Search

No temperate oilseeds crops are available that produce oil with a high saturated fatty acid content. To achieve such a profile, Brassica napus cv. DH12075 was engineered by simultaneous seed-specific over-expression of a native fatty acyl- ACP thioesterase B [Bn FatB(2)] and artificial micro RNA-mediated down-regulation of eight endogenous genes encoding putative stearoyl- ACP desaturases (Bn SADs). Semi-quantitative RT- PCR analysis of transformed lines showed that the Bn FatB(2) gene was highly over-expressed and the eight putative SAD genes were strongly down-regulated in developing seed demonstrating the successful application of micro RNA as a tool for down-regulation of genes in the allotetraploid plant B. napus. Analysis of seed triacylglycerol ( TAG) composition revealed that all lines contained high levels of palmitic acid (16:0) and moderately increased levels of stearic acid (18:0). Total saturated fatty acid content was increased from 7.4% in the control to 37.3-45.6% in the transformed lines, with FatB over-expression as the dominant trait. A twofold increase in 16:0 was observed in seed polar lipids. The melting point of oil from mature seeds was increased from −10 °C in DH12075 to 15 °C in the line with the highest saturated fatty acid content. TAG composition showed a shift from predominantly C54 TAG to C50 and C52 TAGs enriched in palmitic acid. Seedling establishment at low temperature was compromised in lines with high saturated fatty acid content. Results suggested that transcript encoding stearoyl- ACP desaturase in developing B. napus seeds is present in considerable excess of the level required for efficient desaturation of 18:0. [ABSTRACT FROM AUTHOR]

Abstract: Although triose phosphate/phosphate translocator is known to play an important role in regulating the distribution of assimilates in wheat chloroplasts, the mechanism of triose phosphate/phosphate translocator gene control has not yet been clearly elucidated. We first showed that glucose inhibited the expression of triose phosphate/phosphate translocator gene in wheat by reverse transcription-polymerase chain reaction and Western blotting. The triose phosphate/phosphate translocator expression was seriously impaired by 5mmol/L glucose, and it responded slowly, more than 48h, to level as low as 1mmol/L glucose. Both glucose and 2-deoxyglucose inhibited the expression of triose phosphate/phosphate translocator gene, but 2-deoxyglucose-6-P, product of phosphorylated 2-deoxyglucose, cannot be further metabolized, therefore the further metabolism of phosphorylated glucose by hexokinase is not a prerequisite for triggering glucose-regulated expression of triose phosphate/phosphate translocator gene. Glucose had little inhibitory effect on the expression of triose phosphate/phosphate translocator gene when hexokinase activity was reduced or eliminated by transforming wheat protoplasts with a hexokinase antisense construct or treating protoplasts with glucosamine, an inhibitor of hexokinase. Therefore, it appears essential for hexokinase to retain phosphorylation activity for glucose to regulate the expression of triose phosphate/phosphate translocator gene. The treatment of protoplasts with glucose-6-phosphate resulting in no inhibition of triose phosphate/phosphate translocator expression demonstrated that phosphorylation via hexokinase is necessary for glucose inhibiting triose phosphate/phosphate translocator expression. All the data suggest that triose phosphate/phosphate translocator is regulated by glucose via a hexokinase-dependent pathway. [Copyright &y& Elsevier]

The root of Croton crassifolius has been used as a traditional Chinese medicine (TCM), called Radix Croton Crassifolius, and commonly known as "Ji Gu Xiang" in Chinese. Its medicinal value has been recorded in several medical books or handbooks, such as "Sheng Cao Yao Xing Bei Yao", "Ben Cao Qiu Yuan" and "Zhong Hua Ben Cao". It has been traditional employed for treating sore throat, stomach-ache, rheumatism and cancer. At present, there are limited studies on the evaluation of low-polarity extracts of roots in C. crassifolius. Consequently, the aim of this study was to evaluate the antitumor effect of the low-polarity extract of C. crassifolius root. Extracts were obtained by supercritical fluid extraction. The extracts were tested for antitumor effects in vitro on several cancer cell lines. A CCK-8 kit was used for further analysis of cell viability. A flow cytometer and propidium iodide staining were used to evaluate the cell cycle and apoptosis. Hoechst staining, JC-1 staining and the fluorescence probe DCFH-DA were used to evaluate apoptotic cells. Molecular mechanisms of action were analyzed by quantitative RT‒PCR and Western blotting. Immunohistochemistry was used for the evaluation of xenograft tumors in male BALB/c mice. Finally, molecular docking was employed to predict the bond between the desired bioactive compound and molecular targets. Eleven diterpenoids were isolated from low-polarity C. crassifolius root extracts. Among the compounds, chettaphanin II showed the strongest activity (IC 50 = 8.58 μM) against A549 cells. Evaluation of cell viability and the cell cycle showed that Chettaphanin II reduced A549 cell proliferation and induced G2/M-phase arrest. Chttaphanin II significantly induced apoptosis in A549 cells, which was related to the level of apoptosis-related proteins. The growth of tumor tissue was significantly inhibited by chettaphanin II in experiments performed on naked mice. The antitumor mechanism of chettaphanin II is that it can obstruct the mTOR/PI3K/Akt signaling pathway in A549 cells. Molecular docking established that chettaphanin II could bind to the active sites of Bcl-2 and Bax. Taken together, the natural diterpenoid chettaphanin II was identified as the major antitumor active component, and its potential for developing anticancer therapies was demonstrated for the first time by antiproliferation evaluation in vitro and in vivo. [Display omitted] • Eleven diterpenoids were obtained from the SFE extract of C. crassifolius roots. • Chettaphanin II showed the strongest antitumor activity against A549 cells. • Chettaphanin II inhibited A549 cell proliferation and arrested cells in G2/M-phase. • Chettaphanin II induced A549 cell apoptosis by inhibiting PI3K/AKT/mTOR pathway. • Chettaphanin II significantly inhibited the growth of tumor tissue in nude mice. [ABSTRACT FROM AUTHOR]

