Yebo Gao

PAR2-mediated upregulation of BDNF contributes to central sensitization in bone cancer pain

BackgroundBone cancer pain is currently a major clinical challenge for the management of cancer patients, and the cellular and molecular mechanisms underlying the spinal sensitization remain unclear. While several studies demonstrated the critical role of proteinase-activated receptor (PAR2) in the pathogenesis of several types of inflammatory or neuropathic pain, the involvement of spinal PAR2 and the pertinent signaling in the central sensitization is not determined yet in the rodent model of bone cancer pain.FindingsImplantation of tumor cells into the tibias induced significant thermal hyperalgesia and mechanical allodynia, and enhanced glutamatergic strength in the ipsilateral dorsal horn. Significantly increased brain-derived neurotrophic factor (BDNF) expression was detected in the dorsal horn, and blockade of spinal BDNF signaling attenuated the enhancement of glutamatergic strength, thermal hyperalgesia and mechanical allodynia in the rats with bone cancer pain. Significantly increased spinal PAR2 expression was also observed, and inhibition of PAR2 signaling ameliorated BDNF upsurge, enhanced glutamatergic strength, and thermal hyperalgesia and mechanical allodynia. Inhibition of NF-κB pathway, the downstream of PAR2 signaling, also significantly decreased the spinal BDNF expression, glutamatergic strength of dorsal horn neurons, and thermal hyperalgesia and mechanical allodynia.ConclusionThe present study demonstrated that activation of PAR2 triggered NF-κB signaling and significantly upregulated the BDNF function, which critically contributed to the enhancement of glutamatergic transmission in spinal dorsal horn and thermal and mechanical hypersensitivity in the rats with bone cancer. This indicated that PAR2 - NF-κB signaling might become a novel target for the treatment of pain in patients with bone cancer.

Engagement of signaling pathways of protease-activated receptor 2 and μ-opioid receptor in bone cancer pain and morphine tolerance.

Pain is one of the most common and distressing symptoms suffered by patients with progression of cancer. Using a rat model of bone cancer, recent findings suggest that proteinase‐activated receptor 2 (PAR2) signaling pathways contribute to neuropathic pain and blocking PAR2 amplifies antinociceptive effects of systemic morphine. The purpose of our study was to examine the underlying mechanisms responsible for the role of PAR2 in regulating bone cancer‐evoked pain and the tolerance of systemic morphine. Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats and this evoked significant mechanical and thermal hyperalgesia. Our results showed that the protein expression of PAR2 and its downstream pathways (protein kinases namely, PKCε and PKA) and transient receptor potential vanilloid 1 (TRPV1) were amplified in the dorsal horn of the spinal cord of bone cancer rats compared to control rats. Blocking spinal PAR2 by using FSLLRY‐NH2 significantly attenuated the activities of PKCε/PKA signaling pathways and TRPV1 expression as well as mechanical and thermal hyperalgesia. Also, inhibition of PKCε/PKA and TRPV1 significantly diminished the hyperalgesia observed in bone cancer rats. Additionally, blocking PAR2 enhanced the attenuations of PKCε/PKA and cyclic adenosine monophosphate induced by morphine and further extended analgesia of morphine via μ‐opioid receptor (MOR). Our data revealed specific signaling pathways, leading to bone cancer pain, including the activation of PAR2, downstream PKCε/PKA, TRPV1 and resultant sensitization of MOR. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of bone cancer pain often observed in clinics.

The mechanism of μ-opioid receptor (MOR)-TRPV1 crosstalk in TRPV1 activation involves morphine anti-nociception, tolerance and dependence

Initiated by the activation of various nociceptors, pain is a reaction to specific stimulus modalities. The μ-opioid receptor (MOR) agonists, including morphine, remain the most potent analgesics to treat patients with moderate to severe pain. However, the utility of MOR agonists is limited by the adverse effects associated with the use of these drugs, including analgesic tolerance and physical dependence. A strong connection has been suggested between the expression of the transient receptor potential vanilloid type 1 (TRPV1) ion channel and the development of inflammatory hyperalgesia. TRPV1 is important for thermal nociception induction, and is mainly expressed on sensory neurons. Recent reports suggest that opioid or TRPV1 receptor agonist exposure has contrasting consequences for anti-nociception, tolerance and dependence. Chronic morphine exposure modulates TRPV1 activation and induces the anti-nociception effects of morphine. The regulation of many downstream targets of TRPV1 plays a critical role in this process, including calcitonin gene-related peptide (CGRP) and substance P (SP). Additional factors also include capsaicin treatment blocking the anti-nociception effects of morphine in rats, as well as opioid modulation of TRPV1 responses through the cAMP-dependent PKA pathway and MAPK signaling pathways. Here, we review new insights concerning the mechanism underlying MOR-TRPV1 crosstalk and signaling pathways and discuss the potential mechanisms of morphine-induced anti-nociception, tolerance and dependence associated with the TRPV1 signaling pathway and highlight how understanding these mechanisms might help find therapeutic targets for the treatment of morphine induced antinociception, tolerance and dependence.

