The circular RNA circSlc7a11 promotes bone cancer pain pathogenesis in rats by modulating LLC-WRC 256 cell proliferation and apoptosis.

Treatment of bone cancer pain (BCP) caused by bone metastasis in advanced cancers remains a challenge in clinical oncology, and the underlying mechanisms of BCP are poorly understood. This study aimed to investigate the pathogenic roles of circular RNAs (circRNAs) in regulating cancer cell proliferation and BCP development. Eight differentially expressed circRNAs in the rat spinal cord were validated by agarose gel electrophoresis and Sanger sequencing. Expression of circRNAs and mRNAs was detected by quantitative RT-PCR. MTS assay and flow cytometry were performed to analyze cell proliferation and apoptosis, respectively. Differentially expressed mRNA profiles were characterized by deep RNA sequencing, hierarchical clustering, and functional categorization. The interactions among circRNAs, microRNAs (miRNAs), and mRNAs were predicted using TargetScan. Additionally, western blot was performed to determine the protein levels of Pax8, Isg15, and Cxcl10. Multiple circRNAs were differentially expressed in the spinal cords of BCP model rats; of these, circSlc7a11 showed the greatest increase in expression. The overexpression of circSlc7a11 significantly promoted cell proliferation and repressed apoptosis of LLC-WRC 256 and UMR-106 cells, whereas circSlc7a11 silencing produced the opposite effects. Altered expression of circSlc7a11 also induced substantial changes in the mRNA expression profiles of LLC-WRC 256 cells; these changes were linked to multiple apoptotic processes and signaling pathways, such as the chemokine signaling pathway, and formed a complex circRNA/miRNA/mRNA network. Additionally, Pax8, Isg15, and Cxc110 protein level in LLC-WRC 256 cells was consistent with the mRNA results. The circRNA circSlc7a11 regulates rat BCP development by modulating LLC-WRC 256 cell proliferation and apoptosis through multiple-signaling mechanisms.

circStrn3 is involved in bone cancer pain regulation in a rat model.

Bone cancer pain (BCP) is a common chronic pain that is caused by a primary or metastatic bone tumor. More detailed molecular mechanisms of BCP are warranted. In this study, we established a BCP rat model. The von Frey hair test, body weight, and hematoxylin and eosin staining were employed. We screened differentially expressed circRNAs (DECs) between the BCP group and sham group. The results revealed that 850 DECs were significantly up-regulated and 644 DECs were significantly down-regulated in the BCP group. Furthermore, we identified 1177 differentially expressed genes (DEGs) significantly up-regulated and 565 DEGs significantly down-regulated in the BCP group. Gene Ontology annotation of all 1742 DEGs revealed that biological regulation of metabolic processes, cellular processes, and binding were the top enriched terms. For Kyoto Encyclopedia of Genes and Genomes analysis, phagosome, HTLV-I infection, proteoglycans in cancer, and herpes simplex infection were significantly enriched in this study. In addition, we identified four selected circRNAs, chr6:72418120|72430205, chr20:7561057|7573740, chr18:69943105|69944476, and chr5:167516581|167558250, by quantitative real time PCR. chr6:72418120|72430205 (circStrn3) was selected for further study based on expression level and the circRNA-miRNA-mRNA network table. Western blot analysis suggested that knockdown of circStrn3 could effectively induce Walker 256 cell apoptosis. In summary, our study provided a more in-depth understanding of the molecular mechanisms of BCP.

MicroRNA-365 alleviates morphine analgesic tolerance via the inactivation of the ERK/CREB signaling pathway by negatively targeting ß-arrestin2.