Chronic inflammation is a fundamental symptom of many diseases. Catechin possesses anti-oxidant and anti-inflammatory properties. However, the mechanism of catechin to prevent inflammation in 3T3-L1 adipocytes caused by TNF-α remains unknown. Therefore, the effects of catechin on the gene expression of cytokines and the activation of cell signals in TNF-α induced 3T3-L1 adipocytes were investigated. The effects of catechin on adipogenesis and cell viability were detected by Oil Red O staining and CCK-8 assay, respectively. The genes expression of cytokines was determined by real-time RT-PCR. The expression of NF-κB, AMPK, FOXO3a and SIRT1 on translation level was determined by western blotting analysis. The results demonstrated that catechin significantly enhanced adipogenesis and cell viability. catechin inhibited the gene expression of pro-inflammatory cytokines including IL-1α, IL-1β, IL-6, IL-12p35, and inflammatory enzymes including iNOS and COX-2, but enhanced the gene expression of anti-inflammatory cytokines including IL-4 and IL-10. Catechin also inhibited the activation of NF-κB, AMPK, FOXO3a and SIRT1, but increased the phosphorylation level of the above factors. All these results indicated that as a potential therapeutic strategy catechin has the ability of attenuating inflammatory response triggered by TNF-α through signaling cascades involved in inflammation and cytokines. [ABSTRACT FROM AUTHOR]

[Display omitted] • Compound 2h is the most potent against A549 cells with the IC 50 value of 0.27 µM; • Compound 2h inhibits A549 proliferation and arrest A549 cells at G2/M cycle; • Compound 2h can influence A549 cell migration and invasion and induce cells apoptosis; • Compound 2h can inhibit the activation of PI3K/Akt/mTOR signaling pathway in vivo ; Fangchinoline (Fan) are extracted from the traditional Chinese medicine Stephania tetrandra S. , which is a bis-benzyl isoquinoline alkaloids with anti-tumor activity. Therefore, 25 novel Fan derivatives have been synthesized and evaluated for their anti-cancer activity. In CCK-8 assay, these fangchinoline derivatives displayed higher proliferation inhibitory activity on six tumor cell lines than the parental compound. Compared to the parent Fan, compound 2h presented the anticancer activity against most cancer cells, especially A549 cells, with an IC 50 value of 0.26 μM, which was 36.38-fold, and 10.61-fold more active than Fan and HCPT, respectively. Encouragingly, compound 2h showed low biotoxicity to the human normal epithelial cell BEAS-2b with an IC 50 value of 27.05 μM. The results indicated compound 2h remarkably inhibited the cell migration by decreasing MMP-2 and MMP-9 expression and inhibited the proliferation of A549 cells by arresting the G2/M cell cycle. Meanwhile, compound 2h could also induce A549 cell apoptosis by promoting endogenous pathways of mitochondrial regulation. In nude mice presented that the growth of tumor tissues was markedly inhibited by the consumption of compound 2h in a dose-dependent manner, and it was found that compound 2h could inhibit the mTOR/PI3K/AKT pathway in vivo. In docking analysis, high affinity interaction between 2h and PI3K was responsible for drastic kinase inhibition by the compound. To conclude, this derivative compound may be useful as a potent anti-cancer agent for treatment of NSCLC. [ABSTRACT FROM AUTHOR]

