A metabolomics approach reveals metabolic disturbance of human cholangiocarcinoma cells after parthenolide treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Tanacetum parthenium (L.) Schultz-Bip, commonly known as feverfew, has been traditionally used to treat fever, migraines, rheumatoid arthritis, and cancer. Parthenolide (PTL), the main bioactive ingredient isolated from the shoots of feverfew, is a sesquiterpene lactone with anti-inflammatory and antitumor properties. Previous studies showed that PTL exerts anticancer activity in various cancers, including hepatoma, cholangiocarcinoma, acute myeloid leukemia, breast, prostate, and colorectal cancer. However, the metabolic mechanism underlying the anticancer effect of PTL remains poorly understood. AIM OF THE STUDY: To explore the anticancer activity and underlying mechanism of PTL in human cholangiocarcinoma cells. MATERIAL AND METHODS: In this investigation, the effects and mechanisms of PTL on human cholangiocarcinoma cells were investigated via a liquid chromatography/mass spectrometry (LC/MS)-based metabolomics approach. First, cell proliferation and apoptosis were evaluated using cell counting kit-8 (CCK-8), flow cytometry analysis, and western blotting. Then, LC/MS-based metabolic profiling along with orthogonal partial least-squares discriminant analysis (OPLS-DA) has been constructed to distinguish the metabolic changes between the negative control group and the PTL-treated group in TFK1 cells. Next, enzyme-linked immunosorbent assay (ELISA) was applied to investigate the changes of metabolic enzymes associated with significantly alerted metabolites. Finally, the metabolic network related to key metabolic enzymes, metabolites, and metabolic pathways was established using MetaboAnalyst 5.0 and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database. RESULTS: PTL treatment could induce the proliferation inhibition and apoptosis of TFK1 in a concentration-dependent manner. Forty-three potential biomarkers associated with the antitumor effect of PTL were identified, which primarily related to glutamine and glutamate metabolism, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, arginine biosynthesis, arginine and proline metabolism, glutathione metabolism, nicotinate and nicotinamide metabolism, pyrimidine metabolism, fatty acid metabolism, phospholipid catabolism, and sphingolipid metabolism. Pathway analysis of upstream and downstream metabolites, we found three key metabolic enzymes, including glutaminase (GLS), γ-glutamyl transpeptidase (GGT), and carnitine palmitoyltransferase 1 (CPT1), which mainly involved in glutamine and glutamate metabolism, glutathione metabolism, and fatty acid metabolism. The changes of metabolic enzymes associated with significantly alerted metabolites were consistent with the levels of metabolites, and the metabolic network related to key metabolic enzymes, metabolites, and metabolic pathways was established. PTL may exert its antitumor effect against cholangiocarcinoma by disturbing metabolic pathways. Furthermore, we selected two positive control agents that are considered as first-line chemotherapy standards in cholangiocarcinoma therapy to verify the reliability and accuracy of our metabolomic study on PTL. CONCLUSION: This research enhanced our comprehension of the metabolic profiling and mechanism of PTL treatment on cholangiocarcinoma cells, which provided some references for further research into the anti-cancer mechanisms of other drugs.

Case report: Systemic muscle involvement as the primary clinical manifestation of chronic active Epstein-Barr virus infection: A case-based review.

Chronic active Epstein-Barr virus infection (CAEBV) is common in Asian countries and characterized by recurrent or persistent infectious mononucleosis-like symptoms. Here, we describe a rare case of CAEBV-associated generalized myositis with extranodal NK/T-cell lymphoma, who initially presented with swelling and muscle soreness in the extremities and was diagnosed as polymyositis at the initial stage. CAEBV-associated generalized myositis is different from polymyositis and other types of myositis. Furthermore, it is prone to lymphoma with poor prognosis.

Factors influencing psychological distress and effects of stepwise psychological care on quality of life in patients undergoing chemotherapy after breast cancer surgery.

