Novel (-)-arctigenin derivatives inhibit signal transducer and activator of transcription 3 phosphorylation and P-glycoprotein function resensitizing multidrug resistant cancer cells in vitro and in vivo.

Multidrug resistance (MDR) is considered one of the significant chemotherapy failures of cancer patients and resulting in tumor recurrence and refractory cancer. The collateral sensitivity phenomenon is suggested as a potential alternative therapy for coring multidrug resistance in cancer. To achieve better effects and reduce toxicity, a polypharmacology strategy was applied. Arctigenin has been reported as a signal transducer and activator of transcription 3 (STAT3) inhibitor as an anticancer drug with low toxicity. However, the effective dosage of arctigenin was too high for re-sensitization in MDR cell lines. Therefore, we have designed and synthesized arctigenin derivatives and have evaluated their chemoreversal effects in KBvin and KB cells. The results conveyed that compounds 9, 10, and 12 displayed significant collateral sensitivity effects on MDR cancer cells, and the corresponding calculated RF values were 32, 174, and 133, respectively. In addition, compounds 9, 10, and 12 were identified to influence the activation of STAT3 and the function of P-glycoprotein in KBvin cells. Combining the active compounds (9, 10, and 12) with paclitaxel significantly inhibits MDR tumor growth in a zebrafish xenograft tumor model without toxicity. Thus, this study provided novel effective arctigenin derivatives and is considered a potential co-treatment with paclitaxel for treating MDR tumors.

Alleviation of Hyperuricemia by Strictinin in AML12 Mouse Hepatocytes Treated with Xanthine and in Mice Treated with Potassium Oxonate.

Hyperuricemia, an abnormally high level of blood uric acid, is a major risk factor for gout. Although xanthine oxidase inhibitors were clinically used to lower blood uric acid level, the concerned side effects restricted their utilization. In this study, strictinin, an abundant polyphenol in Pu'er tea, was evaluated for its preventive effects on hyperuricemia. The results showed that the xanthine oxidase activity, uric acid production, and inflammation in AML12 mouse hepatocytes treated with xanthine were significantly reduced by the supplementation of strictinin. Detailed analyses revealed that strictinin inhibited xanthine-induced NLRP3 inflammasome activation. Consistently, the elevated blood uric acid level and the enhanced xanthine oxidase activity in mice treated with potassium oxonate were effectively diminished by strictinin supplementation. Moreover, for the first time, strictinin was found to promote healthy gut microbiota. Overall, strictinin possesses a great potential to be utilized as a functional ingredient for the prevention of hyperuricemia.

Constituents from the Fruiting Bodies of Trametes cubensis and Trametes suaveolens in Vietnam and Their Anti-Inflammatory Bioactivity.

It is reported that various fungi have been used for medicine and edible foods. The tropical Trametes genus is popular and well-known in Vietnam for its health effects and bioactivities. In this study, the fruiting bodies of the edible fungi T. cubensis and T. suaveolens were collected in Vietnam. The preliminary bioactivity screening data indicated that the methanol extracts of the fruiting bodies of T. cubensis and T. suaveolens displayed significant inhibition of superoxide anion generation and elastase release in human neutrophils. Therefore, the isolation and characterization were performed on these two species by a combination of chromatographic methods and spectrometric analysis. In total, twenty-four compounds were identified, and among these (1-3) were characterized by 1D-, 2D-NMR, and HRMS analytical data. In addition, the anti-inflammatory potentials of some purified compounds were examined by the cellular model for the inhibition of superoxide anion generation and elastase release in human neutrophils. Among the isolated compounds, (5,14), and (19) displayed significant anti-inflammatory potential. As the results suggest, the extracts and isolated compounds from T. cubensis and T. suaveolens are potential candidates for the further development of new anti-inflammatory lead drugs or natural healthy foods.

Chemoreversal Agents from Taiwanofungus Genus and Their More Potent Methyl Derivatives Targeting Signal Transducer and Activator of Transcription 3 (STAT3) Phosphorylation.