The present work studies the immunomodulatory potential of nervonic acid (NA) on the growth and proliferation of murine RAW264.7 macrophages. The immunomodulatory effects of NA were assessed through the evaluation of nitric oxide (NO) levels, cytokine secretion, phagocytic activity, reactive oxygen species (ROS) generation, and nuclear factor-κB (NF-κB) signaling pathway of RAW264.7 macrophages. The methodology used included a cell counting kit-8 (CCK-8) technique, enzyme-linked immunosorbent assay (ELISA), neutral red phagocytosis test, flow cytometry, western blotting, and immunofluorescence, respectively. Obtained outcomes pointed to NA as a potential promoter of the production of NO, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and ROS in RAW264.7 cells. Meanwhile, the expression of iNOS, TNF-α, IL-1β, and IL-6 mRNA was upregulated. Besides, the expression of TLR4 protein and the phosphorylation level of NF-κB were increased in RAW264.7 cell lines in a concentration-dependent manner when compared against the control. As a conclusion, NA can activate the NF-κB signaling pathway through the TLR4 signaling pathway, which has immunomodulatory potential. [ABSTRACT FROM AUTHOR]

Xanthine oxidase (XO) is a key enzyme in the generation and development of hyperuricemia. Thiazolidine-2-thione, a typical heterocyclic compound, have been widely used in the field of drug synthesis. In this study, a series of novel thiazolidine-2-thione derivatives were synthesized as XO inhibitors, and the XO inhibitory potencies of obtained compounds were evaluated by in vitro enzyme catalysis. The result shown that compound 6k behaved the strongest XO inhibitory activity with an IC50 value of 3.56 μmol/L, which was approximately 2.5-fold more potent than allopurinol. The structure-activity relationship revealed that the phenyl-sulfonamide group was indispensable for thiazolidine-2-thione derivatives to produce XO inhibitory activity. The enzyme inhibition kinetics analyses confirmed that compound 6k exerted a mixed-type XO inhibition. Additionally, the molecular docking results suggested that the 4-fluorophenyl-sulfonyl moiety could interact with Gly260 and Ile264 in the innermost part of the active pocket through 2 hydrogen bonds, while the thiazolidinethione moiety could form two hydrogen bonds with Glu263 and Ser347 in hydrophobic pockets. In summary, the results described above suggested that compound 6k could be a valuable lead compound for the treatment of hyperuricemia as a novel XO inhibitor. [ABSTRACT FROM AUTHOR]

[Display omitted] • Fan@EM-HGB were designed and prepared using spontaneous emulsification and ionic cross-linking. • The released behavior of Fan@EM-HGB followed a pH-controlled mechanism. • Fan@EM-HGB promote the apoptosis of A549 cells in vitro. • Fan@EM-HGB inhibit the PI3K/Akt/mTOR signaling pathway in nude mice. • Emulsions-filled hydrogel beads could be considered as a potential carrier to delivery hydrophobic active composition. Fangchinoline (Fan) is a natural alkaloids compound with a series of remarkable bioactivity, but the poor aqueous solubility limits the clinical application. Emulsions (EM) systems are commonly used to encapsulate and deliver hydrophobic active compound to enhance the bioavailability. Hydrogel beads (HGB) are three-dimensional hydrophilic polymer networks, which are able to immobilize colloidal delivery systems, resulting to the enhanced stability and controlled release in the gastrointestinal tract. In order to give full play to the bilateral advantages of emulsion and hydrogel, Fan loaded EM-filled sodium alginate HGB (Fan@EM-HGB) were designed and prepared in this paper. The average size of Fan@EM was 121.6 ± 2.7 nm and the zeta potential was -17.7 ± 0.3 mV. Physicochemical characterization demonstrated that Fan was successfully encapsulated in HGB with entrapment efficiency of 93.98 % and drug loading of 5.18 mg/g. The released behavior of Fan@EM-HGB followed a pH-controlled mechanism that was consistent with the first-order model. In vitro activity research shown that Fan@EM-HGB could significantly promote the apoptosis of A549 cells, with IC 50 value more than 2.37 times higher than that of Fan. The in vivo results indicated that Fan@EM-HGB had an obvious anti- cancer effect, and molecular mechanism shown that Fan@EM-HGB could promote tumor cell apoptosis by inhibiting the activation of the PI3K/Akt/mTOR signaling pathway. The above research results suggest that nanoemulsions-filled hydrogel beads have potential application in delivery system for hydrophobic composition. [ABSTRACT FROM AUTHOR]

