Butein, a potential drug for the treatment of bone cancer pain through bioinformatic and network pharmacology.

Bone cancer pain is a difficult-to-treat pathologic condition that impairs the patient's quality of life. The effective therapy options for BCP are restricted due to the unknown pathophysiology. Transcriptome data were obtained from the Gene Expression Omnibus database and differentially expressed gene extraction was performed. DEGs integrated with pathological targets found 68 genes in the study. Butein was discovered as a possible medication for BCP after the 68 genes were submitted to the Connectivity Map 2.0 database for drug prediction. Moreover, butein has good drug-likeness properties. To collect the butein targets, we used the CTD, SEA, TargetNet, and Super-PRED databases. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed butein's pharmacological effects, indicating that butein may aid in treating BCP by altering the hypoxia-inducible factor, NF-kappa B, angiogenesis, and sphingolipid signaling pathways. Moreover, the pathological targets integrated with drug targets were obtained as the shared gene set A, which was analyzed by ClueGO and MCODE. Biological process analysis and MCODE algorithm further analyzed that BCP related targets were mainly involved in signal transduction process and ion channel-related pathways. Next, we integrated targets related to network topology parameters and targets of core pathways, identified PTGS2, EGFR, JUN, ESR1, TRPV1, AKT1 and VEGFA as butein regulated hub genes by molecular docking, which play a critical role in its analgesic effect. This study lays the scientific groundwork for elucidating the mechanism underlying butein's success in the treatment of BCP.

Voltage-gated sodium channels, potential targets of Tripterygium wilfordii Hook. f. to exert activity and produce toxicity.

ETHNOPHARMACOLOGY RELEVANCE: Tripterygium wilfordii Hook. f. has been widely used in clinical practice due to its good anti-inflammatory and analgesic activities. However, its application is limited by potential toxicity and side effects. AIM OF THE STUDY: The study aimed to identify the mechanisms responsible for the pharmacological activity and cardiotoxicity of the main monomers of Tripterygium wilfordii. MATERIALS AND METHODS: Database analysis predicted that ion channels may be potential targets of Tripterygium wilfordii. The regulatory effects of monomers (triptolide, celastrol, demethylzeylasteral, and wilforgine) on protein Nav1.5 and Nav1.7 were predicted and detected by Autodock and patch clamping. Then, we used the formalin-induced pain model and evaluated heart rate and myocardial zymograms to investigate the analgesic activity and cardiotoxicity of each monomer in vivo. RESULTS: All four monomers were able to bind to Nav1.7 and Nav1.5 with different binding energies and subsequently inhibited the peak currents of both Nav1.7 and Nav1.5. The monomers all exhibited analgesic effects on formalin-induced pain; therefore, we hypothesized that Nav1.7 is one of the key analgesic targets. Demethylzeylasteral reduced heart rate and increased the level of creatine kinase-MB, thus suggesting a potential cardiac risk; data suggested that the inhibitory effect on Nav1.5 might be an important factor underlying its cardiotoxicity. CONCLUSION: Our findings provide an important theoretical basis for the further screening of active monomers with higher levels of activity and lower levels of toxicity.

Prediction and verification of potential lead analgesic and antiarrhythmic components in Corydalis yanhusuo W. T. Wang based on voltage-gated sodium channel proteins.

Corydalis yanhusuo W. T. Wang, a traditional Chinese herbal medicine, has been used as an analgesic for thousands of years and it also promotes blood circulation. In this study, 33 Corydalis yanhusuo alkaloid active components were acquired from Traditional Chinese Medicine Database and Analysis Platform (TCMSP). A total of 543 pain-related targets, 1774 arrhythmia targets, and 642 potential targets of these active components were obtained using Swiss Target Prediction, GeneCards, Open Target Platform, and Therapeutic Target Database. Fifty intersecting targets were visualized through a Venn diagram, KEGG and GO pathway enrichment analysis. The analysis proposed that sodium ion channels are likely potential targets of Corydalis yanhusuo active components as analgesia and anti-arrhythmia agents. Molecular docking showed that the 33 components could bind to Nav1.7 and Nav1.5 (two subtypes of ion channel proteins) with different binding energies. In a patch clamp study, dihydrosanguinarine and dihydrochelerythrine, two monomers with the strongest binding effects, could inhibit the peak currents and promote both activation and inactivation phases of Nav1.5. Meanwhile, dihydrosanguinarine and dihydrochelerythrine could also inhibit peak currents and promote the activation phase of Nav1.7. Therefore, the findings from this study provide valuable information for future uses of traditional Chinese medicines to treat pain and cardiovascular disease.

Analgesic effect of the main components of Corydalis yanhusuo (yanhusuo in Chinese) is caused by inhibition of voltage gated sodium channels.