Review on the Applications and Molecular Mechanisms of Xihuang Pill in Tumor Treatment

Xihuang pill (XH) is a complementary and alternative medicine that has been used in traditional Chinese medicine (TCM) for the treatment of tumors since the 18th century. XH has clinical effects on non-Hodgkin lymphoma, breast cancer, gastric cancer, liver cancer, and bone metastasis. XH can also inhibit the growth of tumor cells and cancer stem cells, prevent tumor invasion and angiogenesis, and regulate the tumor microenvironment. XH is composed of Ru Xiang (olibanum), Mo Yao (Commiphora myrrha), She Xiang (Moschus), and Niu Huang (Calculus bovis). Some of the compounds found in these ingredients exert multiple antitumor effects and may synergize with the other ingredients. We aimed to summarize the clinical applications and molecular mechanisms of XH and its chemical composition. This review will provide potential new strategies and alternative perspectives for tumor treatments and basic research into complementary and alternative medicine.

New insights of nociceptor sensitization in bone cancer pain

Introduction: Numerous studies have shown that an intact CNS is required for the conscious perception of cancer-induced bone pain (CIBP) and that changes in the CNS are clearly evident. Accordingly, the blockage of nociceptive stimulus into the CNS can effectively relieve or markedly attenuate CIBP, revealing the clinical implication of the blockage of ongoing peripheral inputs for the control of CIBP. Areas covered: In this review, the heterogeneity and excitability of nociceptors in bone are covered. Furthermore, their role in initiating and maintaining CIBP is also described. Expert opinion: Developing mechanistic therapies to treat CIBP is a challenge, but they have the potential to fundamentally change our ability to effectively block/relieve CIBP and increase the functional status and quality of life of patients with bone metastasis. Further studies are desperately needed at both the preclinical and clinical levels to determine whether the targets as mentioned in this review are viable and feasible for patient populations.

Sinomenine inhibits A549 human lung cancer cell invasion by mediating the STAT3 signaling pathway.

Increasing evidence suggests that the failure of lung cancer treatment may occur as a result of tumor invasion and metastasis. Signal transducer and activator of transcription 3 (STAT3), an epithelial-mesenchymal transition-inducing transcription factor, is a key signaling molecule involved in the proliferation, apoptosis, invasion and metastasis of tumor cells. Sinomenine is an alkaloid compound with an antineoplastic potential against a variety of cancer cells. The aim of the present study was to assess the antitumor mechanisms of sinomenine in the A549 human lung cancer cell line. The results demonstrated that sinomenine manifested dose-dependent cytotoxicity and induced apoptosis in A549 cells. The protein expression of Janus kinase 2, STAT3, phosphorylated-STAT3, Snail, N-cadherin and vimentin decreased in sinomenine-treated cells, while E-cadherin protein expression increased. The regulation of STAT3, N-cadherin and E-cadherin by sinomenine was further confirmed by reverse transcription-quantitative polymerase chain reaction and immunofluorescent staining. It was demonstrated that sinomenine exerts inhibitory effects on A549 human lung cancer cell invasion, possibly through the inhibition of STAT3 signaling. These results provide a novel insight into the role of sinomenine in the treatment of non-small cell lung cancer.