Astragali Radix (AR) is the dry root of the leguminous plants Astragalus membranaceus (Fisch) Beg. var. mongholicus (Beg) Hsiao, and Astragalus membranaceus (Fisch) Bge., being used as a medicinal and edible resource. AR is used in traditional Chinese medicine prescriptions to treat hyperuricemia, but this particular effect is rarely reported, and the associated mechanism of action is still need to be elucidated. To research the uric acid (UA)-lowering activity and mechanism of AR and the representative compounds through the constructed hyperuricemia mouse and cellular models. In our study, the chemical profile of AR was analysed by UHPLC-QE-MS, as well as the mechanism of action of AR and the representative compounds on hyperuricemia was studied through the constructed hyperuricemia mouse and cellular models. The main compounds in AR were terpenoids, flavonoids and alkaloids. Mice group treated with the highest AR dosage showed significantly lower (p < 0.0001) serum uric acid (208 ± 9 μmol/L) than the control group (317 ± 11 μmol/L). Furthermore, UA increased in a dose-dependence manner in urine and faeces. Serum creatinine and blood urea nitrogen standards, as well as xanthine oxidase in mice liver, decreased (p < 0.05) in all cases, indicating that AR could relieve acute hyperuricemia. UA reabsorption protein (URAT1 and GLUT9) was down-regulated in AR administration groups, while the secretory protein (ABCG2) was up-regulated, indicating that AR could promote the excretion of UA by regulating UA transporters via PI3K/Akt signalling pathway. This study validated the activity, and revealed the mechanism of AR in reducing UA, which provided experimental and clinical basis for the treatment of hyperuricemia with it. [Display omitted] • Astragali Radix (AR) main compounds were terpenoids, flavonoids and alkaloids. • Mice treated with the highest AR dose showed significantly lower serum uric acid (UA). • Reduced creatinine and urea nitrogen indicated that AR could relieve acute hyperuricemia. • The UA reabsorption protein (URAT1 & GLUT9) was down-regulated in AR groups. • AR could promote the excretion of UA by regulating PI3K/Akt signalling pathway. [ABSTRACT FROM AUTHOR]

Seed oils containing unusual triacylglycerol (TAG) molecules, where one fatty acid of a TAG is substituted by an acetate group (Ac), are uncommon but of considerable interest as potential low‐viscosity biofuels and lubricants or reduced calorie food ingredients. Although the properties and pathway of biosynthesis of 3‐acetyl‐1,2‐diacyl‐sn‐glycerols (sn‐3‐acTAGs) have been described, little is known about the occurrence of 2‐acetyl‐1,3‐diacyl‐sn‐glycerols (sn‐2‐acTAGs). Prompted by a report of sn‐2‐acTAGs in the seeds of Polygala virgata, a study of the seed oil of seven members of this genus, and two related species is conducted. The presence of sn‐2‐acTAG and lesser amounts of conventional TAG is conclusively demonstrated in Polygala seed oil by Matrix‐Assisted Laser Desorption/Ionization Time‐of‐Flight Mass Spectrometry (MALDI‐TOF MS) and high resolution C13 nuclear magnetic resonance spectroscopy (C13 NMR). Analysis of seed fatty acids reveals a diversity of composition with oils from P. myrtifolia and P. fruticosa dominated by the medium‐chain fatty acid (MCFA) myristic acid (tetradecanoic acid) at an average of 79.8 and 74.1% of total seed fatty acids, respectively. In contrast, MCFAs are absent from oils from P. tenuifolia and P. virgata, with the very‐long‐chain fatty acid (VLCFA) gondoic acid (cis‐11‐eicosenoic acid) being most abundant. Polygala species therefore represent a rich source of sn‐2‐acTAGs and uncommon fatty acids. Practical applications: The seed oils of Polygala species contain a highly unusual combination of sn‐2‐acTAGs and uncommon fatty acids. These plants can serve as a unique genetic resource for the elucidation of the pathways of biosynthesis of these lipids and the identification of genes for the engineering of novel oils in transgenic plants. As Polygala is morphologically diverse genus ranging from annual herbs to small trees, identification of species with suitable seed production and agronomic characteristics may allow the commercial production of novel oils for specific higher value uses. Plant seed oils are generally composed primarily of triacylglycerol (TAG). In this article, the authors examine the seed oils of seven species in the genus Polygala and report the occurrence of an unusual lipid, 2‐acetyl‐1,3‐diacyl–sn‐glycerol (sn‐2 acTAG). These plants also produce unusual fatty acids in their seed oil, with Polygala tenuifolia being enriched in gondoic acid (cis‐11‐eicosenoic acid, 20:1Δ11) and Polygala myrtifolia containing myristic acid (tetradecanoic acid, 14:0). The genus Polygala represents a potential source of novel oil and a resource for the characterization of sn‐2 acTAG biosynthesis. [ABSTRACT FROM AUTHOR]

Potentilla discolor has been used as the Traditional Chinese Medicine ingredient in prescription for over 400 years, and scientific evidences have confirmed its effectiveness as an anticancer agent. The present study is undertaken to assess, for the first time, the chemical composition, potential in vitro anti-tumor activities and related mechanisms of the essential oil, which was extracted from Potentilla discolor fresh roots by supercritical CO 2 fluid extraction technology. Twenty-nine compositions were identified by gas chromatography-mass spectrometry. The anti-tumor activity of the essential oil was screened against four cancer cell lines and the lowest IC 50 value was 19.02 μg/mL on T24 cell line. Then, T24 was selected as a representative cell line for the related mechanism research. As a result, cell cycle assay confirmed that the cell growth was inhibited by Potentilla discolor essential oil and cell cycle was arrested in DNA synthesis phase. A series of apoptosis analysis indicated that Potentilla discolor essential oil induced apoptosis through mitochondrion-mediated intrinsic pathway. This study revealed that Potentilla discolor essential oil has significant anti-tumor activity. It should be useful in the search for new potential anti-tumor agents and pharmaceutical industries. [ABSTRACT FROM AUTHOR]