OBJECTIVE: To investigate factors influencing psychological distress and the effect of stepwise psychological care on the quality of life in patients undergoing chemotherapy after breast cancer surgery. METHODS: A retrospective study was conducted on 96 patients undergoing chemotherapy after breast cancer surgery. The patients were evenly divided into a routine care group (control group) and a stepwise psychological care group (observation group) according to the care method. The correlation between the psychological distress and the Self-Rating Anxiety Scale (SAS) score was investigated. The impact of care intervention on the psychological distress, SAS score, and the quality of life of patients before and after intervention were explored. Relevant factors that affect the psychological distress of patients undergoing chemotherapy after breast cancer surgery were also investigated. RESULTS: A univariate analysis showed that age, residence, monthly income, education level, medical insurance status, occupation, surgery method, and anxiety score all contributed to the degree of psychological distress in patients with breast cancer mastectomy (all P<0.05). A multivariate regression analysis demonstrated that young age, low monthly income, no medical insurance, mastectomy, and high SAS score were risk factors for the psychological distress of patients who underwent mastectomy (all P<0.05). The psychological distress was positively correlated with anxiety scores of patients undergoing chemotherapy after breast cancer surgery (r=0.249, P=0.005). Both psychological distress and anxiety scores of the observation group after stepwise psychological care were significantly lower than those before treatment and those of the control group (both P<0.05). After treatment, both groups of patients showed better scores in additional concerning items, social/family well-being, functional well-being, physical well-being, emotional well-being, and overall quality of life than before treatment (all P<0.05). Of note, the observation group demonstrated better quality of life than that of the control group. CONCLUSION: Age, low monthly income, radical mastectomy, and no medical insurance prior to undergoing chemotherapy after breast cancer surgery are independent factors that affect psychological distress. The distress was positively correlated with anxiety. Thus, stepwise psychological care may alleviate patients' psychological distress and anxiety.

A Method of Multiple Dynamic Objects Identification and Localization Based on Laser and RFID.

In an indoor environment, object identification and localization are paramount for human-object interaction. Visual or laser-based sensors can achieve the identification and localization of the object based on its appearance, but these approaches are computationally expensive and not robust against the environment with obstacles. Radio Frequency Identification (RFID) has a unique tag ID to identify the object, but it cannot accurately locate it. Therefore, in this paper, the data of RFID and laser range finder are fused for the better identification and localization of multiple dynamic objects in an indoor environment. The main method is to use the laser range finder to estimate the radial velocities of objects in a certain environment, and match them with the object's radial velocities estimated by the RFID phase. The method also uses a fixed time series as "sliding time window" to find the cluster with the highest similarity of each RFID tag in each window. Moreover, the Pearson correlation coefficient (PCC) is used in the update stage of the particle filter (PF) to estimate the moving path of each cluster in order to improve the accuracy in a complex environment with obstacles. The experiments were verified by a SCITOS G5 robot. The results show that this method can achieve an matching rate of 90.18% and a localization accuracy of 0.33m in an environment with the presence of obstacles. This method effectively improves the matching rate and localization accuracy of multiple objects in indoor scenes when compared to the Bray-Curtis (BC) similarity matching-based approach as well as the particle filter-based approach.

13-Step Total Synthesis of Atropurpuran.

Herein, we report a concise total synthesis of atropurpuran, a unique and synthetically challenging pentacyclic diterpene that bears a tetracyclo[5.3.3.04,9.04,12]-tridecane skeleton that is unprecedented among natural terpenes. This 13-step approach features a strategy that include early stage rapid skeleton formation and the late-stage introduction of reactive functional groups, thus allowed a high overall synthetic efficiency with minimal use of PGs. The key transformations of our work include a facile construction of the spiro[5.5]undecane moiety through an ring-closing enyne metathesis reaction and an efficient formation of the tetracyclo[5.3.3.04,9.04,12]-tridecane scaffold via an regioselective double oxidative dearomatization/intramolecular Diels-Alder reaction cascade. This efficient approach should also inspire further advances in the synthesis of related complex diterpenes and diterpenoid alkaloids.

MRTF-A mediates the activation of COL1A1 expression stimulated by multiple signaling pathways in human breast cancer cells.