BACKGROUND: Morphine is widely used in clinical practice for a class of analgesic drugs, long-term use of morphine will cause the action of tolerance. MicroRNAs have been reported to be involved in morphine analgesic tolerance.. METHODS: Forty male SD rats were selected and randomly divided into 5 groups: the control group, morphine tolerance group, miR-365 mimic + morphine (miR-365 mimic) group, miR-365 inhibitor + morphine (miR-365 inhibitor) group and miR-365 negative control (NC) + morphine (miR-365 NC) group. After the administration of morphine at 0 d, 1 d, 3 d, 5 d and 7 d, behavioral testing was performed. A dual luciferase reporter gene assay was performed to confirm the relationship between miR-365 and ß-arrestin2, RT-qPCR was used to detect miR-365, ß-arrestin2, ERK and CREB mRNA expressions, western blotting was used to evaluate the protein expressions of ß-arrestin2, ERK, p-ERK, CREB and p-CREB, ELISA was used to detect the contents of IL-1ß, TNF-α and IL-18, while immunofluorescence staining was used to measure the GFAP expression. Intrathecal injection of mir365 significantly increased the maximal possible analgesic effect (%MPE) in morphine tolerant rats. ß-arrestin2 was the target gene of miR-365. RESULTS: The results obtained showed that when compared with the morphine tolerance group, there was an increase in miR-365 expression and a decrease in the ß-arrestin2, ERK, CREB protein expressions, contents of IL-1ß, TNF-α, IL-18 and GFAP expression in the miR-365 mimic group, while the miR-365 inhibitor group displayed an opposite trend. CONCLUSIONS: The results of this experiment suggest that by targeting ß-arrestin2 to reduce the contents of IL-1ß, TNF-α and IL-18 and by inhibiting the activation of ERK/CREB signaling pathway, miR-365 could lower morphine analgesic tolerance.

Gold Nanoparticles with Dexmedetomidine Regulate GSK-3ß to Reduce Neurocognitive Effects in Anesthetized Rats.

The aim of this study was to explore the neurocognitive effects of dexmedetomidine-loaded gold nanoparticles (AuNPs-dexmedetomidine) on anesthetized rats. Sixty Sprague Dawley rats (age, 2-3 weeks; weight, 250-280 g) were randomly divided into three groups (n = 20): the control group and two groups that received intraperitoneal injection of AuNPs-dexmedetomidine at 50 and 100 µg/kg each. Western blotting and RT-PCR were used to determine the protein and mRNA expression of GSK-3ß, respectively. Compared with that in the control group, GSK-3ß expression in AuNP-dexmedetomidine groups increased (P < 0.05). The protein expression of GSK-3ß was higher and mRNA expression was significantly lower in the 100 µg/kg AuNP-dexmedetomidine group (P < 0.05). AuNPs-dexmedetomidine reduced the neurocognitive effect on anesthetized rats through the regulation of the GSK-3ß signaling pathway.

Retraction Note to: Spinal circRNA-9119 Suppresses Nociception by Mediating the miR-26a-TLR3 Axis in a Bone Cancer Pain Mouse Model.

The authors have retracted this article [1] because in further experiments, they found that some experimental data cannot be verified repeatedly.

Spinal circRNA-9119 Suppresses Nociception by Mediating the miR-26a-TLR3 Axis in a Bone Cancer Pain Mouse Model.

Altered expression of circular RNA (circRNA) is recognized as a contributor to malignant pain where microRNA (miRNA) exerts an essential effect. We generated a murine model for bone malignancy pain in which 2472 osteolytic sarcoma cells were injected into the femurs of mice. CircRNA microarray and quantitative PCR (qPCR) and revealed that circ9119 expression was repressed in the spinal cord of bone malignancy pain model mice, which is the first relay site involved in the transmission of nociceptive information to the cerebrum of mice that receive spinal analgesics for malignancy pain. Overexpression of circ9119 by plasmid injection in the model mice reduced progressive thermal hyperalgesia and mechanical hyperalgesia. Bioinformatics prediction and dual-luciferase reporter assay showed that circ9119 functions as a sponge of miR-26a, which targets the TLR3 3'-untranslated region. Furthermore, expression of miR-26a was elevated and TLR3 level was repressed in bone malignancy pain model mice, which were counteracted by circ9119 in the spinal cord of tumor-bearing mice. Moreover, excessive expression of miR-26a was involved in the recovery of mice from progressive thermal hyperalgesia and mechanical hyperalgesia triggered via circ9119. TLR3 knockdown in bone malignancy pain model mice thoroughly impaired pain in the initial stages and reduced the effects of circ9119 on hyperalgesia. Our research findings indicate that targeting the circ9119-miR-26a-TLR3 axis may be a promising analgesic strategy to manage malignancy pain.

