Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy

Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.

Effects of bicarbonate/lactate-buffered neutral peritoneal dialysis fluids on angiogenesis-related proteins in patients undergoing peritoneal dialysis

Background In order to facilitate the safe and long-term delivery of peritoneal dialysis (PD), it is necessary to improve the biocompatibility of peritoneal dialysis fluids (PDFs). The novel bicarbonate/lactate-buffered neutral PDFs (B/L-PDFs) are expected to be improved biocompatible. This study evaluated the biocompatibility of B/L-PDFs by analysis on the profile of angiogenesis-related proteins in drained dialysate of patients undergoing PD. Methods Concentrations of 20 angiogenesis-related proteins in the dialysate were semi-quantitatively determined using a RayBio® Human Angiogenesis Antibody Array and were compared between B/L-PDFs and conventional lactate-buffered neutral PDFs (L-PDFs). Results The expression of growth-related oncogene (GRO α/β/γ), which belongs to the CXC chemokine family, decreased significantly after use of the B/L-PDFs compared to the L-PDFs (P = 0.03). The number of the proteins with lower level in the B/L-PDFs compared with L-PDFs was significantly negatively correlated with the PD duration (Spearman ρ = − 0.81, P = 0.004). Conclusion This study suggested that B/L-PDFs are more biocompatible than conventional PDFs.

Bioinformatics Analyses Reveals a Comprehensive Landscape of CXC Chemokine Family Functions in Non-Small Cell Lung Cancer

Backgrounds. Lung cancer is a major source of tumor-related death each year with non-small cell lung cancer (NSCLC) being a prevalent subtype. The metastasis from NSCLC to the brain usually imposes many neuron disorders. Previous studies have suggested that communications among cancer cells and interstitial cells are essential in tumorigenesis and are influenced by chemokines. In the tumor microenvironment, CXC chemokines can participate in the shifting of immune cells and manage tumor cell condition, thus affecting the progression of cancer and patient destinies. However, the expression and values of CXC chemokine family in NSCLC have not been systematically illustrated using public databases. Methods. UALCAN, STRING, ONCOMINE, GeneMANIA, cBioPortal, GEPIA, TISIDB, TRRUST, TIMER, Kaplan-Meier Plotter, and R software were utilized in this study. Results. Based on the TIMER and UACLCAN databases, in LUAD patients, the expression levels of CXCL10, CXCL13, and CXCL14 were significantly elevated while the transcriptional levels of CXCL2/3/4/7/12/16 were significantly reduced; in LUSC patients, the expression levels of CXCL6/10/13/14 were significantly elevated while the expression levels of CXCL2/3/4/5/7/11/12/16/17 were significantly reduced. We found remarkable relevance between the pathological stages of LUAD patients and the expressions of CXCL8 (positive) and CXCL17 (negative). Similarly, there are significant correlations between the pathological stages of LUSC patients and the expressions of CXCL1/2/6/17. In LUAD, patients with low expression levels of CXCL1/4/7/8 and patients with high expression levels of CXCL12/14/16 were associated with a significantly better prognosis. But in LUSC, all correlations between chemokines and prognosis are statistically insignificant. Pairwise expression correlation analysis among CXC chemokines shows that there are 7 significant correlations (between CXCL1 and CXCL2, between CXCL1 and CXCL3, between CXCL1 and CXCL8, between CXCL2 and CXCL3, between CXCL4 and CXCL7, between CXCL9 and CXCL10, and between CXCL9 and CXCL11) in LUAD and 4 significant correlations (between CXCL1 and CXCL8, between CXCL2 and CXCL3, between CXCL4 and CXCL7, and between CXCL10 and CXCL11) in LUSC. Significant correlations between the expressions of CXC chemokines and the infiltration of six common types of immune cells were also discovered in both LUAD and LUSC. Conclusions. We provided a comprehensive landscape of the CXC chemokine family in LUAD and LUSC using the bioinformatics method and found differences between LUSC and LUAD in the field of CXC chemokines. Our study may help validate and identify known novel immunotherapeutic targets and prognostic biomarkers.

