Effect of low dose naloxone on the immune system function of a patient undergoing video-assisted thoracoscopic resection of lung cancer with sufentanil controlled analgesia - a randomized controlled trial.

BACKGROUND: Perioperative immune function plays an important role in the prognosis of patients. Several studies have indicated that low-dose opioid receptor blockers can improve immune function. METHODS: Sixty-nine patients undergoing video-assisted thoracoscopic resection of the lung cancer were randomly assigned to either the naloxone group (n = 35) or the non-naloxone group (n = 34) for postoperative analgesia during the first 48 h after the operation. Both groups received sufentanil and palonosetron via postoperative analgesia pump, while 0.05 µg·kg- 1·h- 1 naloxone was added in naloxone group. The primary outcomes were the level of opioid growth factor (OGF) and immune function assessed by natural killer cells and CD4+/CD8+ T-cell ratio. Second outcomes were assessed by the intensity of postoperative pain, postoperative rescue analgesia dose, postoperative nausea and vomiting (PONV). RESULTS: The level of OGF in the naloxone group increased significantly at 24 h (p<0.001) and 48 h after the operation (P < 0.01). The natural killer cells (P < 0.05) and CD4+/CD8+ T-cell ratio (P < 0.01) in the naloxone group increased significantly at 48 h after the operation. The rest VAS scores were better with naloxone at 12 and 24 h after operation(P < 0.05), and the coughing VAS scores were better with naloxone at 48 h after the operation(P < 0.05). The consumption of postoperative rescue analgesics in the naloxone group was lower (0.00(0.00-0.00) vs 25.00(0.00-62.50)), P < 0.05). Postoperative nausea scores at 24 h after operation decreased in naloxone group(0.00 (0.00-0.00) vs 1.00 (0.00-2.00), P < 0.01). CONCLUSION: Infusion of 0.05 µg·kg- 1·h- 1 naloxone for patients undergoing sufentanil-controlled analgesia for postoperative pain can significantly increase the level of OGF, natural killer cells, and CD4+/CD8+ T-cell ratio compared with non-naloxone group, and postoperative pain intensity, request for rescue analgesics, and opioid-related side effects can also be reduced. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry on January 26, 2019 (ChiCTR1900021043).

CXCR4 receptor overexpression in mesenchymal stem cells facilitates treatment of acute lung injury in rats.

Novel therapeutic regimens for tissue renewal incorporate mesenchymal stem cells (MSCs) as they differentiate into a variety of cell types and are a stem cell type that is easy to harvest and to expand in vitro. However, surface chemokine receptors, such as CXCR4, which are involved in the mobilization of MSCs, are expressed only on the surface of a small proportion of MSCs, and the lack of CXCR4 expression may underlie the low efficiency of homing of MSCs toward tissue damage, which results in a poor curative effect. Here, a rat CXCR4 expressing lentiviral vector was constructed and introduced into MSCs freshly prepared from rat bone marrow. The influence of CXCR4 expression on migration, proliferation, differentiation, and paracrine effects of MSCs was examined in vitro. The in vivo properties of CXCR4-MSCs were also investigated in a model of acute lung injury in rats induced by lipopolysaccharide. Expression of CXCR4 in MSCs significantly enhanced the chemotactic and paracrine characteristics of the cells in vitro but did not affect self-renewal or differentiation into alveolar and vascular endothelial cells. In vivo, CXCR4 improved MSC homing and colonization of damaged lung tissue, and furthermore, the transplanted CXCR4-MSCs suppressed the development of acute lung injury in part by modulating levels of inflammatory molecules and the neutrophil count. These results indicated that efficient mobilization of MSCs to sites of tissue injury may be due to CXCR4, and therefore, increased expression of CXCR4 may improve their therapeutic potential in the treatment of diseases where tissue damage develops.

Scorpion Venom peptide, AGAP inhibits TRPV1 and potentiates the analgesic effect of lidocaine.

