Hand-foot syndrome (HFS) is a common capecitabine-based chemotherapy-related adverse event (CRAE) in patients with colorectal cancer (CRC). It is of great significance to comprehensively identify susceptible factors for HFS, and further to elucidate the biomolecular mechanism of HFS susceptibility. We performed an untargeted multi-omics analysis integrating DNA methylation, transcriptome, and metabolome data of 63 Chinese CRC patients who had complete CRAE records during capecitabine-based chemotherapy. We found that the metabolome changes for each of matched plasma, urine, and normal colorectal tissue (CRT) in relation to HFS were characterized by chronic tissue damage, which was indicated by reduced nucleotide salvage, elevated spermine level, and increased production of endogenous cytotoxic metabolites. HFS-related transcriptome changes of CRT showed an overall suppressed inflammation profile but increased M2 macrophage polarization. HFS-related DNA methylation of CRT presented gene-specific hypermethylation on genes mainly for collagen formation. The hypermethylation was accumulated in the opensea and shore regions, which elicited a positive effect on gene expression. Additionally, we developed and validated models combining relevant biomarkers showing reasonably good discrimination performance with the area under the receiver operating characteristic curve values from 0.833 to 0.955. Our results demonstrated that the multi-omics variations associated with a profibrotic phenotype were closely related to HFS susceptibility. HFS-related biomolecular variations in CRT contributed more to the relevant biomolecular mechanism of HFS than in plasma and urine. Spermine-related DNA hypermethylation and elevated expression of genes for collagen formation were closely associated with HFS susceptibility. These findings provided new insights into the susceptible factors for chemotherapy-induced HFS, which can promote the implementation of individualized treatment against HFS.
This cross-sectional study investigated whether the catechol-O-methyltransferase (COMT) gene acts as a significant regulator of pain signaling pathways, regulates b-endorphin, and contributes to ethnic differences in pain sensitivity. One-hundred-sixty healthy subjects were enrolled in this study, with Han and Uyghur groups each consisting of 80 participants. Subjects went through six pain threshold experiments. From venous blood, COMT polymorphisms were genotyped, and serum b-endorphin levels were measured. Bivariate correlation analysis and multiple linear regression were used to identify the relationships among genotypes or b-endorphin levels and different types of pain thresholds. Han and Uyghur ethnic differences were determined in terms of acute-pressure pain-perception thresholds, blunt-pressure pain-perception thresholds, blunt-pressure pain-tolerance thresholds, electric pain-tolerance thresholds, b-endorphin levels, and distributions of rs4680 and rs4633 COMT polymorphisms. b-endorphin levels did not correlate with COMT rs4680 or rs4633 genotypes in both Han and Uyghur. Statistical predictors for a lower pain-threshold performance included being young, Uyghur, female, and having a low body mass index, low b-endorphin level, and the rs4680 GA or GG allele. There is the significant difference in pain sensitivity between healthy Han and Uyghur. COMT gene variants and b-endorphin levels contribute to ethnic differences in pain sensitivity.
Background: Chemotherapy-induced adverse effects (CIAEs) remain a challenging problem due to their high incidences and negative impacts on treatment in Chinese colorectal cancer (CRC) patients. We aimed to identify risk factors and predictive markers for CIAEs using food/nutrition data in CRC patients receiving post-operative capecitabine-based chemotherapy. Methods: Food/nutrition data from 130 Chinese CRC patients were analyzed. Univariate and multivariate analyses were used to identify CIAE-related food/nutrition factors. Prediction models were constructed based on the combination of these factors. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the discrimination ability of models. Results: A total of 20 food/nutrition factors associated with CIAEs were identified in the univariate analysis after adjustments for total energy and potential confounding factors. Based on multivariate analysis, we found that, among these factors, dessert, eggs, poultry, and milk were associated with several CIAEs. Most importantly, poultry was an overall protective factor; milk and egg were risk factors for hand-foot syndrome (HFS) and bone marrow suppression (BMS), respectively. Developed multivariate models in predicting grade 1 to 3 CIAEs and grade 2/3 CIAEs both had good discrimination (AUROC values from 0.671 to 0.778, 0.750 to 0.946 respectively), which had potential clinical application value in the early prediction of CIAEs, especially for more severe CIAEs. Conclusions: Our findings suggest that patients with high milk and egg intakes should be clinically instructed to control their corresponding dietary intake to reduce the likelihood of developing HFS and BMS during capecitabine-based chemotherapy, respectively. Trial registration: ClinicalTrials.gov Identifier: NCT03030508.
Aim. Connexin 43 (Cx43) has been identified to be important for cerebral ischemia/reperfusion (I/R) injury as well as protection from it. This study was aimed at investigating the relationship between phosphorylated Cx43 (p-Cx43), transforming growth factor-β1 (TGF-β1)/Smad2/3 signaling pathway, and isoflurane postconditioning (ISPOC), which has effects on brain injury in rats with cerebral ischemia/reperfusion (I/R) injury. Methods. The middle cerebral artery occlusion (MCAO) model was induced in 96 male Sprague-Dawley rats, weighing 250-300 g. The rats were randomized into 12 groups, namely, sham, middle cerebral artery occlusion (MCAO)/I/R, I/R+1.5% ISPOC, I/R+LY2157299 (blocker of TGF-β1), I/R+LY2157299+1.5% ISPOC, I/R+Ro318220 (inhibitor of p-Cx43), I/R+Ro318220+1.5% ISPOC, I/R+18β-GA (activator of p-Cx43), I/R+18β-GA+1.5% ISPOC, I/R+1.5%ISPOC+LY2157299+Ro318220, dimethyl sulfoxide (DMSO), and 1.5% ISPOC+DMSO. The protective effect of 1.5% ISPOC was tested by neurological deficit scoring and 2,3,5-triphenyl tetrazolium chloride staining (TTC staining). The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) method and hematoxylin-eosin (HE) staining were used to observe apoptosis of CA1 cells in the hippocampus. The function of protein synthesis in neurons was tested by Nissl staining. Expression levels of TGF-β1, Smad2/3, phosphorylated Smad2/3 (p-Smad2/3), Cx43, and phosphorylated Cx43 (p-Cx43) were measured by Western blot, immunofluorescence (IF), and quantitative real-time polymerase chain reaction (qRT-PCR). Results. Neurological deficit scores, brain infarct volume, and damaged neurons in the I/R group significantly increased compared to those in the sham group (P<0.05). However, in the ISPOC group, damage of the brain was significantly ameliorated (P<0.05). qRT-PCR showed more p-Cx43 mRNA expression in the hippocampal tissue of the ISPOC group than of the I/R group (P<0.05). Western blot and immunofluorescence results showed similar changes in p-Cx43 protein levels of both groups. The expression levels of related proteins (TGF-β1 and p-Smad2/3) both increased in the ISPOC group (P<0.05), whereas total Smad2/3 and total Cx43 expression did not change in all groups. However, when a TGF-β1 inhibitor (LY2157299) was applied, expression levels of p-Cx43 significantly decreased as well as neuronal density (P<0.05). By contrast, expression levels of TGF-β1 did not change significantly after the application of a p-Cx43 inhibitor (Ro318220) or the p-Cx43 activator 18β-GA (P>0.05). Conclusion. Isoflurane postconditioning (ISPOC) may alleviate cerebral I/R injury through upregulating the expression of p-Cx43, and the TGF-β1/Smad2/3 signaling pathway may be involved in the process.
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