Multidrug resistance (MDR), for which the mechanisms are not yet fully clear, is one of the major obstacles to cancer treatment. In recent years, signal transducer and activator of transcription 3 (STAT3) were found to be one of the important MDR mechanism pathways. Based on the previous research, zhankuic acid A, B, and C were found to have collateral sensitivity effects on MDR cancer cells, and MDR inhibitory activity of zhankuic acid methyl ester was found to be better than that of its acid. Therefore, we executed a systematic examination of the structure-activity relationship of zhankuic acid methyl ester derivatives to collateral sensitivity in MDR cancer cells. The results showed that compound 12 is the best in terms of chemoreversal activity, where the reversal fold was 692, and the IC50 value of paclitaxel combined with 10 µM compound 12 treatment was 1.69 nM in MDR KBvin cells. Among all the derivatives, methyl ester compounds were found to be better than their acids, and a detailed discussion of the structure-activity relationships of all of the derivatives is provided in this work. In addition, compounds 8, 12, and 26 were shown to influence the activation of STAT3 in KBvin cells, accounting for part of their chemoreversal effects. Our results may provide a new combined therapy with paclitaxel to treat multidrug-resistant cancers and provide a new therapy option for patients.

Bioactive naphthoquinones and triterpenoids from the fruiting bodies of Taiwanofungus salmoneus.

Drug resistance of cancer cells stands for the major problem of the treatment failure for chemotherapy or target therapy. Overexpression of efflux pumps leading to multidrug resistance (MDR) is still an important issue needed to be solved. In the present study, Taiwanofungus salmoneus was selected as the topic and eleven undescribed constituents including four naphthoquinones salmonones A-D (1-4) and seven triterpenoids salmoneatins A-G (5-11), along with one chromanone (12) and two benzenoids (13 and 14) reported from the natural sources for the first time, as well as twenty-one known compounds were characterized. The structures of undescribed compounds were established by the spectroscopic and spectrometric analyses. In addition, the plausible biosynthetic mechanism of purified naphthoquinones was proposed and these compounds may be the excellent chemotaxonomic markers. Moreover, the isolates were evaluated for their P-gp inhibitory effects and the results showed that most of the examined compounds were effective. Among the tested compounds, 5, 10, 2,3-dimethoxy-5-(2',5'-dimethoxy-3',4'-methylenedioxyphenyl)-7-methyl-[1,4]naphthoquinone, zhankuic acid A methyl ester, and camphoratin F can reverse the resistance of paclitaxel or vincristine with the reversal folds in the range of 51093.3 and 259.5. These experimental data would initiate the possible development of Taiwanofungus salmoneus for the cancer therapy in the future.

A new triterpenoid and other compounds from lichens Cryptothecia faveomaculata Makhija & Patw.

Ten compounds (1-10) were purified from the extract of lichens C. faveomaculata, and among these one new triterpenoid, cryptothecin A (1) was characterized through mass spectrometric and 2D NMR spectroscopic analyses. Some of the isolated compounds were assessed for their antimicrobial (1, 6, and 8) and cytotoxic activity (1, 4-5, and 7-9), but only weak inhibitory effects were observed.

Triterpenoids and steroids from the fruiting bodies of Hexagonia tenuis and their cytotoxicity.

One new triterpenoid, hexagonin F (1) was characterized from the fruiting bodies of Hexagonia tenuis with the assistance of spectroscopic and spectrometric analytical methods. In addition, two triterpenoids and two steroids were also identified by comparison of their physical and spectroscopic data with those reported. The purified compounds were examined for their cytotoxicity against five tumor cell lines, however, only weak cytotoxicity was demonstrated.

Effects of Sesamin, the Major Furofuran Lignan of Sesame Oil, on the Amplitude and Gating of Voltage-Gated Na+ and K+ Currents.

Sesamin (SSM) and sesamolin (SesA) are the two major furofuran lignans of sesame oil and they have been previously noticed to exert various biological actions. However, their modulatory actions on different types of ionic currents in electrically excitable cells remain largely unresolved. The present experiments were undertaken to explore the possible perturbations of SSM and SesA on different types of ionic currents, e.g., voltage-gated Na+ currents (INa), erg-mediated K+ currents (IK(erg)), M-type K+ currents (IK(M)), delayed-rectifier K+ currents (IK(DR)) and hyperpolarization-activated cation currents (Ih) identified from pituitary tumor (GH3) cells. The exposure to SSM or SesA depressed the transient and late components of INa with different potencies. The IC50 value of SSM needed to lessen the peak or sustained INa was calculated to be 7.2 or 0.6 µM, while that of SesA was 9.8 or 2.5 µM, respectively. The dissociation constant of SSM-perturbed inhibition on INa, based on the first-order reaction scheme, was measured to be 0.93 µM, a value very similar to the IC50 for its depressant action on sustained INa. The addition of SSM was also effective at suppressing the amplitude of resurgent INa. The addition of SSM could concentration-dependently inhibit the IK(M) amplitude with an IC50 value of 4.8 µM. SSM at a concentration of 30 µM could suppress the amplitude of IK(erg), while at 10 µM, it mildly decreased the IK(DR) amplitude. However, the addition of neither SSM (10 µM) nor SesA (10 µM) altered the amplitude or kinetics of Ih in response to long-lasting hyperpolarization. Additionally, in this study, a modified Markovian model designed for SCN8A-encoded (or NaV1.6) channels was implemented to evaluate the plausible modifications of SSM on the gating kinetics of NaV channels. The model demonstrated herein was well suited to predict that the SSM-mediated decrease in peak INa, followed by increased current inactivation, which could largely account for its favorable decrease in the probability of the open-blocked over open state of NaV channels. Collectively, our study provides evidence that highlights the notion that SSM or SesA could block multiple ion currents, such as INa and IK(M), and suggests that these actions are potentially important and may participate in the functional activities of various electrically excitable cells in vivo.

Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis.

Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton have been purified from Croton tonkinensis. METHODS: We examined any modifications of croton components (i.e., croton-01 [ent-18-acetoxy-7α-hydroxykaur-16-en-15-one], croton-02 [ent-7α,14ß-dihydroxykaur-16-en-15-one] and croton-03 [ent-1ß-acetoxy-7α,14ß-dihydroxykaur-16-en-15-one] on either hyperpolarization-activated cation current (Ih) or erg-mediated K+ current identified in pituitary tumor (GH3) cells and in rat insulin-secreting (INS-1) cells via patch-clamp methods. RESULTS: Addition of croton-01, croton-02, or croton-03 effectively and differentially depressed Ih amplitude. Croton-03 (3 µM) shifted the activation curve of Ih to a more negative potential by approximately 11 mV. The voltage-dependent hysteresis of Ih was also diminished by croton-03 administration. Croton-03-induced depression of Ih could not be attenuated by SQ-22536 (10 µM), an inhibitor of adenylate cyclase, but indeed reversed by oxaliplatin (10 µM). The Ih in INS-1 cells was also depressed effectively by croton-03. CONCLUSION: Our study highlights the evidence that these ent-kaurane diterpenoids might conceivably perturb these ionic currents through which they have high influence on the functional activities of endocrine or neuroendocrine cells.

Constituents and Anti-Multidrug Resistance Activity of Taiwanofungus camphoratus on Human Cervical Cancer Cells.

Resistance to anti-cancer drugs is one of the main factors of treatment failure resulting in high morbidity. Among the reasons of resistance, overexpression of efflux pumps leading to multidrug resistance is an important issue that needs to be solved. Taiwanofungus camphoratus has been used as a nutritional supplement to treat various cancers. However, its effects on the resistance to chemotherapeutic agents are still unknown. In this study, we report four new chemical constituents of T. camphoratus isolated from an ether extract: camphoratins K (1) and N (2) and benzocamphorins G (3) and I (4). Furthermore, we evaluated zhankuic acids A-C for their P-glycoprotein (P-gp) inhibitory effects. The results showed that zhankuic acid A was the most potent P-gp inhibitor compound and (at 20 µM) could reverse drug resistance in human cancer cells, restoring an IC50 of 78.5 nM for doxorubicin, of 48.5 nM for paclitaxel, and of 321.5 nM for vincristine, indicating a reversal fold of 48, 38, and 45 times, respectively. This study provides support for the use of T. camphoratus in the further development of cancer therapy.

The Constituents of the Stems of Cissus assamica and Their Bioactivities.

Fifty-five compounds were isolated from the fresh stems of Cissus assamica, including 14 benzenoids, 11 triterpenes, nine steroids, five tocopherols, five chlorophylls, four flavonoids, two benzoquinones, two tannins, and three other compounds. Their structures were constructed by 1D and 2D nuclear magnetic resonance (NMR) and mass spectral data, and were also identified by a comparison of their spectral data with those reported in the literature. Among these isolates, 1,2-bis-(5--tocopheryl) ethane (51) was reported for the first time from natural sources. Some purified compounds were examined for their anti-inflammatory and anticancer bioactivities. The results indicated that betulinic acid (16) exhibited strong inhibition of superoxide anion generation with IC50 value of 0.2 ± 0.1 µM, while betulinic acid (16) and pheophytin-a (47) inhibited elastase release with IC50 value of 2.7 ± 0.3 and 5.3 ± 1.0 µM, respectively. In addition, betulinic acid (16) and epi-glut-5(6)-en-ol (18) exhibited potential cytotoxicity to non-small-cell lung carcinoma (NCI-H226) and colon cancer (HCT-116) cell lines with IC50 values in the range of 1.6 to 9.1 µM.

Chemical constituents from the fruiting bodies of Phellinus igniarius.