Small berries have become an attractive topic of research due to their high content in phenolic compounds and reported antioxidant activity. However, there are currently few reports on the deep characterization of their polyphenol composition. Five kinds of berries (raspberry, blackberry, blueberry, mulberry and black chokeberry) were studied to compare the antioxidant activities and polyphenol compositions of both berry juice and pomace (by-products in processing). Results showed that pomaces were more potent antioxidants than juices, especially those that originated from red raspberry. The polyphenol contents in pomaces ranged from 137 to 222 mg/g, this was higher than juices that ranged from 2.75 to 8.88 mg/g, with mulberry accounting for the highest content. The main compounds in pomaces were phenolic compounds with different relative contents found by UPLC-MS/MS. A total of 568 compounds were identified, including 238 flavonoids and 131 phenolic acids. PCA, HCA and OPLS-DA analyses were performed to find similarities on the polyphenol and metabolomic profile of the sampled berries. This analysis unveiled that all studied berries presented a significantly different polyphenol profile, on which raspberry and blackberry were the most similar. Results suggested that berry pomaces can be valuable sources of phenolic compounds of which the major components are anthocyanins and phenolic acids, with potential applications as antioxidant food additives, or raw materials for pharmaceuticals, nutraceuticals, and cosmetics. [Display omitted] • The antioxidant and phenolic composition of berry juice and pomace was evaluated. • Pomaces had higher antioxidant activity than the juices, highlighting red raspberry. • Phenolics in pomaces ranged from 137 to 221 mg/g, and in juices ranged from 2.75 to 8.88 mg/g. • 238 flavonoids and 131 phenolic acids were identified in pomace samples. [ABSTRACT FROM AUTHOR]

To extend shelf-life and develop new bayberry products, the effects of storage time and temperature on polyphenolic content and qualitative characteristics of freeze-dried and spray-dried bayberry power were studied. Results showed that the retention of total polyphenols, gallic acid, protocatechuic acid, cyanidin-3-o-glucoside and anthocyanins in the freeze-dried bayberry powder was in most cases higher than in the spray-dried powder when they were stored for the same period. The content of these components in both the freeze-dried and spray-dried bayberry powder decreased gradually with the longer storage time. No significant difference was detected for the retention of these compounds whether they were stored at 4 °C or 25 °C. The browning index of both the freeze-dried and spray-dried powder significantly increased during a 50-day storage period. The ΔE value of the bayberry powder stored at 25 °C was distinctly higher than that of the other treated samples; a value of the spray-dried powder was slightly higher than that of the other samples. All presented results indicate that freeze-drying and 4 °C storage is an efficient and convenient method to maintain the bioactive polyphenolic components and high-qualitative characteristics of bayberry fruits. [ABSTRACT FROM AUTHOR]

Three new lupane-triterpenoids (1–3) along with six known compounds (4–9) were isolated from the ethanolic extract of whole plant of Potentilla discolor Bunge. The structures of Compounds 1–3 were established by extensive 1D and 2D NMR together with other spectrum analysis, indicating that their C-27 positions were highly oxygenated, which were rarely found in nature. Their in vitro anti-proliferative activities against HepG-2, MCF-7 and T-84 cell lines were evaluated by Cell Counting Kit-8 (CCK-8) assay, and the results showed different activities for three cell lines with IC50 values ranging from 17.84 to 40.64 μM. In addition, the results from Hoechst 33258 and AO/EB staining as well as annexinV-FITC assays exhibited Compound 1 caused a markedly increased HepG-2 cellular apoptosis in a dose-dependent manner. The further mechanisms of Compound 1-induced cellular apoptosis were confirmed that 1 induced the production of ROS and the alteration of pro- and anti-apoptotic proteins, which led to the dysfunction of mitochondria and activation of caspase-9 and caspase-3 and finally caused cellular apoptosis. These results would be useful in search for new potential antitumor agents and for developing semisynthetic lupane-triterpenoid derivatives with high antitumor activity. [ABSTRACT FROM AUTHOR]

