A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain

Maladaptive plasticity involving increased expression of AMPA‐type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell‐permeable, high‐affinity (~2 nM) peptide inhibitor, Tat‐P$_4$‐(C5)$_2$, of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat‐P$_4$‐(C5)$_2$ disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA‐receptor surface expression in vivo. Moreover, Tat‐P$_4$‐(C5)$_2$ administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat‐P$_4$‐(C5)$_2$ as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non‐tandem protein–protein interaction domains

Safety and Efficacy of Topical Calcineurin Inhibitors in the Treatment of Facial and Genital Psoriasis: A Systematic Review

Facial and genital psoriasis impairs quality of life and is challenging to treat because of increased percutaneous penetration and, consequently, increased risk of adverse effects. Topical calcineurin inhibitors are recognized as a valid off-label treatment for these sensitive skin areas, but data on safety and efficacy are limited. This systematic review of the literature included 24 of 3,322 studies (5 randomized controlled trials, 9 open-label studies, 2 case series and 8 case reports). All studies demonstrated positive efficacy; 11 studies found statistically significant reductions in psoriasis severity. Local stinging, burning and itching were the most common short-term adverse effects and were reported in 18 studies. Topical calcineurin inhibitors appear to have an important role in the treatment of facial and genital psoriasis. The drugs are effective and generally well-tolerated with few adverse effects.

Genome-Wide Association Study of Genetic Variants in LPS-Stimulated IL-6, IL-8, IL-10, IL-1ra and TNF-α Cytokine Response in a Danish Cohort

<div><p>Background</p><p>Cytokine response plays a vital role in various human lipopolysaccharide (LPS) infectious and inflammatory diseases. This study aimed to find genetic variants that might affect the levels of LPS-induced interleukin (IL)-6, IL-8, IL-10, IL-1ra and tumor necrosis factor (TNF)-α cytokine production.</p><p>Methods</p><p>We performed an initial genome-wide association study using Affymetrix Human Mapping 500 K GeneChip® to screen 130 healthy individuals of Danish descent. The levels of IL-6, IL-8, IL-10, IL-1ra and TNF-α in 24-hour LPS-stimulated whole blood samples were compared within different genotypes. The 152 most significant SNPs were replicated using Illumina Golden Gate® GeneChip in an independent cohort of 186 Danish individuals. Next, 9 of the most statistical significant SNPs were replicated using PCR-based genotyping in an independent cohort of 400 Danish individuals. All results were analyzed in a combined study among the 716 Danish individuals.</p><p>Results</p><p>Only one marker of the 500 K Gene Chip in the discovery study showed a significant association with LPS-induced IL-1ra cytokine levels after Bonferroni correction (<i>P</i><10⁻⁷). However, this SNP was not associated with the IL-1ra cytokine levels in the replication dataset. No SNPs reached genome-wide significance for the five cytokine levels in the combined analysis of all three stages.</p><p>Conclusions</p><p>The associations between the genetic variants and the LPS-induced IL-6, IL-8, IL-10, IL-1ra and TNF-α cytokine levels were not significant in the meta-analysis. This present study does not support a strong genetic effect of LPS-stimulated cytokine production; however, the potential for type II errors should be considered.</p></div

Top 9 SNPs showing the highest evidence of association with IL-6, IL-8, IL-10, IL-1ra and TNF-α LPS stimulated plasma levels among healthy individuals with the most associated <i>P</i>-values <5×10⁻⁵ in the discovery stage or <i>P</i>-values <0.05 in the first replication stage (<i>n</i> = 716).

<p>Chromosomal positions are from NCBI build 36 (hg 18).</p

Manhattan plots showing <i>P</i>-values of association of each of the SNPs in the analysis with LPS stimulated plasma cytokine levels.

<p>SNPs are plotted on the X-axis to their position on each chromosome against cytokine levels on the Y-axis (shown as –log₁₀<i>P</i>-value).</p