A new tirucallane-type triterpenoid igniarine (1), and four known compounds meshimakobnol A (2), meshimakobnol B (3), ergosterol (4) and ergosterol peroxide (5), were purified from the methanol extracts of the fruiting bodies of Phellinus igniarius (DC. ex Fr.) Quél. The structure of 1 was elucidated using a combination of 1D and 2D NMR techniques and HR-ESI-MS analyses. In addition, the isolated compounds were examined for their cytotoxicity against several tumour cell lines and part of the tested compounds demonstrated weak cytotoxicity.

Effect of teapot materials on the chemical composition of oolong tea infusions.

BACKGROUND: The flavor and quality of tea are widely believed to be associated with the pot in which the tea is made. However, this claim is mostly by experiences and lacks solid support from scientific evidence. The current study investigated and compared the chemical compositions of oolong tea made with six different teapot materials, namely Zisha, Zhuni, stainless steel, ceramic, glass and plastic. RESULTS: For each tea sample, polyphenols and caffeine were examined by HPLC-UV, volatile compounds by GC/MS, amino acids by LC/MS and minerals by ICP-MS. The results suggested that tea infusions from Zisha and Zhuni pots contain higher levels of EGC, EGCG and total catechins and less caffeine than those from ceramic, glass and plastic pots and tend to have the lowest total mineral contents, potassium and volatile compounds in tea soup. The statistical differences were not all significant among Zisha, Zhuni and stainless steel pots. CONCLUSION: Based on the overall chemical composition of the tea infusion, Yixing clay pots (Zisha and Zhuni) produce tea infusions that are presumably less bitter and more fragrant and tend to contain more healthful compounds than tea infusions from other pots. The results could partially explain why Yixing clay pots are among the most popular teapots. The beneficial effects of long-term repeated use of these teapots warrants further study. © 2017 Society of Chemical Industry.

The functional property of royal jelly 10-hydroxy-2-decenoic acid as a melanogenesis inhibitor.

BACKGROUND: It has been reported that royal jelly would reduce melanin synthesis and inhibit the expression of melanogensis related proteins and genes. In this study, we evaluate the anti-melanogenic and depigmenting activity of 10-hydroxy-2-decenoic acid (10-HDA) from royal jelly of Apis mellifera. METHODS: In this study, we assesses the 10-HDA whitening activity in comparison with the changes in the intracellular tyrosinase activity, melanin content and melanin production related protein levles in B16F1 melanoma cells after treating with 10-HDA. Furthermore, the skin whitening effect was evaluated by applying a cream product containing with 0.5%, 1% and 2% of 10-HDA onto the skin of mice (C57BL/6 J) for 3 week to observe the effect of DL*-values. RESULTS: The results showed that 10-HDA inhibited the MITF protein expression (IC50 0.86 mM) in B16F1 melanoma cells. Western blot analysis revealed that 10-HDA inhibited the activity of tyrosinase and the expression of tyrosinase-related protein 1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor (MITF) in B16F1 melanoma cells. In addition, the 10-HDA was applied on the skin of mice show significantly increased the average skin-whitening index (L value). CONCLUSIONS: The validation data indicated the potential of 10-HDA for use in suppressing skin pigmentation. The 10-HDA is proposed as a candidate to inhibit melanogenesis, thus it could be developed as cosmetics skin care products.

Bioactive chemical constituents from the root bark of Morus australis.

Two new pyranoflavonoids, morustralins A (1) and B (2), a new natural benzene derivative, one benzenoid (Z)-1-hydroxy-4-(2-nitroethenyl)benzene (3), and thirty known compounds were isolated and characterized from the root bark of Morus australis. The structures of the new compounds were established from spectroscopic and spectrometric analyses. Ten isolates (1-10) were examined for inhibitory effects on adenosine diphosphate (ADP)-, arachidonic acid (AA)-, and platelet-aggregating factor (PAF)-induced platelet aggregation. Among the tested compounds, compound 3 displayed the most significant inhibition of ADP- and AA-induced platelet aggregation with IC50 values of 9.76±5.54 and 9.81±2.7µM, respectively. In addition, eight purified compounds (3-10) were examined for inhibition of nitric oxide (NO) production in RAW 264.7 cells and six compounds (3-8) displayed significant inhibitory effects with IC50 values ranging from 2.1±0.3 to 6.3±0.6µM.

Mechanistic Study of Tetrahydrofuran- acetogenins In Triggering Endoplasmic Reticulum Stress Response-apotoposis in Human Nasopharyngeal Carcinoma.