Hyperuricemia is a common metabolic disease and is one of the factors that could induce chronic kidney disease (CKD). Geniposide (GEN) is a typical natural iridoid glucoside compound with a series of biological activities, but the poor bioavailability of GEN limits its clinical application. In this context, the pharmacological activity of the geniposide-phospholipid complex (GEN-PLC) in ameliorating posthyperuricemia CKD was evaluated by in vitro and in vivo experiments in this study. In vitro cell experiments showed that GEN-PLC treatment markedly decreased inflammatory cytokine levels and reactive oxygen species levels compared with those of GEN in uric acid-treated HKC cells. In vivo research results confirmed that a high concentration of uric acid could cause CKD by increasing inflammatory cytokines and reactive oxygen species in hyperuricemic mice. At the same time, GEN-PLC could regulate the PI3K/AKT/NF-κB and Keap1/Nrf2/HO-1 signaling pathways to effectively inhibit the inflammatory response and oxidative stress, thereby ameliorating posthyperuricemia CKD, and the therapeutic effect was better than that of GEN. In addition, the preparation technology of GEN-PLC was optimized, and the physiochemical analysis explained the intermolecular interactions of the two components. Based on the research results, GEN-PLC could enhance the bioavailability of GEN and become a promising candidate for clinical drug development. [Display omitted] [ABSTRACT FROM AUTHOR]

Scheme 1. Synthesis of nuciferine derivative 1a-1r,2a-2l. Reagents and conditions: (a) 48% HBr solution, glacial acetic acid, 70 °C; (b) Et 3 N, N 2 , CH 2 Cl 2 , 25℃, 1h; (c) NaH, N 2 , DMF, 0 °C, 2h. [Display omitted] • The inhibition effect of compound 1j (104.46 ± 4.07%) was roughly the same as benzbromarone (101.44 ± 6.21%) in UA-induced HK-2 cells model; • Compound 1j inhibited the expression of URAT1 and GLUT9 through repressing PI3K/Akt pathway in HK-2 cells; • Compound 1j can promote the excretion of uric acid and thereby increase the fraction of uric acid excretion in vivo ; • Compound 1j can ameliorate renal inflammation and reduce the level of renal inflammatory factors; • Compound 1j shows nephroprotective effect through regulate TLR4/IκBα/NF-κB signaling pathway; Hyperuricemia is a common metabolic disease with a series of complications. Nuciferine, a typical aporphine alkaloid natural compound extracted from the leaves of Nelumbo nucifera Gaertn., was confirmed to have an antihyperuricemia effect. In the present study, 30 novel nuciferine derivatives were designed and synthesized. The effects of all derivatives on the regulation of URAT1 were studied in a uric acid-induced HK-2 cell model with benzbromarone as a positive control. The results indicated that Compound 1j showed the optimal URAT1 inhibitory activity through repressing PI3K/Akt pathway in HK-2 cells and the inhibitory effect was similar to that of benzbromarone. In addition, in vivo experiments demonstrated that Compound 1j could reduce uric acid levels and ameliorate kidney damage in hyperuricemic mice. On the one hand, Compound 1j could inhibit the expression of URAT1 and GLUT9 to increase the uric acid excretion index. On the other hand, Compound 1j could regulate the TLR4/IκBα/NF-κB signaling pathway to reduce the levels of inflammatory cytokines, thereby alleviating kidney damage. Meanwhile, a molecular docking assay revealed the potential molecular binding power (-9.79 kcal/mol) between Compound 1j and URAT1, which was more tightly bound than the lead compound nuciferine (-7.44 kcal/mol). Based on these results, Compound 1j may be a future drug for the development of new potential antihyperuricemia and nephroprotective drug candidates. [ABSTRACT FROM AUTHOR]

Hyperuricemia is a metabolic disease caused by abnormal purine metabolism in the body. Long-term high levels of uric acid in the body will lead to gout and kidney disease. Xanthine oxidase (XOD) is a key enzyme in the pathogenesis of hyperuricemia. In this context, a series of geniposide derivatives were designed, synthesized and evaluated as xanthine oxidase inhibitors. Most of these compounds exhibited potent XOD inhibitory activities in vitro , and representatives 6a , 6c , 6g and 6j were found to be the most potent inhibitors against the enzyme with IC 50 values of 2.15 ± 1.03, 1.37 ± 0.26, 4.14 ± 0.79 and 1.86 ± 0.13 μM, which were 33.03–158.37 fold more active than geniposide, respectively. Compounds 6a , 6c , 6g and 6j were evaluated in hyperuricemia mice, and the results demonstrated that compound 6c showed the strongest anti-hyperuricemia and renal protective activity in vivo. Subsequently, the molecular mechanism of compound 6c was studied in this investigation. In vitro cell experiments showed that compound 6c inhibited the inflammation of HK-2 cells under high uric acid conditions by inhibiting the expressions of TGF-β, TNF-α and IL-1β, and reduced the cell fibrosis by decreasing the expressions of α-SMA and Collagen I. The results of the mice experiments indicated that compound 6c efficiently decreased the level of serum uric acid (SUA) in hyperuricemia mice by inhibiting the XOD activity. Moreover, compound 6c effectively reduced the urate accumulation in the kidney and simultaneously decreased inflammation by regulating the expression of the TLR4/IκBα/NF-κB signaling pathway. In addition, consistent with cell experiments, compound 6c also reduced renal fibrosis in hyperuricemia mice, which may be due to compound 6c inhibiting the expression of inflammatory factor TGF-β. Furthermore, a molecular docking study was performed to gain insight into the binding mode of compound 6c with XOD. These results suggest that compound 6c has the potential to be developed into a novel medicine to reduce blood uric acid and treat renal diseases caused by hyperuricemia. [Display omitted] • 42 novel geniposide derivatives were designed and synthesized for the purpose of discovering an efficient XOD inhibitor. • Compound 6c was the most potent XOD inhibitor in vitro , showing 117.81-fold more active than that of geniposide. • Compound 6c effectively inhibited XOD activity in hyperuricemic mice. • Compound 6c could regulate the TLR4/IκBα/NF-κB signal pathway, thereby reducing the level of inflammatory factors. • Compound 6c could inhibit renal fibrosis by reducing the expression of TGF-β. [ABSTRACT FROM AUTHOR]