Association between Tumor Vasculogenic Mimicry and the Poor Prognosis of Gastric Cancer in China: An Updated Systematic Review and Meta-Analysis

Background. Vasculogenic mimicry can promote tumor growth and metastasis. This article is aimed at conducting a systematic meta-analysis to explore the clinicopathological and prognostic significance of vasculogenic mimicry and gastric cancer. Methods. We searched Pubmed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and the VIP and Wanfang Database for eligible studies. We manually searched for printed journals and relevant textbooks. Subgroups analyses were performed based on the region, manuscript quality, methods of vasculogenic mimicry identification, pathology, and number of patients. Results. Nine studies with 997 patients were included in this meta-analysis. A significant association was observed between vasculogenic mimicry-positive patients and those with gastric cancer with poor overall survival (hazard ratio = 2.24, 95% confidence interval: 1.45–3.47), poor pathological grading, high tumor node metastasis clinical stage, lymph node metastasis, deep tumor invasion, and distant metastasis. Conclusions. Vasculogenic mimicry is associated with a poor prognosis in patients with gastric cancer in China. Clinical studies with large samples are needed worldwide and standardized protocols should be adopted in the future to achieve a better understanding of the relationship between gastric cancer and vasculogenic mimicry.

Protease-activated receptor 2 antagonist potentiates analgesic effects of systemic morphine in a rat model of bone cancer pain.

Background and Objectives Bone cancer pain affects the quality of life of cancer patients. This study was aimed at investigating the analgesic effects of combined therapies with an antagonist of proteinase-activated receptor (PAR) 2 and morphine on pain-related behaviors in a rat model of bone cancer pain. Methods Female Wistar rats were inoculated intramedullarily with Walker 256 cells into their tibias. The analgesic effects of intraperitoneal treatment with morphine and/or intrathecal with the PAR2 antagonist, FSLLRY-NH2, on bone cancer pain–related behaviors in rats were examined. Results Treatment with morphine at 3 or 10 mg/kg significantly improved limb-use and weight-bearing scores and reduced the number of spontaneous flinches in rats. Treatment with FSLLRY-NH2 at 10 mmol/L also significantly improved limb use and weight bearing scores, and reduced the number of spontaneous flinches in rats. Combination a sub-analgesic dose of FSLLRY-NH2 (0.1 mmol/L) and morphine further elevated limb-use and weight-bearing scores and reduced the number of flinches compared with the effects of morphine alone in rats. Conclusions Our data indicate that the combination of morphine and FSLLRY-NH2 has potent analgesic effects on bone cancer pain and our findings may aid in design of new strategies for the treatment of bone cancer pain.

New insights into protease-activated receptor 4 signaling pathways in the pathogenesis of inflammation and neuropathic pain: a literature review

Pain is an unpleasant sensory and emotional experience that is commonly associated with actual or potential tissue damage. Despite decades of pain research, many patients continue to suffer from chronic pain that is refractory to current treatments. Accumulating evidence has indicated an important role of protease-activated receptor 4 (PAR4) in the pathogenesis of inflammation and neuropathic pain. Here we reviewed PAR4 expression and activation via intracellular signaling pathways and the role of PAR4 signaling pathways in the development and maintenance of pain. Understanding PAR4 and its corresponding signaling pathways will provide insight to further explore the molecular basis of pain, which will also help to identify new targets for pharmacological intervention for pain relief.

Chinese patent medicine Fei-Liu-Ping ointment as an adjunctive treatment for non-small cell lung cancer: protocol for a systematic review

Introduction Fei-Liu-Ping ointment has been widely applied as adjunctive drug in the treatment of non-small cell lung cancer (NSCLC). However, there has been no systematic review of research findings regarding the efficacy of this treatment. Here, we provide a protocol for assessing the effectiveness and safety of Fei-Liu-Ping ointment in the treatment of NSCLC. Methods and analysis The electronic databases to be searched will include MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Excerpt Medica Database (EMBASE), China National Knowledge Infrastructure (CNKI), China Scientific Journal Database (VIP), Wanfang Database and Chinese Biomedical Literature Database (CBM). Papers in English or Chinese published from inception to 2016 will be included without any restrictions. We will conduct a meta-analysis of randomised controlled trial if possible. The therapeutic effects according to the standard for treatment of solid tumours by the WHO and the quality of life as evaluated by Karnofsky score and weight will be applied as the primary outcomes. We will also evaluate the data synthesis and risk of bias using Review Manager 5.3 software. Dissemination The results of this review will offer implications for the use of Fei-Liu-Ping ointment as an adjunctive treatment for NSCLC. This knowledge will inform recommendations by surgeons and researchers who are interested in the treatment of NSCLC. The results of this systematic review will be disseminated through presentation at a conference and publication of the data in a peer-reviewed journal. Trial registration number PROSPERO CRD42016036911.