For past three decades, numerous studies have elucidated the antiproliferative effects of acetogenins in hopes of developing a new class of clinical anticancer agents. However, clear and definitive action mechanisms of acetogenins were less clarified. In the present study, three tetrahydrofuran (THF)-containing acetogenins were found to have potent and selective antiproliferative activity against human nasopharyngeal carcinoma (NPC) cell lines and their methotrexate-resistant counterparts. The THF-containing acetogenins induced G2/M phase arrest, mitochondrial damage and apoptosis, and increased cytosolic and mitochondrial Ca2+ in NPCs. Microarray analysis of NPC-TW01 cells treated with squamostatin A, a non-adjacent bis-THF acetogenin, demonstrated an increased endoplasmic reticulum (ER)-stress response (ESR). Enhanced ESR in squamostatin A-treated cells was confirmed by real-time PCR, Western blot and shRNA gene knockdown experiments. Although our results showed that squamostatin A-induced ESR was independent of extracellular Ca2+, the presence of extracellular Ca2+ enhanced the antiproliferative effect of acetogenins. In vivo analyses demonstrated that squamostatin A showed good pharmacokinetic properties and significantly retarded NPC tumor growth in the xenograft mouse model. Conclusively, our work demonstrates that acetogenins are effective and selective inducers of the ESR that can block NPC proliferation, and illustrate a previously unappreciated antitumor mechanism of acetogenins that is effective against nasopharyngeal malignancies.

Ionone Derivatives from the Mycelium of Phellinus linteus and the Inhibitory Effect on Activated Rat Hepatic Stellate Cells.

Three new γ-ionylideneacetic acid derivatives, phellinulins A-C (1-3), were characterized from the mycelium extract of Phellinus linteus. The chemical structures were established based on the spectroscopic analysis. In addition, phellinulin A (1) was subjected to the examination of effects on activated rat hepatic stellate cells and exhibited significant inhibition of hepatic fibrosis.

Chemical Constituents from the Fruiting Bodies of Hexagonia apiaria and Their Anti-inflammatory Activity.

A chemical investigation of the fruiting bodies of Hexagonia apiaria resulted in the identification of nine compounds including five new triterpenoids, hexagonins A-E (1-5), along with four known compounds. The purified constituents were examined for their anti-inflammatory activity. Among the tested compounds, hexatenuin A displayed the most significant inhibition of superoxide anion generation and elastase release. These triterpenoids may have potentials as anti-inflammatory agents.

Chemical constituents from the leaves of Annona reticulata and their inhibitory effects on NO production.

In the present study, the chemical investigation of the leaves of Annona reticulata has resulted in the identification of nine compounds, including annonaretin A, a new triterpenoid. The purified compounds were subjected to the examination of their effects on NO inhibition in LPS-activated mouse peritoneal macrophages and most of them exhibited significant NO inhibition, with IC50 values in the range of 48.6 ± 1.2 and 99.8 ± 0.4 µM.

Physalin F induces cell apoptosis in human renal carcinoma cells by targeting NF-kappaB and generating reactive oxygen species.

BACKGROUND: The aim of this study was to determine the molecular mechanisms of physalin F, an effective purified extract of Physalis angulata L. (Solanacae), in renal carcinoma A498 cells. METHODOLOGY/PRINCIPAL FINDINGS: Physalin F was observed to significantly induce cytotoxicity of three human renal carcinoma A498, ACHN, and UO-31 cells in a concentration-dependent manner; this was especially potent in A498 cells. The physalin F-induced cell apoptosis of A498 cells was characterized by MTT assay, nuclear DNA fragmentation and chromatin condensation. Using flow cytometry analysis, physalin F induced A498 cell apoptosis as demonstrated by the accumulation of the sub-G1 phase in a concentration- and time-dependent manner. Moreover, physalin F-mediated accumulation of reactive oxygen species (ROS) caused Bcl-2 family proteins, Bcl-2, and Bcl-xL degradation, which led to disruption of mitochondrial membrane potential and release of cytochrome c from the mitochondria into the cytosol. These effects were associated with induction of caspase-3 and caspase-9 activity, which led to poly(ADP-ribose) polymerase cleavage. However, the antioxidant N-acetyl-(L)-cysteine (NAC) and glutathione (GSH) resulted in the inhibition of these events and reversed physalin F-induced cell apoptosis. In addition, physalin F suppressed NF-κB activity and nuclear translocation of p65 and p50, which was reversed by NAC and GSH. CONCLUSION: Physalin F induced cell apoptosis through the ROS-mediated mitochondrial pathway and suppressed NF-κB activation in human renal cancer A498 cells. Thus, physalin F appears to be a promising anti-cancer agent worthy of further clinical development.