[Display omitted] • 10 of the 20 synthetic derivatives exhibited significant antitumor activity. • Compound 4g shows the most potent against A549 cells (14.34-fold of d- Tet). • Compound 4g inhibits A549 proliferation, migration, invasion and arrest G2/M cycle. • Compound 4g can induce apoptosis by inactivating the PI3K/Akt/mTOR pathway. Cancer treatment is one of the major public health issues in the world. Tetrandrine (Tet) and fangchinoline (d -Tet) are two bis -benzyl isoquinoline alkaloids extracted from Stephania tetrandra S. Moore, and their antitumor activities have been confirmed. However, the effective dose of Tet and d -Tet were much higher than that of the positive control and failed to meet clinical standards. Therefore, in this study, as a continuation of our previous work to study and develop high-efficiency and low-toxic anti-tumor lead compounds, twenty new Tet and d -Tet derivatives were designed, synthesized and evaluated as antitumor agents against six cancer cell lines (H460, H520, HeLa, HepG-2, MCF-7, SW480 cell lines) and BEAS-2B normal cells by CCK-8 analysis. Ten derivatives showed better cytotoxic effects than the parent fangchinoline, of which 4g showed the strongest cell growth inhibitory activity with an IC 50 value of 0.59 μM against A549 cells. Subsequently, the antitumor mechanism of 4g was studied by flow cytometry, Hoechst 33258, JC-1 staining, cell scratch, transwell migration, and Western blotting assays. These results showed that compound 4g could inhibit A549 cell proliferation by arresting the G2/M cell cycle and inhibiting cell migration and invasion by reducing MMP-2 and MMP-9 expression. Meanwhile, 4g could induce apoptosis of A549 cells through the intrinsic pathway regulated by mitochondria. In addition, compound 4g inhibited the phosphorylation of PI3K, Akt and mTOR, suggesting a correlation between blocking the PI3K/Akt/mTOR pathway and the above antitumor activities. These results suggest that compound 4g may be a future drug for the development of new potential drug candidates against lung cancer. [ABSTRACT FROM AUTHOR]

• Two new ergostane steroids were isolated from macro fungus Ganoderma lingzhi. • Compound 2 incorporates an unusual 1,2-dioxolane fragment. • The new steroids showed significant cytotoxicity against A549 & MCF-7 tumor cells. Two new ergostane-type steroids (1 and 2) have been isolated from the fruiting body of a medicinal macro fungus Ganoderma lingzhi. The structures including the absolute configurations of them were elucidated by a combination of different spectroscopic analyses especially 13C NMR and ECD calculations. Compound 2 features an unusual 1,2-dioxolane moiety. Our bioassays revealed that the two steroids showed remarkable cytotoxicity against human A549 (lung) and MCF-7 (breast) tumor cell lines, with IC 50 values ranging from 5.15 to 8.57 μg/mL. [ABSTRACT FROM AUTHOR]