The current study was designed to test the hypothesis that BmK AGAP (AGAP) potentiates the analgesic effect of lidocaine. The chronic constrictive injury was performed on 72 rats to induce a rapid onset and long-lasting pain. The rats were randomly assigned to one of six groups; Group A (n = 12) received an intrathecal administration of saline, Group B (n = 12) received an intrathecal injection of lidocaine, Group C (n = 12) received an intrathecal administration of AGAP, Group D, E, and F (n = 12 each) received an intrathecal administration of lidocaine 0.005 mg/ml + AGAP 25, 50, 100 µg/kg respectively. The von Frey filaments were used to assess mechanical allodynia. Nav1.7 and TRPV1 currents were recorded by the whole-cell aspiration patch-clamp technique, and KCNQ2/3 currents were recorded by the whole-cell drilling patch-clamp technique. The whole-cell aspiration patch-clamp technique showed that AGAP inhibited TRPV1and KCNQ2/3 currents and increased the analgesic effect of lidocaine. AGAP may have a synergistic effect with lidocaine which demonstrates a potential therapeutic approach for optimizing post-operative analgesia.

Corrigendum: Scorpion Venom Analgesic Peptide, BmK AGAP Inhibits Stemness and Epithelial-Mesenchymal Transition by Down-Regulating PTX3 in Breast Cancer.

[This corrects the article DOI: 10.3389/fonc.2019.00021.].

Levobupivacaine inhibits proliferation and promotes apoptosis of breast cancer cells by suppressing the PI3K/Akt/mTOR signalling pathway.

OBJECTIVE: This study aimed to test the hypothesis that levobupivacaine has anti-tumour effects on breast cancer cells. RESULTS: Colony formation and transwell assay were used to determine breast cancer cells proliferation. Flow Cytometry (annexin V and PI staining) was used to investigate breast cancer cells apoptosis. The effects of levobupivacaine on cellular signalling and molecular response were studied with Quantitative Polymerase Chain Reaction and western blot. Induction of apoptosis was confirmed by cell viability, morphological changes showed cell shrinkage, rounding, and detachments from plates. The results of the western blot and Quantitative Polymerase Chain Reaction indicated activation of active caspase-3 and inhibition of FOXO1. The results of the flow Cytometry confirmed that levobupivacaine inhibited breast cancer cell proliferation and enhanced apoptosis of breast cancer cells. Quantitative Polymerase Chain Reaction and Western blot analysis showed increased p21 and decreased cyclin D. Quantitative Polymerase Chain Reaction and western blot analysis showed that levobupivacaine significantly increased Bax expression, accompanied by a significant decreased Bcl-2 expression and inhibition of PI3K/Akt/mTOR signalling pathway. These findings suggested that levobupivacaine inhibits proliferation and promotes breast cancer cells apoptosis in vitro.

Whole-Course Application of Dexmedetomidine Combined with Ketorolac in Nonnarcotic Postoperative Analgesia for Patients with Lung Cancer Undergoing Thoracoscopic Surgery: A Randomized Control Trial.

BACKGROUND: Opioid-based postoperative analgesia provides adequate analgesia with much adverse effects and immunosuppression. Dexmedetomidine and ketorolac have properties of opioid-sparing, antiinflammation, and immune protection. OBJECTIVES: To investigate the efficacy and safety of whole-course application of dexmedetomidine combined with ketorolac in nonnarcotic postoperative analgesia and its effect on inflammatory response and immune function in thoracoscopic surgery of lung cancer. STUDY DESIGN: Double-blind, randomized control trial. SETTING: The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China. METHODS: Sixty patients scheduled for thoracoscopic surgery were enrolled and randomly divided into 2 groups to receive a combination of intraoperative usage of dexmedetomidine and postoperative patient-controlled intravenous analgesia of dexmedetomidine 0.1 µg/kg/h and ketorolac 3 mg/kg (DEX group) or only postoperative patient-controlled intravenous analgesia of sufentanil 1.5 µg/kg and ketorolac 3 mg/kg (SUF group) for 48 hours. Vital signs, postoperative Visual Analog Scale (VAS) score, Ramsay sedation score, patient-controlled analgesia pressing times, consumption of sufentanil and rescue drug, and complications were compared between the 2 groups. The levels of inflammatory factors and immune function were also compared. RESULTS: A significant reduction in median blood pressures and heart rates within 48 hours after surgery and perioperative consumption of sufentanil were observed in the DEX group compared with the SUF group (P < 0.05). No statistically significant difference was found in VAS scores, patient-controlled analgesia pressing times, and rescue drug consumption between the 2 groups (P > 0.05). The incidence of nausea was significantly lower in the DEX group compared with the SUF group (P < 0.05). A significant decrease of interleukin (IL)-1 beta, IL-6, tumor necrosis factor (TNF)-alpha, and increased CD4+ and CD4+/CD8+ were observed in the DEX group compared with the SUF group at 24 and 48 hours after surgery (P < 0.05). There was no difference in the levels of CD8+ and natural killer cells between the 2 groups (P > 0.05). LIMITATIONS: This study was limited by its sample size. CONCLUSIONS: Whole-course application of dexmedetomidine combined with ketorolac in nonnarcotic postoperative analgesia provided adequate and safe postoperative analgesia, reduced sufentanil consumption, analgesia-related complications, alleviated inflammatory response, and immunosuppression compared with sufentanil-based analgesia in thoracoscopic surgery. KEY WORDS: Dexmedetomidine, ketorolac, sufentanil, thoracoscopic surgery, postoperative analgesic, patient-controlled analgesia, inflammatory response, immune function.