ETHNOPHARMACOLOGY RELEVANCE: Pain often causes a series of abnormal changes in physiology and psychology, which can lead to disease and even death. Drug therapy is the most basic and commonly used method for pain relief and management. Interestingly, at present, hundreds of traditional Chinese medicines have been reported to be used for pain relief, most of which are monomer preparations, which have been developed into new painkillers. Corydalis yanhusuo is a representative of one of these medicines and is available for pain relief. AIM OF THE STUDY: This study aims to determine the analgesic effect and the potential targets of the monomers derived from Corydalis yanhusuo, and to explore any possible associated cardiac risk factors. MATERIALS AND METHODS: In this study, four monomers derived from Corydalis yanhusuo (tetrahydropalmatine, corydaline, protopine, dehydrocorydaline) were tested in vivo, using the formalin-induced pain model to determine their analgesic properties. Their potential targets were also determined using whole cell patch clamp recordings and myocardial enzyme assays. RESULTS: The results showed that all monomers showed analgesic activity and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.7, which indicating that Nav1.7 might be involved in the analgesic mechanism of Corydalis yanhusuo. Protopine increased the level of creatine kinase-MB (CK-MB) and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.5, indicating that Nav1.5 might be involved in the cardiac risk associated with protopine treatment. CONCLUSION: These data showed that tetrahydropalmatine produced the best analgesic effect and the lowest cardiac risk. Thus, voltage gated sodium channels (VGSCs) might be the main targets associated with Corydalis yanhusuo. This study, therefore, provides valuable information for future studies and use of traditional Chines medicines for the alleviation of pain.

CircHIPK3 regulates melanoma cell behaviors by binding with miR-215-5p to upregulate YY1.

OBJECT: To investigate the role of circHIPK3 in melanoma. METHODS: Bioinformatics analysis and experiments including RT-qPCR, Pearson's correlation analysis, luciferase reporter, Western blot, and RIP assays were applied to explore the function and mechanism of circHIPK3 in melanoma. RESULTS: CircHIPK3 expression was strikingly upregulated while miR-215-5p was downregulated in melanoma tissues and cell lines. Pearson's correlation analysis unveiled circHIPK3 expression was positively correlated with Ki-67 (a marker of proliferation), which implied that circHIPK3 may play a vital role in the progression of melanoma. In mechanism, luciferase reporter and RIP assays validated that circHIPK3 was able to bind with miR-215-5p. Moreover, we confirmed that overexpression of circHIPK3 could facilitate cell proliferation and depress cell apoptosis in melanoma while overexpression of miR-215-5p exerted opposite effects. Besides, our findings indicated that miR-215-5p overexpression significantly reversed the circHIPK3 overexpressing-mediated promotive effect on cell proliferation and inhibitory effect on cell apoptosis. Furthermore, we found that miR-215-5p could directly target YY1. Upregulation of YY1 could notably offset the inhibitory effect of circHIPK3 downregulation on cell proliferation and the promotive effect on cell apoptosis. CONCLUSION: Our study corroborated that circHIPK3 regulated melanoma cell behaviors via the miR-215-5p/YY1 axis, which might provide a novel insight for the treatment of melanoma patients.

[Lymphomatoid papulosis: a clinicopathologic study of 22 cases].

OBJECTIVE: To investigate the clinical presentation, histopathological features, progression, and treatment of lymphomatoid papulosis (LyP). METHODS: A retrospective review was performed on clinicopathological data of 22 patients diagnosed with LyP from June 2010 to March 2015 in Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College. RESULT: The mean age of the 22 LyP patients was 39 years (range: 7-83 years). The male-to-female ratio was 1:1. The areas predominantly affected were the trunks, followed by limbs and face. Most lesions presented as recurrent eruption of erythema, papule, nodules, ulcer, necrosis and crusting. Some of them leaved hyperpigmentation or atrophic scars on healing. Histopathologically, LyP were devided into types A, B, C, D and E, with 12, 1, 1, 3, and 4 cases in each type, respectively, and one case of mixed type B and C. One of the patients was also diagnosed with primary cutaneous anaplastic large-cell lymphoma besides the diagnosis of LyP. Among the 15 patients with follow-up information available, 11 patients were treated with regimens including oral corticosteroids, methotrexate, tripchlorolide, intramuscular injection of interferon, phototherapy, and topical corticosteroids. The mean follow-up time was 22 (1-54) months.All the patients were alive at the end of the follow-up period. CONCLUSIONS: LyP is a low-grade malignant T-cell lymphoma with a benign clinical course but histologically malignant features. Multi-agent chemotherapy is unnecessary. Patients with LyP are likely to have an favorable prognosis.