Correction to: Spinal circRNA-9119 Suppresses Nociception by Mediating the miR-26a-TLR3 Axis in a Bone Cancer Pain Mouse Model.

The original version of this article unfortunately contained a mistake in Fig. 2.

microRNA-329 reduces bone cancer pain through the LPAR1-dependent LPAR1/ERK signal transduction pathway in mice.

BACKGROUND: Bone cancer pain (BCP) is a common symptom occurring among patients with cancer and has a detrimental effect on their quality of life. Growing evidence has implicated microRNA-329 (miR-329) in the progression of bone diseases. In the present study, we aimed to elucidate the potential effects of miR-329 on BCP in a BCP mouse model via binding to lysophosphatidic acid receptor 1 (LPAR1) through the LPAR1/extracellular signal-regulated kinase (ERK) signaling pathway. METHODS: Initially, a BCP mouse model was established via injection of 4 × 104 murine breast tumor (4T1 cell) cells (4 µl). The interaction between miR-329 and LPAR1 was identified using a bioinformatics website and dual luciferase reporter gene assay. The modeled mice were subsequently treated with miR-329 mimic, LPAR1 shRNA, or both, in order to examine the effect of miR-329 on the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) of mice, the expression of LPAR1/ERK signaling pathway-related genes. RESULTS: The positive expression rate of LPAR1 protein and extent of ERK1/2 phosphorylation were increased in BCP mouse models. LPAR1 is a target gene of miR-329, which can inhibit the expression of LPAR1. In response to miR-329 overexpression and LPAR1 silencing, BCP mice showed increased PWT and PWL, along with decreased LPAR1 expression and ratio of p-ERK/ERK. CONCLUSIONS: Altogether, the results obtained indicated that miR-329 can potentially alleviate BCP in mice via the inhibition of LPAR1 and blockade of the LPAR1/ERK signaling pathway, highlighting that upregulation of miR-329 could serve as a therapeutic target for BCP treatment.

[Effects of different doses of dexmedetomidine on cognitive dysfunction in elderly patients early after laparoscopic surgery for colorectal cancer].

OBJECTIVE: To investigate the effect of different doses of dexmedetomidine (Dex) on early postoperative cognitive dysfunction in elderly patients undergoing laparoscopic surgery for colorectal cancer. METHODS: Eighty ASAI-III elderly patients (over 65 years) were randomized equally into 4 groups including a control group without dexmedetomidine and 3 dexmedetomidine groups (groups D1, D2, and D3) with loading dexmedetomidine doses of 0.2, 0.5, and 0.8 µg/kg and maintenance doses of 0.2, 0.5, and 0.8 µg·kg(-1)·h(-1), respectively. Dex was discontinued 30 min before the end of surgery. The time of operation, adverse reactions, time from the end of surgery to spontaneous breathing recovery (TR), time from spontaneous breathing recovery to opening eyes (TO), and time from opening eyes to extubation (TE) were recorded. Mini-Mental State (MMSE) test was used to assess the cognitive function 1 day before and at 1 day and 3 days after the operation. RESULTS: The incidence of postoperative cognitive dysfunction (POCD) was significantly lower in groups D2 and D3 than in the control group and group D1 (P<0.05). The incidences of hypotension and bradycardia were the highest in group D3 (P<0.05), which also had longer significantly TO and TE than the other 3 groups (P<0.05). CONCLUSION: Dexmedetomidine with a loading dose of 0.5 µg/kg followed by maintenance doses of 0.5 and 0.8 µg·kg(-1)·h(-1) (preferentially 0.5 µg·kg(-1)·h(-1)) can reduce the incidence of POCD in elderly patients undergoing laparoscopic surgery for colorectal cancer.