Systematic Analyses of a Chemokine Family-Based Risk Model Predicting Clinical Outcome and Immunotherapy Response in Lung Adenocarcinoma

Chemokines exhibited complicated functions in antitumor immunity, with their expression profile and clinical importance of lung adenocarcinoma (LUAD) patients remaining largely undetermined. This study aimed to explore the expression patterns of chemokine family in LUAD and construct a predictive chemokine family-based signature. A total of 497 samples were downloaded from the Cancer Genome Atlas (TCGA) data portal as the training set, and the combination of 4 representative Gene Expression Omnibus (GEO) datasets, including GSE30219, GSE50081, GSE37745, and GSE31210, were utilized as the validation set. A three gene-based signature was constructed using univariate and stepwise multivariate Cox regression analysis, classifying patients into high and low risk groups according to the overall survival. The independent GEO datasets were utilized to validate this signature. Another multivariate analysis revealed that this signature remained an independent prognostic factor in LUAD patients. Furthermore, patients in the low risk group featured immunoactive tumor microenvironment (TME), higher IPS scores and lower TIDE scores, and was regarded as the potential beneficiaries of immunotherapy. Finally, the role of risky CCL20 was validated by immunohistochemistry (IHC), and patients possessed higher CCL20 expression presented shorter overall survival ( P = 0.011).

Evolution of fold switching in a metamorphic protein

Metamorphic proteins switch between different folds, defying the protein folding paradigm. It is unclear how fold switching arises during evolution. With ancestral reconstruction and nuclear magnetic resonance, we studied the evolution of the metamorphic human protein XCL1, which has two distinct folds with different functions, making it an unusual member of the chemokine family, whose members generally adopt one conserved fold. XCL1 evolved from an ancestor with the chemokine fold. Evolution of a dimer interface, changes in structural constraints and molecular strain, and alteration of intramolecular protein contacts drove the evolution of metamorphosis. Then, XCL1 likely evolved to preferentially populate the noncanonical fold before reaching its modern-day near-equal population of folds. These discoveries illuminate how one sequence has evolved to encode multiple structures, revealing principles for protein design and engineering.

M174. REDUCED CHEMOKINE SIGNALLING CAPACITY IS ASSOCIATED WITH INHIBITORY INTERNEURON DYSFUNCTION IN SUBCORTICAL BRAIN REGIONS IN SCHIZOPHRENIA AND BIPOLAR DISORDER

Background The subependymal zone (SEZ) adjacent to the lateral ventricles represents the largest reservoir of postnatally-generated cortical and striatal inhibitory interneurons in the human brain. Expression of markers representing the generation of neuronal progenitors from neural stem cells is reduced in the adult SEZ in schizophrenia and bipolar disorder; however, underlying mechanisms and relationships to inhibitory interneuron dysfunction remain unknown. Stem cell maintenance, neuronal migration and cell survival are regulated by signaling of the CXC motif chemokine 12 (CXCL12) through CXC motif chemokine receptors 4 (CXCR4) and 7 (CXCR7), which are increasingly implicated in the pathophysiology of psychiatric disorders. Methods Post-mortem tissue was obtained from 33 schizophrenia, 32 bipolar disorder and 33 control cases from the Stanley Medical Research Institute. SEZ and caudate nucleus tissue was dissected from 60 µm sections for RNA isolation and cDNA synthesis. Gene expression of CXCL12, CXCR4 and CXCR7 were determined by quantitative polymerase chain reactions. Semi-partial correlations were performed to assess whether CXC chemokine family member mRNAs may correlate with markers of neural stem cells (PROM1, GFAPD), neuronal progenitors (SOX2, ASCL1) and inhibitory interneurons (CALB2, NPY) in the SEZ and caudate nucleus. Results In the SEZ, CXCL12 mRNA was decreased in schizophrenia compared to controls and bipolar disorder (14–24%, all p≤0.03). CXCR4 and CXCR7 mRNAs were both decreased in schizophrenia and bipolar disorder compared to controls (9–33%, all p≤0.05). CXCL12, CXCR4 and CXCR7 expression positively correlated with PROM1, GFAPD, SOX2 and ASCL1 mRNAs (0.28≥sr≤0.61). In the caudate nucleus, CXCL12 mRNA was decreased in schizophrenia and bipolar disorder compared to controls (19–26%, all p≤0.05). CXCR4 mRNA was decreased in schizophrenia compared to controls (20%, p=0.01), while CXCR7 expression did not significantly differ across diagnostic groups. CALB2 and NPY mRNAs were increased in bipolar disorder compared to controls (13–27%, all p≤0.05). CXCR4 expression positively correlated with CALB2 mRNA (sr=0.26), while CXCR7 expression negatively correlated with NPY mRNA (sr=0.26). Discussion These findings provide the first molecular evidence of decreased CXC chemokine family member expression in the SEZ and caudate nucleus in psychiatric disorders, with exacerbated deficits in schizophrenia compared to bipolar disorder. Dysregulated CXC chemokine family member expression may hamper neural stem cell maintenance and neuronal differentiation, which may contribute to inhibitory interneuron dysfunction in psychiatric disorders. Future work will determine the cellular localisation of CXCR4 and CXCR7 expression in the SEZ and caudate nucleus to disentangle the regulatory role of CXCL12 signalling in the generation, migration and survival of inhibitory interneurons in the human brain.