Deposition of type I collage in ECM is an important property of various fibrotic diseases including breast cancer. The excessive expression of type I collagen contributes to the rigidity of cancer tissue and increases the mechanical stresses which facilitate metastasis and proliferation of cancer cells via the activation of TGF-ß signaling pathway. The increased mechanical stresses also cause the compression of blood vessels and result in hypoperfusion and impaired drug delivery in cancer tissue. Additionally, type I collage functions as the ligand of α2ß1-integrin and DDR1/2 receptors on the membrane of cancer cells to initiate signal transduction leading to metastasis. The expression of type I collage in cancer cells is previously shown to be inducible by TGF-ß however the detailed mechanism by which the synthesis of type I collagen is regulated in breast cancer cells remains unclear. Herein, we report that MRTF-A, a co-activator of SRF, is important for the regulation of type I collagen gene COL1A1 in breast cancer cells. MRTF-A physically interacted with the promoter of COL1A1 to facilitate histone acetylation and RNA polymerase II recruitment. The RhoC-ROCK signaling pathway which controls the nuclear localization of MRTF-A regulated the transcription of COL1A1 in human breast cancer cells. TGF-ß and Wnt signaling increased the expression of both MRTF-A and COL1A1. Furthermore, depletion of MRTF-A abolished the upregulation of COL1A1 in response to the TGF-ß or Wnt signaling, indicating the importance of MRTF-A in the synthesis of type I collagen in breast cancer. Given the crucial roles of type I collagen in the formation of metastasis-prone and hypoperfusion microenvironment, MRTF-A would be a potential target for the development of anti-breast cancer activities.

The Wnt-ß-catenin signaling regulated MRTF-A transcription to activate migration-related genes in human breast cancer cells.

MRTF-A is a transcriptional co-activator being critical for multiple processes including tissue fibrosis and cancer metastasis. The Rho-actin signaling stimulates the nuclear translocation and transcriptional activity of MRTF-A with little effect on the expression of MRTF-A gene. High expression of MRTF-A was observed in pancreatic cancer tissues and in TGF-ß treated breast cancer cells. However, the mechanism for the upregulation of MRTF-A gene remains unclear. In this study, we showed that the transcription of MRTF-A was regulated by the Wnt-ß-catenin signaling in breast cancer cells. LiCl treatment, Wnt3a treatment or ß-catenin overexpression enhanced the transcription of MRTF-A gene. In agreement, depletion of ß-catenin with siRNA diminished MRTF-A transcription. With ChIP assays, ß-catenin was identified to interact with the MRTF-A promoter whereby it increased histone H4 acetylation and RNA polymerase II association. Further, results of RT-qPCR and Western-blotting supported that the transcriptional co-activator activity of MRTF-A was controlled by both the Rho-actin and the Wnt-ß-catenin signaling pathways. MRTF-A was required for cell migration stimulated by the Wnt-ß-catenin signaling. Taken together, our results suggest that MRTF-A integrates the Rho-actin and the Wnt-ß-catenin signaling to regulate migration-related genes and consequently increases the mobility of breast cancer cells.

Performance and microbial community of completely autotrophic nitrogen removal over nitrite (CANON) process in two membrane bioreactors (MBR) fed with different substrate levels.

To study the influence of substrate on completely autotrophic nitrogen removal over nitrite (CANON) process, two membrane bioreactors (MBR) with identical setup but fed with different substrate levels (R1 with low ammonia, R2 with high ammonia), were adopted in this study. The nitrogen removal performance, bioactivity, biodiversity and distribution of the functional microorganisms in two reactors were investigated. Both the aerobic ammonia-oxidizing bacteria (AerAOB) and anaerobic ammonia-oxidizing bacteria (AnAOB) in R2 showed higher bioactivity than those in R1, while nitrite-oxidizing bacteria (NOB) showed the contrary result. Nitrosomonas and Candidatus Kuenenia stuttgartiensis were detected as predominant functional microbes in the two reactors while Nitrobacter only existed in R1. High influent ammonia possibly led to the higher biodiversity of AerAOB and the more densely packed distribution. Meanwhile, this study has demonstrated the feasibility of increasing ammonia for rapid start-up, and decreasing HRT for high-rate nitrogen removal in CANON process.

Autotrophic nitrogen removal from domestic sewage in MBR-CANON system and the biodiversity of functional microbes.