Monitoring the Early Antiproliferative Effect of the Analgesic-Antitumor Peptide, BmK AGAP on Breast Cancer Using Intravoxel Incoherent Motion With a Reduced Distribution of Four b-Values.

Background: The present study aimed to investigate the possibility of using intravoxel incoherent motion (IVIM) diffusion magnetic resonance imaging (MRI) to quantitatively assess the early therapeutic effect of the analgesic-antitumor peptide BmK AGAP on breast cancer and also evaluate the medical value of a reduced distribution of four b-values. Methods: IVIM diffusion MRI using 10 b-values and 4 b-values (0-1,000 s/mm2) was performed at five different time points on BALB/c mice bearing xenograft breast tumors treated with BmK AGAP. Variability in Dslow, Dfast, PF, and ADC derived from the set of 10 b-values and 4 b-values was assessed to evaluate the antitumor effect of BmK AGAP on breast tumor. Results: The data showed that PF values significantly decreased in rBmK AGAP-treated mice on day 12 (P = 0.044). PF displayed the greatest AUC but with a poor medical value (AUC = 0.65). The data showed no significant difference between IVIM measurements acquired from the two sets of b-values at different time points except in the PF on the day 3. The within-subject coefficients of variation were relatively higher in Dfast and PF. However, except for a case noticed on day 0 in PF measurements, the results indicated no statistically significant difference at various time points in the rBmK AGAP-treated or the untreated group (P < 0.05). Conclusion: IVIM showed poor medical value in the early evaluation of the antiproliferative effect of rBmK AGAP in breast cancer, suggesting sensitivity in PF. A reduced distribution of four b-values may provide remarkable measurements but with a potential loss of accuracy in the perfusion-related parameter PF.

Scorpion Venom Analgesic Peptide, BmK AGAP Inhibits Stemness, and Epithelial-Mesenchymal Transition by Down-Regulating PTX3 in Breast Cancer.

A scorpion peptide reported to exhibit both analgesic and antitumor activity in animal models may present as an alternative therapeutic agent for breast cancer. We aimed to investigate the effect of Buthus martensii Karsch antitumor-analgesic peptide (BmK AGAP) on breast cancer cell stemness and epithelial-mesenchymal transition (EMT). We treated MCF-7 and MDA-MB-231 cells with different concentrations of rBmK AGAP and observed that rBmK AGAP inhibited cancer cell stemness, epithelial-mesenchymal transition (EMT), migration, and invasion. Analysis by qPCR, ELISA, western blot, immunofluorescence staining, sphere formation, colony assay, transwell migration, and invasion assays demonstrated rBmK AGAP treatment decreased the expressions of Oct4, Sox2, N-cadherin, Snail, and increased the expression of E-cadherin. rBmK AGAP inhibited breast cancer cell stemness, EMT, migration, and invasion by down-regulating PTX3 through NF-κB and Wnt/ß-catenin signaling Pathway in vitro and in vivo. Xenograft tumor model confirmed inhibition of tumor growth, stem-like features, and EMT by rBmK AGAP. Thus, rBmK AGAP is a potential therapeutic agent against breast cancer and related pain.

Fentanyl Promotes Breast Cancer Cell Stemness and Epithelial-Mesenchymal Transition by Upregulating α1, 6-Fucosylation via Wnt/ß-Catenin Signaling Pathway.

