD3100 on day 8 of SNI exhibited attenuated abnormal pain behaviors. The neuropathic pain established following SNI was also impaired by i.t. administration of a CXCL12-neutralizing antibody. Moreover, repetitive i.t. AMD3100 administration prevented the activation of ERK in the spinal cord. The mechanical hypersensitivity induced in naïve rats by i.t. CXCL12 was alleviated by pretreatment with the MEK inhibitor PD98059. Collectively, our results revealed that TNF-a might mediate the upregulation of CXCL12 in the DRG and spinal cord following SNI, and that CXCL12/CXCR4 signaling via ERK activation contributes to the development and maintenance of neuropathic pain.

No abstract

TMEM206 has been recently identified as an evolutionarily conserved chloride channel that underlies ubiquitously expressed, proton-activated, outwardly rectifying anion currents. Here, we report the cryo–electron microscopy structure of pufferfish TMEM206, which forms a trimeric channel, with each subunit comprising two transmembrane segments and a large extracellular domain. An ample vestibule in the extracellular region is accessible laterally from the three side portals. The central pore contains multiple constrictions. A conserved lysine residue near the cytoplasmic end of the inner helix forms the presumed chloride ion selectivity filter. Unprecedentedly, the core structure and assembly closely resemble those of the epithelial sodium channel/degenerin family of sodium channels that are unrelated in amino acid sequence and conduct cations instead of anions. Together with electrophysiology, this work provides insights into ion conduction and gating for a new class of chloride channels that is architecturally distinct from previously characterized chloride channel families.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies with rising incidence and persistently high mortality. Previous researches have demonstrated that some PLOD family members are associated with tumor progression and metastasis in most human cancers. However, the prognostic and biological roles of PLODs in HCC remain largely unknown. Methods: ONCOMINE, HPA, UALCAN, GEPIA, cBioPortal, GeneMANIA, NetworkAnalyst, Metascape, DAVID 6.8, and TIMER were used to determine the prognostic values and biological function of PLOD family members in HCC. Results: The mRNA and protein expression patterns of PLOD family members were noticeably upregulated in HCC compared to normal tissue. The high expression levels of PLOD1 and PLOD2 genes were significantly correlated with higher tumor grades in HCC patients. In addition, the high expression levels of PLOD1-3 were remarkably associated with poor overall survival in HCC patients, while high PLOD1 and PLOD3 expression were markedly associated with worse disease-free survival. In the coexpression gene analysis, 20 genes were primarily associated with the differentially expressed PLOD family members in HCC cases. Through functional enrichment analysis, the biological functions of PLODs in HCC were mainly involved in collagen fibril organization, lysine degradation, collagen biosynthesis, and modifying enzymes. Furthermore, the expression levels of PLOD1-3 were positively correlated with the activities of tumor-infiltrating immune cells, including macrophages, neutrophils, CD4+ T cells, and dendritic cells. Besides, the expression levels of PLOD2 and PLOD3 were positively correlated with the infiltrating levels of B cells. Conclusion: The findings of this study could provide novel insights into the identification of prognostic biomarkers for HCC patients.

No abstract

Viral infections still threaten human health all over the world, and many people die from viral diseases every year. However, there are no effective vaccines or drugs for preventing or managing most viral diseases. Thus, the discovery and development of broad-spectrum antiviral agents remain urgent. Here, we expressed and purified a venom peptide, Ev37, from the scorpion Euscorpiops validus in a prokaryotic system. We found that rEv37 can inhibit dengue virus type 2 (DENV-2), hepatitis C virus (HCV), Zika virus (ZIKV), and herpes simplex virus type 1 (HSV-1) infections in a dose-dependent manner at noncytotoxic concentrations, but that it has no effect on Sendai virus (SeV) and adenovirus (AdV) infections in vitro. Furthermore, rEv37 alkalized acidic organelles to prevent low pH-dependent fusion of the viral membrane-endosomal membrane, which mainly blocks the release of the viral genome from the endosome to the cytoplasm and then restricts viral late entry. Taken together, our results indicate that the scorpion venom peptide Ev37 is a broad-spectrum antiviral agent with a specific molecular mechanism against viruses undergoing low pH-dependent fusion activation during entry into host cells. We conclude that Ev37 is a potential candidate for development as an antiviral drug.

Atherosclerosis (AS), with associated risk of stroke or cerebrovascular disease, is one of the most common causes of death globally. It has been well established that tripartite motif‐containing protein 7 Tripartite Motif‐containing 7 (Trim7), as an E3 ubiquitin protein ligase, is involved in protein ubiquitination and thus regulating cellular proliferation. Moreover, TRIM7 is upregulated in advanced carotid AS. However, the detailed mechanism of TRIM7 on regulation of AS remains unclear. In the present study, we firstly discovered that TRIM7 expression was robustly induced in platelet‐derived growth factor type BB‐treated vascular smooth muscle cells (VSMCs) and human atherosclerotic plaques. Functional approaches established that knockdown of TRIM7 inhibited proliferation and migration of VSMCs, as well as arrested the cell cycle at G1‐S, thus suppressing AS progression. Our results also identified that c‐Jun/activator protein 1 (AP‐1) signaling pathway was activated by TRIM7. Moreover, gain‐ and loss‐of‐function studies revealed that TRIM7 could promote proliferation and migration of VSMCs via activation of c‐Jun/AP‐1 signaling pathway. Finally, by using atherogenic apolipoprotein E‐deficient (apoE–/–) C57BL/6 mice with high‐fat diet AS model, we demonstrated that interference of TRIM7 could effectively mitigate in vivo AS via inactivation of c‐Jun/AP‐1 signaling pathway. In general, activation of c‐Jun/AP‐1 signaling pathway via TRIM7 could be an important mechanism in AS progression, thus shedding light on the development of novel therapeutics to the treatment of the disease.