PDB-1 inhibits cell proliferation by downregulating the expression of CDK1 and cyclin B1 and upregulating the expression of p21 to induce cell G2/M phase arrest. PDB-1 induces autophagy and apoptosis of tumor cells, by down-regulation the PI3K/AKT/mTOR pathway. These data provide a new clue to understand the potential antitumor mechanism of PDB-1 in A549 cells. • PDB-1 has significant selectivity to cancer cell lines, particularly for A549. • PDB-1 inhibits A549 proliferation and colony formation by arresting G2/M cell cycle. • PDB-1 can induce apoptosis and autophagy by inactivating the mTOR/PI3K/AKT pathway. PDB-1 is a new C-27-carboxylated-lupane-triterpenoid derivative isolated from Potentilla discolor Bunge. In our previous research, PDB-1 was suggested to have an obvious selectivity for tumor cells. This study focused on clarifying PDB-1's anticancer mechanism in the inhibition of proliferation and in the induction of apoptosis and autophagy in A549 cells. In general, A549 cells were treated with PDB-1 for different times, and cell survival was assessed by a CCK8 assay. The assessment of intracellular reactive oxygen species, a mitochondrial membrane potential assay, a cell cycle assay, an annexin V-FITC/PI assay, and MDC staining were performed in A549 cells treated with PDB-1. Moreover, the mRNA and protein expression of cell cycle-, apoptosis- and autophagy-related factors were detected by RT-qPCR and western blotting. The results showed that PDB-1 inhibited A549 cell proliferation and colony formation in a dose- and time-dependent manner. The decrease in the viability of A549 cells was due to a G2/M cell cycle arrest. Moreover, PDB-1 induced cell apoptosis, accompanied by an increase in the Bax/Bcl-2 ratio and an increase in the expression levels of cleaved caspase-3/caspase-9. We also found that PDB-1 induced autophagy by increasing the conversion of LC3-I to LC3-II and elevating Beclin-1. In addition, further studies indicated that pretreatment with a specific PI3K inhibitor (LY294002) enhanced the effects of PDB-1 on the expression of proteins associated with apoptosis and autophagy, demonstrating that the PI3K/Akt/mTOR pathway was related to PDB-1-induced apoptosis and autophagy. These results indicated that PDB-1 may be considered a potential candidate for the future treatment of lung adenocarcinoma. These findings should benefit the development of the C 14 -COOH type of pentacyclic triterpenoids. [ABSTRACT FROM AUTHOR]

Chemical fractionation of the ethanolic extract of Eclipta prostrata yielded a series of unreported terpenoid constituents, including a rare 6/6/6/6-fused tetracyclic triterpenoid, a pentacyclic triterpenoid, two pentacyclic triterpenoid saponins, a diterpenoid and a sesquiterpenoid. Structures were assigned to these compounds on the basis of comprehensive spectroscopic analyses, with the absolute configurations of the tetracyclic triterpenoid, the diterpenoid and the sesquiterpenoid being determined via explanation of electronic circular dichroism data. Screening of these isolates in an array of bioassays revealed antibacterial, cytotoxic and α -glucosidase inhibitory activities for selective compounds. Of particular interest, the tetracyclic triterpenoid showed very strong inhibition against α -glucosidase with an IC 50 of 0.82 ± 0.18 μM, being 103-fold as active as the positive control acarbose. Six unreported terpenoids including a rare 6/6/6/6 tetracyclic triterpenoid were isolated from Eclipta prostrata. Their antibacterial, cytotoxic and α -glucosidase inhibitory activities were evaluated. Image 1 • Six unreported terpenoid constituents were obtained from the aerial parts of Eclipta prostrata. • Experimental and calculated ECD data were compared to establish absolute configurations. • An oleanane-type triterpenoid saponin showed mild antibacterial activity against S. aureus. • Two 28-noroleanane-type triterpenoid saponins showed cytotoxicity against two cancer cells. • A rare lemmaphyllane-type triterpenoid displayed strong inhibition against α -glucosidase. [ABSTRACT FROM AUTHOR]

• Compound 3i was most effective against A549 cells with an IC 50 value of 0.61 µM. • Compound 3i is less toxic to normal human liver cells with an IC 50 value of 27.53 μM. • Compound 3i arrests A549 cells in the G2 / M phase to prevent their proliferation. • Compound 3i induced apoptosis in A549 cells via the mitochondrial pathway. • The study shows that compound 3i is an excellent anti-tumor potential drug candidate. The isolation and modification of natural products play an important role in the synthesis of anti-tumor drugs for the treatment of cancer. The present study was designed to evaluate the effects of fangchinoline derivatives against cancer cells. In vitro cytotoxicity of all derivatives against five cancer cell lines (A549, Hela, HepG-2, MCF-7 and MDA-MB-231 cell lines) and HL-7702 normal cells was assessed using the CCK-8 assay, and the results showed that most of the synthesized compounds displayed better cytotoxic effects on all the tested cells compared to that of the parent fangchinoline. In particular, compound 3i had the strongest inhibitory effect on cell proliferation, with an IC 50 value of 0.61 µM against A549 cells. Compared with fangchinoline and HCPT (hydroxycamptothecine), the anti-proliferative activity of compound 3i was significantly increased. More interestingly, compound 3i had slight toxic side effects on normal cells, with an IC 50 value of 27.53 µM. Moreover, the cell viability and cell cycle assays revealed that compound 3i inhibited A549 cell proliferation and arrested A549 cells at the G2/M-phase. The apoptosis-inducing effects of compound 3i and the associated molecular mechanisms were assessed using flow cytometry, cell staining, reactive oxygen species assays, RT-qPCR and Western blot analysis. These results suggested that compound 3i induces apoptosis through a mitochondria-mediated intrinsic pathway. This study revealed that compound 3i is a promising candidate for future development as an anti-tumor drug. [ABSTRACT FROM AUTHOR]