Cancer pain is a common and severe complication of human breast cancer, and relieving pain is fundamental strategy in the treatment. Fentanyl, as an opioid analgesic, is widely used in breast cancer patients. However, little is known about its effects on stemness and epithelial-mesenchymal transition (EMT) of breast cancer cells. Aberrant protein glycosylation is involved in cancer malignancy. The α1, 6-fucosylation is an important type of glycosylation, and the elevated α1, 6-fucosylation catalyzed by fucosyltransferase VIII (FUT8) is found in many tumors. However, whether 1, 6-fucosylation is involved in regulating stemness and EMT, and stimulated by fentanyl is not clear. In this study, we found that fentanyl induced stemness and EMT in MCF-7 and MDA-MB-231 breast cancer cells by analysis of sphere formation, expression of stemness markers (Sox2, Oct4) and EMT markers (N-cadherin, E-cadherin and Vimentin). Results also showed that fentanyl upregulated FUT8 gene and protein expression by qPCR, Western blot and immunofluorescent staining, as well as α1, 6-fucosylation level by Lectin blot and Lectin fluorescent staining. Furthermore, decreased or blocked α1, 6-fucosylation by FUT8 siRNA transfection or LCA Lectin blockage reduced stemness and EMT. Additionally, fentanyl activated the key molecules and target genes in Wnt/ß-catenin signaling pathway. LGK-974 (an inhibitor of Wnt ligands) suppressed fentanyl-mediated upregulation of α1, 6-fucosylation, stemness and EMT. The results of tumor xenograft demonstrated that fentanyl enhanced tumor growth, α1, 6-fucosylation, stemness and EMT. Taken together, our study reveals that fentanyl upregulated FUT8 expression, which increased α1, 6-fucosylation level through activation of Wnt/ß-catenin signaling pathway, thereby, induce stemness and EMT of breast cancer cells. This study suggest a potential side effect of fentanyl in the treatment of cancer, which may guide the safety of fentanyl in the clinical application.

Astaxanthin reduces isoflurane-induced neuroapoptosis via the PI3K/Akt pathway.

Astaxanthin is an oxygen-containing derivative of carotenoids that effectively suppresses reactive oxygen and has nutritional and medicinal value. The mechanisms underlying the effects of astaxanthin on isoflurane­induced neuroapoptosis remain to be fully understood. The present study was conducted to evaluate the protective effect of astaxanthin to reduce isoflurane­induced neuroapoptosis and to investigate the underlying mechanisms. The results demonstrated that isoflurane induced brain damage, increased caspase­3 activity and suppressed the phosphatidylinositol 3­kinase (PI3K)/protein kinase B (Akt) signaling pathway in an in vivo model. However, treatment with astaxanthin significantly inhibited brain damage, suppressed caspase­3 activity and upregulated the PI3K/Akt pathway in the isoflurane­induced rats. Furthermore, isoflurane suppressed cell growth, induced cell apoptosis, enhanced caspase­3 activity and downregulated the PI3K/Akt pathway in organotypic hippocampal slice culture. Administration of astaxanthin significantly promoted cell growth, reduced cell apoptosis and caspase­3 activity, and upregulated the PI3K/Akt pathway and isoflurane­induced neuroapoptosis. The present study demonstrated that downregulation of the PI3K/Akt pathway reduced the effect of astaxanthin to protect against isoflurane­induced neuroapoptosis in the in vitro model. The results of the current study suggested that the protective effect of astaxanthin reduces the isoflurane-induced neuroapoptosis via activation of the PI3K/Akt signaling pathway.

Morphine promotes cancer stem cell properties, contributing to chemoresistance in breast cancer.

Morphine is an opioid analgesic drug commonly used for pain relief in cancer patients. Here, we report that morphine enhances the mammosphere forming capacity and increases the expression of stemness-related transcription factors Oct4, Sox2 and Nanog. Treatment with morphine leads to enrichment of a side population fraction in MCF-7 cells and the CD44+/CD24(-/low) population in BT549 cells. Consistently, morphine activates Wnt/ß-catenin signaling to induce epithelial to mesenchymal transition and promotes metastasis. Moreover, morphine decreases the sensitivity of traditional anti-cancer drugs in breast cancer cells. Nalmefene, an antagonist of morphine, reverses morphine-induced cancer stem cell properties and chemoresistance in breast cancer. In addition, nalmefene abolishes morphine enhancing tumorigenesis in a NOD/SCID mouse model. In conclusion, our findings demonstrate that morphine contributes to chemoresistance via expanding the population of cancer stem cells and promotes tumor growth, thereby revealing a novel role of morphine and providing some new guides in clinical use of morphine.