BACKGROUND:Postoperative pain after colorectal cancer surgery has a significant impact on postoperative physical and mental health. Vitamin D deficiency has been correlated with both acute pain states, including postoperative and post-traumatic pain, and several chronic pain diseases. The effects of hypovitaminosis D on preoperative pain threshold and perioperative opioid use in colorectal cancer surgery still need to be studied. OBJECTIVES:To find the relationship between hypovitaminosis D on pain threshold, perioperative opioid use, and postoperative complications in colorectal cancer surgery. STUDY DESIGN:A total of 112 patients, who were enrolled in this prospective, observational trial, were divided into 2 groups based on their preoperative serum 25-hydroxyvitamin D (25 [OH] D3) levels: (1) group D: vitamin D-deficient group (< 20 ng/mL); and (2) group S: vitamin D-sufficient group (>= 20 ng/mL). METHODS:Primary outcomes were pain threshold indexes, perioperative dosages of opioid use, and postoperative pain. Secondary outcomes were other postoperative complications. RESULTS:Preoperative serum level of vitamin D was 14.94 ± 3.10 ng/mL in group D and 24.20 ± 4.80 ng/mL in group S. Significant differences were showed in the 3 indexes of pain threshold and analgesic consumption between the 2 groups (P < 0.05). A low 25 (OH) D3 level was associated with a higher opioid dose of sufentanil. There was an association between 25 (OH) D3 and pain enduring threshold (PET), beta coefficient beta = 0.532, 95% confidential interval  (0.440, 0.623), P < 0.001. The history of diabetes mellitus (DM) and vitamin C and vitamin D levels may be risk factors of surgical site infections (SSI), and the binary logistics regression model is statistically significant, chi-squared = 35.028, P < 0.001. LIMITATIONS:There is room for further expansion in the sample size. Our study lacked objective indicators to measure pain threshold. Intestinal recovery time and total hospital stay were not included in the final analysis. In the follow-up study, the vitamin D supplementation group should be set and the specific site of colorectal cancer surgery also needs to be divided more carefully. CONCLUSIONS:On the basis of the study results, hypovitaminosis D is associated with increased perioperative opioid consumption in colorectal cancer surgery. Sensory perception and pain threshold of patients with insufficient 25 (OH) D3 concentration were more sensitive, and PET was lower. History of DM, vitamin D, and vitamin C may be factors related with SSI. Future studies are needed to investigate their relationship further and discover if postoperative pain and pain threshold can benefit from vitamin D supplementation in these patients.

OBJECTIVES Neuro-inflammation induced by microglia is crucial in the pathogenesis of sepsis-associated encephalopathy (SAE). The endogenous lipid mediator, Resolvin D1 (RvD1), which is synthesized from docosahexaenoic acid, has been extensively reported to attenuate inflammation in various diseases by its anti-inflammation and pro-resolving functions. However, the effect of RvD1 on SAE remains unclear. In this study, we aimed to ex the function and mechanism of RvD1 on SAE mice. METHODS In our study, the SAE mice model was established by the method of cecal ligation and perforation (CLP). C57BL/6J mice were randomly divided into three groups: the Sham group, the CLP group and the CLP+RvD1 group. Cognitive impairment of the mice was assessed by Morris water maze. Iba1 immunohistochemistry was conducted to observe the activation of microglia in hippocampus of the mice from different groups. The production of cytokines, including TNF-α, IL-6 and IL-1β, and their mRNA levels were evaluated by ELISA and Q-PCR. The expression of the molecules from inflammatory signaling pathways was assessed by Western blot. RESULTS xaRvD1 treatment significantly improved the learning and cognitive ability of SAE mice. The activation of microglia and the production of inflammatory cytokines in hippocampal tissues were inhibited in CLP+RvD1 group. We also found that the inflammation of microglia was attenuated by RvD1 treatment both in vivo and in vitro. Moreover, the activation of NF-κB, MAPK and STAT signaling pathways were inhibited by RvD1 treatment, which partly explained the anti-inflammation function of RvD1 on SAE mice. CONCLUSIONS RvD1 could improve the learning and cognitive ability of SAE mice by inhibiting the systemic and local inflammation. It could attenuate the inflammation in microglia by inhibiting the activation of inflammatory signaling pathways and then decreasing the production of cytokines. These findings are helpful to better understand the pathophysiology of SAE, which also provide a novel therapeutic method in clinic.

Paclitaxel is a common chemotherapeutic agent in cancer treatment, while it often causes chemotherapy-induced peripheral neuropathy (CIPN), which manifested as hyperalgesia and allodynia, and its mechanism remains largely unknown. The previous study has shown that matrix metalloproteinase-2 (MMP-2) plays a pivotal role in spinal nerve ligation (SNL) induced neuropathic pain, but its function in CIPN and exact molecular mechanisms underlying upregulation is not explored. Our present study revealed that MMP-2 is also upregulated in paclitaxel induced neuropathic pain (NP), and knockdown it by siRNA can ameliorate mechanical allodynia. Since DNA methylation is closely related to gene transcription, we explored the methylation status of the MMP-2 gene and demonstrated that MMP-2 upregulation is related to the reduced methylation level of its promoter. DNA methylation is mediated by DNA methyltransferases (DNMTs), and previous studies suggested that three main types of DNMTs can undergo SUMOylation. Our next study revealed that SUMO1 modification of DNMT3b is significantly enhanced. Intrathecal administration of SUMOylation inhibitor, ginkgolic acid (GA), could reverse enhanced SUMO1 modification of DNMT3b and upregulation of MMP-2 in the model rats. Further investigation suggested that DNMT3b binding activity to the promoter region of the MMP-2 gene is significantly decreased in paclitaxel treated rats, and the administration of GA can reverse these effects, which is also accompanied by changes in the promoter methylation status of the MMP-2 gene. Our study demonstrates that MMP-2 up-regulation mediated by DNMT3b SUMOylation is essential for paclitaxel induced NP development, which brings us new therapeutic options for CIPN.

Vincristine is a common chemotherapeutic agent in cancer treatment, while it often causes chemotherapy-induced peripheral neuropathy(CIPN), which brings patients a great disease burden and associated economic pressure. The mechanism under CIPN remains mostly unknown. The previous study has shown that cell-type-specific spinal synaptic plasticity in the dorsal horn plays a pivotal role in neuropathic pain. Downregulation of GABA transmission, which mainly acts as an inhibitory pathway, has been reported in the growing number of research. Our present study found that GAD67, responsible for > 90% of basal GABA synthesis, is down-regulated, while its relative mRNA remains unchanged in vincristine-induced neuropathy. Considering microRNAs (miRNAs) as a post-transcription modifier by degrading targeted mRNA or repressing mRNA translation, we performed genome-wide miRNA screening and revealed that miR-30d might contribute to GAD67 down-regulation. Further investigation confirmed that miR-30d could affect the fluorescence activity of GAD67 by binding to the 3 'UTR of the GAD67 gene, and intrathecal injection of miR-30d antagomir increased the expression of GAD67, partially rescued vincristine-induced thermal hyperalgesia and mechanical allodynia. In summary, our study revealed the molecule interactions of GAD67 and miR-30d in CIPN, which has not previously been discussed in the literature. The results give more profound insight into understanding the CIPN mechanism and hopefully helps pain control.