The feasibility of completely autotrophic nitrogen removal over nitrite (CANON) process for treating domestic sewage was investigated in membrane bioreactor (MBR), for which conventional activated sludge was seeded at ambient temperature. By gradually decreasing hydraulic retention time under the oxygen-limited condition, CANON was successfully started-up for 78 days. Finally the MBR-CANON system was adopted for treating domestic sewage, nitrogen and COD removal achieved to 0.97 kg m(-3) d(-1), 80%, respectively, with the effluent turbidity below 1.0 NTU. DGGE profiles showed a distinct community shift of the functional bacteria after seeded to the reactor, and phylogenetic results indicated the predominance of Nitrosomonas and Candidatus Kuenenia stuttgartiensis for nitrogen removal in the reactor. FISH results showed the predominance of aerobic ammonia oxidizing bacteria (AerAOB) and anaerobic ammonia oxidizing bacteria (AnAOB) in the system, both of whose proportion reduced when treated domestic sewage.

Expression of both matrix metalloproteinase-2 and its tissue inhibitor-2 in tunica media of radial artery in uremic patients.

OBJECTIVE: To investigate the expression and clinical significance of both matrix metalloproteinase-2 (MMP-2) and its tissue inhibitor (tissue inhibitor of metalloproteinase-2 (TIMP-2)) in tunica media of radial artery in uremic patients. METHODS: The modified radial arteries from 80 uremic patients during internal arteriovenous fistula surgery were selected and used as experimental specimens. The calcification of tunica media was observed by alizarin red staining, and the expression status of MMP-2, TIMP-2, osteoprotegerin (OPG), and osteopontin (OPN) in tunica media of radial arteries of these patients was detected by immunohistochemical method. The semiquantitative analysis and comparison were conducted based on the calcification grading and the expression of each test protein in tunica media of radial artery. RESULTS: Of the 80 cases of radial artery specimens, 37 cases were presented with various degrees of calcification of tunica media, and the calcification rate was 46.25%; the expression of MMP-2, TIMP-2, OPG, and OPN could be detected in the calcificated tunica media of the radial artery and was positively correlated with the degree of vascular calcification (p < 0.05). CONCLUSION: The incidence of vascular calcification in uremic patients was high. The occurrence of calcification in tunica media of the radial artery was correlated with the expression of MMP-2 and TIMP-2.

Total synthesis of (-)-Przewalskin B.

The first total synthesis of (-)-Przewalskin B has been accomplished with an intramolecular nucleophilic acyl substitution (INAS) reaction and an intramolecular aldol condensation as key steps.

Biomimetic total synthesis of (+)-chabranol.

A concise, biomimetic total synthesis of the unprecedented terpenoid skeleton (+)-chabraol has been accomplished via 6 steps from the chiral epoxide 7, involving an intramolecular Prins double cyclization to yield the bicyclo[2.2.1] core of the natural product as the key step. The absolute configuration of natural chabranol was also designated through the first asymmetric total synthesis.

Pt-catalyzed tandem 1,2-acyloxy migration/intramolecular [3 + 2] cycloaddition of enynyl esters.

A platinum-catalyzed tandem reaction involving enynyl ester isomerization and subsequent intramolecular [3 + 2] cyclization has been developed. This strategy provides an efficient approach to five-, six-, or seven-membered cyclic polyfunctional compounds.

Efficient asymmetric total syntheses of cryptocarya triacetate, cryptocaryolone, and cryptocaryolone diacetate.

Concise and efficient asymmetric total syntheses of three substituted alpha-pyrone-type natural products have been accomplished via 7-9 steps from 5b in high overall yields, which involve linchpin coupling, ring-closing metathesis, and a tandem sequence of deacetylation and intramolecular oxa-Michael addition as the key steps.

Application of a domino Friedel-Crafts acylation/alkylation reaction to the formal syntheses of (+/-)-taiwaniaquinol B and (+/-)-dichroanone.

An efficient acid-promoted domino Friedel-Crafts (FC) acylation/alkylation reaction has been developed for the construction of the core 6,5,6-ABC tricyclic skeleton of taiwaniaquinoids. The formal total syntheses of diterpenoids (+/-)-taiwaniaquinol B and (+/-)-dichroanone based on this strategy have been achieved.